The Translational Science and Systems medicine (TranSYS) in Personalized Medicine European Training Network (ETN), an EU-funded project (2019-2024, coordinated by Prof Kristel Van Steen at the Catholic University of Louvain and University of Lige, Belgium) hosted its final conference to share the project outputs, and to explore innovative strategies and collaborative approaches in the translation of precision medicine. The meeting, Bridging Research to Patient Management and Care for a Healthier Tomorrow, gave a platform to early stage researchers (ESRs) from the network to showcase their work, demonstrating the relevance of the ETN work undertaken over the past 5 years1.

NCMMs Marieke Kuijjer was invited to deliver the first keynote talk of the Day 2 session: Building bridges and tearing down silos. In her talk, titled "Unlocking Cellular Complexity: Multiomics Integration for Personalized Regulatory Networks", she gave an introduction to network medicine, highlighting some of her group's recent tools SCORPION2, a single-cell gene regulatory network modelling algorithm, and CAVACHON3, a multi-omic data integration approach based on deep learning. Interestingly, by presenting a case study on glioblastoma (an aggressive form of brain cancer), Marieke triggered discussions from participants who were working on glioblastoma either from a patients perspective, or to design clinical trials. By sharing their insights, the importance of the computational biology research undertaken by the Kuijjer group can have on the disease diagnostic and treatment, was emphasised.

Throughout the meeting, excellent talks by the ESRs from the TranSYS network, covering a wide range of topics in bridging computational approaches with precision medicine, such as by integrating data in head scans with genetic information, with deep learning, to uncover new cancer subtypes and drivers of obesity, were presented. Marieke was able to discuss with the ESRs their pertinent queries regarding their projects, and the use of the tools designed by her group at NCMM. It enabled her to appreciate the reach of her teams work, and how it influences the work of others. She said: "It was my highlight of the conference as it is always so motivating to discuss science with talented and smart ESRs".

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Building bridges and tearing down silos for precision medicine - Universitetet i Oslo

Introduction

Refrain from smoking is the main therapeutic intervention effective in curbing and reducing the patients respiratory functional decline. It is reported in the COPD guidelines.13 The main consequence of a long-time cigarette exposure is airflow limitation involving both large and small airways.4 A major component of bronchial obstruction is represented by small airways which is characterized by inflammation of bronchioles and airway wall narrowing.

The evolution of the disease can be influenced by the presence of exacerbations that correlate with the degree of obstruction, influencing mortality.5,6

The purpose of the present study is to point out the benefit of quit smoking on respiratory functional and metabolic parameters.

From April to December 2021, 120 patients who referred to a smoking cessation outpatients service were recruited and retrospectively analyzed. The setting was a university hospital, at the outpatient anti-smoking center of the pulmonology operating unit.

Exclusion criteria were: patients who were taking oral steroid therapy or bronchodilators were ruled out as well as patients with severe comorbidities.

Inclusion criteria were the following: patients smokers for at least 20 pack-years who were not taking neither therapy for lipid metabolism nor bronchodilators. The expected duration of the smoking cessation program was six months The assessment was done at baseline and at one month after smoking cessation. Data management was by the physicians attached to the smoke-free center and an expert statistician.

Smoking cessation program was accomplished through motivational counselling along with a drug that reduces addiction. It was varenicline that acts as a partial agonist on 42 nicotinic-acetylcholine receptor. Counselling was also applied consisting of a psycho-behavioural analysis by identifying the stage of change according to the transtheoretical approach. Smoking abstinence was achieved as the eCO value was less than 7 ppm.

Several tests and questionnaires were being administered: the test for nicotine dependence (FTND) (range 02 no dependence, 34 low, 57 moderate, 810 high dependence), the questionnaire COPD assessment test, CAT (range 040),7 the questionnaire for detection of dyspnea, mMRC (range 04).8 The Wests test for the assessment of motivation to quit was also performed. The spirometry (Jaeger system masterscreen, Germany) was performed according to the ERS-ATS guidelines.

Post-bronchodilation values were obtained by inhaling 400 g of salbutamol.9 A smokerlyzer device was used for eCO detection (Bedfont, USA).10 Each patient underwent a 6 min walking test (WT) with walking distance detection (NoninMed Inc., Plymouth,MN, USA).11 Finally, a venous blood sample was taken for detection of cholesterol, HDL and vitamin D total level. The time of detection was at baseline and at one month after smoking cessation.

The study was approved by Sapienza Ethic Committee. Each patient provided the consent to the study. The patients were informed about the purpose of the study. Our study complies with the Declaration of Helsinki.

Data are represented as mean SD or median interquartile range as appropriate.

Data comparison before and after smoking cessation was performed by the Wilcoxon signed rank test.

The statistical significance value was set at p<0.05. SPSS 24.0 for windows was the statistical program used for the analysis of data (Chicago, Il).

The baseline values are shown in Table 1: the mean age is 62 years.

Table 1 Demographic Baseline Data

Males were prevalent: 65 versus 55. Hypertension was the main comorbidity.

At baseline smoking exposure was major than 20 pack-years which represent the cutoff about the risk of developing COPD. The mean daily consumption of cigarettes exceeded the packet. The Fagestroms test indicates a moderate level of nicotine dependence.

By contrast, the Wests test revealed a high motivation and therefore a good probability to achieve smoking cessation. The mean value of body mass index was in the normal range. Finally the average of CAT value (152.5) indicates a moderate increase of the risk of exacerbation.

In Table 2 we can find the variation of the parameters one month after smoking cessation from baseline. No significant differences between different genders were detected.

Table 2 Differences Among Baseline and at the Follow-Up One Month After Quit. Gender: 55 Females, 65 Males

A significant increase of the main obstruction parameters was observed. Notably FEV 1 absolute value in litres was significantly increased (p<0.02), as well as indices of capacity and volume such as FVC were increased.

An index of peripheral airway obstruction such as the FEF 25/75% of predicted was also increased in a short time (p<0.05) as an expression of reduced inflammation. The six minute walking test results show that a significant increase of the walking distance was obtained along with a reduction of heart rate (p<0.05). This goes hand in hand with improved respiratory symptoms and exercise tolerance. In fact the other parameter of respiratory symptoms,CAT, decreased (p<0.01) whereas mMRC test which refers to the extent of dyspnea improved by 0.5 (p<0.0.05).

The main index of smoking exposure, as a tobacco combustion product, such as exhaled CO was reduced (p<0.02).

Regarding metabolic parameters and molecules examined on peripheral venous blood, the data show an improvement. In particular, an important decrease of total cholesterol had been achieved without the use of specific drugs, as well as vitamin D levels had been raised (Respectively p<0.02, p<0.01).

The purpose of this study was to highlight the effects of smoking cessation in the short term, not only on clinical and respiratory function indices but also on metabolic indices and in particular on the level of macromolecules important for many of our functions, such as cholesterol and vitamin D. To our knowledge it is the first study that highlights the rapid benefits of smoking cessation therapy on symptoms and metabolism-expressing molecules. Our findings suggest that smoking cessation confirms its efficacy on respiratory obstruction parameters. Its effectiveness is also extended to the effect of reducing the level of a cholesterol, which when in excess, increases the risk of heart and vascular disease. Similar studies highlighted that cigarette smoke increases the level of fatty acids and glycerol.12

In previous studies a higher concentration of high-density lipoprotein cholesterol (HDL-C) in ex-smokers than smokers has consistently been observed.13 Our findings suggest that there is a recovery of HDL and total cholesterol levels by quitting smoking.

We know that smoke exposure is the main cause of COPD that is the third cause of mortality and it is closely smoke-related. Under the continuous stimulus of tobacco smoke, large and small airways are affected by inflammation and structural remodeling.14,15

In the present study, the effects of smoking cessation on respiratory function in the short time are shown and an improvement of all considered parameters was achieved in both large and small airways.

We know that long-term smoking patients experience a respiratory function decline, furthermore there is an association of bronchial obstruction with nicotine metabolism rate.16

Chronic inflammation of the airways causes COPD, which in turn is characterized by flow limitation that occurs in the small and large bronchial branches.15

Lung function decline is closely related to age and smoking habit leading to symptoms worsening, conversely smoking cessation allow an improvement of functional and clinical parameters.17,18

Our findings provide novel insights in the clinical approach and evolution of bronchial obstruction highlighting a benefit in lipid metabolism, too.

As we know small airways are involved in smoke-induced inflammation by an alteration of the basal cells differentiation.1921

With regard to smoking cessation therapy, the first-line treatment of smoking cessation, aside from replacement therapy, is represented by varenicline which increases the percentage of quit smoking.22 The latter showed its efficacy both as a brief treatment and as a maintenance treatment.23

Smoking can affect the lungs local immune defenses by reducing them, and at the same time it can alter the local bacterial flora by increasing the pathogenic power of microorganisms. This ultimately promotes exacerbations in COPD patients.24

Regarding the effects of smoking on metabolism, it is associated with an increase of triglycerides and cholesterol lipoproteins, due to the interference of cigarette smoking with cytochrome enzyme system involved in lipid, cholesterol metabolism and its transport.25

Cigarette smoking promotes an altered level of cholesterol and lipoproteins26,27 and we demonstrated that after smoking cessation the levels improve without any therapeutic supplement. Finally, the increased level of vitamin D after smoking cessation suggests that smoking reduces bowel absorption of the vitamin and conversely smoking cessation leads to a fast improvement of its level.28

The study has some limitations mainly due to the small sample of patients, however it lends itself as a basis for further clinical and biological studies.

Smoking cessation confirms its efficacy leading to an improvement of all respiratory functional parameters including symptoms and obstruction parameters in the short time. It also affects lipid metabolism leading to a decrease of total cholesterol and at the same time it brings about an increase of HDL cholesterol level. Patients who quit benefit about their quality of life, by reducing dyspnea, and other respiratory symptoms, eventually preventing bronchitis exacerbations.

The authors would like to acknowledge and thank all the patients who agreed to take part in this research. The abstract of this paper took its cue from the abstract that was presented at the XXIV National Congress of Italian Pulmonology as a poster presentation talk with interim findings. The posters abstract was published in Poster Abstracts in Journal Respiration Hyperlink https://doi.org/10.1159/000531211 with DOI: 10.1159/000531211.

Professor Giuseppe Tonini reports on advisory board for Molteni, MSD, Novartis, Roche, and Pharmamar, outside the submitted work. The authors report no other conflicts of interest in this work.

1. Lareau SC, Fahy B, Meek P, Wang A. Chronic obstructive pulmonary disease (COPD). Am J Respir Crit Care Med. 2019;199:1P2.

2. Global Initiative for Chronic Obstructive Lung Disease Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease Global Initiative for Chronic Obstructive Lung Disease; 2020.

3. Pezzuto A, Spoto C, Vincenzi B, Tonini G. Short-term effectiveness of smoking-cessation treatment on respiratory function and CEA level. J Comp Eff Res. 2013;2:335343.

4. Song Q, Zhao YY, Zeng YQ, et al. The characteristics of airflow limitation and future exacerbations in different GOLD groups of COPD patients. Int J Chronic Obstr Pulm Dis. 2021;16:14011412.

5. Suissa S, DellAniello S, Ernst P. Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality. Thorax. 2012;6:957963.

6. Seemungal TA, Hurst JR, Wedzicha JA. Exacerbation rate, health status and mortality in COPD--a review of potential interventions. Int J Chron Obstruct Pulmon Dis. 2009;4:203223. doi:10.2147/copd.s3385

7. Jones PW, Tabberer M, Chen WH. Creating scenarios of the impact of COPD and their relationship to COPD Assessment Test (CAT) scores. BMC Pulm Med. 2011;11:42. doi:10.1186/1471-2466-11-42

8. Hayata A, Minakata Y, Matsunaga K, Nakanishi M, Yamamoto N. Differences in physical activity according to mMRC grade in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:22032208.

9. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:111117.

10. Deveci S, Deveci F, Aik Y, Ozan A. The measurement of exhaled carbon monoxide in healthy smokers and non smokers. Respir Med. 2004;98:551556.

11. Laszlo G. Standardization of lung function testing: helpful guidance from the ATS/ERS Task Force. Thorax. 2006;61:744746.

12. Kershbaum A, Bellet S, Dickstein ER, Feinbergl J. Effect of cigarette smoking and nicotine on serum free fatty acids based on a study in the human subject and the experimental animal. Circ Res. 1961;9:631638. doi:10.1161/01.res.9.3.631.

13. Forey BA, Fry JS, Lee PN, Thornton AJ, Coombs KJ. The effect of quitting smoking on HDL-cholesterol - a review based on within-subject changes. Biomark Res. 2013;1(1):26. doi:10.1186/2050-7771-1-26.

14. Mirza S, Clay RD, Koslow MA. Scanlon PD2 COPD Guidelines: a Review of the 2018 GOLD Report. Mayo Clin Proc. 2018;93:14881502.

15. Rennard SI, Vestbo J. Natural histories of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5:878883. doi:10.1513/pats.200804-035QC

16. Pezzuto A, Lionetto L, Ricci A, Simmaco M, Borro M. Inter-individual variation in CYP2A6 activity and chronic obstructive pulmonary disease in smokers: perspectives for an early predictive marker. Biochim Biophys Acta Mol Basis Dis. 2021;1867(1):165990.

17. Maci E, Comito F, Frezza AM, Tonini G, Pezzuto A. Lung nodule and functional changes in smokers after smoking cessation short-term treatment. Cancer Investig. 2014;32:388393.

18. Pezzuto A, Stellato M, Catania G, et al. Short term benefit of smoking cessation along with glycopyrronium on lung function and respiratory symptoms in mild COPD patients: a retrospective study. J Breath Res. 2018;12:046007.

19. Polosa R. Cessation of smoking in COPD: a reality check. Intern Emerg Med. 2021;16:20292030. doi:10.1007/s11739-021-02740-w

20. Wohnhaas CT, Gindele JA, Kiechle T, et al. Cigarette smoke specifically affects small airway epithelial cell populations and triggers the expansion of inflammatory and squamous differentiation associated basal cells. Int J Mol Sci. 2021;22(14):7646. doi:10.3390/ijms22147646.

21. Churg A, Tai H, Coulthard T, Wang R, Wright JL. Cigarette smoke drives small airway remodeling by induction of growth factors in the airway wall. Am J Respir Crit Care Med Churg. 2006;174(12):13271334. doi:10.1164/rccm.200605-585OC.

22. Tashkin DP. Smoking cessation in COPD: confronting the challenge. Intern Emerg Med. 2021;16:545547.

23. Tonstad S, Tnnesen P, Hajek P, Williams KE, Billing CB, Reeves KR, for the Varenicline Phase 3 Study Group. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA. 2006;296:6471.

24. Ghosh B, Gaike AH, Pyasi K, et al. Bacterial load and defective monocyte-derived macrophage bacterial phagocytosis in biomass smoke-related COPD. Eur Respir J. 2019;53(2):1702273. doi:10.1183/13993003.02273-2017.

25. Vicol C, Buculei I, Melinte OE, et al. The lipid profile and biochemical parameters of COPD patients in relation to smoking status. Biomedicines. 2022;10(11):2936. doi:10.3390/biomedicines10112936.

26. Freyberg J, Landt EM, Afzal S, Nordestgaard BG, Dahl M. Low-density lipoprotein cholesterol and risk of COPD: Copenhagen general population study. ERJ Open Res. 2023;9(2):004962022.

27. He BM, Zhao SP, Peng ZY. Effects of cigarette smoking on HDL quantity and function: implications for atherosclerosis. J Cell Biochem. 2013;114(11):24312436.

28. Zhang C, Zhu Z.Associations among vitamin D, tobacco smoke, and hypertension: a cross-sectional study of the NHANES 2001-2016 by Wu et al. Hypertens Res. 2023;46(6):1615.

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Short-term benefits of smoking cessation | COPD - Dove Medical Press

Blood vessels are responsible of the appropriate and efficient delivery of nutrients and oxygen to the whole body. To do so, they must grow and branch to reach every cell in a process called angiogenesis. The precise regulation of the sprouting and pruning of blood vessels is complex and partly unknown, but endothelial cells, those lining the inner part of the vessels, are known to play an important role.

The growth and proliferation of endothelial cells is promoted by a protein known as mTORC1. Controlling its activity is important to organise a coherent branching of blood vessels and alterations in this process may lead to vascular malformations.

New research from the Mariona Graupera's lab (Josep Carreras Leukaemia Research Institute), published yesterday at the top journal Science Signaling, has just found that PI3K-C2b, a family member of the PI3K kinases, is responsible of the mTORC1 fine tuning through its inhibition. In a series of experiments using mice models and human cells, researchers found that animals with an inactive form of PI3K-C2a displayed aberrantly enlarged blood vessels. Similarly, when PI3K-C2b was transiently inactivated, endothelial cells appeared larger than usual. Both effects correlated with an increased expression of mTORC1 and were restored upon its external repression.

The findings are important since mutations in components of the PI3K family of proteins are frequent in patients with congenital vascular disorders. Understanding the link between one and the other may be useful to find new therapeutic targets in the future.

The present work was a collaborative initiative including researchers from the Josep Carreras Leukaemia Research Institute, the CNIO, the Universittsmedizin Berlin, the Max Delbrck Center for Molecular Medicine in the Helmholtz Association and the University College London. Funders of the project were the Spanish Ministry for Science and Innovation, the PTEN Foundation, "La Caixa" Foundation, the Spanish Association Against Cancer and the BBVA Foundation.

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Key protein in blood vessel's growth identified - Science Daily

image:

Top: A person is infected by the Alpha variant of SARS-CoV-2. Within a few weeks, antibodies are made that protect the person against the Alpha variant as well as Beta and Gamma variants which are very similar to the Alpha variant. Bottom: A person who (1) has recovered from COVID-19 and who (2) has received mRNA vaccine with components of the Alpha variant develops a strong immune response within a few weeks. The antibodies that are made in the body protect against the Alpha variant, the closely related Beta and Gamma variants as well as the more distantly related Delta and Omicron variants. People who have recovered from COVID-19 and then received the mRNA vaccine are also protected against new variants of SARS-CoV-2. Ill: Gerda Kaynova

Credit: Gerd Kaynova

Vaccines help boost the production of antibodies, providing effective protection against serious illness and death, says Mona Hyster Fenstad.

Fenstad is a senior consultant at the blood bank at St. Olavs Hospital in Trondheim.

We are already well into autumn, and the COVID-19 virus is rife all over Norway. The Norwegian Institute of Public Health recommends people in risk groups to get vaccinated.

They point out that elderly people in particular will be vulnerable to serious illness if they are infected with COVID-19. However, since the vast majority of us have already had COVID-19 at least once, do we really need to think about getting vaccinated?

Yes, say the scientists.

The saying what doesnt kill you makes you stronger is not true in this context. The inflammation that occurs in the body during infections such as influenza, COVID-19 and pneumonia can be harmful. Especially for people with heart or lung disease, or where other risk factors are involved, says Fenstad.

Fenstand and her international colleagues have recently published a study that looked at the effect of vaccination on people who became ill with COVID-19 before vaccines were available. This work has been closely linked to the search for antibodies that can be used as medicine against COVID-19.

At the beginning of 2020, the World Health Organization (WHO) asked scientists and therapists around the world to look for treatments for COVID-19. Among the treatments proposed was convalescent plasma therapy, which uses plasma from blood donors who have recovered from the illness. Along with colleagues from NTNU (the Norwegian University of Science and Technology), we chose to take a closer look at how the antibodies in this plasma were able to neutralize new virus variants that emerged, says Fenstad.

While big pharmaceutical companies were working hard to develop vaccines and medicines, scientists had already begun to look at the use of blood plasma from COVID-19 patients as a possible treatment.

Many of these patients had large amounts of antibodies in their blood. Plasma containing these antibodies was therefore given to seriously ill patients to help them fight the virus. It turned out that convalescent plasma therapy was primarily effective in patients who had immunodeficiencies, says Fenstad.

We were looking for so-called super-neutralizers, people who develop specific antibodies that effectively neutralize different variants of SARS-CoV-2, says Denis Kainov, a professor in NTNUs Department of Clinical and Molecular Medicine who was part of the research team.

These antibodies were eventually cultivated and cloned, and then turned into medicines used to fight COVID-19.

In Norway, the first COVID-19 outbreak occurred in February 2020. The first Alpha variant was quickly followed by new, mutated variants named Beta and Delta. Omicron, which is currently the prevailing variant, was first reported in late 2021.

By April 2020, blood banks across Norway had begun collecting blood plasma from patients who had recovered from COVID-19. At St. Olavs Hospital, 72 patients were selected for a more detailed study of the antibodies in their blood plasma.

It turned out that half of these patients had serum containing antibodies that effectively neutralized the Beta variant, says Kainov.

Kainov has been searching for active substances to use in the treatment of COVID-19 and other viral diseases.

He is now looking for antibodies that could provide wider protection, including against new COVID-19 variants that might emerge.

They noticed that four patients had antibodies that effectively neutralized the COVID-19 variant that was dominant in Trondheim at the time.

We followed up by taking new samples from these patients and found that their antibodies also neutralized other COVID-19 variants. In fact, they were also effective on new virus variants, says Kainov.

The conclusion is thus that it is a good idea to get vaccinated even if you have already had COVID-19 and even if the virus has mutated since the vaccine was made.

Out of the four patients, the scientists picked the one whose antibodies had been least effective against the Omicron variant. This patient had received their first vaccine dose four months after recovering from COVID-19. The efficacy of the vaccine was striking.

The vaccine boosted the production of immune cells and antibodies against all tested variants of the virus, including Omicron, says Kainov.

Kainovs colleagues in Estonia could then proceed with blood plasma from the patient, cloning and cultivating antibodies that neutralised COVID-19 viruses on a wide scale.

The results have also provided the scientists with useful knowledge about the effect of the vaccine on convalescents.

When it comes to vaccines, it is always a race. The virus is always one step ahead, and the vaccines and medicines will never be completely up to date, Fenstad said

Our study is an in-depth study of just one patient, and it constitutes only a tiny piece of research in this field. However, large studies in other countries confirm our findings. Vaccines boost the production of antibodies that are also effective against new variants of the virus, she said.

The finding demonstrate that it is a good idea to get vaccinated even if you have already had COVID-19 and even if the virus has mutated since the vaccine was made. It may not prevent you from being reinfected, but it will provide protection against serious illness and death.

When you get sick with COVID-19, you develop antibodies, but the effects of these diminish and are gone after six to nine months. This is why people can get infected again and again by new variants of SARS-CoV-2. The virus mutates to avoid the immune response we have developed through previous infections or vaccines, says Kainov.

That is why vaccination is important now that we are heading towards winter.

The studies we have conducted here on COVID-19 patients are extremely important, because there will be new outbreaks of the virus. Almost seven million people have died from COVID-19. We must avoid getting into the same situation again, says Kainov.

Reference: Mona Hyster Fenstad et al.:Boosted production of antibodies that neutralized different SARS-CoV-2 variants in a COVID-19 convalescent following messenger RNA vaccination a case study.International Journal of Infectious Diseases. Volum 137, December 2023 https://doi.org/10.1016/j.ijid.2023.10.011

International Journal of Infectious Diseases

Experimental study

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Boosted production of antibodies that neutralized different SARS-CoV-2 variants in a COVID-19 convalescent following messenger RNA vaccination - a case study

1-Nov-2023

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Why you should be vaccinated even if you have had COVID-19 - EurekAlert

Lyudmila A. Bazhenova, MD

With the integration of neoadjuvant, adjuvant and perioperative chemoimmunotherapy approaches into the nonsmall cell lung cancer (NSCLC) treatment paradigm, it is increasingly vital for clinicians to accurately identify patients with unresectable disease displaying key oncogenic drivers, such as EGFR and ALK mutations, before deciding on a therapeutic approach, according to Lyudmila A. Bazhenova, MD.

Its important to highlight that [genetic] testing is necessary for patients [with unresectable lung cancer], and remember that the phase 3 PACIFIC trial [(NCT02125461) regimen] is the standard of care [SOC] right now in this space, Bazhenova said regarding a recent OncLive Institutional Perspectives in Cancer webinar on lung cancer, which she chaired.

In an interview with OncLive, Bazhenova, who is a medical oncologist and professor of medicine at the University of California San Diego (UCSD) Moores Cancer Center in California, expanded on key topics in lung cancer that were discussed by her colleagues at UCSD Health. This included key considerations when navigating the use of perioperative immunotherapy for patients with or without oncogenically-driven lung cancers, the importance of collaboration between oncologists and other specialists when deciding on a treatment plan, and the need for increased and earlier implementation of biomarker testing in all patients with lung cancer.

Bazhenova: 2023 has been a very busy year in lung cancer and several important publications have been presented. Many [of the emerging agents presented] do not have FDA approvals yet, so its hard to apply these data to current practice. However, it is important to be aware of what agents are coming down the lineonce they are FDA approved, we can utilize that treatment modality.

Its important to know which cancers are resectable and which are unresectable. It is very important to work with your multidisciplinary team to make that decision. [Clinicians should not] forget that durvalumab [Imfinzi] is the SOC for patients with unresectable disease. I would not consider durvalumab for patients with oncogenic drivers, especially EGFR and ALK mutations.

The challenge with this approach is the fact that there is no consensus because we have options for our patients. You can give them adjuvant, neoadjuvant or perioperative immunotherapy. We do not have any randomized trials telling us what the right thing to do is, so whatever works [at a given clinicians] institution is appropriate. At UCSD, we are believers in neoadjuvant and perioperative immunotherapy, so thats what we offer our patients. Again, like with unresectable disease, multidisciplinary care is vital. Clinicians should make sure to discuss [the patients situation] with a radiation oncologist as well as surgeon and determine a treatment plan in the beginning once all the specialists have evaluated the patient.

For patients with EGFR mutations and ALK rearrangements, we know that immunotherapy generally does not work very well. For those patients, I would not consider neoadjuvant chemoimmunotherapy or adjuvant immunotherapy. Those patients will generally go to surgery. One could consider neoadjuvant chemotherapy if theyre dealing with a stage III cancer where this approach would be appropriate. After the completion of neoadjuvant treatment, it is important to make sure that [clinicians] offer those patients adjuvant osimertinib [Tagrisso], which is currently FDA approved.

Although adjuvant alectinib [Alecensa] has not yet been FDA approved, the phase 3 ALINA trial [NCT03456076] is very important. I hope that adjuvant alectinib will eventually become an FDA-approved option. It is also important to make sure that clinicians test patients for those abnormalities; ideally, one would want to test patients before selecting a neoadjuvant approach because your decision depends on the presence or absence of given mutations.

At UCSD, we have the [phase 2 TRUST-II study (NCT04919811)] with taletrectinib for ROS1rearranged lung cancer. The preliminary efficacy [data] showed a high response rate [with the agent] and responses appear to be durable. The interesting fact about taletrectinib is that it does not inhibit trkB. So the adverse effect profile is different, and in my opinion better, than the safety profile of entrectinib (Rozlytrek) and repotrectinib (Augtyro).

My main message is biomarkers, biomarkers, biomarkers! [Clinicians should] make sure that patients are being tested for molecular abnormalities and should understand the difference between DNA testing and RNA testing. [We should understand] the additional benefit that RNA testing brings, especially for patients with gene fusions, which are common in lung cancer.

[Lastly], we need to know the issues surrounding cell-free DNA. Its a great tool for patients, but approximately 30% of cell-free DNA tests will produce a false negative. If an oncologist performs a liquid biopsy and didnt discover the mutation, it is not appropriate to stop there. We want to make sure that tissue next-generation sequencing is being performed so we dont miss patients who display oncogenic drivers.

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Multidisciplinary Collaboration and Molecular Testing Are Integral to ... - OncLive

A map of Stony Brook University marked with the locations of crimes that occurred on campus from Saturday, Nov 18. to Friday, Nov 24. ILLUSTRATED BY BRITTNEY DIETZ/THE STATESMAN

All reports are taken directly from the University Police Department and cannot be independently verified by The Statesman.

On Saturday, Nov. 18, there was a report of missing kitchen scissors last seen on Oct. 30 in Chapin Hall. The case was closed by investigation.

On Monday, Nov. 20, a patient struck another patient in Stony Brook University Hospital. The case was closed after the victim refused to cooperate.

On Monday, Nov. 20, there was a report of a phone scam in the Centers for Molecular Medicine. The case was closed and referred to another agency.

On Tuesday, Nov. 21, there was a report of a missing pair of jeans and dorm key in the Walter J. Hawrys Campus Recreation Center. The case is still open.

On Tuesday, Nov. 21, a dispute was reported between a motorist and pedestrian in a motor vehicle accident at Circle Road and Engineering Drive. An MV-104 was completed, and no injuries were reported. The case was closed after the victim refused to cooperate, and there was a student referral.

On Wednesday, Nov. 22, a social media scam was reported in Greeley Hall. The case is still open, and the victim was transported to the Comprehensive Psychiatric Emergency Program.

On Wednesday, Nov. 22, there was a report of a vehicle driving through a gate arm, damaging the Stony Brook University Hospital parking garage. The case is still open.

On Thursday, Nov. 23, a patient slapped a staff member on the arm in Stony Brook University Hospital. The case was closed after the victim refused to cooperate.

On Friday, Nov. 24, a patient struck three employees in Stony Brook University Hospital. The case was closed after the victims refused to cooperate.

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SBU Crime Watch: Nov. 18 Nov. 24 The Statesman - Stony Brook Statesman

CHICAGO -- GE HealthCare (GEHC) brought new CT and MRI scanners and a range of AI software applications to McCormick Place for RSNA 2023.

CT

In CT, GEHCshined the spotlight on its Revolution Ascend scanner, which was first introduced at ECR in March. With onsite detector upgrades, Ascend can be upgraded from a 20-mm coverage system for routine scanning to a 40-mm coverage system that delivers better low-contrast detectability, according to the vendor.

The scanner also comes with True Enhance DL, an AI-based application that generates deep learning-based monochromatic-like images from a single-energy x-ray acquisition. This capability is designed to increase contrast resolution and is especially useful for challenging oncology exams, GEHC said.

GE HealthCare's new Revolution Ascend CT scanner.

GEHC also pointed to upgrades for its Revolution Apex scanner, including ECG-less Cardiac for acquiring cardiac images without the need for an ECG signal or trace. Whats more, GEHC has launched Tube Watch, which uses digital twin technology to remotely monitor and predict tube failures or potential issues in Apexs x-ray generation chain.

In addition, the vendor said that its TrueFidelity DL software is available on both Apex and Ascend. Based on a deep neural network, TrueFidelity DL is designed to generate high-definition, low-noise CT images. TrueFidelity DL features for the lung and extremity are available exclusively, however, on the Apex.

Both Apex and Ascend come with GEHCs Effortless Workflow CT workflow automation software and Smart Subscription services for easy software updates.

In photon-counting CT technology developments, GEHC said that researchers at Stanford Medicine have begun scanning human subjects using its photon-counting CT prototype. The research will produce technical feedback to assist GEHC in assessing the systems reconstruction methods, image presentation workflow, and clinical benefits for specific pathologies and disease types.

MRI

GEHC unveiled Signa Champion, a 1.5-tesla, wide-bore scanner that features AI-supported workflow features such as the firms AIR Recon DL image reconstruction software and Sonic DL software for accelerating image acquisition. The company also highlighted the patient comfort benefits of Champions wide bore and short scan times. Notably, Champion has the smallest footprint and is the most power-efficient among GEHCs wide-bore systems.

GE HealthCare's Signa Champion 1.5-tesla scanner.

Via a partnership with Brazilian automation technology provider Ionic Health, GEHC has also added remote scanning capability as part of anew version of its Digital Expert Access software. Ionic Healths nCommand Lite technology, which is currently pending U.S. Food and Drug Administration (FDA) 510(k) clearance, is designed to support vendor-agnostic remote scanning capabilities

As a result of the new technology, remote clinical users can currently initiate a scan on GEHCs MR devices from inside or outside the radiology suite or at any clinical facility, according to the firm.

Informatics/AI

GEHC featured App Orchestrator, an AI application orchestration platform for facilitating integration of multiple third-party apps into existing workflow. App Orchestrator is compatible with most major PACS, according to the company.

The company also unveiled Theranostics Pathway Manager Tile, an application designed to aid in coordinating the theranostics care pathway, as well as identifying and tracking potential theranostics candidates. Its available on GEHCs Command Center Software Platform.

GEHC also introduced version 2.0 of its Imaging 360 for Operations platform. The latest release supports operational analytics, remote scan assistance, protocol management, dose management, and scheduling.

Interventional

In image-guided surgery activities, GEHC showcased two new AI applications previously presented at ECR 2023. Embo Assist AI automatically segments vascular structures to facilitate embolization workflow planning, while Liver Assist Virtual Parenchyma 3D provides AI-based virtual parenchymography.

Interact Touch is a new feature for GEHCs Allia image-guided surgery platform that enables clinicians to control up to three different third-party devices including Avvigo+ multimodality guidance system from Boston Scientific -- through one single touch panel.

GEHC has also added an interventional augmented reality (AR) application via a partnership with MediView for OmnifyXR Interventional Suite, which allows users to simultaneously display up to four customized holographic projections of liver imaging. 3D volume images can also be displayed in AR for improved anatomy visualization.

In addition, the company said it has continued its collaboration with Centerline Biomedical for its Intra-Operative Positioning System (IOPS) and has also partnered with Proximie to incorporate real-time collaboration and access to data insights.

Molecular imaging

In molecular imaging, GEHC emphasized the launch of its Precision DL for PET/CT imaGEHC processing software, which is now available on its Omni Legend PET/CT scanner.

GEHC has also brought its Effortless Workflow technology to its molecular imaging portfolio. Available on GEHCs Omni PET/CT and StarGuide SPECT/CT scanners, the AI-based Effortless Workflow service automates patient positioning and suggests protocols to enable time savings for molecular imaging studies, according to the firm.

In theranostics developments, GEHC has formed a collaboration with cancer treatment center BAMF Health to provide its PETtrace Solid Target gallium production platform; Omni Legend; Signa PET/MR AIR scanner; StarGuide SPECT/CT scanner; and software such as Precision DL, AIR Recon DL, and Q.Thera AI.

GEHC also displayed its Signa PET/MR AIR system, which was introduced at the annual Society of Nuclear Medicine and Molecular Imaging (SNMMI) conference in June.

Ultrasound

In ultrasound developments, GEHC discussed the addition of Caption Guidance AI software to its Venue family of point-of-care ultrasound systems. With Caption Guidance, even healthcare providers without specialized training or experience can perform cardiac ultrasound exams and acquire diagnostic-quality cardiac images, according to the vendor.

GEHC acquired caption guidance developer Caption Health earlier this year and said it plans to integrate the software into other ultrasound systems in its portfolio, including handheld units.

GE also introduced bkActive, an ultrasound system that provides real-time surgical visualization and improved control over procedures supporting surgeons and clinicians in urology, neurosurgery, hepato-pancreato-biliary surgeries, colorectal and pelvic floor surgeries, and laparoscopic surgeries. The system was developed by GEHC company BK Medical.

Other ultrasound scanners on display included GEHCs Logiq E10, Fortis, Invenia ABUS 2.0, Vscan AIR SL, and Voluson Expert systems. The company also showed its Vivid series of cardiovascular ultrasound scanners.

Additionally, GE pointed to its Verisound suite of ultrasound software applications, including Verisound Reporting, Verisound Fleet Management, Verisound Collaboration, and Vscan Digital Tools.

Meanwhile, a new version of GEs ViewPoint software, 6.14, enables data to be distributed directly from the ultrasound scanner to populate reports.

Womens imaging

GEHC introduced MyBreastAI Suite, an AI platform that currently integrates three AI applications from partner iCAD, including the following: ProFound AI for DBT, PowerLook Density Assessment, and SecondLook for 2D Mammography.

To help practices start a new contrast-enhanced mammography program, GEHC has launched Pristina Bright, which combines SenoBright HD, Pristina Serena, and Serena Bright with an education program that provides dedicated onsite support, CME-accredited self-assessment, and access to a user club to collaborate with experts around the globe, the firm said.

X-ray

In radiologys oldest modality, GEHC once again emphasized Definium 656 HD, an overhead tube suspension system with the highest weight capacity in the companys fixed x-ray portfolio. At RSNA 2023, the firm announced upgrades to Definium 656 HD aimed at improving image quality and consistency, reducing acquisition errors, and streamlining workflows.

The company also debuted Precision CRF, a fluoroscopy system featuring an overhead tube suspension, digital detectors, intelligence exposure control, and image processing software. It supports both radiography and fluoroscopic imaging.

Another introduction, Definium Pace, is a fixed x-ray system available at a value price point, according to GEHC. It comes with a range of automation and enhanced workflow features, the company said.

In other news, GE announced that users of its legacy AMX 200, 220, or 240 systems can now be upgraded to an AMX fixed-column configuration, as well as a modern user interface and software functionalities.

Pharmaceutical diagnostics

The company pointed to a recent study that validated the use of AI models for predicting patient response to therapy. In research presented at the Society for Immunotherapy of Cancer in San Diego in November, the AI models yielded 70%-80% accuracy for predicting treatment response.

Cardiology

In cardiology, GEHC introduced CardioVision for AFib, a software tool for management of patients with atrial fibrillation. The software automatically compiles longitudinal data for disease progression from multiple data sources and generates therapy recommendations based on guidelines, according to the vendor.

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New CT, MR scanners and AI top GE HealthCare highlights at ... - AuntMinnie

Daniel Muoz, MD, MPA

by Matt Batcheldor

Daniel Muoz, MD, MPA, associate professor of Medicine, and Francis Miller, MD, professor of Medicine, have been named interim directors of the Division of Cardiovascular Medicine at Vanderbilt University Medical Center. Their appointments are effective Dec. 1.

Muoz, also the executive director of Vanderbilt Heart and Vascular Institute (VHVI), will be responsible for clinical affairs. Miller, a physician-scientist investigator in the Division of Cardiovascular Medicine and chief of Cardiology at the VA Tennessee Valley Healthcare System, will be responsible for academic affairs.

Muoz and Miller will assume the directorship duties of Jane Freedman, MD, professor of Medicine, who has been named to serve as interim chair of the Department of Medicine and physician-in-chief for VUMC, also effective Dec. 1.

Muoz graduated from Princeton University with a bachelors degree in Economics. He went on to receive his medical degree from Johns Hopkins University and his masters degree in Public Administration from Harvard Universitys John F. Kennedy School of Government in 2005. He continued to serve in the Johns Hopkins Hospital and Health System, where he completed his residency in 2008, chief residency in 2010 and cardiology fellowship in 2011. After completing a research fellowship at Duke University, he came to Vanderbilt for further subspecialty training, after which he joined the faculty in 2013.

In his decade on the VUMC faculty, Muoz has served in various leadership roles, including medical director of the Cardiovascular Intensive Care Unit (CVICU), medical director for Quality at VHVI and as interim division co-director for Clinical Affairs from 2020-2021.

Muoz currently serves as an attending physician in the CVICU, where he is known as an effective teacher and a skilled clinician. His outpatient practice is focused on the realms of preventive and general cardiology.

His research has focused on developing innovative strategies for lowering cardiovascular risk and improving patient outcomes in high-risk primary prevention settings. This includes widely recognized work with the polypill in underserved areas of the rural South. This research, published in The New England Journal of Medicine, demonstrated that a polypill approach to the management of hypertension and cholesterol could effectively improve these measurements of cardiovascular health in an underserved population.

Miller obtained his bachelors degree in Biology and a medical degree from the University of Iowa. He completed an internal medicine residency at the University of Texas Southwestern Medical Center in Dallas before returning to the University of Iowa for a cardiology fellowship. He remained at the University of Iowa as a faculty member, rising to professor before relocating to Duke University and the Durham VA Medical Center in 2016 as a professor of Medicine. In 2020, Miller became the chief of Cardiology at the Salisbury VA Medical Center and a professor at Wake Forest University. He joined VUMC and VA Tennessee Valley Healthcare System in 2022.

Miller has served on several national committees, including as a member of the board of directors of the Federation of American Societies for Experimental Biology, committee chair for the Society for Redox Biology and Medicine, chair of an oversight advisory committee for the American Heart Association, and president of the American Federation for Medical Research.

He has contributed to several editorial boards and study sections. and is a deputy editor of Circulation Research. His research has been funded by the National Institute of Health, National Science Foundation, Department of Defense, Department of Veterans Affairs, and American Heart Association.

The central goal of Millers research is to understand the molecular and cellular roles of reactive oxygen species in cardiovascular disease. His work on NADPH oxidases in the blood vessels has received international recognition.

As a practicing cardiologist, he strives to unite findings in the research lab with human disease. His current research has resulted in several patents using synthetic RNA ligands as novel therapies. Miller is an avid supporter of the physician-scientist and has received awards for house staff teaching and mentorship of graduate students.

I am delighted with Drs. Muoz and Millers appointments to serve as joint interim directors of the Division of Cardiovascular Medicine, Freedman said. I am confident that their expertise and experience in academic, clinical and educational affairs will support the division during an exciting time of ongoing growth and expansion.

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Daniel Muoz and Francis Miller named interim directors of the ... - VUMC Reporter

At left is Hyeong-Reh Kim, Ph.D., with her lab members in the School of Medicine Department of Pathology.

The National Cancer Institute has awarded the Wayne State University School of Medicine $3,032,353 over five years to fund a study that holds the potential to introduce a new class of drugs tailored for patients with therapy-resistant cancers.

Professor of Pathology Hyeong-Reh Kim, Ph.D., is the principal investigator on the project, A novel AR degrader in castrate-resistant prostate cancer.

The goal is to develop a new class of drugs that effectively degrade both wild-type androgen receptor (AR) proteins and AR variants in prostate cancer. The Kim laboratory has been working to uncover the molecular and cellular mechanisms underlying human cancer progression and metastasis, to identify therapeutic targets and to develop novel therapeutics for patients with therapy-resistant cancers, including advanced head and neck cancers and castrate-resistant metastatic prostate cancer.

The receptors for androgens, the group of male sex hormones, play a critical role in all stages of prostate cancer. While many prostate cancer patients initially respond to hormone therapies, significant numbers of patients develop castrate-resistant prostate cancer.

Clinical studies have shown that castrate-resistant prostate cancer often involves androgen receptor variants that lack the ligand binding domain, making this hormone receptor constitutively active and resistant to hormone therapy.

The innovations in our study include the development of a new therapeutic platform usingautophagy-targetingchimera (AUTOTAC)for oncoprotein degradation, she said.This novel therapeutic platform is composed of a target-binding small molecule linked to an autophagy ligand. The AUTOTAC brings the targeted oncoprotein to the protein degradation machinery, involving autophagosome and lysosome, leading to the efficient removal of oncoproteins.

Using a natural ligand or a synthetic small molecule that binds the protein of interest, the AUTOTAC can be utilized for the removal of unwanted proteins. Our study will help establish the foundation for arevolutionary drug development platform in a wide array of human diseases, Dr. Kim added.

In collaboration with Radiation Oncology Professor Harold Kim, M.D., and Associate Professor Joseph Rakowski, Ph.D., and the new Barber Integrative Metabolic Research Team, the Kim laboratory is engaged in the development of radiosensitizers utilizing the AUTOTACplatform or inducers of lipolysis.

This is a truly collaborative project involving many co-investigators, including Dr. Yong Tae Kwon at Seoul National University; and Drs. Elisabeth Heath (Oncology), Seongho Kim (Oncology), Dongping Shi (Pathology), Michael Cher (Urology), Lisa Polin (Oncology) and Sijana Dzinic (Oncology) at the Wayne State University School of Medicine. In my laboratory, Drs. Abdo Najy and Tri Pham, Alaleh Zamiri, M.D. a Ph.D. student and Jenna Poole will work on this project. We hope to recruit more student and post-doctoral fellows to work on this project, Dr. Kim said.

The number for this National Institute of Health award is R01CA282040.

Originally posted here:

School of Medicine's Kim lab secures more than $3 million from ... - Wayne State University

Request for Information on Themes for the NIAMS Strategic Plan for Fiscal Years 2025-2029

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) supports research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. NIAMS is updating its Strategic Plan to help guide the research, training, and information dissemination programs it supports between fiscal years 2025 through 2029. The new Plan will focus on cross-cutting thematic research opportunities that position the Institute to make a difference in the lives of all Americans.Because public input is a crucial step in this effort, the Institute issued a Request for Information (NOT-AR-22-023) and hosted a meeting attended by approximately 160 researchers, patient representatives, and staff from other Federal entities to gain insight into topics that could be included in the new Strategic Plan.

Through this Request for Information, NIAMS invites feedback from researchers in academia and industry, health care professionals, patient advocates and health advocacy organizations, scientific or professional organizations, Federal agencies, and other interested members of the public on the Institutes distillation of the input received to date. Professional societies and patient organizations are strongly encouraged to submit a single response that reflects the views of their entire membership.

Please provide your perspective on the following potential cross-cutting themes, examples, and bold aspirations. NIAMS is particularly interested in suggestions for additional or alternative:

Examples:

Bold Aspirations:

Examples:

Bold Aspiration:

Note: Efforts to identify and reduce health disparities and provide all Americans with equitable access to clinical and epidemiologic studies and healthcare should be considered for NIAMS-funded research projects whenever possible.

Examples:

Bold Aspirations:

Examples:

Bold Aspiration:

Note: Consistent with the note under Health disparities and health equity, studies of lifestyle factors and environmental exposures should include efforts to identify and reduce health disparities and provide all Americans with equitable access to clinical and epidemiologic studies and healthcare whenever possible.

Examples:

Bold Aspiration:

Note: Consistent with the note under Health disparities and health equity, clinical and epidemiologic research should include efforts to identify and reduce health disparities and provide all Americans with equitable access to clinical and epidemiologic studies and healthcare whenever possible.

Examples:

Bold Aspiration:

Examples:

Bold Aspiration:

Note: Training and workforce efforts are essential for the pursuit of all cross-cutting thematic research areas in the new NIAMS Strategic Plan.

Examples:

Bold Aspiration:

Examples:

Bold Aspirations:

Responses to this RFI must be submitted electronically at https://rfi.grants.nih.gov/?s=654a7bc81e7ccb6f7d03d792.

Responses must be received by Monday, January 1, 2024.

Responses to this RFI are voluntary. Do not include any proprietary, classified, confidential, trade secret, or sensitive information in your response. The responses will be reviewed by NIAMS staff, leadership, and Advisory Council members. Individual feedback will not be provided to any respondent. NIAMS will use the information submitted in response to this RFI at its discretion and will not provide comments to any respondents submission. Respondents are advised that the Government is under no obligation to acknowledge receipt of the information received or provide feedback to respondents with respect to any information submitted.The Government reserves the right to use any submitted information on public NIH websites, in reports, in summaries of the state of the science, in any possible resultant solicitation(s), grant(s), or cooperative agreement(s), or in the development of future funding opportunity announcements.

This RFI is for information and planning purposes only and shall not be construed as a solicitation, grant, or cooperative agreement, or as an obligation on the part of the Federal Government, the NIH, or individual NIH Institutes and Centers to provide support for any ideas identified in response to it. The Government will not pay for the preparation of any information submitted or for the Governments use of such information. No basis for claims against the U.S. Government shall arise as a result of a response to this request for information or from the Governments use of such information.

We look forward to your input and hope that you will share this RFI document with your colleagues.

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NOT-AR-23-022: Request for Information on Themes for the NIAMS ... - National Institutes of Health (.gov)

image:

When human biliary tract cancer cells are transfected with miR-451a, cell proliferation within the cell aggregates is inhibited. Researchers from Okayama University Hospital, Japan, show this occurs due to the suppression of PI3K/AKT pathway, partially through the downregulation of MIF.

Credit: Dr. Koichiro Tsutsumi from Okayama University Hospital, Japan

Biliary tract cancers (BTCs) including cholangiocarcinoma (CCA) and gallbladder cancer (GBC) are becoming more prevalent globally. An effective chemotherapeutic agent for the treatment of BTCs is gemcitabine. Other novel molecular targeted drugs have also been developed; however, they are only effective at treating a few cases of BTCs. In addition, very few drugs are effective against GEM-resistant BTCs. While surgery is the best option for the treatment of BTCs, many patients are diagnosed late, due to a lack of symptoms. Another challenge for physicians treating BTCs is identifying an appropriate treatment approach due to the complexity of the hepatobiliary-pancreatic system. Therefore, developing novel treatment strategies for BTCs, especially for GEM-resistant BTCs, is the need of the hour.

Nucleic acid-based therapies built around microRNAs (miRNAs) are the next frontier of cancer treatment. miRNAs play a role in gene expression, and their dysregulation is believed to contribute to cancer pathogenesis. Now, researchers from Japan are exploring the prospects of microRNA-451a (miR-451a), a miRNA identified in gallbladder tissue, as a viable targeted nucleic acid BTC therapy. The team, led by Assistant Professor Koichiro Tsutsumi, along with Dr. Taisuke Obata and Dr. Motoyuki Otsuka, all from the Department of Gastroenterology Okayama University Hospital, Japan, recently uncovered the mechanism of miR-451as antineoplastic effects. Their findings were published in Molecular Therapy: Nucleic Acids on 28 October 2023.

Apart from gemcitabine, very few effective drugs are available for the treatment of BTCs. Therefore, there is an urgent need for new therapies. Additionally, we dont know a lot about the miRNA targets that can be used to improve the prognosis of BTCs, especially in the context of resistance to GEM, explains Dr. Tsutsumi while discussing his motivation behind this research. The team had evidence from previous experiments that miR-451a was downregulated in patients with GBC, and they decided to build on other research that showed that the miRNA inhibited cell proliferation when introduced into human GBC cells. They transfected miR-451a into GBC, gemcitabine-resistant GBC (GR-GBC), and gemcitabine-resistant CCA (GR-CCA) cells to understand its effects on tumor progression. They also studied the gene expression profile in these three groups following transfection, to gauge how cell-signaling pathways were altered by miR-451a.

Under experimental conditions that mimicked those of the cancer environment, we found that miR-451a significantly diminished cell proliferation, induced cell death, and reduced the occurrence of chemoresistant cell types in GBC, GR-CCA, and GR-GBC cells, says Dr. Tsutsumi. He adds, One of the factors known to promote metastasis and chemoresistance was the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This pathway was suppressed partially through the downregulation of macrophage migration inhibitory factor (MIF) after the transfection of miR-451a. These findings underpin miR-451as use as a replacement therapy for GEM-resistant BTCs. miR-451as effects at the molecular level were reflected in 2D or 3D cell culture experiments where GR-CCA and GR-GBC cells were rendered less viable following treatment.

Dr. Tsutsumi is looking to the future, and the group is planning future studies to evaluate the effective delivery of miR-451a and validate its clinical application. He concludes, Nucleic acid-based treatments are not mature enough to be considered first-line treatments for BTCs, so chemotherapy and immunotherapy still have their place. However, given miR-451as antineoplastic activity against GEM-resistant BTCs, I anticipate them to be mainstream alternatives with further developments.

About Okayama University, Japan As one of the leading universities in Japan, Okayama University aims to create and establish a new paradigm for the sustainable development of the world. Okayama University offers a wide range of academic fields, which become the basis of integrated graduate schools. This not only allows us to conduct the most advanced and up-to-date research, but also provides an enriching educational experience. Website: https://www.okayama-u.ac.jp/index_e.html

About Assistant Professor Koichiro Tsutsumi from Okayama University, Japan Dr. Koichiro Tsutsumi is an Assistant Professor in the Department of Gastroenterology at Okayama University Hospital. He earned his Doctor of Medicine from Tohoku University in 2001, and Doctor of Philosophy from Okayama University in 2013. His research explores themes across gastroenterology, tumor diagnostics and therapeutics. Dr. Tsutsumi has published over 120 peer-reviewed articles since 2003 and received the Japanese Biliary Society International Exchange Encouragement Award in 2016.

Molecular Therapy Nucleic Acids

Experimental study

Cells

MicroRNA-451a inhibits gemcitabine-refractory biliary tract cancer progression by suppressing the MIF-mediated PI3K/AKT pathway

28-Oct-2023

The authors declare no competing interests.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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A novel targeted molecular therapy for drug-resistant biliary tract ... - EurekAlert

Researchers at the University of California (UC) San Diego School of Medicine have made significant discoveries in understanding the complex relationship between bacterial vaginosis and adverse sexual and reproductive health outcomes.

Bacterial vaginosis, a common condition affecting nearly 29 percent of women between the ages of 14 and 49 in the United States, has long been associated with pregnancy loss, preterm birth, postsurgical infections, pelvic inflammatory disease, and sexually transmitted infections. Reporting in Science Translational Medicine, researchers are now shedding light on the mechanisms by which certain bacterial species disrupt the delicate balance of the vaginal microbiome, leading to these severe health complications.

Bacterial vaginosis is known to be linked to pregnancy loss, preterm birth, postsurgical infections, pelvic inflammatory disease, and sexually transmitted infections, emphasized Warren G. Lewis, an assistant professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at UC San Diego School of Medicine. The study not only highlights the severity of the conditions associated with bacterial vaginosis but also provides a deeper understanding of its underlying molecular mechanisms.

The researchers analyzed epithelial cells that line the vagina as crucial players in the interaction between bacteria and the human body. These cells are densely coated with sugar chains known as glycans, which play pivotal roles in cell biology and disease. The team discovered that in bacterial vaginosis, specific bacteria release enzymes called sialidases, which partially dismantle protective glycan molecules on the surface of epithelial cells. Remarkably, they were able to induce a bacterial-vaginosis-like state in normal epithelial cells by treating them directly with sialidase enzymes produced in the laboratory.

Amanda Lewis, a professor in the Department of Obstetrics, Gynecology & Reproductive Sciences, said, The fact that we were able to replicate some of the effects of bacterial vaginosis suggests that we may be on the right track to finding a common cellular origin for the various complications associated with this condition. According to the researchers, this breakthrough opens the door to potential diagnostic advancements, as studying the surface of vaginal epithelial cells at such a detailed biochemical level could aid in identifying subsets of individuals at the greatest risk for negative health outcomes, including recurrence.

While the study provides a blueprint of the glycans present on vaginal epithelial cells, Warren Lewis acknowledges that further research is needed to fully comprehend the functions of glycans in the vaginal epithelium and how bacterial vaginosis impacts these functions. As this research progresses, clinicians are urging individuals with vaginas to be vigilant about the symptoms of bacterial vaginosis and to refrain from practices such as douching or using scented products, which may exacerbate microbial imbalances.

In unraveling the complexities of the vaginal microbiome, this research not only contributes to our understanding of bacterial vaginosis but also holds the promise of more effective diagnostics and targeted interventions for individuals at risk. The authors believe that the implications of this study reach beyond gynecology, touching on broader aspects of reproductive health and paving the way for innovative approaches to tackle related complications.

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Understanding the Vaginal Microbiome's Impact on Health and ... - Inside Precision Medicine

Leading University of Cape Town (UCT) scholar and scientist Professor Kelly Chibale has been awarded an honorary doctorate from the Faculty of Science at the University of Basel, Switzerland a world-leading research university and one of the oldest in Europe.

Professor Chibale was one of seven scholars who received honorary doctorates during the Dies Academicus ceremony in Basel on 24November. But his was the only one awarded by the universitys Faculty of Science.

The annual Dies Academicus celebration is held in St Martins Church on the last Friday of each November and commemorates the opening of the university on 4April1460 at the Basel Minster. The ceremony is also an occasion to honour early-career researchers for their achievements through awards sponsored by companies, foundations or associations.

The University of Basel is the oldest university in Switzerland; its goal is to remain one of the best research universities worldwide and to make important contributions to research and social development through scientific knowledge and innovation.

Exceptional and inspiring

Chibale is a South African National Research Foundation A-rated scholar and holds the Neville Isdell Chair in African-centric Drug Discovery and Development at UCT. He isthe founder and director of H3D, UCTs drug discovery and development centre based in the Department of Chemistry and the Institute of Infectious Disease and Molecular Medicine (IDM).

The commendation for his honorary doctorate reads: At the Dies Academicus of the University of Basel, the faculties award honorary doctorates to outstanding personalities in science or society. I am delighted to inform you that the Faculty of Science has decided to award you with this years honorary doctorate.

It is to honour your exceptional and inspiring curriculum vitae, your outstanding academic achievements and last, but not least, your continuous and ongoing support of the Swiss Tropical and Public Health Institute, an associate Institute of the University of Basel.

It continues: Professor Kelly Chibale [is] one of the most influential scientists in the research and development of new drugs for malaria, tuberculosis and understudied tropical diseases. The researcher, who is currently working in South Africa, was part of the Next Generation Scientist program run by Novartis and the University of Basel for over a decade.

Speaking to UCT News after the event, Chibale said, The ceremony at a packed church was movingly symbolic as a church is a place of worship for me. I was there in the church worshiping, thanking, and giving glory to God for being the source of this award given to me.

The celebratory banquet that followed was out of this world and the largest I have ever attended.

After the event, Chibale presented a Novartis public lecture titled Fostering drug discovery in Africa at the breathtakingly impressive Novartis Pavillon.

It was a fantastic day of celebrations with my Swiss friends. In the process I boosted the economy of Switzerland with the many Swiss chocolate gifts I was presented with by my Swiss friends who in turn boosted the South African economy with the South African wine I took to Switzerland for them.

With the Royal Society Africa Prize and Schmidt Futures AI2050 Senior Fellowship, the two other individual awards already received this year, this honorary doctorate is like icing on the cake. An individual award like this is also an opportunity for me to thank my present and past team members (both in my academic group and H3D), as well as research and funding partners because as the saying goes, It takes a village to raise a child.

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Honorary doctorate for Kelly Chibale in Switzerland - University of Cape Town News

Research Education & Training is excited to welcome Dr. Haley du Bois back to campus as a new postdoctoral fellow in the lab ofDr. Conor Lynch. Dr. du Bois first visited campus in May as part of the inaugural cohort of the Moffitt Innovators of Tomorrow (MIOT) Symposium, our newest postdoctoral recruitment program.

The Office of Postdoctoral Affairs hosts the MIOT Symposium twice a year, each time bringing a cohort of 10 advanced doctoral researchers and recent graduates to campus to present their research, meet with Moffitt faculty and learn about postdoctoral fellowship opportunities. The attendees are competitively selected and represent top emerging talent in basic science, quantitative science and population science cancer research.

A large focus of the event is showcasing the collaborative research environment Moffitt offers, as well as the extensive scientific and professional support available to Moffitt postdocs through the Cores and Office of Postdoctoral Affairs.

Dr. du Bois received her PhD in Cellular Biology earlier this year from the New York University Grossman School of Medicine, where she studied under the direction of Dr. Amanda Lund. The Office of Postdoctoral Affairs interviewed Dr. du Bois as part of our new Meet the Postdocs series, to learn about her, her research and how the Innovators of Tomorrow Symposium helped bring her to Moffitt.

Can you tell us a bit about your doctoral research?

My graduate work was focused on understanding how a primary tumor communicates regionally and systemically with the host and how this long-range molecular communication may prime tissues for metastasis. Given that the lymph node is the most common site of metastasis for most solid tumors, I used a melanoma model to test whether the primary tumor secretes proteins that activate the lymph node as a pre-metastatic niche.

Testing this, I found that indeed tumor-secreted proteins are able to activate the pre-metastatic lymph node, even in the absence of extracellular vesicles. Using a chemical biology approach termed BONCAT (bioorthogonal non-canonical amino acid tagging), I was able to identify the melanoma-secreted proteins transported to a pre-metastatic lymph node. From these, I found that one such protein, CSPG4, is cleaved from the primary tumor cell surface and transported to the lymph node, priming it for metastasis. Furthermore, I found that CSPG4's chondroitin sulfate decorations were necessary for CSPG4-dependent lymph node pre-metastatic niche establishment, and that targeted removal of them can prevent lymph node metastasis.

Why did you decide to do your postdoc at Moffitt?

Attending MIOT was pivotal to my decision. I was incredibly fortunate to attend the inaugural MIOT symposium during a time in my graduate training that I was beginning to solidify my next goals. MIOT was a very comprehensive introduction to Moffitt's outstanding resources, exemplary faculty and innovative environment. The immersive experience showcased how collaborative and creative the teams here at Moffitt are and it was clear to me that this is a place where I would be supported to accomplish my goals.

Can you tell us a bit about yourself, what youre most looking forward to about your life in Tampa and your hobbies outside of the lab?

Coming from New York City, I am most looking forward to spending more time outside being active. I really enjoy gardening, hiking, and kayaking which are much more accessible here in Tampa. Aside from the outdoor activities I enjoy, I also like to cook and play board games with friends.

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Moffitt Innovators of Tomorrow Symposium Welcomes Its First ... - Moffitt Cancer Center

One person in the UK has been infected by a strain of flu similar to viruses spreading in pigs, health officials have announced.

But what is the strain, what are the symptoms in humans and are experts worried?

Heres what we know so far.

Influenza A(H1) viruses are native to swine populations in most regions of the world, but viruses in pigs can occasionally infect humans, usually after direct or indirect exposure to pigs or contaminated environments.

Influenza A(H1N2)v is similar to flu viruses currently circulating in pigs in the UK but this is the first detection of this particular strain of flu in a human in the UK.

Theres been a total of 50 human cases of influenza A(H1N2)v reported globally since 2005, but no human deaths from this strain have been reported.

Human infections with swine influenza viruses also known as swine flu occur sporadically, according to the UKs Health Security Agency (UKHSA). It becomes a variant influenza virus when detected in a person.

The infection found in the UK is slightly different from recent human cases of the flu strain globally, health officials say, but similar to viruses in UK pigs.

The case was detected as part of routine national flu surveillance undertaken by UKHSA and the Royal College of General Practitioners. The individual was tested by their GP after experiencing respiratory symptoms and influenza A(H1N2)v virus was detected. They experienced a mild illness and have fully recovered.

In 2009, there was a pandemic in humans caused by an influenza virus (official name: influenza A H1N1(pdm09)) commonly referred to as swine flu.

But that virus contained genetic material from viruses circulating in pigs, birds and humans in the 1990s and 2000s. Its now circulating in humans on a seasonal basis and is no longer referred to as swine flu.

It is distinct from the viruses currently circulating in pigs. The case of flu found in the UK is classed as swine flu because its influenza from a pig, but what was previously called swine flu in 2009 is now not referred to as that.

The source of the individuals infection has not yet been found and remains under investigation, but close contacts of the case are being followed up by the UKHSA and partner organisations, and will be offered testing and advised on any necessary further care if they have symptoms or test positive.

The UKs Chief Veterinary Officer, Dr Christine Middlemiss, said: In this case we are providing specialist veterinary and scientific knowledge to support the UKHSA investigation.

Pig keepers must also report any suspicion of swine flu in their herds to their local vet immediately.

People who are contacted and asked to test are encouraged to do so in order to assist in the detection of cases and assessment of transmission.

Those with any respiratory symptoms should continue to follow the existing guidance, including avoiding contact with other people while symptoms persist, particularly if the people they are coming into contact with are elderly or have existing medical conditions.

Martin Michaelis, professor of molecular medicine at the University of Kent, told FactCheck that as the pig influenza case detected in the UK was mild and efforts are ongoing to trace and break potential transmission chains, it does not seem very likely that this could be the beginning of a large, dangerous pig influenza outbreak in humans.

However, he added that you can never be entirely sure, because mutations can happen that change the nature of this virus strain, if it keeps spreading in humans.

But he noted that this pig H1N2 influenza virus infection of a human is a stark reminder that influenza viruses that spread between different species are posing a continuous risk to humans.

Paul Hunter, professor in medicine at the University of East Anglia, told the Science Media Centre: Overall the evidence is that influenza A(H1N2) does not cause any more severe disease than other more commonly circulating types of influenza.

Also, person to person transmission does not appear to be very efficient and sustained person to person transmission has not been reported so far.

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FactCheck: are experts worried about first UK 'pig' flu case? - Channel 4 News

Dear members of UCTs research community

The University of Cape Towns (UCT) research portfolio increasingly delivers cutting edge research, working across disciplinary boundaries to both create first-in-world new knowledge relevant to our context and to deliver societal impact, as well as improving the quality of life of our people in Cape Town, South Africa and Africa.

By its nature, this type of research crosses faculties, disciplines and applications as is evidenced across a variety of UCTs flagship institutes, centres and units such as the African Centre for Cities(ACC), African Climate Development Initiative(ACDI), SALabour Development Unit(SALDRU), Humanities for Africa(HUMA), Future Water, the Neurosciences Institute(NI) and the Cape Heart Institute(CHI), to name a few. Many of these have soft-funded researchers at their centre.

An outstanding example is UCTs Institute of Infectious Disease and Molecular Medicine(IDM), launched in 2005 by ProfessorWieland Gevers as a new collaborative model for research. TheIDM now accounts for some one third ofUCTs research income and an impressive component of UCTs research output.

It is the critical mass of the IDM and its component units and centres, alongside exceptional scientists drawn from across the Health Sciences, Science, and Engineering & the Built Environment faculties that drives these contributions. For example, in a research highlight, IDM fellow DrMunyaradzi Musvosvi and full member Professor Tom Scriba from the South African TB Vaccine Initiative (SATVI) published a landmark study in Nature Medicine with colleagues from Stanford University in which they used cutting edge-technology to identify new targets for novel TB vaccine candidates. Illustrating the IDMs focus on translational research, the Genital Inflammation Test(GIFT) developed by IDM members, ProfessorJo-Ann Passmore and DrLindi Masson, together with their dynamic team, reached a major milestone by entering into field testing to evaluate its potential as a low-cost rapid test to detect vaginal inflammation, a major driver of HIV risk in young women.

Since its launch in the IDM a year ago, the Africa Microscopy Initiative(AMI) has acted on its mandate for broader imaging training. AMIhosted the second Imaging Africa workshop in October2022, providing advanced and hands-on imaging training to 24early-career scientists from across Africa in the AMI Imaging Centre. Inpartnership with Global BioImaging, South Africa BioImaging, and the African BioImaging Consortium, AMI then hosted a cohort of 30international participants and faculty at the IDM for an Imaging Facility Management Training workshop in October 2023. As an innovative new model for research capacity strengthening in Africa, AMI was described in a paper published recently in Nature Cell Biology.

As 2023 draws to a close, the leadership of the IDM is set to change. ProfessorValerie MizrahiFRS will be stepping down as director as she retires from UCT. As a university community, it is fitting to pay tribute to the tireless and exceptional leadership she has demonstrated since taking up the role in 2011 and the much-appreciated mentorship she has given to so many researchers.

Filling her shoes is a big task and we are pleased to share with the UCT community that ProfessorDigby Warner will take on this challenge, serving as the IDM director from the start of 2024. ProfessorWarner is well known to the UCT community and has made his mark in many ways, including his world leading research on tuberculosis and mycobacteriology, his skilful negotiations in bringing the Africa Microscopy Initiative to UCT as an iconic approach to shared infrastructure on our continent, and the outreach programme, Eh!woza, which he established with his former PhDstudent, Anastasia Koch.

Research groupings such as the IDM, those mentioned above and the others that make up our 87accredited research groupings are critical to UCTs research portfolio and its reputation. They are key sources of new knowledge of global reach, agents of societal change and underpin the focus of UCT as a university in Africa, for Africa. Iwould like to express appreciation for all UCT researchers who contribute with passion and energy to achieving this.

With kind regards

Professor Sue Harrison Deputy Vice-Chancellor: Research and Internationalisation

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UCT's Institute of Infectious Disease and Molecular Medicine ... - University of Cape Town News

image:

Researchers create mini-brains from skin cells in the lab. The mini-brains are used to test out medicines and gene therapy. The work has provided new knowledge and ideas for the treatment of patients with childhood dementia, Alzheimer's, ALS, Parkinson's and DOOR syndrome.

Credit: Julie Gloppe Solem, NTNU

A lot of research has been done over many decades on diseases that are widespread in large parts of the population, such as cancer and heart disease. As a result, treatment methods have improved enormously thanks to long-term research efforts on diseases that affect many people.

However, there are many diseases that affect just a handful people. These diseases often fly under the radar and are far less researched. They include quite a few rare, hereditary diseases, such as DOOR syndrome, which is especially found in Canada and the Middle East.

A team of scientists is now in the process of trying to change this.

For some hereditary, rare diseases, there is currently no cure. However, gene therapy is a possible solution, and we are now testing various strategies using gene therapy, says Magnar Bjrs, a professor at the Norwegian University of Science and Technology(NTNU's) Department of Clinical and Molecular Medicine.

He has established a research team at NTNU and Oslo University Hospital that conducts basic research on rare, hereditary diseases with a long-term goal of finding new therapies.

One of the rare diseases for which there is currently no medication or treatment is called DOOR syndrome.

This is a congenital disorder that involves multiple abnormalities. DOOR is an acronym for the main features of the disorder: Deafness, Onychodystrophy (short or absent nails), Osteodystrophy (short fingers and toes) and developmental delay and intellectual disability (previously called mental Retardation).

DOOR syndrome is hereditary and is caused by the lack of a specific protein in the genes called OXR1 (OXidation Resistance gene 1).

Due to lack of this protein, the brain cells are unable to develop as they should. As a result, the brain cells either become dysfunctional or simply die, says Magnar Bjrs.

In order to investigate whether there is a way to prevent this from happening, the Bjrs team has carried out tests inside mini-brains that they grow in their lab.

The Bjrs team has been working on growing mini-organs such as mini-brains, mini-lungs and mini-eyes since 2018. The scientists use the mini-organs to test drugs and gene therapy.

In order to grow mini-brains for their research on DOOR syndrome, the research team needed cells from people who have this disease.

A number of cases have been registered in Canada and the Middle East, and the research being done in Norway is based on skin cells from people who have DOOR syndrome.

In the laboratory, we have transformed the skin cells into embryo cells. We have reversed the development in the skin cells so that they return to the foetal stage and become like the first cells that form in humans. We have then used these stem cells to create mini-brains, says Bjrs.

Using skin cells from people with DOOR syndrome, the scientists have recreated the disease in the mini-brains. They can then use these mini-brains to test out therapies for this disease.

The process of developing mini-brains takes several months and is painstaking and expensive.

The work has given the scientists insight into the reasons why patients develop disease and thus also ideas for treatment strategies. Gene therapy is one possible treatment where the brain cells can be made to start producing the missing protein.

A virus is actually used as a messenger that delivers the necessary production information to the brain cells.

As a follow-up to our published work, we are now testing virus-based gene therapy as a treatment for this disease," Bjrs said. "We create a harmless virus in the lab and then put a healthy OXR1 gene into the virus genome, and this gene has the ability to produce the protein that brain cells lack in people with DOOR syndrome."

The virus is then injected into the mini-brains.

The virus is absorbed into the brain and brain cells. The gene introduced into the brain cells via the virus can then begin to produce the missing protein," he said. "If this protein can be overproduced, it helps to stop and, at best, reverse the disease. In order to treat DOOR syndrome, patients will need to start gene therapy at a very early stage, probably as soon as the first symptoms of disease are noticed."

Gene therapy research has evolved greatly over the past 20 years.

In 2007, only one clinical trial of gene therapy took place. Today, there are thousands of clinical trials involving gene therapy,Bjrs said.

The research has not only provided new knowledge and ideas for the treatment of patients with DOOR syndrome, but also for other diseases.

What is particularly interesting about the OXR1 protein that patients with DOOR syndrome lack is that this gene therapy method also has an interesting potential for treating other diseases, says Bjrs.

The OXR1 protein reduces inflammation, which is a characteristic of most degenerative diseases of the brain, such as childhood dementia, Alzheimers, ALS and Parkinsons.

The researchers have used new, advanced technology. The mini-brains that they have grown are made from skin cells from DOOR syndrome patients and from healthy individuals.

The mini-brains have been used to study brain development and the scientists have created different parts of the brain that control different functions, such as memory, learning, motor skills, fluid balance, hormone balance and temperature control.

It has been shown for the first time in a human model that OXR1 promotes protein methylation during brain development in space and time. Protein methylation is one of several important chemical processes that control gene expression.

The study provides new insights into pathological traits associated with OXR1 deficiency in patients.

References: Genome Biology. A loss-of-function mutation in human Oxidation Resistance 1 disrupts the spatialtemporal regulation of histone arginine methylation in neurodevelopment

https://genomebiology.biomedcentral.com/articles/10.1186/s13059-023-03037-1

Experimental study

Cells

A loss-of-function mutation in human Oxidation Resistance 1 disrupts the spatialtemporal regulation of histone arginine methylation in neurodevelopment

29-Sep-2023

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New therapy can treat rare and hereditary diseases - EurekAlert

Joaqun Ramrez Ramrez (holding board) enjoys trying out different styles of teaching and seeing what works.Credit: Mara Paula Garca

Eleven years ago, James Carey swapped life as a postdoctoral researcher in molecular and cellular biology to become a science teacher. He settled into his current role at a small secondary school in Norwell, Massachusetts, in 2013. Some friends, he says, still wonder why he spent so long studying, only to take up a job that doesnt require that level of education. But for Carey, this was the right path. When he was an early-career scientist, he thought a non-academic career meant you were kind of a failure, he says. He now sees this as a very silly mentality.

I dont think that my journey would be nearly as fulfilling as it is if I had done it a different way, he says. I realize now that it doesnt matter how you get there, or where you end up. Its just what you do with what youve got when youre there. Im trying to make the most of everything that Ive learnt through science and through life, and bring that into the classroom.

Carey got his PhD at the University of Washington in Seattle in 2005, but his research wasnt leading him towards the shining academic career that hed dreamt of. He didnt publish as much as he wanted, and when his postdoc at University of Massachusetts (UMass) Chan Medical School in Worcester came to an end in 2011, he found it difficult to get an academic post, leaving him dejected.

With a second child on the way, he knew he needed more stability. When I sat back to reassess and re-evaluate what I liked about science, he says, I kept going back to how I really enjoyed mentoring young scientists, helping them learn the techniques, connect the dots, find their own story and put the pieces of that puzzle together.

Carey is not the only academic researcher to find happiness and career satisfaction as a science teacher at the secondary-school level. The work can be challenging, and the pay might be lower than in academia, but job stability and passing on a passion for science to the next generation more than make up for it. Here, those whove jumped from the university lecture hall to the school classroom share what inspired them, and highlight why others pursuing PhDs might also find their calling in secondary-school teaching (see Considering being a schoolteacher?). When he was a school student, it was my science teacher who lit that spark in me, says Carey. If I could do that for even just one kid, that would be worth it.

Teachers with PhDs give tips for making the transition.

Its not for people who want long holidays. Its really for people who have a vocation, says retired teacher Suzanne Kalka, who now works in science communication in Manchester, UK.

Get into the classroom as a temporary teacher to see if its right for you

You certainly get a feel for the type of audience that you would have by standing in for someone else, says Cindy Sparks, a teacher at Wachusett Regional High School in Holden, Massachusetts. Would-be teachers should check that out first and make sure they can handle that.

Teaching can be rewarding, but its also challenging and wont be the right fit for everyone. Anne Gillies moved into teaching after her PhD, but ended up burnt out and now works in quality assurance for a biotechnology company in Seattle, Washington. I knew from the beginning that teaching was exhausting, she says. I really wanted to give every single student 110% of myself, but she found that having 150 teenagers in a day, I dont have 150 pieces of me to give.

Try to find joy, says Joaqun Ramrez Ramrez, who teaches at the Tecnolgico de Monterrey high school in Cuernavaca, Mexico. Let go, leave your past behind. Youre not failing at science. Youre just a scientist thats become an educator.

Even though we know our subjects inside out and upside down, knowing something and teaching it is completely different, says Kalka. The qualifications needed will vary depending on where you live many teaching jobs at secondary-school level require some sort of professional certification, such qualified teacher status in England and Wales, even if you already have a PhD in the subject you want to teach.

Many of the scientists-turned-teachers whom Nature spoke to cannot pinpoint a moment that made them switch paths. Instead, they experienced a growing discontentment with elements of their scientific work, and a realization that greater job satisfaction could be found elsewhere.

This was the case for Ben Still, who became a schoolteacher in 2014, five years after getting his PhD in neutrino physics at the University of Sheffield, UK. As a postdoc, Still worked on the T2K neutrino experiment in Japan, using machine learning to process data. He liked the international nature of the collaboration, but the administrative demands began to take their toll. I wasnt having as much time to focus on the physics analyses that I really enjoyed. I could see that the career path was going towards administration, politics, funding applications, he says.

James Carey (in red) prefers the worklife balance that teaching offers.Credit: Jennifer Greenberg

A series of writing and outreach projects reignited his passion, including a collaboration with artist Nelly Ben Hayoun that involved filling a railway arch at London Bridge station with silver balloons to evoke the interior of the Super-Kamiokande neutrino detector in Japan. I had this interest and passion in explaining the science more than I did in the administration and the politics to drive the science, he says.

At the end of his postdoc in 2014, he started work at a private school in north London. His first day on the job involved overseeing 30 11-year-olds. It was a baptism of fire, he says. He went on to earn his teaching qualification and has been a teacher ever since.

For Carey, whose father died when he was 14, teaching gave him the opportunity to be there for his own children as they grew up. Unfortunately, a life in academia isnt always conducive to that [if you spend] long hours working with live organisms, you cant necessarily say, Hold on, wait, lets not do this experiment yet, my kids got a soccer match.

Although working in a secondary school is demanding and often involves overtime, teaching roles still offer more flexibility than academic ones.

Balancing a career with family life was an issue for Cindy Sparks, who got her PhD in molecular cell biology in 1995 at the UMass Chan Medical School. She wanted to pursue research but knew it would require long hours in the laboratory. When, as a postdoc, she gave birth to twins in 1998, it became nearly impossible to navigate that track, she says.

Cindy Sparks switched to teaching after giving birth to twins made it nearly impossible to remain on the academic path.Credit: Sammie Doxsey

In 2007, when her children were in school, Sparks went back to research at UMass as a postdoc in molecular medicine, benefiting from a US National Institutes of Health re-entry grant, an award that encourages scientists to return to work after time off for family commitments. She taught lecture and lab courses on the side, and in secondary schools as a visiting scientist. I knew that I was good at that and, gradually, I became aware of how rewarding it was to inspire people and make a difference. Research was making a difference too, [but] it was taking too much of my life to do.

In 2012, Sparks moved to teaching full-time, and she has spent the past ten years as a biology and chemistry teacher at Wachusett Regional High School in Holden, Massachusetts. Apart from loving what she does, she also appreciates the security of her role. I make good money. And Im in a union. So Im in a very secure job, she says, adding that many postdocs and pre-tenure faculty members at universities have comparatively less security and lower pay.

Some scientists who choose to teach after their PhDs are driven by the chance to open up science as a career path to secondary-school students who hadnt previously considered it. Suzanne Kalka started teaching physics at a state-run school in Manchester, UK, 32 years ago, after getting her PhD in cryogenic infrared spectroscopy. Her primary motivation, she says, was to inspire others to get into science.

I didnt come from a traditional research scientists background. My family was a lower socio-economic group: blue-collar workers, no experience of university, she says. She discovered in secondary school that science was her passion, but at university, she encountered very few people studying physical sciences who shared her background. I wanted to encourage girls and [members of] under-represented communities to take science courses, she says.

Although she could easily have got a job at a prestigious private school, it wasnt the demographic of students that I wanted to work with, she says. There were too many students getting left behind who werent aware that they could have a scientific career, particularly girls.

She wanted to reach those students as early as possible, when their enthusiasm for science is still high. Theyve got to get the idea when theyre 11 or 12 that there are viable careers for them, she says.

Christine Yu challenges her students with hands-on experiments and international science competitions.Credit: Christine Yu

Still was similarly motivated. As the first member of his family to go to university, he says he was lucky to have had the chance to study science in the way he did. Hopefully I can offer opportunities that I didnt have to students from similar schooling backgrounds to myself.

Now based at the private St Pauls School in London, Still spends much of his time focusing on educational outreach projects, such as a residential summer-school programme, that are also open to students from state-run schools. Being at an institution with well-resourced facilities, he wants to be able to share the benefits as far and wide as possible, he says. He hopes these projects will make an impact on students, in that they would be exposed to stuff that they may not have even realized existed.

Still also spent a couple of years at Imperial College London teaching a postgraduate certificate in education (PGCE) course, which aimed to get scientists with masters degrees and PhDs into teaching. Hes been able to pass on his own experience and inspire others to follow a similar path.

Hong Kong-based biology teacher Christine Yu also thinks that the best time to foster young peoples love of science is when they are in secondary school. After earning a PhD in biotechnology at the University of Hong Kong in 2007, she took up a postdoc that included some teaching responsibilities and found that the teaching was where she really shone.

Yu also initiated a science, technology, engineering and mathematics (STEM) programme with a focus on biotechnology, for students aged 1315. In this hands-on programme, students modify bacterial genes, visit a university laboratory and speak to working scientists. Together with other schoolteachers and university science academics, she has helped to set up or take teams to science competitions involving research projects submitted by students from Hong Kong and neighbouring Chinese cities, with the opportunity to progress to international competitions.

Yu gets great satisfaction from her students success she speaks proudly about former pupils who are now doing PhDs at prestigious universities abroad. Im lucky, she says. I have a chance to channel them to take part in challenging competitions to widen their horizons and connect them with other STEM students globally.

Scientists who come to schoolteaching after years as postdocs often realize that this has given them a strong footing in their new career. For biologist Charlotte Wood, who made the move after 20 years as a postdoctoral fellow at the University of Nottingham, UK, the depth of her experience gave her confidence in the classroom. Although she admits to initial feelings of impostor syndrome when applying for teacher-training courses in her forties, once she started teaching, she found that her years as a working scientist allowed her to explain controversial topics to her students clearly.

Im completely confident in rigorous scientific research and the importance of integrity and honesty like when weve talked about the [alleged link between] MMR vaccine and autism, she says. I can pull up the original paper, and we can compare it to a new paper.

Years of experience as a bench scientist gives Charlotte Wood confidence when discussing controversial topics with students.Credit: Jessica Stringer

Undertaking a PhD prepares teachers for the classroom, with communication and presentation skills being transferable. It is also essential to have a can-do attitude in a tough classroom environment. Perseverance is very important during a PhD, says Yu, and this is a skill she wants to embody for her students. Most of the time we fail in the experiment, and then we think about how to solve the problem.

Joaqun Ramrez Ramrez likes to bring experimentation into the classroom. A chemistry and biology teacher at the Tecnolgico de Monterrey high school in Cuernavaca, Mexico, he might structure lessons in a systematic way, or adopt a more open-ended approach. I have this idea or hypothesis [that] I can try in the classroom, he says, and he can get immediate feedback from students test scores.

For Kalka, the best preparation for teaching was working flat out on her PhD. Doing a science PhD is hard work, physically, she says. And its like that teaching science in school. You are literally on your feet 12 hours or more a day in a science lab in a school, and you do everything mop the floors, clean up.

Although worklife balance and a desire to inspire are big factors for many teachers, others are drawn to education for a different reason to correct what they see as a systemic flaw. Our education system has killed the scientist inside me, says Pankaj Jain, director of educational charity Seed2Sapling in Bengaluru, India. The organization, which he co-founded after getting his PhD in molecular biophysics, focuses on promoting constructive learning letting students experiment and discover answers through play and exploration. The focus should be on nurturing childrens creativity and natural curiosity, he says, instead of just giving them all the answers.

At least in India, and Im sure most countries, he says, the focus of science or mathematics education is knowing all the concepts, but [with] hardly any exposure to how did they discover it?.

Jain and his team work with more than 2 dozen schools that serve around 10,000 students in total. Team members also provide input to committees at the state and national level that plan Indias curriculum. Jain recognizes that thats a drop in the ocean in a country of 1.4 billion people, but like many working in education, hes happy to make a positive difference, however small.

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Why these PhD scientists swapped research for secondary-school ... - Nature.com

For a long time, most people thought about diabetes as just two categories: type 1 diabetes and type 2 diabetes, with a handful of cases falling into an other bucket.

Yet research over the past few decades shows this disease is complex and multifaceted. Among the hundreds of millions of diabetes patients worldwide, there are a myriad of genetic mutations, biomarkers, symptoms and potential complications that can all manifest at different life stages.

Precision medicine involves customizing interventions to the unique genetic and molecular makeup of individual patients rather than relying on symptoms or broad categories.

This approach, long associated with cancer treatment, is becoming increasingly critical for diabetes prevention and care.

Precise diagnosis and disease characterization affect not only treatment choices but life planning, other health considerations, and even family members well-being. It means providing the right diagnosis, best care and insights into outcomes for all people with diabetes.

We want to eliminate guesswork from diabetes care, said Louis Philipson, MD, PhD, the James C. Tyree Professor of Diabetes Research and Care of Medicine and Director of the Kovler Diabetes Center at UChicago Medicine. Precision diabetes medicine involves understanding as much of a patients biology as possible as soon as we can ideally before prescribing treatment, in the context of their personal history and community.

UChicago Medicine faculty members including Siri Greeley, MD, PhD, Rochelle Naylor, MD, PhD, and Philipson (serving on the steering committee) recently contributed to the Second International Consensus Report On Precision Medicine In Diabetes. A consortium of more than 200 diabetes experts outlined efforts to translate current and future precision medicine research into clinical practice.

The authors celebrated clear progress, such as advancements in diagnosing specific forms of monogenic diabetes through genomic insights that lead to personalized treatment choices.

The report also identified genetic risk classification as an implementable strategy for preventing type 1 diabetes. In gestational diabetes, scientists have identified specific maternal characteristics that can help predict treatment success, allowing for tailored treatment plans.

Despite these promising areas, the report calls for improved research methods and standardized precision medicine trials to bridge existing knowledge gaps.

The report also acknowledged concerns that precision medicine as a whole should not only be for wealthy countries or individuals.

These ideas need to be translatable into any country and any kind of health system, Philipson said. Some treatments are expensive, but by using simple clinical measures to personalize treatments, we can do a lot more with what we have.

He said patients and policymakers alike can get involved in making precision medicine approaches accessible through advocacy and research funding.

Precision medicine gives us a framework that helps us ask the right questions to learn what we still need to know, said Philipson. The next generation of physicians and scientists are primed to think about heterogeneity in diabetes.

Some genetic and molecular insights are already allowing physicians and researchers to integrate precision medicine into patients diabetes care plans.

One of the most amazing interventions we have is actually no intervention at all, said Philipson.

Glucokinase maturity-onset diabetes of the young (GCK-MODY also called MODY2) is a rare subset of the disease that generally develops before age 25. A key enzyme mutation lowers the amount of insulin produced by the pancreas.

Patients with the GCK-MODY mutation have slightly elevated blood sugar levels for their entire lives. But they remain stable and healthy without treatment.

Doctors are sometimes tempted to treat the numbers on a patients chart, said Philipson. Identifying this kind of diabetes has huge implications for physicians and patients. Blood sugar doesnt necessarily have to be normal to avoid the complications of diabetes without burdensome treatment.

Similarly, another type of MODY that involves a mutation in the HNF1A gene responds well to low, inexpensive doses of an old and well-established drug. Eligible patients can often rely on this drug as their only treatment instead of insulin or other drugs.

Its a huge win when genetic tests reveal that a patient with diabetes has mutations that are uniquely treatable, said Philipson.

In some cases, proactive testing of people with family histories of diabetes can allow for preventative precision treatment for patients at risk for type 1 diabetes. The drug teplizumab, created at the University of Chicago over 30 years ago, can delay the onset of type 1 diabetes in people with specific antibodies in their blood. But it must be administered early, before the disease progresses to actual diabetes.

Early detection can make all the difference when considering the best precision medicine approach. Generations of UChicago researchers have been committed to the genetic characterization of diabetes in hopes they may provide insight for precise treatment approaches.

For example, UChicago is one of the lead centers for a large, NIH-funded study called RADIANT designed to understand atypical diabetes. The study is already yielding interesting genetic findings and more, Philipson said.

On top of precise targeting for existing drugs, research is uncovering entirely new treatments. UChicago Medicine researcher Raghu Mirmira, MD, PhD, recently co-authored a study providing preliminary evidence in favor of a new type 1 diabetes treatmentthat can be taken as a pill. The medication protects pancreas cells rather than simply replacing missing insulin.

UChicago researchers, including Greeley, have partnered with colleagues from Indiana University to evaluate the drug in a study called TADPOL.

Patients also benefit from best practices for holistic care at the Kovler Diabetes Center. Treatments have been informed by personalized medicine since the center was founded in 2006.

It stinks to have diabetes; everyone can benefit from some attention in the mental health department. For many, it can be life-changing, said Philipson.

A team of health and wellness professionals led by Executive Director Peggy Hasenauer, MS, RN, and Tina Drossos, PhD, Associate Professor of Psychiatry partner with diabetes care teams with no barriers preventing opportunities to help patients.

Diabetes educators, pharmacists and social workers are embedded within the endocrine clinic as key resources, ensuring a comprehensive understanding of insurance and medication options. These elements can play key roles in precision medicine-informed treatment plans.

Everyone, from our educators and researchers to our nurses and directors, has come together to make the Kovler Diabetes Centerthe unique place it is today, said Philipson.

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Transforming diabetes care with precision medicine - UChicago Medicine

RICHMOND - Preclinical research published in the Journal for ImmunoTherapy of Cancer points to a promising new treatment option for people with pancreatic cancer. Researchers from VCU Massey Comprehensive Cancer Center and the VCU Institute of Molecular Medicine (VIMM) suggest that when used in a form that can be delivered directly into the tumor cell, polyinosinepolycytidylic acid (pIC) suppresses tumor growth, induces cancer cell death and enhances survival in animal models with the most common form of pancreatic cancer.

Researchers also concluded that when used alone or in combination with a standard-of-care medication such as gemcitabine, pIC a double-stranded RNA which acts as an immunostimulant is safe and non-toxic to normal pancreatic cells, indicating this approach may have translational potential to improve the survival of people with pancreatic ductal adenocarcinoma (PDAC).

PDAC is one of the most difficult cancers to treat effectively, with a one-year survival rate of 24% and a five-year survival rate of just 9%. In the article, researchers co-led by Paul B. Fisher, M.Ph., Ph.D., FNAI, the Thelma Newmeyer Corman Endowed Chair in Cancer Research at Massey and director of the VIMM, showed the treatment combination significantly enhances the survival of immune-competent mice with PDAC tumors which capture the properties of human pancreatic cancer.

This research is the extension of pioneering work originally done by Fisher and colleagues to define ways of enhancing the anti-cancer activity of pIC. Previous clinical trials with pIC showed limited activation of the immune response and no detectable antitumor effects in melanoma or other cancers. However, when delivered into the tumor cells cytoplasm using polyethyleneimine (PEI), a synthetic, water-soluble polymer, pIC can successfully enter the cell and stimulate tumor cell death.

The current work, co-authored with Luni Emdad, M.B.B.S., Ph.D., associate professor in VCUs Department of Human and Molecular Genetics and a member of the VIMM, and others documents a profound response in animals with PDAC when pIC is effectively delivered into tumor cells using PEI.

Previous laboratory and preclinical studies have shown this method to also be effective in a number of other cancers, including breast, melanoma and liver cancer, said Fisher, who is also a professor in the Department of Human and Molecular Genetics at VCU School of Medicine. In studying this phenomenon in mice with an intact immune system, we found that it worked exceptionally well in PDAC, extending life to an amazing degree just on its own, and enhanced even further in combination with gemcitabine. Nothing like this has been seen before when looking at the original pIC molecule without the use of PEI or other therapeutic modalities in PDAC.

The study also demonstrates the mechanism of pICs effectiveness, and the immune systems profound role in that pathway. The pIC activates Stat1, a gene expression stimulatory molecule, which in turn activates chemokines proteins that stimulate immune cell migration to heighten the immune systems response to the cancerous cells. The reaction converts tumor-associated M2 macrophages into M1 macrophages, turning the molecular machinery that was responsible for creating cancerous cells into a system that attacks the cancer.

Since the toxicity profiles of both gemcitabine and pIC are known, said Emdad, scientists can feel confident that the approach is safe to proceed to test its effectiveness in human studies.

PDAC is a devastating disease. Our survival data is so encouraging in these mice, we consider the potential impact of our treatment on humans will be significant, said Emdad.

In another promising takeaway from the study, pretreatment of mice with pIC prior to cancer development slowed eventual tumor growth by approximately 60%, suggesting that the molecule induced a protective, vaccine-like effect in the mice. This is an area the researchers identified as needing further study, to investigate possible cancer prevention implications.

Fisher said that though this studys positive results are demonstrated specifically in pancreatic cancer, the approach should work in multiple cancer types and could become a generalized therapy in combination with cancer-specific standards of care. Moreover, encouraging data in phase I studies using pIC-PEI (BO-112) as a single agent, or in combination with the immune checkpoint inhibitor anti-PD-1, was found safe and manageable in patients with aggressive solid cancers other than PDAC.

The big picture is that this approach works, and its ready to go into the clinic to treat patients with pancreatic cancer, said Fisher. Translating discoveries that originate in the laboratory into effective therapies is a major challenge that, when accomplished, represents the ultimate achievement of basic medical research. For PDAC patients, we think there could be a light at the end of the tunnel.

Collaborators on this study include Praveen Bhoopathi, Ph.D., Amit Kumar, Ph.D., Anjan K. Pradhan, Ph.D., Santanu Maji, Ph.D., Padmanabhan Mannangatti, Ph.D., Jolene J. Windle, Ph.D., Mark A. Subler, Ph.D., Dongyu Zhang, M.D., Vignesh Vudatha, M.D., Jose G. Trevino, M.D., Esha Madan, Ph.D., Azeddine Atfi, Ph.D., Devanand Sarkar, M.B.B.S., Ph.D., Rajan Gogna, Ph.D., and Swadesh K. Das, Ph.D., from the VCU School of Medicine.

This research was supported by the Thelma Newmeyer Corman Endowment (PBF), developmental funds from the VCU Institute of Molecular Medicine (PB, LE, SKD, PBF), research support from the Department of Human and Molecular Genetics (PB, LE) and National Cancer Institute Cancer Center Support Grant to VCU Massey Cancer Center P30 CA16059.

About VCU Massey Comprehensive Cancer Center

VCU Massey Comprehensive Cancer Center is working toward a future without cancer one discovery, one successful therapy and one life saved at a time. Recognized as an NCI-designated Comprehensive Cancer Center, Massey is among the top 4 percent of cancer centers in the country influencing a new standard of care through research, education and community engagement. Introducing a new generation of community-centered cancer centers, Massey is leading the nation in establishing a 21st-century model of equity for cancer research and care. Community informs and partners with Massey on its research to best address the cancer burden and disparities of those the cancer center serves, with a local focus and

a global impact. Massey conducts cancer research spanning basic, translational, clinical and population sciences; offers state-of-the-art cancer therapies and clinical trials, including a network that brings trials to communities statewide; provides oncology education, teaching and training; and promotes cancer prevention. At Massey, oncology experts collaborate in multidisciplinary teams to provide award-winning, comprehensive cancer care at multiple sites throughout Virginia. Visit Massey online at masseycancercenter.org or call 877-4-MASSEY for more information.

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New approach to pancreatic cancer treatment expands therapeutic ... - Brunswicktimes Gazette