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Bengaluru: An international collaboration of over 100 scientists and geneticists have traced the genetic origin of modern domestic horse, the Equus caballus, to Russia.

The research narrows the location of horse domestication the steppes of Western Europe, where the Volga and Don rivers intersect, to 4,200 years ago from where and when horses spread to the rest of the world.

The study was led by molecular archaeologist Ludovic Orlando at University of Paul Sabatier in Toulouse, France. Genetic analysis was performed on 273 reconstructed ancient horse genomes from fossils of ancient horses found in various parts of Europe and Asia.

The team further identified two genes in horses, the GSDMC and ZFPM1 genes, which provided modern horses locomotive and behavioral adaptations that helped with horse-back riding and domestication.

The research is thought to be the most comprehensive analysis of available genetic data and the findings were authored by 162 researchers. The paper was published in the journal Naturethis week.

The Bronze Age spread through Europe and Asia between 5,000 and 4,000 years ago, which is when writing systems, pottery, codified law, city-states, warfare, and agriculture came into existence in human society.

Analysis of human genomes from this era has previously revealed a massive expansion and spreading out of population from the Western Eurasian steppes into the regions of Central and Eastern Europe in around the 3rd millennium BCE. Historical records also indicate a rapid expansion in the population of horses across Eurasia at this time.

This is also the time period where horse ancestors that roamed grasslands in North America came over to Asia by crossing over the fully frozen Bering land bridge.

Based on their findings, the authors write that the people who lived in the region where the Volga and Don rivers intersect, bred horses, which moved along with humans.

However, researchers also identify other species of horse that were domesticated in pockets, whose populations were eventually replaced by horses that came from this region, called the DOM2 horses as they spread out in the second millennium, around 2200 BCE.

The journey of horses and humans is traced together with equestrian culture, which shows expansion of objects like spoke-wheeled chariots.

Also read: 85% world population inhabit areas directly affected by human-induced climate change, study says

Horse ancestors are thought to have roamed the grasslands in North America, and came over to Asia by crossing over the fully frozen Bering land bridge before the Bronze Age.

To the early days of the Bronze Age, four lineages of horses were identified. One lineage was traced to a different species called Equus lenensis, which existed in northeastern Siberia. A second lineage was spread out over the western parts of Europe. A third lived in the Urals, while the fourth, the DOM2, lived in the Western Eurasian steppes.

Genetic analyses traced the DOM2 to have originated in the region where the Volga and the Don rivers intersected, and where the existing human population domesticated these horses for specific genes by breeding. The DOM2 horses eventually replaced the populations of other native horses thanks to favourable genetics that allowed them to live with humans.

The authors used data about the analysis of human expansion and compared the expansion of the modern horse genome with it.

From bones of horses buried with spoke-wheeled chariots during around 2000 BCE, authors surmised them to be of the DOM2 horses. Such horses were also found in Central Anatolia; visual representations from about 1900 BCE are available. They also identified other geographic regions where the horses pre-dated chariots, indicating that horseback riding spread before chariots.

The two genes identified indicated key behaviours that humans bred horses for the GSDMC gene is responsible for a strong spine, back, and gait, while the ZFPM1 gene is involved in mood regulation and aggression. The combination of the genes indicated that horses were bred to be more mobile, including being able to run long distances and bear weight, and also to be more docile to be able to live and work alongside humans.

The findings finally provide an answer to extensive debates about the origins and the spread of modern domestic horses.

Along with horses, the research also explains the evolution of two family of languages as different groups of peoples spread across Eurasia.

All European languages have evolved from the hypothetical Proto-Indo-European (PIE) language, which then has sub-families of languages. In the Indo-Iranian group of languages, which consists of languages spoken in the Persian region and in northern India, there is an extensive vocabulary for horse- and equestrian culture-related words, while the earlier parent PIE language has a sparse vocabulary for equine words.

We thus conclude that the new package of chariotry and improved breed of horses, including chestnut coat colouration documented both linguistically and genetically, transformed Eurasian Bronze Age societies globally within a few centuries after about 2000 BC, write the authors.

(Edited by Paramita Ghosh)

Also read: Astronomers discover first planet that survived its stars death, still orbits white dwarf

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Adapted from a story that originally appeared here in the University of Utah Health newsroom.

When Faith Bowman was deciding where to attend graduate school, the University of Utah wasnt exactly at the top of her list. Coming from Wisconsin, she didnt know much about the school or the state. But during her recruitment visit, an informal gathering with students from the all-inclusive University of Utah SACNAS (Society for Chicanos/Hispanics and Native Americans in Science) chapter helped her see things differently. After talking with them, she knew that if she came, she would be surrounded by a supportive community. She chose the U, and three years later, that prediction has held true.

To me, SACNAS is a community away from home, says Bowman, now president of the U chapter. Its a place that has created a sense of belonging for me on campus while helping me to achieve my professional goals.

Bowmans experience isnt unique. The bioscience graduate programs have collaborated with the U SACNAS community in its annual recruitment activities since 2017. These efforts, which included hosting the 2017 SACNAS National Conference in Salt Lake City, have resulted in tripling recruitment of students from historically underrepresented (UR) backgrounds. UR students now comprise 33% of the domestic class, and racial and ethnic minorities comprise 28%, reflecting the national talent pool.

Knowing this diverse, all-inclusive community is here helps recruits decide, in parallel to the awesome research, that we are their best fit, says Jeanette Ducut-Sigala, U SACNAS manager.

The ability to make meaningful change in diversity and inclusion has earned U SACNAS national recognition. In a virtual ceremony held on Oct. 13, the national organization designated the U group Chapter of the Year along with six other local chapters of the 133 located in the U.S. and Puerto Rico.

U SACNAS officially launched in 2014 with the goal of training and supporting the next generation of diverse STEM talent. From students to professionals, the parent organization fosters success in attaining advanced degrees, careers and positions of leadership within STEM. The U chapter mainly serves graduate students, postdocs and staff while a sub-chapter centered on main campus is open to both undergraduates and graduate students. Ducut-Sigala, biochemistry faculty Minna Roh-Johnson and Paul Sigala and human genetics faculty Clement Chow operate as advisors.

Its clear that across the country there is a great need for organizations like this one. According to SACNAS, the national STEM workforce is only 6% Hispanic, 4.8% Black, and 0.2% Native American, numbers that are significantly lower than in the overall U.S. workforce. A lack of diversity hurts all of us, the organization explains, because diverse voices bring creative solutions to our worlds most pressing scientific problems.

U of U SACNAS helps its members to grow through authentic inclusion: hosting talks by professionals to inspire career aspirations and create connections with role models, supportive peer mentoring, outreach and leadership development. In collaboration with the University Counseling Center, Health and Wellness Center and Center for Student Wellness, they hold sessions where members can talk through troublesome issues and learn strategies for balancing their lives in and outside of science. Knowing that role modeling can make all the difference, particularly in young children, they also perform outreach with local K-12 schools to show that science is for everyone.

The organization has provided a sense of belonging to member Jesse Velasco-Silva, a biochemistry graduate student and the chapters vice president. The SACNASfamiliaalways encourages me to bring, show and celebrate my strength, resilience, culture, traditions and science, he says. He explains that being a first-generation Mexican-American immigrant and college student has come with challenges. The guidance and support hes received from the SACNAS community has helped him to overcome them.

As for Bowman, her experience has come full circle. She benefitted from the openness of the U SACNAS community when she was making the difficult decision of where to get her doctoral degree. Now, she does the same for the next sets of prospective students.

I get to show the recruits, particularly the first-gen BIPOC students, how we belong on campus, belong in our programs, and thrive here because we have a community like SACNAS, she says. We have a supportive, collaborative environment at Utah and really, a university committed to equity and inclusion.

Read the original:
Changing the face of science | @theU - @theU

Abstract

The results of multiple studies have shown that a substantial proportion of men with advanced prostate cancer carry germline DNA repair mutations. Germline testing in prostate cancer may inform treatment decisions and consideration for clinical trials. There are 2 FDA approved PARP inhibitors (PARPi), olaparib (Lynparza) and rucaparib (Rubraca), for the treatment of advanced prostate cancer with DNA repair deficiency. Increasing demand for germline testing in prostate cancer and a shortage of genetic counselors have created a need for alternative care models and encouraged oncologists to take a more active role in performing germline testing. This article summarizes recommendations for germline testing in prostate cancer and describes care models for providing counseling and testing.

Genetic testing in men with prostate cancer has become more widespread since the discovery that men with metastatic prostate cancer are more likely to carry germline DNA repair gene mutations and the approval of PARP, or poly adenosine diphosphate-ribose polymerase, inhibitors (PARPi) for prostate tumors with DNA repair deficiency. The resulting substantial increase in men with prostate cancer who are eligible for germline testing, with time-sensitive treatment implications, challenges the traditional in-person, time- and resource-intensive cancer genetics care delivery model, and calls for alternative approaches. Urologists, oncologists, and other medical providers are encouraged to take a more active role in delivering germline testing, and they should be aware of current guidelines and optimal pretest and posttest counseling components. This article focuses on the implementation of germline testing in the care of patients with prostate cancer.

Germline genetic testing evaluates for inherited mutations (otherwise known as pathogenic or likely pathogenic variants) that are found in virtually all cells of the body and are derived from the fundamental DNA of an individual. DNA from no cancerous, healthy cells (eg, leucocyte or saliva/buccal swab cells) are used for germline genetic testing. The goals of germline genetic testing are to evaluate for an inherited cancer syndrome; to inform individual and family cancer risks; and to guide cancer prognosis and treatment decisions. Germline testing should be distinguished from recreational and somatic (tumor-specific) testing. Direct-to-consumer recreational genetic testing consists of an at-home test that is advertised to help understand the customers ancestry. Recreational genetic panels look for inherited variants in saliva/buccal swab cells to inform genealogy, and they are not primarily intended to guide medical decisions as they lack gene coverage and clinical-grade precision. None of the recreational genetic tests include a comprehensive assessment of the BRCA1/2 or other DNA damage repair genes and are inadequate for medical purposes. Somatic testing panels are designed to identify alterations in a tumors DNA. A somatic test may occasionally identify mutations expected to be germline, in which case follow-up dedicated germline tests are needed. Examples of somatic panels that report germline mutations include Tempus and UW-Oncoplex. However, many somatic panels use bioinformatics algorithms that may filter out, miss, and/or choose not to report germline mutations. Thus, in general, somatic panels should not be considered adequate for germline conclusions; at most, they should prompt confirmatory germline testing. This articlefocuses on dedicated clinical-grade germline testing.

Germline testing in men with prostate cancer is being performed more often since an important number of prostate cancer cases have a heritable component.1,2 Germline mutations in DNA repair genes, such as BRCA1/2, contribute to hereditary prostate cancer risk and are present in up to 11.8% of men with metastatic prostate cancer,3 compared with 4.6% among men with localized prostate cancer and 2.7% in persons without a known cancer diagnosis.3,4

Germline BRCA1/2 mutations are associated with increased risk of prostate cancer: up to a 3.8-fold increase with BRCA1 and an 8.6-fold increase with BRCA2 mutations.5 Men who carry germline BRCA1/2 mutations are not only at increased risk of developing prostate cancer but are also at risk of a more aggressive prostate cancer phenotype. In their study, Castro et al found that patients with prostate cancer with germline BRCA1/2 mutations at the time of diagnosis were more likely to have higher Gleason score (8) and more advanced stage (T3/4, nodal involvement, and metastases) compared with noncarriers. Men with germline BRCA1/2 mutations also had shorter cancer-specific survival (CSS) than noncarriers (15.7 vs 8.6 years; P=.015).6 Men with localized prostate cancer and germline BRCA1/2 mutations have worse outcomes after definitive treatment with surgery or radiation compared with noncarriers: 5-year metastasis-free survival, 72% vs 94%; P <.001; 5-year CSS, 76% vs 97%; P <.001.7 The prospective PROREPAIR-B study found that germline BRCA2 status is an independent prognostic factor for CSS in patients with metastatic castration-resistant prostate cancer (mCRPC; 17.4 vs 33.2 months; P = .027).8

Based on the study results above and others, the current National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer (version 1.2022)9 recommend germline testing for the subsets of patients with prostate cancer who are more likely to have germline DNA repair mutations (Figure 1).

The NCCN guidelines recommend offeringgermline testing to the following groups of patients with prostate cancer9:

I. Men with node positive, high-risk or very highrisk localized prostate cancer

II. Men with metastatic prostate cancer

III. Men meeting family history criteria (Table 1)

NCCN recommends considering germline testing for men with personal history of prostate cancer and:

I. intermediate risk prostate cancer and intraductal/cribriform histology

II. personal history of exocrine pancreatic, colorectal, gastric, melanoma, pancreatic, upper tract urothelial, glioblastoma, biliary tract or small intestinal cancers

Several commercial vendors provide germline testing panels, including Invitae, Color, and Ambry. Further details and information on available panels can be found on the vendors websites. Panel sizes vary from dedicated BRCA1/2 testing to 91-gene panels. The NCCN guidelines for prostate cancer9 recommend that germline testing panels include genes associated with Lynch syndrome (MLH1, MSH2, MSH6, PMS2) and homologous recombination genes (BRCA1/2, ATM, PALB2, CHEK2).9,10 Broader panels might be appropriate for men with mCRPC, especially if clinical trial participation is being considered. Average turnaround time for germline testing is between 10 and 30 days, which varies depending on the particular panel. The cost of germline testing varies depending on insurance coverage. Some companies offer provide testing for a flat out-of-pocket fee (eg, $250), and a benefit of participating in certain research studies may be no-cost testing.

NCCN guidelines recommend germline testing for a large subset of patients with prostate cancer, but the best care model to offer education and testing is unclear. The traditional clinical care delivery model for cancer genetics includes 2 in-person visits with a genetic counselor, the first for pretest risk assessment and education and the second to discuss the results. This is the most established pathway and, historically, has been utilized the most. However, broadening recommendations for germline testing create great demand that cannot be currently met in a timely fashion by the approximately 4000 genetic counselors in the United States.11,12 Therefore, oncologists and other providers are increasingly performing pretest counseling, ordering genetic testing, and providing posttest counseling for their patients, or following hybrid models (Table 2).13

The provider-led germline testing model has been tested in breast and ovarian cancer but is new in prostate cancer.14-18 Scheinberg et al reported results of a multicenter prospective study evaluating provider-led germline testing for men with prostate cancer. Twelve oncologists received training about the role of germline testing and in counseling patients, and then offered germline testing to patients with mCRPC in their practice. Those patients who accepted germline testing received pretest counseling and educational materials, and later discussed test results in the oncologists office. If a germline mutation was identified, the patient was referred to a genetic counselor to discuss the further implications of the results and to initiate cascade testing. Most patients (63 of 66; 95%) accepted the germline testing and high satisfaction rates were achieved among both oncologists and patients.19 A provider-led germline testing model in the Veterans Affairs health care system was also evaluated. Patients with metastatic prostate cancer were offered germline testing by their oncologists during regular clinic visits. Pretest counseling was provided by oncologists and study coordinators and saliva for the test was collected in the clinic. Posttest counseling sessions with genetic counselors were provided over the phone by the testing panel company. Again, most patients (190 of 227 approached veterans; 84%) accepted testing, and the test completion rate was 80% (182/227).20 Results of early studies suggest that provider-led germline testing in prostate cancer could be effective and satisfactory for both patients and providers.

The need to streamline germline testing also calls for the utilization of new technologies, such as video- or phone-based counseling. The EMPOWER study (NCT04598698) assessed mens preference of in-person genetic counseling vs video-based genetic education21; results indicated that in-person genetic counseling was preferred by men with less education and higher anxiety levels, and it resulted in greater improvement of cancer genetics knowledge. The rates of genetic testing uptake were similar for video-based and in-personcounseling groups.21 Video-based counseling was also evaluated by Tong et al, who compared 2 models of streamlined germline testing in prostate cancer: (a) a take-home genetic kit provided by an oncologist, followed by referral to a genetic counselor if subsequent results are concerning; and (b) a genetic testing station, at which the patient participated in a video call from a genetic counseling assistant for genetics education and collection of family history, which was followed by saliva sample collection and, later, referral to a genetic counselor if any mutation was identified. The latter approach resulted in a lower rate of incomplete tests and a higher rate of follow-up with genetic counselors for positive results. Authors suggested that utilization of video education and involvement of genetic counselor assistants may improve access to germline testing among patients with prostate cancer.22 Several studies are ongoing to evaluate other care models to provide genetic testing in prostate cancer (eg, NCT02917798, NCT03076242, NCT03328091, NCT03503097).23

Oncologists who choose to perform germline testing need to be comfortable with several aspects of genetic counseling and to remain current on the ethics of informed consent and posttest counseling for germline testing (Figure 2). The 2019 Philadelphia Prostate Cancer Consensus Conference suggests that optimal pretest consent should include discussion of the purpose of testing, types of possible results (ie, pathogenic/likely pathogenic; benign/likely benign; variant of unknown significance; no variants identified), the possibility of identifying hereditary cancer syndrome and/or other cancer risks, testings potential cost, the importance of cascade family testing, and the Genetic Information Nondiscrimination Act (GINA) law.12 The GINA law protects against discrimination based on genetics in employment and health insurance; however, it is not applicable to life insurance, long-term care disability insurance, Indian Health services, and patients enrolled into federal employee, Veterans Administration, and US military health benefit plans.23,24 These gaps in protection by GINA law are important to discuss with patients, who may need to consider them before proceeding with the germline testing. Providers should also consider discussing the different panels available for testing, the privacy of genetic tests, and genetic laboratories policies related to sharing and selling of data.12

Providers ordering germline tests also must accept responsibility to follow up with patients if reclassification occurs of a variant of (currently) unknown significance (VUS). VUS are reported in about 30% of men with prostate cancer who undergo germline testing.4 VUS results do not change clinical recommendations, and the majority of them end up being reclassified as benign.25,26 In the Find My Variant Study, 38 of 63 VUS (61%) were reclassified: 32 of 38 (84%) as benign/likely benign and 6 of 38 (16%) as pathogenic/likely pathogenic.27,28 In the rare case when a VUS is reclassified as pathogenic or likely pathogenic, the provider who ordered the test is notified and they are responsible for disclosing the reclassification to the patient. Regardless of the model used, genetic counselor referral is recommended if a patient has a germline mutation identified and/or if clinical suspicion is high for an inherited cancer predisposition. Collaborative efforts are needed to educate oncology providers on aspects of germline testing counseling and to create shared printed and video resources for patients to facilitate informed consent.

Germline testing in men with prostate cancer can potentially benefit not only the patient but also family members. If a germline mutation is identified in a patient, testing for the same mutation in family members (cascade testing) should be performed. For instance, identifying family members with BRCA1/2 mutations could inform potentially lifesaving risk-reducing interventions, eg, prophylactic salpingo-oophorectomy for female BRCA1 mutation carriers. The IMPACT study (Identification of Men with a Genetic Predisposition to Prostate Cancer: Targeted screening ingBRCA1/2mutation carriers and controls) evaluated the utility of prostate-specific antigen (PSA) screening in men aged 40 to 69 years with germline BRCA1/2 mutations compared with its utility in noncarriers.29,30 The study enrolled 3027 men with no personal history of prostate cancer: 919 BRCA1 carriers, 902 BRCA2 carriers, 709 BRCA1 noncarriers, and 497 BRCA2 noncarriers. Preliminary results, reported after 3 years of follow-up, showed that BRCA2 mutation carriers, compared with noncarriers, have a higher incidence of prostate cancer and a younger age of diagnosis. The results for BRCA1 carriers were not definitive, and further investigation is needed. The results from IMPACT suggest annual PSA screening for BRCA2 mutation carriers aged between 40 and 69 years, using PSA cutoff of 3.0 ng/ml.30 Studies evaluating the predictive value of lower PSA cutoff and prostate MRI are ongoing (eg, NCT03805919, NCT01990521).

Advanced disease

PARPi. Patients with DNA repair mutations have higher responserates toPARPiand platinum chemotherapy.31,32 In 2020, two PARPi received FDA approval for treatment of mCRPC with germline or somatic DNA damage repair gene mutations. Rucaparib was approved based on the phase 2 TRITON2 (NCT02952534) study; it reported a 51% (50/98) radiographic response rate among men with mCRPC and BRCA1/2 alterations.33 The benefit for men with non-BRCA DNA repair mutations was less clear, and rucaparib is currently approved only for carriers of BRCA1/2 mutations. 33-35 The olaparib label includes a larger number of mutated genes eligible for treatment (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L), based on results of the phase 3 ProFOUND study (NCT02987543). ProFOUND compared olaparib with enzalutamide or abiraterone and showed improved radiographic progression-free survival (5.8 months vs 3.5 months) with olaparib. 36 Several other ongoing studies are evaluating the efficiency of PARPi monotherapy and combined therapies in mCRPC. Table 3 summarizes study results reporting response rates to PARPi in prostate cancer. 37

Platinum chemotherapy. Historically, platinum chemotherapy has been used to treat tumors, such as ovarian or pancreatic cancer, that have a high frequency of DNA repair mutations.38,39 Early data suggest that platinum chemotherapy is also effective in prostate tumors with DNA repair deficiency.40-43 A retrospective case series by Cheng et al showed that 3 of 3 patients with prostate cancer who had biallelic inactivation of BRCA2 had an exceptional response to platinum chemotherapy after progressing on several therapies.40 The results of a larger retrospective study supported this observation, reporting that 75% (6/8) of patients with mCRPC and withgermline BRCA2 mutations had a PSA50 response (ie, decline of prostate-specific antigen by 50% from baseline) to platinum chemotherapy compared with 17% (23/133) of mCRPC patients without gBRCA2 mutations.41 Mota et al reported a 53% (8/15) PSA50 response to platinum chemotherapy among men with mCRPC and DNA damage repair mutations (ie, BRCA2, BRCA1, ATM, PALB2, FANCA, and CDK12).43

NCCN guidelines recommend considering DNA repair mutation status when discussing the possibility of active surveillance. Germline mutations in BRCA1/2 or ATM are associated with a higher likelihood of grade reclassification among men undergoing active surveillance.44 Mutation carriers should be closely monitored; they could potentially benefit from an earlier definitive treatment approach.

BRCA1/2 carriers have worse outcomes with conventional definitive therapies. Castro et al evaluated the response of BRCA1/2 carriers with localized prostate cancer to 2 radical treatmentsdefinitive radiation and radical prostatectomyand reported that BRCA status is an independent prognostic factor for metastasis-free survival (HR, 2.36; P = .002) and CSS (HR, 2.17; P = .016).7 New treatment approaches in earlier disease stages are being evaluated in clinical trials for patients with prostate cancer and DNA repair deficiency. Targeted therapies, such as PARPi, are being actively investigated in the biochemically recurrent stage of prostate cancer (eg, NCT03047135, NCT03810105, NCT04336943, NCT0353394) and as neoadjuvant therapy in localized disease (eg, NCT04030559).

Germline testing is becoming more commonplace with advances in precision oncology and expanding treatment implications of the results of this testing. The NCCN prostate cancer guidelines recommend germline testing for men with high-risk or very highrisk localized prostate cancer; men with metastatic prostate cancer; patients with intraductal histology of the prostate; and patients meeting family history criteria. These recommendations have created a need for germline testing of many prostate cancer patients, which calls for a change in the traditional cancer genetics delivery model to meet the new demand.45 Oncologists are encouraged to take a more active role in performing germline testing, but the optimal approach is unclear. Until the results of larger trials focusing on various testing delivery models are available, joint efforts are needed to build collaborative relationships between oncologists and genetic specialists. Further efforts are required to create dedicated resources to support providers in this new era of genetic testing and precision oncology in prostate cancer, which is marked by near-constant change.

ACKNOWLEDGMENTS: We gratefully acknowledge support from the Institute for Prostate Cancer Research, NIH/NCI CCSG P30CA015704, NIH SPORE CA097186, NCI T32CA009515 award, Congressional Designated Medical Research Program (CDMRP) award W81XWH-17-2-0043, and the Prostate Cancer Foundation.

Conflict of interest/disclosures: AOS has no conflicts to disclose; HHC receives research funding to her institution fromClovis Oncology, Color Genomics, Janssen Pharmaceuticals, Medivation, Inc. (Astellas Pharma Inc), Phosplatin Therapuetics, and Sanofi S.A., and has a consulting or advisory role withAstraZeneca.

Sokolova is from the Division of Medical Oncology at Oregon Health Science University (OHSU) and the OHSU Knight Cancer Institute.

Cheng is from the Division of Medical Oncology at the University of Washington and the Division of Clinical Research at Fred Hutch Cancer Research Center.

1. Mucci LA, Hjelmborg JB, Harris JR, et al; Nordic Twin Study of Cancer (NorTwinCan) Collaboration. Familial risk and heritability of cancer among twins in Nordic countries. JAMA. 2016;315(1):68-76. doi:10.1001/jama.2015.17703

2. Hjelmborg JB, Scheike T, Holst K, et al. The heritability of prostate cancer in the Nordic Twin Study of Cancer. Cancer Epidemiol Biomark Prev. 2014;23(11):2303-2310. doi:10.1158/1055-9965.EPI-13-0568

3. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453. doi:10.1056/NEJMoa1603144

4. Nicolosi P, Ledet E, Yang S, et al. Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines. JAMA Oncol. 2019;5(4):523-528. doi:10.1001/jamaoncol.2018.6760

5. Giri VN, Beebe-Dimmer JL. Familial prostate cancer. Semin Oncol. 2016;43(5):560-565. doi:10.1053/j.seminoncol.2016.08.001

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7. Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi:10.1016/j.eururo.2014.10.022

8. Castro E, Romero-Laorden N, Del Pozo A, et al. PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2019;37(6):490-503. doi:10.1200/JCO.18.00358

9. NCCN Clinical Practice Guidelines in Oncology. Prostate cancer, version 1.2022. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed 9/10/2021

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11. Abacan MA, Alsubaie L, Barlow-Stewart K, et al. The global state of the genetic counseling profession. Eur J Hum Genet. 2019;27(2):183-197. doi:10.1038/s41431-018-0252-x

12. Giri VN, Knudsen KE, Kelly WK, et al. Implementation of germline testing for prostate cancer: Philadelphia Prostate Cancer Consensus Conference 2019. J Clin Oncol. 2020;38(24):2798-2811. doi:10.1200/JCO.20.00046

13. Giri VN, Hyatt C, Gomella LG. Germline testing for men with prostate cancer: navigating an expanding new world of genetic evaluation for precision therapy and precision management. J Clin Oncol. 2019;37(17):1455-1459. doi:10.1200/JCO.18.02181

14. George A, Riddell D, Seal S, et al. Implementing rapid, robust, cost-effective, patient-centred, routine genetic testing in ovarian cancer patients. Sci Rep. 2016;6:29506. doi:10.1038/srep29506

15. Yoon SY, Bashah NSAhmad, Wong SW, et al. LBA4_PR. Mainstreaming genetic counselling for genetic testing of BRCA1 and BRCA2 in ovarian cancer patients in Malaysia (MaGiC study). Ann Oncol. 2017;28(suppl 10):x187. doi:10.1093/annonc/mdx729.004

16. Enomoto T, Aoki D, Hattori K, et al. The first Japanese nationwide multicenter study of BRCA mutation testing in ovarian cancer: CHARacterizing the cross-sectionaL approach to Ovarian cancer geneTic TEsting of BRCA (CHARLOTTE). Int J Gynecol Cancer. 2019;29(6):1043-1049. doi:10.1136/ijgc-2019-000384

17. Kemp Z, Turnbull A, Yost S, et al. Evaluation of cancer-based criteria for use in mainstream BRCA1 and BRCA2 genetic testing in patients with breast cancer. JAMA Netw Open. 2019;2(5):e194428. doi:10.1001/jamanetworkopen.2019.4428

18. Colombo N, Huang G, Scambia G, et al. Evaluation of a streamlined oncologist-led BRCA mutation testing and counseling model for patients with ovarian cancer. J Clin Oncol. 2018;36(13):1300-1307. doi:10.1200/JCO.2017.76.2781

19. Scheinberg T, Goodwin A, Ip E, et al. Evaluation of a mainstream model of genetic testing for men with prostate cancer. JCO Oncol Pract. 2021;17(2):e204-e216. doi:10.1200/OP.20.00399

20. Sokolova A, Cheng HH, Montgomery B. Implementation of systematic germline genetic testing (GT) for metastatic prostate cancer (mPC) patients at the Puget Sound VA Prostate Oncology Clinic. J Clin Oncol. 2020;38(15 suppl):abstr 1578. doi:10.1200/JCO.2020.38.15_suppl.1578

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Germline Testing in Prostate Cancer: When and Who to Test - Cancer Network

By 2050, 13.5 million people in the United States will live with Alzheimers disease unless early diagnosis and treatment can delay the onset of the disease. Current treatment centers around slowing the progression of the disease.

In the journal EMBO Molecular Medicine, scientists revealed this week that circulating microscopic nucleotides assembled amino acids that bind directly to messenger ribonucleic acids (mRNAs) can identify cellular imbalance in the brain. These nucleotides, called microRNAs, are easily measured blood proteins that may identify the early risk of Alzheimers disease.

The role of these microRNAs in directing mRNAs to protect the brain from inflammation means that targeting them for therapy could inhibit cellular damage in the brain and delay the onset of dementia.

Verna R. Porter, M.D., commented on the pivotal aspects of this research for Medical News Today. Dr. Porter is a neurologist and the director of programs for dementia, Alzheimers disease, and neurocognitive disorders at Providence Saint Johns Health Center in Santa Monica, CA.

Alzheimers disease is usually diagnosed at a relatively advanced/symptomatic stage of the disease with relatively advanced biomarker/molecular pathology for example, the amyloid deposit in the brain is already well-established. The problem has been that by the time the disease is diagnosed, the current treatments have been essentially ineffective in terms of disease modification.

Dr. Verna R. Porter

The molecular brain changes linked to Alzheimers disease often occur many years before those affected manifest clinical symptoms. Therefore, these researchers designed a model to compare biomarker results in healthy adults with those in people with cognitive decline.

In a multifaceted study, based on the similarities between human and murine neurophysiology, research scientists scored young people aged below 30 years for cognitive function. Then, they identified microRNAs present in the blood that matched their cognitive function. Finally, the scientists linked these microRNAs to larger mRNAs associated with cognitive decline.

Once the researchers had made this connection, they studied microRNAs as possible biomarkers for early cognitive decline.

Aging mice can develop cognitive decline, similar to humans. Therefore, the researchers designed a follow-up experiment measuring these same biomarkers in healthy and aging mice. The scientists could now study the before and after of these microRNA biomarkers, looking for their presence in the blood of both mice that were healthy and those that had cognitive decline.

Dr. Islam, Prof. Fischer, and colleagues from the German Center for Neurodegenerative Diseases and the University Medical Center in Gttingen, Germany, found seven microRNAs frequently linked to age-related cognitive decline in mice. They then correlated these microRNAs to their known functions in human genes, which genome-wide association studies (GWAS) had identified.

The scientists compared their mouse microRNA results with the 709 human genes related to cognitive function in healthy individuals. Three microRNAs that regulate genes in cognitively impaired mice were repeatedly linked to crucial genes in human cognitive function.

To further support their results, the researchers imposed the three microRNAs onto cell cultures of the murine hippocampus, a part of the brain responsible for memory. They confirmed that increased expression of these three microRNAs (directing mRNAs) in cell culture impaired neural function and plasticity the ability of nerves to modify themselves in response to experience and injury.

The scientists then directly measured the three microRNAs present in the brains of cognitively impaired mice and found high levels. Finally, they compared their results with those of prior studies, tentatively linking these microRNAs to neuroinflammation and cellular stress. Dr. Porter summarized:

These researchers noted that circulating microRNAs are linked to cognitive function in young/healthy individuals. Using mouse models, these researchers have identified circulating three-microRNA signatures in the blood, which are increased in patients with mild cognitive impairment (MCI) and suggest an enhanced risk of future conversion from MCI to [Alzheimers disease].

In mice, high levels of the three microRNAs correlated with cognitive decline. But is it possible to extrapolate these results to humans? And could the amount of the three microRNAs predict cognitive impairment before clinical signs of dementia appear?

The researchers studied participants from different age groups in cross-sectional settings. First, they analyzed the plasma of individuals with MCI. In comparison with cognitively healthy people, those living with MCI had significantly increased levels of the microRNAs.

The scientists wondered whether the three microRNAs were higher in people with MCI who go on to develop Alzheimers disease. By analyzing past blood samples, they learned that people with higher levels of the three microRNAs were more likely to progress from stable MCI to Alzheimers disease than those with lower levels.

They also measured the microRNAs in the cerebrospinal fluid of people living with MCI and found significantly elevated levels.

Proposing possible mechanisms in humans, the researchers studied human brain cell cultures, treating them with the three microRNAs. Similar to the previously studied mouse brain cell cultures, they found decreased neuronal synaptic function and increased cellular stress.

So, can we intervene in the function of these elevated three microRNAs and reverse brain cell damage?

The answer is maybe. To test this, the scientists developed an inhibitor of each of the three microRNAs. They injected the three microRNA inhibitors (anti-miRs) into mice with Alzheimers-like pathology, finding that this improved the animals performance in hippocampal-dependent learning strategies, such as escaping from a water maze.

The therapeutic hope is that by targeting these early biomarkers of disease (i.e., targeting all three microRNAs using anti-miRs), we may be able to ameliorate cognitive decline in humans, as has been shown using mouse models.

Dr. Verna R. Porter

The researchers acknowledge that many other complex risk factors likely play a role in Alzheimers disease. Due to this, highly effective therapy may require the regulation of several molecular processes.

MNT queried Dr. Porter on why treatments dealing with the onset of Alzheimers disease have been so elusive. Dr. Porter described how researchers have rigorously studied a protein deposit in the brain, called beta-amyloid, as a potential cause of Alzheimers disease. It seems that beta-amyloid accumulation in the brain may interfere with communication between brain cells in people living with Alzheimers disease. She recounted:

A great deal of research effort has been focused on the amyloid cascade hypothesis of [Alzheimers disease] pathology. The numerous clinical trial failures, utilizing various anti-amyloid therapeutic interventions, have been very disappointing []. It has been suggested that the numerous failed clinical trials that have largely focused on beta-amyloid deposits [indicate] that beta-amyloid may not be the main driver of the disease.

Instead, (the) deposition of beta-amyloid in the brain may be a biological response to some other potential trigger. In this view, beta-amyloid deposits would represent residual scars (after-effects) like the scar that seals a wound, rather than the primary driving process of the disease. It may be that anti-amyloid therapies are simply administered too late in the disease progression.

Newer research is looking more broadly at other potential driving factors of the disease, such as tau protein deposition, and the potential preventive role of lifestyle modifications for example, diet, nutrition, exercise, sleep, and appropriate supplements as another potential way forward in the prevention of the disease.

Tau is a protein involved in brain cell stabilization. In some people living with Alzheimers disease, it is dysfunctional, causing neurofibrillary tangles and disturbing synaptic communication between neurons.

The most promising result of the new study is that the three microRNAs appear to be a suitable, minimally invasive biomarker. They are also easy to measure in routine blood samples even in a finger prick. Moreover, the data support that this three-microRNA-signature test could be a first step in helping detect individuals at risk of cognitive disease.

For people living with cognitive decline, early detection may increase their chances of successful therapeutic intervention with existing treatment or future novel RNA-based approaches targeting the three-microRNA signature.

In conclusion, Dr. Porter noted to MNT:

Presently, there is an urgent need for molecular biomarkers that are minimally invasive, able to detect an individual at risk of developing disease, and [able to] detect biomarkers of disease as early as possible even in the setting of multiple disease pathologies, e.g., mixed Alzheimers and vascular pathology. The hope is that simple approaches, such as a blood test, could be applicable in the context of routine screening approaches with the [aim] of identifying individuals at risk for developing Alzheimers disease, who could then undergo further diagnostic/confirmatory evaluations.

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Dementia: Early biomarkers in the blood may predict cognitive decline - Medical News Today

Some people get severely sick with COVID-19. Others don't even notice they've caught the infection.

Understanding the role of genetic variants in infection outcomes could help prevent or treat infectious diseases by restoring deficient immunity.

Over the past months, several studies have shown that some genes are potentially involved in the congenital resistance some people have towards COVID-19.

Blood types and COVID resistance

For example, the authors wrote that evidence suggested that people with O type blood groups may be slightly more resistant than people with other blood types.

In vitro studies have identified candidate genes that might be involved in how SARS-CoV2 enters human cells and triggers the infection.

SARS-CoV-2 penetrates human cells by binding the ACE2 receptor, which sits in the cell's membrane.

Scientists have discovered that a rare variant located close to ACE2 confers protection against COVID-19.

The hypothesis is that the variant decreases ACE2 expression.

In other in vitro studies, scientists found that some human ACE2 polymorphisms (a gene is polymorphic if more than one allele occupies that gene's locus) bind the SARS-CoV-2 spike protein with different affinities.

The role of genetic variants

Historically, therapeutics for infectious diseases have focused primarily on the pathogen rather than the host.

The most common idea has been to prevent the disease by vaccinating against the pathogen or stop the infection by interfering with the pathogen using drugs.

Understanding the role of genetic variants in infection outcomes could help prevent or treat infectious diseases by restoring deficient immunity.

"These variants are of particular interest for two reasons," the authors wrote.

"First, they can provide a deep understanding of the essential biological pathways involved in infection with SARS-CoV-2.

Second, they will allow for the development of innovative therapeutic interventions to prevent or treat SARS-CoV-2 infection in others."

The proof of principle for this second reason has been provided by CCR5 - a genetic mutation occurring in roughly one per cent of the population, which prevents HIV from binding to the surface of white blood cells.

Medicine mimicking genetics

After discovering CCR5, scientists developed an anti-retroviral drug called maraviroc, which mimics the effect of the mutation.

"No specific drug effective against COVID-19 has been discovered since the start of the pandemic," the authors wrote.

"Lessons learned [from genetics] could potentially guide us toward such specific treatments for COVID-19."

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A lucky few are unusually resistant to COVID-19. Scientists are trying to find a reason in their genes. - Mandurah Mail

Rochelle dos Santos embraces her daughter, who was born with microcephaly in 2016 after dos Santos contracted Zika during her pregnancy in midwest Brazil. Ueslie Marcilino/Undark Magazine hide caption

Rochelle dos Santos embraces her daughter, who was born with microcephaly in 2016 after dos Santos contracted Zika during her pregnancy in midwest Brazil.

Rochelle dos Santos learned that her daughter would probably be born with microcephaly a condition where a baby's head is much smaller than expected when she was seven months pregnant. It was 2016 and Brazil was going through an unprecedented microcephaly outbreak associated with the mosquito-borne virus Zika. After the baby was born and the diagnosis of congenital Zika syndrome was confirmed, several researchers approached dos Santos to see if she'd join relevant clinical studies. Eager to understand her daughter's condition, she agreed.

Dos Santos says she was surprised to learn through a social media post last year that an international study that she participated in had been published in the journal Brain & Development. The study took over a year to be completed, and dos Santos had taken her daughter multiple times to the hospital for evaluations. As the head of an association for families of children affected by Zika in Gois state in midwest Brazil, dos Santos wanted to share the findings with the other caregivers. She says she had to reach out directly to Hlio van der Linden, a neurologist at the Dr. Henrique Santillo State Center for Rehabilitation and Readaptation who authored the study in partnership with researchers in Brazil and the United States, to ask that a copy be shared with her. But she says he told her there was no point because it was written in English.

"Of course, we get upset," she recalled in her native Portuguese. "We want to have this feedback and better understand this situation that is new for everyone." Dos Santos who noted that while she speaks only a little English, her husband reads and speaks English capably said she feels used and that many other families share the same sentiment. "We know that COVID is now the priority," dos Santos adds, "but our children are still here, they still have needs."

The study's author sent her the article, and dos Santos says her husband translated it for her though she adds that she was also asked by van der Linden not to share it. (Van der Linden told Undark by email that while he did point out to dos Santos that the article was written in English, his main concern was running afoul of the journal's publishing rules. His request not to share it, he added, was for social media posts. "There was no problem in sharing the article with other mothers," he wrote, "but I believe this wasn't clear to the mother of the patient.")

Children with congenital Zika syndrome face numerous health issues, all originating from the peculiar way in which Zika attacks the developing brain. In addition to the condition's most pronounced feature reduced head size many have rigid muscles, difficulty swallowing and breathing and problems with the retina and optic nerve, as well as other symptoms that emerge as the children grow. "The doctors say that only time will tell how our children will be tomorrow," dos Santos says, "because there are no adults with this syndrome."

Dos Santos is not the only caregiver who felt left behind by scientists. Family groups like the one she heads have sprung up across the country, and members are increasingly at odds with the scientists who have used their children for research. The grandmother and caretaker of a boy with congenital Zika syndrome, Alessandra Hora dos Santos (no relation to Rochelle), launched one of these associations in Alagoas state in northeast Brazil in 2017. She says that lately she has been declining requests to participate in new studies although such invitations are becoming rare because there haven't been new outbreaks of the syndrome since 2016 and she noticed that other families are doing the same.

Scientists who conducted the studies on Zika during the peak and the aftermath of the outbreak admit that communicating the results to families is not always effective, and that it was not the top priority during the Zika crisis. In the rush to collect data, not all researchers took the time to explain in detail what their projects were about and set clear expectations. Busy caretakers, on the other hand, were hardly able to carefully read the informed consent forms they were signing to authorize investigators to collect data from their children. Over the last few years, these families have demanded to participate more actively in the scientific discussion around Zika.

"We feel diminished," says Alessandra Hora dos Santos. "It's like we were lab rats. They come in nicely, collect information, collect exams on the child, and in the end, we don't know of any results. It's like we are being used without even knowing why that is being done."

Left: Dos Santos helps her daughter, pictured, with physical therapy. Many children with congenital Zika disorder are physically disabled. Right: Due to difficulties swallowing, dos Santos' daughter uses a feeding tube, which is attached to her wheelchair. Ueslie Marcilino/Undark Magazine hide caption

Left: Dos Santos helps her daughter, pictured, with physical therapy. Many children with congenital Zika disorder are physically disabled. Right: Due to difficulties swallowing, dos Santos' daughter uses a feeding tube, which is attached to her wheelchair.

Left: Dos Santos' daughter uses leg braces to help her stand. Other symptoms of the disorder emerge as children grow. Right: Dos Santos guides her daughter to create a finger painting. "Our children are still here, they still have needs," she says. Ueslie Marcilino/Undark Magazine hide caption

Left: Dos Santos' daughter uses leg braces to help her stand. Other symptoms of the disorder emerge as children grow. Right: Dos Santos guides her daughter to create a finger painting. "Our children are still here, they still have needs," she says.

By the time physicians started to notice a surge in microcephaly in Brazil in mid-2015, researchers had to scramble to design studies, get funding and conduct analyses. Eventually, scientists from multiple institutions coalesced in the Microcephaly Epidemic Research Group (MERG). They began the research efforts even before the link with Zika had been established and had a crucial role in guiding public health strategies to tackle the epidemic. "There was a lot of pressure coming from the media and the health ministry," says infectious disease expert Demcrito de Barros Miranda-Filho, a member of MERG and a professor at the University of Pernambuco. "We had to develop all the projects from scratch and submit them to the ethics committees within a deadline," he says, adding that there was also pressure to give answers to the families.

One of the group's concerns was to immediately share individual results of tests and clinical evaluations that could directly impact the child's treatment. But when it comes to the general findings at the end of the study, says Miranda-Filho, the researchers didn't properly communicate them to the participants.

"It is very complex to decode biological questions and put them into a more understandable language," says Thlia Velho Barreto de Arajo, an epidemiologist at the Federal University of Pernambuco and a member of MERG. "We haven't figured out a way to do that yet, and we would need research resources to get advice for transforming technical language into something palatable." Ricardo Arraes de Alencar Ximenes, an epidemiologist at both the University of Pernambuco and the Federal University of Pernambuco, notes that one of the obstacles to develop well-thought-out communication strategies is getting dedicated funding.

Physician Camila Ventura, one of the coordinators of an ambitious project with the goal of evaluating the neurodevelopment of about 200 children with congenital Zika syndrome over five years, says she is familiar with the families' demands and agrees with them. But there are other obstacles beyond adequate funding, she says. For example, with funding from the United States National Institutes of Health, the project is being developed at the Altino Ventura Foundation, a Brazilian health nonprofit, in partnership with the U.S. research organization RTI International. Because the project is done in partnership with other organizations, Ventura says it's not solely up to her to provide this feedback.

"This criticism applies to our own institution and I try my best to push for these answers" from our research partners, says Ventura. "The mothers see that we're collecting data and they want to know: What about my kid?" she adds. "Is he getting better?"

Van der Linden wrote that when he invites a family to participate in a study, he tries to make it clear that the goal is to better understand the condition and that the findings might not benefit the participants themselves. "I explain that after the study is done, there won't be a 'result.' Sincerely, I don't offer or promise to call each one to explain the details, etc. I always make it clear that it is for science," he wrote to Undark by email. "I believe there might have been an over-expectation, or an unrealistic expectation of something that was never promised."

Soraya Fleischer, an anthropologist at the University of Braslia who coordinates a research project on the impact of Zika on the lives of families, says it's also important to consider what these mothers mean when they ask for study results. "For the researchers, the result is what is published in a well-qualified scientific journal or goes into their resume," she says. But for the families, says Fleischer, sometimes the result is a simple blood test that confirms that the child's disabilities were caused by Zika an important document that grants access to certain social benefits reserved for children with the syndrome, which can be difficult to get via the public health system.

Not every parent has had a bad experience with Zika researchers. Jaqueline Silva de Oliveira, the mother of a 5-year-old girl with congenital Zika syndrome, says that whenever she needs these types of reports in order to claim social benefits, she reaches out to the scientist who enrolled her family in a genetics study. The girl's twin brother was not affected by Zika, which caught the attention of a group at the Human Genome and Stem Cell Research Center at the University of So Paulo that wanted to try to identify potential protective genes.

"I participated to be able to help prevent other children from having microcephaly," says de Oliveira. She says she can't explain in her words what the results of the study were and she didn't receive a document describing them. But overall, she thinks having participated in the study was a positive experience. She continues to have a connection with the researchers, and they helped her find a neurologist, one of the best in the state, she says, who managed to control her daughter's epilepsy crises. "I helped the researcher on the study," she says, "and when I needed it, she helped me."

During the initial 2015 Zika outbreak and the years that followed, participation in the Brazilian Zika studies could be difficult. Luciana Lira, a medical anthropologist at the Federal University of Pernambuco, recalls accompanying two mothers to an event in 2018 in Recife, in Pernambuco state, one of the epicenters of the congenital Zika syndrome outbreak. The event was organized by a local university and an association for families of children with rare diseases. While the other mothers attended talks and participated in conversation circles, the mothers of children with congenital Zika syndrome were directed to a hall where researchers organized a task force to collect blood for a research project.

On that occasion, Lira says she watched while a nurse approached a mother to participate in the study. The mother "was so agitated that, when the nurse approached her and started explaining the study, she clearly wasn't paying full attention because there were more urgent things to deal with. Her daughter was having a crying fit, she had to fix her feeding tube, all of that," says Lira. "Then she agreed to participate, signed a paper and that's it. This type of situation has become very commonplace."

The researcher behind the project was Nilson Antonio de Assuno, a chemistry professor at the Federal University of So Paulo who was then studying the biochemical characteristics of blood among children with Zika. The study hasn't been published yet, de Assuno says, adding that he is aware that some families don't fully understand the purpose of his research when they agree to participate. "They get nervous because they are at an event, these are humble people, their children are crying and they end up not understanding very well what we're explaining."

De Assuno says there isn't much to be done about creating better strategies to communicate with families of children participating in studies. "I have been noticing this distrust in families," he says, "but those who end up losing are the families themselves." He says that he has previously tried to explain and educate the population about his work. "No matter what you do," he adds, "there will always be this distrust."

Lira and her colleagues have been observing the relationship between caregivers of children with Zika and biomedical scientists in Recife. Silvana Matos, also an anthropologist at the Federal University of Pernambuco, says that initially the caregivers welcomed the attention from scientists because they wanted to understand what had happened to their children. "The thing they complained the most about, right after this initial period," she says, "was that the test results never came back to them and the researchers, from Brazil or abroad, never reached out again to tell them what happened."

The families' experiences with the medical trials made them wary of researchers more broadly. By the time the anthropologists started working with the families in late 2016, they had to redesign their work to deal with this research fatigue and gain trust, says Lira. The families "had been overwhelmed both by scientists trying to collect organic samples, and by journalists and researchers wanting to interview them," says Fleischer. "There was an eagerness to learn what was happening" among the scientists and journalists, she adds, and the families "were the source."

Lira spent several months following caregivers around before doing any interviews. Fleischer, who is not based in Recife, decided to come back to the city several times over the years to revisit the families and show them what had been produced with the data they had collected before for example, an article or a newspaper story. Realizing that the caretakers were too busy to read long articles, Fleischer's group created a blog to publish short stories about life with Zika that they would print out and distribute to the participants during their visits. The fact that the researchers kept coming back and reporting what they were doing made the families feel respected, according to Fleischer, and it was essential to build trust.

Dos Santos, left, with her daughters. Dos Santos says she feels used and that many other families share the same sentiment. Medical anthropologist Luciana Lira says the families became overwhelmed by scientists and journalists, and that she had to change her approach to gain the families' trust. Ueslie Marcilino/Undark Magazine hide caption

Dos Santos, left, with her daughters. Dos Santos says she feels used and that many other families share the same sentiment. Medical anthropologist Luciana Lira says the families became overwhelmed by scientists and journalists, and that she had to change her approach to gain the families' trust.

In Brazil, the ethical and legal framework for research involving human subjects was established in 1996 through a resolution by the Brazilian National Council of Health. To conduct a study involving human subjects in Brazil, researchers have to submit their proposal to a research ethics committee, much like in the U.S. Every research organization may constitute its own committee, which responds to the National Commission for Research Ethics (CONEP, by its Portuguese acronym).

Before entering a study, participants must sign a free and informed consent form, a document that describes the study, its goals and possible risks and benefits of participating. According to the commission, the document should be written in clear and accessible language.

The need to share the findings with participants, which is at the core of the caregivers' complaints, is not directly covered by the 1996 resolution. But the current ethical norms, in force since 2012, do state that research findings should be communicated to the community if there's a potential to benefit the population, notes biologist Maria Mercedes Bendati, who retired from the municipal health department of Porto Alegre, in southern Brazil, in 2017 and is a CONEP member. "It already says that it is important to give this feedback," she says. The next step, she adds, is to implement the requirement "and make it very clear in the academic education of the researchers that they should fulfill their social role, and know that the research implies giving these answers to the participants."

Bendati participated in the Pan American Health Organization Zika Ethics Consultation in April 2016, which originated an ethics guidance on key issues raised by the Zika outbreak.

Florencia Luna, the chair of the Zika Ethics Consultation, says the goal of the guidance was precisely to prevent situations like the ones the caregivers described. "We were very concerned about doing this research at that moment in the middle of the outbreak. So it's a little bit like now, with COVID," she says. "Even if you want to do [research] fast and quick, and you should do it like that, that doesn't mean you have to avoid ethical standards."

Luna, who is also the director of the bioethics program at the Latin American Faculty of Social Sciences in Argentina, believes that returning to the participants with the results is an ethical obligation. "Personally, I do think it is very important to come back and tell the good or the bad news," she says, especially with Zika, which involves mothers and babies with health conditions. "At least to send them a letter, to call them on the phone," she adds. "Maybe not to make them go to the clinic because it would be too burdensome for them, but there are other ways where you can communicate nowadays, with smartphones, with the internet."

According to the International Ethical Guidelines for Health-related Research Involving Humans, a 2016 document prepared by the Council for International Organizations of Medical Sciences in collaboration with the World Health Organization, researchers "should engage potential participants and communities in a meaningful participatory process" which includes the dissemination of the study's results.

Despite such guidelines, not communicating results to participants is seen by some researchers as business as usual. Carl Elliott, an expert in bioethics and a professor of philosophy at the University of Minnesota, says the situation narrated by Rochelle dos Santos, where the investigator hesitated to send her the study for which her daughter had collaborated, didn't surprise him.

"If I were the research subject or the mother of the research subject, it would offend me and I think justifiably," he says. "That said, I think the vast majority of research subjects don't do that sort of follow-up. They don't ask or are not even particularly interested in the papers." Elliot says he doesn't think the investigator gave the right response, but he imagines he was probably surprised by the request.

In any case, Elliott says he believes that, if a participant actively asks, the researcher must provide the results: "It's shameful that it takes so much effort, and often money, for the public to get access to the results of scientific studies published in the medical literature."

Bioethics expert Carl Elliot says that the situation Rochelle dos Santos (pictured) described, where the investigator hesitated to send her the study for which her daughter had collaborated, didn't surprise him. Ueslie Marcilino/Undark Magazine hide caption

Bioethics expert Carl Elliot says that the situation Rochelle dos Santos (pictured) described, where the investigator hesitated to send her the study for which her daughter had collaborated, didn't surprise him.

In September 2018, the Brazilian caregivers' discontent culminated at the annual Congress of the Brazilian Society of Tropical Medicine in Recife. That year, the program included several sessions about congenital Zika syndrome. According to a paper written by Lira, none of the families' associations had been invited.

During one of the sessions on the main stage, Germana Soares, the mother of a boy with congenital Zika syndrome and the president of one of the largest family associations, requested to speak. She read aloud a letter to the event's organizers. "We believe there is a lack of empathy and sensitivity to our reality, and a lack of respect in the fact that we were underestimated. As if we the mothers, relatives and caretakers would lack the understanding to participate in a technical event to discuss a topic that is of our biggest interest," the letter stated. "Are we mothers so ignorant, without the least bit of education, that we cannot understand a scientific article or a lecture? Or should the researchers be the ones to use a language that is more comprehensible? Are we totally wrong to demand a discussion about ethics in biomedical research? Are we just numbers?"

The organizers were apparently caught by surprise, as Soares' speech wasn't in the program. One of the speakers at the session called Sinval Pinto Brando Filho, the president of the Society, to ask him what to do about it. He advised him to let Soares speak. "Our organization welcomes this debate with great satisfaction because we study the tropical diseases, in terms of controlling them," says Brando Filho, adding that every year the Brazilian Society of Tropical Medicine invites patients of neglected diseases to a public forum during the congress to discuss the problems they face. "I see this as something specific that was immediately recognized that it should be more sensitively incorporated into the tribute session."

Today, only sporadic cases of congenital Zika syndrome still occur, which makes it difficult to get funding for research, scientists say. The research focus has shifted to COVID-19, but the Zika health emergency might have left a legacy when it comes to research ethics.

"My personal reflection about the Zika experience in ethics committees is that perhaps there should have been a dialogue with the researchers to ask them how the findings would be shared with the participants," says Bendati. "When it comes to COVID-19, the CONEP is now being very clear on the need for a proposal of feedback to be given to participants." Learning from the mistakes of Zika might have contributed to this evolution, Bendati adds.

Luna says she's aware that sometimes ethics are viewed as an obstacle to science. Tracking down the participants can be difficult, and researchers who might have moved on to another project often lack the time and the energy to pursue it. "But it's part of what we have to do in order to build trust, to continue working," she says. "If not, these women will not collaborate in any other research in their lives because they were disappointed."

Mariana Lenharo is a science and health journalist whose writing has appeared in Scientific American, Mother Jones, Elemental, BBC News Brazil, among other publications. She is currently based in So Paulo, Brazil.

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To study Zika, they offered their kids. Then they were forgotten. : Goats and Soda - NPR