Category Archives: Gene Medicine

For UMass Medical School researcher Jae-Hyuck Shim, PhD, seeing the strength of families who have a child with a rare, crippling disease motivates him to develop a gene therapy that will help afflicted children retain mobility and be free from debilitating pain. He is also spurred by his own experience as a child, when he was diagnosed with juvenile rheumatoid arthritis.

Fibrodysplasia ossificans progressiva (FOP) occurs at an incidence of one per 1.36 million to 2 million people, according to Dr. Shim, associate professor of medicine in the Division of Rheumatology and a member of the Horae Gene Therapy Center. This disease is characterized by abnormal bone formation in the skeletal muscle and in connective tissues. When there is any trauma to a muscle or other connective tissue, the resulting inflammation causes bone to formlike an extra skeletonthat progressively locks up joints and causes immobility and severe pain.

Its heartbreaking. You have no idea when youre born whether you have FOP or not, said Shim. Then when a kid is little, hes playing soccer or tumbles, and the inflammation doesnt go away. Then three weeks later, somehow bone starts coming up; then two months later, you start to lock up your joints. And thats just the beginning.

Shim said, To me, the most devastating is the parents, because the parents see their kid get worse slowly and progressively.

No effective treatments are available except for high doses of corticosteroids for flare-ups, which can reduce the intense pain and edema, but nothing stops the extra-skeletal bone growth.

Almost 90 percent of patients die by age 40, Shim said.

FOP is a monogenic skeletal rare disease caused by autosomal dominant mutations in the Activin A type 1 receptor, Shim explained, which results in spontaneous activation of bone morphogenic protein signaling pathways and other changes.

Two years ago, Shims lab teamed up with the laboratories of Guangping Gao, PhD, the Penelope Booth Rockwell Professor in Biomedical Research, professor of microbiology & physiological systems, director of the Horae Gene Therapy Center and co-director of the Li Weibo Institute for Rare Diseases Research, and Jun Xie, PhD, associate professor of microbiology & physiological systems, to develop adeno-associated virus (AAV)-mediated gene therapy for FOP.

This research has been supported by the nonprofit International FOP Association (IFOPA) and the startup company AAVAA Therapeutics co-founded by Shim and Dr. Gao. A production crew from IFOPA was recently on the UMass Medical School campus to create a video to support continuing research on FOP.

Shim knows personally how hard it can be for children and their families when a child suddenly develops a life-altering disease.

When I was a kid, just out of high school, I had juvenile rheumatoid arthritis, said Shim. One day I just woke up, I couldnt walk well because it hurt. Most of juvenile rheumatoid arthritis is inherited. My mother doesnt show any rheumatic disease, but she sometimes feels tired.

He continued, I have three sisters, but Im the only son and my family was upside down. My mother was really feeling guilty because she thought it was from her. And my father was upset because he wanted to know what happened.

Twenty years ago in Korea, where Shim grew up, less was known about the role of inflammation, he said. I went to the hospital orthopedic department many times and they just gave me painkillers. For one year, living my life was totally disastrous. I was very sad because I saw my mother cry.

But then one of Shims doctors, who had studied in the United States, brought Shim into his clinic and gave him anti-inflammatory drugs. Its kind of a miracle, said Shim. He killed the inflammation, and everything went away.

The doctor told Shim he could continue to take medication or change his body through lifestyle to keep his auto-immune condition under control.

So, I changed my eating habits and exercise and sleeping, and the chronic inflammation went down, Shim said. The doctor said I didnt need the medicine anymore because my body was actually changed.

Shim hopes that children with FOP can get to experience something similar. If the medicine is there to bring down the flareup, pulling it down to the normal level that is under the threshold, then they can manage it, he said. They could potentially then have surgery to remove the extra-skeleton, which currently would only cause further inflammation and bone growth from trauma to the musculoskeletal system.

The gene therapy that UMass Medical School-affiliated researchers are developing is the only project of its kind for FOP, delivering the therapeutic gene directly to the FOP-causing cell or tissue using the AAV, according to Shim. Using the combinatory expression of a mutant-specific gene silencer and healthy gene, the AAV removes the mutant protein and at the same time, the healthy protein can be expressed. They have had success in human FOP patient-derived cells and animal models.

That progress, in humans, is something families of children with FOP are desperate to reach. Shim saw at IFOPA meetings how strong the community of families was, sharing information and support, and he wants to do all he can to help them.

Many parents feel uncomfortable at first, but in IFOPA they start to share, said Shim. Its a very devastating disease and we need the funding to stop it.

Related stories on UMassMed News:GuangpingGaoand Dan Wang partner with ASC Therapeutics to develop novel gene therapy for maple syrup urine diseaseUMMS establishes gene therapy collaborative research agreement with PfizerGuangping Gao makes list of Nature Biotechnology Top 20 translational researchers

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Behind the research: Jae-Hyuck Shim strives to unlock cure for devastating childhood bone disease - UMass Medical School

Human serine/threonine kinase 4 (STK4) deficiency is a rare, autosomal recessive genetic disorder leading to combined immunodeficiency; however, the extent to which immune signaling and host defense are impaired is unclear. We assessed the functional consequences of a novel, homozygous nonsense STK4 mutation (NM_006282.2:c.871C>T, p.Arg291*) identified in a pediatric patient by comparing his innate and adaptive cell-mediated and humoral immune responses with those of three heterozygous relatives and unrelated controls.The genetic etiology was verified by whole genome and Sanger sequencing. STK4 gene and protein expression was measured by quantitative RT-PCR and immunoblotting, respectively. Cellular abnormalities were assessed by high-throughput RT-RCR, RNA-Seq, ELISA, and flow cytometry. Antibody responses were assessed by ELISA and phage immunoprecipitation-sequencing.The patient exhibited partial loss of STK4 expression and complete loss of STK4 function combined with recurrent viral and bacterial infections, notably persistent Epstein-Barr virus viremia and pulmonary tuberculosis. Cellular and molecular analyses revealed abnormal fractions of T cell subsets, plasmacytoid dendritic cells, and NK cells. The transcriptional responses of the patients whole blood and PBMC samples indicated dysregulated interferon signaling, impaired T cell immunity, and increased T cell apoptosis as well as impaired regulation of cytokine-induced adhesion and leukocyte chemotaxis genes. Nonetheless, the patient had detectable vaccine-specific antibodies and IgG responses to various pathogens, consistent with a normal CD19+B cell fraction, albeit with a distinctive antibody repertoire, largely driven by herpes virus antigens.Patients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells. 2021. The Author(s).

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A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemot... - Physician's Weekly

Approval provides opportunity to treat the underlying cause of CF earlier than ever before in Canada

TORONTO, Aug. 25, 2021 /CNW/ - Vertex Pharmaceuticals Incorporated (Canada) (Nasdaq: VRTX) today announced that Health Canada has granted Marketing Authorization for PrKALYDECO (ivacaftor) for use in children with cystic fibrosis (CF) as young as four months of age who have at least one of the following gating mutations in their cystic fibrosis transmembrane conductance regulator (CFTR) gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R.

Vertex Pharmaceuticals Incorporated (Canada) Logo (CNW Group/Vertex Pharmaceuticals Incorporated (Canada))

"With today's approval, children in Canada as young as 4 months now have a medicine to treat the underlying cause of their disease," said Nia Tatsis, Executive Vice President and Chief Regulatory and Quality Officer, Vertex Pharmaceuticals. "This is another step in our goal to develop medicines to treat people living with CF as early in life as possible."

The label update is based on data from a cohort in the 24-week Phase 3 open-label safety study (ARRIVAL) consisting of six children with CF ages four months to less than six months who have eligible gating mutations.

PrKALYDECO (ivacaftor) is now approved for additional eligible patients in Canada, and Vertex will work with payers to secure access for this new patient population.

About Cystic Fibrosis

Cystic fibrosis (CF) is a rare, life-shortening genetic disease affecting more than 80,000 people globally. CF is a progressive, multi-system disease that affects the lungs, liver, GI tract, sinuses, sweat glands, pancreas and reproductive tract. CF is caused by a defective and/or missing CFTR protein resulting from certain mutations in the CFTR gene. Children must inherit two defective CFTR genes one from each parent to have CF. While there are many different types of CFTR mutations that can cause the disease, the vast majority of all people with CF have at least one F508del mutation. These mutations, which can be determined by a genetic test, or genotyping test, lead to CF by creating non-working and/or too few CFTR proteins at the cell surface. The defective function and/or absence of CFTR protein results in poor flow of salt and water into and out of the cells in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death. The median age of death is in the early 30s.

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About KALYDECO (ivacaftor)

Ivacaftor is the first medicine to treat the underlying cause of CF in people with specific mutations in the CFTR gene. Known as a CFTR potentiator, ivacaftor is an oral medicine designed to keep CFTR proteins at the cell surface open longer to improve the transport of salt and water across the cell membrane, which helps hydrate and clear mucus from the airways.

About Vertex

Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has multiple approved medicines that treat the underlying cause of cystic fibrosis (CF) a rare, life-threatening genetic disease and has several ongoing clinical and research programs in CF. Beyond CF, Vertex has a robust pipeline of investigational small molecule medicines in other serious diseases where it has deep insight into causal human biology, including pain, alpha-1 antitrypsin deficiency and APOL1-mediated kidney diseases. In addition, Vertex has a rapidly expanding pipeline of cell and genetic therapies for diseases such as sickle cell disease, beta thalassemia, Duchenne muscular dystrophy and type 1 diabetes mellitus.

Founded in 1989 in Cambridge, Mass., Vertex's global headquarters is now located in Boston's Innovation District and its international headquarters is in London. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia and Latin America. Vertex is consistently recognized as one of the industry's top places to work, including 11 consecutive years on Science magazine's Top Employers list and a best place to work for LGBTQ equality by the Human Rights Campaign.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, statements made by Nia Tatsis in this press release, and statements regarding the availability of KALYDECO to additional eligible patients in Canada and Vertex's work with payers to secure access for the new patient population. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that data from the company's development programs may not support registration or further development of its compounds due to safety, efficacy or other reasons, and other risks listed under the heading "Risk Factors" in Vertex's most recent annual report and subsequent quarterly reports filed with the Securities and Exchange Commission at http://www.sec.gov and available through the company's website at http://www.vrtx.com. You should not place undue reliance on these statements. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

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Vertex Pharmaceuticals Incorporated

SOURCE Vertex Pharmaceuticals Incorporated (Canada)

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Health Canada Grants Marketing Authorization for KALYDECO (ivacaftor) as First and Only CFTR Modulator to Treat Eligible Infants With CF as Early as...

Introduction

Sjogrens syndrome (SS) is a systemic autoimmune disease primarily characterized by epithelitis in exocrine glands and the development of specific antibodies to SSA/SSB. Europe, North America, and Asia have a wide range of incidence rates for SS, and the prevalence rate in the population of three continents is 60.82 persons per 100,000 inhabitants,1 and the female versus male ratio is 14:1. Patients with SS typically present with dry mouth and eyes, joint pain, and fatigue.2,3 50% of patients present with systemic damage, and they have a 1020-fold increased risk of developing B cell lymphoma.4

The etiology and pathogenesis of the characteristic progressive glandular dysfunction in SS have not been fully clarified. Genetic susceptibility, environmental factors, and immune disorders are thought to play a dominant role. Studies have found that susceptibility genes, such as human leukocyte antigen (HLA), Interferon Regulatory Factor 5 (IRF5), BLK, Interleukin 12A (IL12A), TNFAIP3 interaction protein 1 (TNIP1), and Chemokine receptor 5 (CXCR5), are closely related to the occurrence of SS.5 Activation of the type I interferon pathway, infiltration of T and B lymphocytes, and formation of ectopic germinal centers within salivary glands all cause damage in multiple tissues.6 The histopathology of salivary glands has the potential to both function as a biomarker and provide information regarding the prognostication and stratification in clinical trials.7

The main characteristic of SS upon biopsy, with 80.4% specificity and 86.2% sensitivity, is focal lymphocytic salivary adenitis (FLS).8 The key requirement of FLS is dense aggregates (foci) of 50 lymphocytes based on survey of at least four lobules, and the focus score (FS) calculation was defined as FS 1 focus per 4 mm2 area.9 EULAR-SS task force clinical recommendations state that focal lymphocytic salialitis is considered as an important marker and can be used for the early diagnosis of SS.10 During the early stage of SS, there are no obvious signs of dryness, but the immune microenvironment of the salivary gland changes. Imaging biomarkers, such as ultra-high frequency ultrasound (UHFUS), may help reduce unnecessary and inadequate biopsies, but it has limited evidence of efficacy and is seldom used in the clinic.11 With the rapid development of microarray technologies and bioinformatics analysis in the last few years, microarrays aimed at the genes and pathways of SS-like animals and SS patients have been studied.Nevertheless, single gene can not completely distinguish patients with from those with sicca symptoms or serological manifestations but no SS. Because of the highest item weights (scoring 3) of five items in 2016 American College of Rheumatology/European League Against Rheumatism classification criteria, variable sensitivity and specificity as well as low reproducibility, the diagnosis performance of MSGB could be further explored through multivariate and quantitative analyses of biomarkers.12 Therefore, we analyzed three microarray datasets of salivary glands via bioinformatics analysis and further identified key genes and functions in SS salivary glands for higher sensitivity and specificity of MSGB, and we demonstrated the potential of multiplexed measurement of salivary protein biomarkers compared with FS using diagnosis model.

The salivary gland gene expression profiles of GSE23117 (n = 4 control, n = 11 SS), GSE7451 (n = 10 control, n = 10 SS), and GSE127952 (n = 6 control, n = 8 SS) were obtained from NCBI-GEO (https://www.ncbi.nlm.nih.gov/), which together included 20 healthy controls and 29 SS patients. We used GEO2R online software (http://www.ncbi.nlm.nih.gov/geo/geo2r) to analyze three microarray datasets, including GSE23117, GSE7451, and GSE127952, that were provided by the original submitter in order to determine the DEGs. A P value < 0.05 and log | FC | 1 were used as our standard screening criteria for DEGs. Genes with a log | FC | 1 were considered to be upregulated genes, and those with a log | FC | 1 were considered downregulated genes. We also used the online drawing tool (https://bioinfogp.cnb.csic.es/tools/venny/index.html) on the DEGs of the three datasets to construct Venn diagrams.

ClueGO plugin in Cytoscape 3.7.2 was used to perform Gene Ontology (GO) functions, and we used the David database (https://david.ncifcrf.go) to obtain the KEGG enrichment analysis of the DEGs, and we visualized the obtained data through the R Bioconductor package. DEGs and signaling pathway analysis was performed with the use of GlueGO and KEGG.

All upregulated genes were imported into the STRING database (http://www.string-db.org). The protein species was set to HomoSapiens, the lowest interaction threshold was set as low confidence (0.15), and a PPI network was imported into Cytoscape software for visual analysis. Network topology analysis was carried out to obtain the hub genes with higher degree value. Top 20 degree genes were calculated and identified by CytoHubba as SS preselected hub genes.

In order to confirm the expression of hub genes in SS patients and suspected patients who were not yet diagnosed, 28 labial gland biopsy samples, including SS patients and non-SS patients (Table 1), were obtained from patients admitted to The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, P.R.C, who received a definitive diagnosis of SS (they were diagnosed by the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjgrens syndrome12). Informed consents were received from all enrolled patients prior to MSGB. The Second Affiliated Hospital, Zhejiang Chinese Medical University Ethics Committees approved the protocols, and the International Conference on Harmonization guidelines and the principles of the Declaration of Helsinki were followed. Labial gland samples were fixed, embedded, sectioned (4 m), dewaxed with xylene, rehydrated through an alcohol gradient, and stained with H&E. A STAT1 Rabbit IgG Polyclonal antibody (10144-2-AP) from Proteintech (Wuhan Sanying, D3-3, No. 666, Gaoxin Avenue, Wuhan East Lake Hi-tech Development Zone, Wuhan, Hubei, P.R.C.) and MNDA Rabbit IgG Polyclonal antibody (DF4191), IL-10RA Rabbit IgG Polyclonal antibody (DF6643), and CCR1 Rabbit IgG Polyclonal antibody (DF2710) all from Affinity (Xiangtai Biological Technology Co., Ltd., No. 128, Shen Jiang Bian village, Changzhou, Jiangsu, P.R.C.) were used at a 1:200 dilution in this study. For immunohistochemical analysis, sections were processed for antigen retrieval with citrate buffer solution (pH 6.0) before blocking endogenous peroxidase activity with 3% H2O2 for 15 minutes. Sections were blocked with goat serum for 15 minutes and incubated for 1 hour at 37C. To evaluate antigen expression, each section was photographed at 200 magnification, and five images were taken across sections. The optical density was analyzed by Image-Pro Plus 6.0 (integrated optical density (IOD) = mean optical density area). Receiver operating characteristic (ROC) curves were adopted to analyze the diagnostic value of the IOD of four genes for SS. The plot area under the curve (AUC) was computed through numerical integration of the ROC curves. The genes with the highest AUC value were identified as having the strongest power for diagnosing SS.

Table 1 Patients Clinical and Serological Information

Bioinformatics statistical analysis was performed using R version 4.0.3, and GraphPad Prism version 8.0.2 (GraphPad Software, San Diego, CA, USA) was used for computing ROC analysis. Numerical results were presented as the means standard deviations (SD) or medians with interquartile ranges (IQR), and Wilcoxon MannWhitney U two-sample rank sum test was used to analyze the statistical significance between two groups. P<0.05 was considered statistically significant.

Three microarray datasets, which included SS patients and healthy controls, were analyzed with Venn tool. We identified 53 upregulated DEGs and 15 downregulated DEGs (data not shown) from the GSE23117, GSE7451, and GSE127952 datasets (Figure 1).

Figure 1 Venn diagrams show the DEGs in the salivary glands of patients with SS. Venn diagrams showing the upregulated DEGs (A) and downregulated DEGs (B).

Enrichment analysis was performed on 53 intersecting targets using the ClueGO v2.5.7 plugin. After setting the P value as < 0.05, Kappa Score Threshold as 0.4, and Golevel as 3Minimum#Genes and 4%#Genes, we identified 31 GO terms. The results showed that the genes were mainly functionally enriched in dendritic cell migration, regulation of the extrinsic apoptotic signaling pathway via death domain receptors, lymphocyte homeostasis, regulation of B cell proliferation, and response to type I interferon (Figure 2).

Figure 2 ClueGO enrichment analysis. Significantly enriched GO terms of DEGs in SS based on their GlueGO (Biological Processes) and CluePedia functions (A). The pie chart of ClueGO enrichment analysis (B).

The results of KEGG analysis showed that the upregulated genes were associated with several pathways, including the NOD-like receptor signaling pathway, human cytomegalovirus infection, cytokinecytokine receptor interaction, and herpes simplex virus 1 infection (Figure 3A). Downregulated genes showed low correlation with SS because of low score compared with upregulated genes (Figure 3B).

Figure 3 KEGG pathway terms of DEGs in SS. A histogram of KEGG enrichment analysis of upregulated genes, which shows a gradual change in color from red to purple, indicating the change in the P value from small to large (A). A histogram of KEGG enrichment analysis of downregulated genes (B).

PPI networks of the DEGs were constructed using STRING and Cytoscape. After removing three loose nodes, the PPI network contained a total of 50 nodes and 507 edges. We identified the top 20 hub genes, including PTPRC, CCR1, FGL2, MNDA, TNFSF13B, STAT1, IL10RA, LCP2, GBP5, GBP2, SAMD9L, NLRC5, TAGAP, CD53, IKZF1, GBP1, IFIT3, CXCR4, DOCK8, and XAF1 using Cytohubba according to degree. We found that the degree values were largest for Receptor-type tyrosine-protein phosphatase C (PTPRC), Signal transducer and activator of transcription 1(STAT1), Myeloid cell nuclear differentiation antigen (MNDA), Interleukin-10 receptor alpha (IL10RA), and C-C chemokine receptor type 1(CCR1) (Figure 4).

Figure 4 Proteinprotein interaction (PPI) networks for 53 upregulated DEGs (A) and the top 20 hub genes (B) were constructed using Cytoscape visualization, which shows a gradual change in color from purple to yellow, indicating the change degree value from small to large.

In order to validate the diagnostic value of the hub genes, H&E and immunohistochemistry analysis of four upregulated candidate genes, including STAT1, MNDA, IL10RA, and CCR1, in 14 patients and 14 controls were assessed. There was no obvious atrophy in the glands of non-SS comparator group, and the stroma was infiltrated with scattered lymphocytes and plasma cells. The glands of SS patients exhibited various degrees of acinar atrophy and destruction, ductal dilatation, and interstitial fibrosis as compared to non-SS patients, some SS glands showed granulomatous inflammation, adiposis, and germinal centers as compared to non-SS patients. STAT1, MNDA, IL10RA, and CCR1 proteins had increased expression in the labial gland of SS patients as compared to non-SS patients (Figure 5). The IOD of STAT1 and IL10RA was significantly higher in MSGB from SS patients than from non-SS patients (P < 0.001).

Figure 5 H&E and immunohistochemical analysis (A) of STAT1, MNDA, IL10RA, and CCR1 proteins in minor salivary gland biopsy (MSGB) staining from 14 SS patients and 14 non-SS patients (magnification: 200 for H&E staining and 200 for IHC). Blue marks the nucleus, and brown marks the target protein. The bar graph indicated medians with interquartile ranges of IOD value (B). ***P<0.001.

The IOD obtained from 14 SS and 14 non-SS patients was converted by logistic regression, and then the ROC value of FS and these hub genes was calculated. Each AUC and combined predicted probability were computed. FS showed a good performance with an AUC of 0.893 (Figure 6A). STAT1 (AUC = 0.807; P < 0.001) and IL10RA (AUC = 0.818; P < 0.001) had a high performance, while CCR1 (AUC = 0.587; P < 0.001) had a low performance. The multiple-gene predicted probability (AUC > 0.9) was higher than the single-gene predicted probability and FS, which signified that the above four genes can be used to distinguish SS from non-SS as compared to MSGB (Figure 6B).

Figure 6 The single and combined diagnostic performance of the four genes. The diagnostic performance of FS (A). The diagnostic performance based on the IOD of four genes in SS patients (B). An AUC > 0.8 indicated that the predicted model had good efficacy.

Abbreviations: ROC, receiver operating characteristic; AUC, area under the ROC curve.

Although SS is one of the autoimmune diseases, the early diagnosis and treatment of SS are far less studied than systemic lupus erythematosus and rheumatoid arthritis.13 A better understanding of the pathological processes is still needed.14 MSGB classification criteria have been based on three main classification systems including Chisholm and Mason, which described the degree of T or B lymphocyte infiltration or focus of lymphocytes around the salivary glands, with a sensibility and specificity of 72.1% and 80%, respectively.15 Greenspan and Daniels, defined the concept of the FS and FLS, and Tarpley, which added concepts of acinar destruction and fibrosis. While MSGB facilitates a diagnosis in some seronegative patients, it only has a moderate diagnostic performance and needs to be further refined. Subtle changes in foci size might not be accurately described, and the sensitivity and specificity of these scoring systems have never been compared before.16 There are some patients who have atypical clinical presentations and an FS of zero. The further quantification of foci per 4 mm2 tissue section utilizing key genes expression will help to accurately stratify those patients whose clinical information is not obvious, but have a higher risk of developing as SS.17 Our study identified hub genes through the bioinformatics analysis of three salivary gland datasets from SS patients and healthy controls. The hub genes were validated via MSGB of SS patients and non-SS patients. The ROC of the combined diagnostic model using the four indicators had better performance compared with single indicator or FS.

Our ClueGO and KEGG analysis revealed that genes were mainly enriched in viral infection and interferon and inflammation-related signaling pathways, including the NOD-like receptor signaling pathway and human cytomegalovirus (HCMV) infection. Gland invasion and damage caused by viral infection have been implied as mechanisms of SS. HCMV establishes latency in early myeloid lineage cells, and interferon-responsive genes which are targeted during the establishment of HCMV latency. Patients with compromised immune function will relapse once HCMV reactivation occurs.18 A previous study found that SS patients had a significantly higher prevalence of IgG-anti-EA and IgG-anti-VCA antibodies (which are specific in population with acute EBV infections) than healthy controls, and patients with SS that had higher levels of IgG-anti-EA antibodies, which were linked to low levels of C3 and C4, in a case-control study.19 Interferon (IFN) plays an important role in both the pathophysiology and clinical manifestations of SS.20 Most SS patients express a type I IFN signature in immune cells, which drive the production of auto-antibodies and a range of clinical manifestations.21 Infection and other factors are known to activate the expression of type I IFN and IFN-. These factors activate the NOD-like receptor signaling pathway or transcription of the STAT family, which induce expression of IFN-stimulated genes (ISGs), as well as feedback inhibitory molecules, such as IL-10, in diseased tissues.22 A previous study showed that increased virus-like repetitive elements, such L1 genomic repeat elements, represent endogenous nucleic acid triggers of the type I IFN pathway in SS and may contribute to injury of salivary gland tissue.23

In order to find potential biomarkers for SS, the expression of STAT1 in labial gland biopsy samples was assessed. Phosphorylation of STAT1, a type of signal transducer and transcription activator, mediates cellular inflammation responses in both type I and II IFN signaling pathways.24 Phosphorylated STAT1 induces complex of transcription factors 3(ISGF3) to translocate into the nucleus, where it binds to the IFN stimulation response element (ISRE) to activate the transcription of ISGs, leaving the cell in an antiviral state. Upon stimulation of IFN2b, phosphorylation of STAT1 differed significantly between SS patients and healthy controls. Type I and II IFN-induced gene expression was positively correlated with the IFN-2b-induced phosphorylation of STAT1 in B cells, which was associated with the production of auto-antibodies. Targeting STAT1 may contribute to the treatment of patients with SS.25 A JAK-1 inhibitor was thought to inhibit IFN-induced transcription genes and B lymphocyte stimulator (BLyS) dominating B-cell differentiation, homeostasis in human salivary glands, as well as regulate IFN- and IFN-induced pSTAT-1 in human salivary gland epithelial cells (SGECs).26

Myeloid cell nuclear differentiation antigen (MDNA), considered to be an IFN-inducible gene, is a member of the family of the pyrin and HIN domain containing (PYHIN) proteins, and it plays an important role in innate immunity, especially in human granulocytes and monocytes and earlier stage cells in the myeloid lineage.27 MNDA plays an emerging role in inflammation and apoptosis in SS.28 It has been reported as a worthwhile biomarker in PBMCs, which can lead to highly sensitive and specific detection for SS (AUC = 0.84).29

The IL10 receptor (IL10 R) and IL10 receptor (IL10 R) are members of the IFN receptor (IFNR) family. The IL10 signal is transmitted through two homodimers and a heteroprotein tetramer receptor complex consisting of two IL10 R and two IL10 R. STAT signaling is induced downstream by phosphorylation of the cytoplasmic tail of the IL10 R and IL10 R by JAK1 and Tyk2, respectively.30 IL10 suppresses proinflammatory responses and sometimes plays a protective role in SS. Possible linkage of IL10 polymorphisms to SS susceptibility has a critical role in the clinical symptoms and serological biomarkers.31 Functional mutations in genes, such as IL10 and IL10RA, have also been reported to be associated with immune dysregulation.32 IL10-producing regulatory B (Breg) cells have been shown to inhibit the follicular helper CD4 T cells (Tfh) cell response by promoting STAT5 phosphorylation and exerting an influence on the therapeutic effects in SS.33 Immunohistochemistry of salivary gland adipose tissue demonstrated that SS patients candidate genes leading to inflammation, such as IL10, IL10RA, and IFN production.33

C-C chemokine receptor 1 (CCR1) is one of the dominant regulators of leukocyte recruitment to resting sites in inflammatory disease. A previous study showed that CCR1-deficient mice exhibited blood and spleen defects, in addition to depletion of eosinophil numbers in the lungs.34 Another study reported that CCR1 antagonists had long-term anti-inflammatory effects and were effective in blocking splenocyte migration in vitro. As such, targeting chemokine receptors is a promising treatment strategy for chronic inflammation diseases.35 The role the CCR receptor family plays in leukocyte recruitment to salivary glands is unclear; therefore, the diagnosis efficacy of CCR1 is not important in this study.

Our results showed that both STAT1 and IL10RA contributed to the sensitive and specific of SS compared with MSGB. Detection of these biomarkers in salivary glands will provide a secondary application of MSGB, and demonstrate the potential of a combined measurement of salivary gland genes for the diagnosis of patients with SS. To our knowledge, this is the first study to develop a gene diagnosis model in SS patients using quantitative data of IHC. Further in vivo and in vitro experiments investigating the epigenetic regulation of interferon genes in lymphocytes are promising, and it is of great significance to the construction of the SS diagnosis model to synchronize interferon genes and inflammatory cytokines at the molecular level, which will help to realize precision medicine approaches of SS as soon as possible. However, it should be noted that this study only covered deficiency of salivary glands. Furthermore, evaluating the diagnostic and prognostic value of combined biomarkers of MSGB in a large cohort of patients with SS is necessary.

GEO, Gene Expression Omnibus database; DEGs, differentially expressed genes; PPI, proteinprotein interaction; ROC, receiver operating characteristic; AUC, area under the ROC curve; MSGB, minor salivary gland biopsy; FLS, focal lymphocytic salivary adenitis; FS, focus score.

This study was performed in accordance with the Declaration of Helsinki. Approval was obtained from the Institutional Ethics Committee of The Second Affiliated Hospital, Zhejiang Chinese Medical University (2021-LW-003-01). Informed consent was waived due to the anonymized processing of patient data.

This research was supported by National Natural Science Foundation of China (82074341).

The authors report no conflicts of interest for this work.

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2. Brito-Zern P, Acar-Denizli N, Ng WF, et al. Epidemiological profile and north-south gradient driving baseline systemic involvement of primary Sjgrens syndrome. Rheumatology. 2020;59:23502359. doi:10.1093/rheumatology/kez578

3. Ramrez Seplveda JI, Kvarnstrm M, Eriksson P, et al. Long-term follow-up in primary Sjgrens syndrome reveals differences in clinical presentation between female and male patients. Biol Sex Differ. 2017;8:25. doi:10.1186/s13293-017-0146-6

4. Cornec D, Devauchelle-Pensec V, Tobn GJ, Pers JO, Jousse-Joulin S, Saraux A. B cells in Sjgrens syndrome: from pathophysiology to diagnosis and treatment. J Autoimmun. 2012;39:161167. doi:10.1016/j.jaut.2012.05.014

5. Lessard CJ, Li H, Adrianto I, et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjgrens syndrome. Nat Genet. 2013;45:12841292. doi:10.1038/ng.2792

6. Campos J, Hillen MR, Barone F. Salivary gland pathology in Sjgrens syndrome. Rheum Dis Clin North Am. 2016;42:473483. doi:10.1016/j.rdc.2016.03.006

7. Baldini C, Ferro F, Elefante E, Bombardieri S. Biomarkers for Sjgrens syndrome. Biomark Med. 2018;12:275286. doi:10.2217/bmm-2017-0297

8. Vitali C, Moutsopoulos HM, Bombardieri S. The European Community Study Group on diagnostic criteria for Sjgrens syndrome. Sensitivity and specificity of tests for ocular and oral involvement in Sjgrens syndrome. Ann Rheum Dis. 1994;53:637647. doi:10.1136/ard.53.10.637

9. Fisher BA, Jonsson R, Daniels T, et al. Standardisation of labial salivary gland histopathology in clinical trials in primary Sjgrens syndrome. Ann Rheum Dis. 2017;76:11611168. doi:10.1136/annrheumdis-2016-210448

10. Brito-Zern P, Theander E, Baldini C, et al. Early diagnosis of primary Sjgrens syndrome: EULAR-SS task force clinical recommendations. Expert Rev Clin Immunol. 2016;12:137156. doi:10.1586/1744666X.2016.1109449

11. Aringhieri G, Izzetti R, Vitali S, et al. Ultra-high frequency ultrasound (UHFUS) applications in Sjogren syndrome: narrative review and current concepts. Gland Surg. 2020;9:22482259. doi:10.21037/gs-20-529

12. Shiboski CH, Shiboski SC, Seror R, et al. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjgrens syndrome: a consensus and data-driven methodology involving three international patient cohorts. Ann Rheum Dis. 2017;76:916. doi:10.1136/annrheumdis-2016-210571

13. Fox RI. Sjgrens syndrome. Lancet. 2005;366:321331. doi:10.1016/S0140-6736(05)66990-5

14. Wang B, Chen S, Zheng Q, et al. Early diagnosis and treatment for Sjgrens syndrome: current challenges, redefined disease stages and future prospects. J Autoimmun. 2021;117:102590. doi:10.1016/j.jaut.2020.102590

15. Cui G, Sugai S, Ogawa Y, Takeshita S, Masaki Y. [Evaluation of the histologic criteria for the diagnosis of Sjgrens syndrome]. Nihon Rinsho Meneki Gakkai Kaishi = Japanese Journal of Clinical Immunology. 1999;22:7279. Japanese. doi:10.2177/jsci.22.72

16. Bautista-Vargas M, Vivas AJ, Tobn GJ. Minor salivary gland biopsy: its role in the classification and prognosis of Sjgrens syndrome. Autoimmun Rev. 2020;19:102690. doi:10.1016/j.autrev.2020.102690

17. Kroese F, Haacke E, Bombardieri M. The role of salivary gland histopathology in primary Sjgrens syndrome: promises and pitfalls. Clin Exp Rheumatol. 2018;36:222233.

18. Elder EG, Krishna BA, Williamson J, et al. Interferon-responsive genes are targeted during the establishment of human cytomegalovirus latency. mBio. 2019;10:e0257419. doi:10.1128/mBio.02574-19

19. Xuan J, Ji Z, Wang B, et al. Serological evidence for the association between Epstein-Barr virus infection and Sjgrens syndrome. Front Immunol. 2020;11:2826. doi:10.3389/fimmu.2020.590444

20. Marketos N, Cinoku I, Rapti A, Mavragani CP. Type I interferon signature in Sjgrens syndrome: pathophysiological and clinical implications. Clin Exp Rheumatol. 2019;37(Suppl 118):185191.

21. Bodewes I, Bjrk A, Versnel M, Wahren-Herlenius M. Innate immunity and interferons in the pathogenesis of Sjgrens syndrome. Rheumatology. 2019;60:25612573.

22. Barrat F, Crow M, Ivashkiv L. Interferon target-gene expression and epigenomic signatures in health and disease. Nat Immunol. 2019;20:15741583. doi:10.1038/s41590-019-0466-2

23. Mavragani C, Sagalovskiy I, Guo Q, et al. Expression of long interspersed nuclear element 1 retroelements and induction of type I interferon in patients with systemic autoimmune disease. Arthritis Rheum. 2016;68:26862696. doi:10.1002/art.39795

24. Rauch I, Mller M, Decker T. The regulation of inflammation by interferons and their STATs. Jak-Stat. 2013;2:e23820. doi:10.4161/jkst.23820

25. Davies R, Hammenfors D, Bergum B, et al. Aberrant cell signalling in PBMCs upon IFN- stimulation in primary Sjgrens syndrome patients associates with type I interferon signature. Eur J Immunol. 2018;48:12171227. doi:10.1002/eji.201747213

26. Lee J, Lee J, Kwok SK, et al. JAK-1 inhibition suppresses interferon-induced BAFF production in human salivary gland: potential therapeutic strategy for primary Sjgrens syndrome. Arthritis Rheumatol. 2018;70:20572066. doi:10.1002/art.40589

27. Briggs RC, Briggs JA, Ozer J, et al. The human myeloid cell nuclear differentiation antigen gene is one of at least two related interferon-inducible genes located on chromosome 1q that are expressed specifically in hematopoietic cells. Blood. 1994;83:21532162. doi:10.1182/blood.V83.8.2153.2153

28. Mondini M, Costa S, Sponza S, Gugliesi F, Gariglio M, Landolfo S. The interferon-inducible HIN-200 gene family in apoptosis and inflammation: implication for autoimmunity. Autoimmunity. 2010;43:226231. doi:10.3109/08916930903510922

29. Hu S, Gao K, Pollard R, et al. Preclinical validation of salivary biomarkers for primary Sjgrens syndrome. Arthritis Care Res. 2010;62:16331638. doi:10.1002/acr.20289

30. Moore KW, de Waal Malefyt R, Coffman RL, OGarra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683765. doi:10.1146/annurev.immunol.19.1.683

31. Colafrancesco S, Ciccacci C, Priori R, et al. STAT4, TRAF3IP2, IL10, and HCP5 polymorphisms in Sjgrens syndrome: association with disease susceptibility and clinical aspects. J Immunol Res. 2019;2019:7682827. doi:10.1155/2019/7682827

32. Cabral-Marques O, Schimke LF, de Oliveira EB, et al. Flow cytometry contributions for the diagnosis and immunopathological characterization of primary immunodeficiency diseases with immune dysregulation. Front Immunol. 2019;10:2742. doi:10.3389/fimmu.2019.02742

33. Lin X, Wang X, Xiao F, et al. IL-10-producing regulatory B cells restrain the T follicular helper cell response in primary Sjgrens syndrome. Cell Mol Immunol. 2019;16:921931. doi:10.1038/s41423-019-0227-z

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Key Genes in Salivary Gland for the Diagnosis of SS | JIR - Dove Medical Press

Alteration of the gut microbiome has been linked to the pathogenesis of systemic lupus erythematosus (SLE). However, a comprehensive view of the gut microbiome in SLE and its interaction with the host remains to be revealed. This study aimed to reveal SLE-associated changes in the gut microbiome and its interaction with the host by a comprehensive metagenome-wide association study (MWAS) followed by integrative analysis.We performed a MWAS of SLE based on shotgun sequencing of the gut microbial DNA from Japanese individuals ( =47, =203). We integrated the result of the MWAS with the genome-wide association study (GWAS) data and plasma metabolite data.Via species level phylogenetic analysis, we identified and validated increases of and in the patients with SLE. Microbial gene analysis revealed increases of -derived genes including one involved in redox reaction. Additionally, microbial pathways related to sulfur metabolism and flagella assembly were altered in the patients with SLE. We identified an overlap in the enriched biological pathways between the metagenome and the germline genome by comparing the result of the MWAS and the GWAS of SLE (ie, MWAS-GWAS interaction). -diversity and -diversity analyses provided evidence of dysbiosis in the metagenome of the patients with SLE. Microbiome-metabolome association analysis identified positive dosage correlation of acylcarnitine with , an SLE-associated taxon.Our MWAS followed by integrative analysis revealed SLE-associated changes in the gut microbiome and its interaction with the host, which contribute to our understanding of the relationship between the microbiome and SLE. Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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Metagenome-wide association study revealed disease-specific landscape of the gut microbiome of systemic lup... - Physician's Weekly

1Department of Otolaryngology Head and Neck Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Peoples Republic of China; 2Department of Otolaryngology Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Peoples Republic of China; 3Department of Thyroid Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, Peoples Republic of China

Correspondence: Dawei SunDepartment of Thyroid Surgery, The Affiliated Hospital of Qingdao University, #16 Jiangsu Road, Qingdao, Shandong, 266000, Peoples Republic of ChinaEmail [emailprotected]

Purpose: This study aimed to evaluate the associations between immune-related gene (FCRL3, NLRP3 and IL2) polymorphisms and the risk of head and neck cancer (HNC).Methods: Six polymorphisms of FCRL3, NLRP3 and IL2 were genotyped in 400 HNC cases and 400 controls using a MassARRAY platform.Results: rs11264799-T was a protective variant against HNC risk, while rs7528684-G, rs35829419-A and rs6822844-T were all risk alleles for HNC (p p p p p Conclusion: The results expand our knowledge on immune-related gene polymorphisms in HNC and provide clues for further functional study on the pathogenesis of HNC.

Keywords: head and neck cancer, HNC, Fc receptor-like 3, FCRL3, NLR family pyrin domain containing 3, NLRP3, interleukin 2, IL2, genetic polymorphisms

Head and neck cancer (HNC) ranks as the sixth most common type of cancer worldwide, with an estimated 500,000 newly diagnosed cases and 325,000 deaths annually.1 The primary sites of HNC mainly include the pharynx, larynx and oral cavity. In recent years, although specific medicine and novel treatment approaches have improved the prognosis of HNC patients to a great extent, it is still necessary to find other ways to decrease the incidence of disease.2 Among researchers, it is believed that HNC is a complicated disease affected by both gene polymorphisms and environmental factors such as smoking and drinking.3 Previous studies have identified a number of variants associated with HNC risk, mainly including single-nucleotide polymorphisms (SNPs) in drug and alcohol metabolism- and cell cycle control-related genes.4 However, the current data represent only a small part of the genetic predisposition to HNC, and there is still an urgent need to identify more novel susceptible SNPs.

Recent clinical trials have revealed that immunotherapy is a promising treatment approach for advanced HNC patients,5 indicating that immune-related genes may play important roles in the progression of HNC. Fc receptor-like 3 (FCRL3) is a member of the FCRL superfamily and is involved in the regulation of the immune system.6 Polymorphisms of FCRL3 have been identified as taking part in the initiation of a diversity of autoimmune diseases,7 whereas little information has been found regarding the contribution of its polymorphisms to HNC risk. NLR family pyrin domain containing 3 (NLRP3) has specific structural domains that form the inflammasome complex NALP3 and are thus involved in the mediation of inflammation and the immune response in the human body.8 Moreover, interleukin 2 (IL2) is an important cytokine that is crucial for the proliferation of T and B cells, and its polymorphisms are associated with various cancers.9 Thus, FCRL3, NLRP3 and IL2 were selected as candidate genes in our study.

Based on previous association studies, six SNPs in FCRL3, NLRP3 and IL2 were selected for investigation. rs11264799 and rs7528684 in FCRL3 have been associated with the progression of multiple autoimmune diseases.10 rs35829419 in NLRP3 has been identified as a risk factor for the occurrence and outcome of colorectal cancer.11 rs10754558 and rs4353135 have been investigated in previous studies on gastric cancer and immune disorders, respectively.12,13 In addition, rs6822844 in IL2 has been proven to be associated with plasma IL2 levels in breast cancer patients, making it a promising biomarker for immune status among cancer patients.14

Considering the above associations between these SNPs and cancer and immune disorders, we speculated that these SNPs may also be involved in the occurrence and development of HNC. In this study, we genotyped the above six SNPs in a case-control cohort and evaluated their association with HNC risk, aiming to better understand the genetic predisposition to HNC.

The present case-control study consists of 400 histopathologically diagnosed HNC cases and 400 healthy controls. The participants were all Chinese Han individuals recruited at the Affiliated Hospital of Qingdao University. All cases were newly diagnosed and previously untreated. The controls were blood donors without a history of cancer, immune disorder or serious disease. We obtained written informed consent from each subject, and the study was approved by the Ethics Department of the Affiliated Hospital of Qingdao University (No. 20120413) and was carried out in accordance with the World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects.

Five milliliters of whole blood was collected from each subject in tubes containing ethylenediaminetetraacetic acid. DNA was extracted using a PureLink Pro 96 Genomic DNA Purification Kit (Invitrogen, Carlsbad, CA). Primers were designed using Sequenom MassARRAY Assay Design 3.0 software. Genotypes were detected by Sequenom MassARRAY RS1000 (Sequenom, San Diego, CA).

Statistical analyses were performed with SPSS package version 20.0 (SPSS, Chicago, IL, USA). Minor allele frequencies (MAFs) in controls were checked for departure from HardyWeinberg equilibrium (HWE) in controls. The associations between SNPs and HNC risk were evaluated using SNPstats (https://www.snpstats.net/start.htm) and are expressed as odds ratios (ORs) and 95% confidence intervals (CIs). Statistical significance was established when p < 0.05.

The basic characteristics of the participants are presented in Table 1, including sex, age, and smoking and drinking status. No significant differences were observed in the distributions of sex and age between the case and control groups, suggesting that the two groups were comparable (p > 0.05). However, there were significantly more smokers and drinkers than in the controls, suggesting that tobacco and alcohol consumption might be risk factors (p < 0.05). The primary sites of HNC cases were 46.75% in the pharynx, 30.50% in the larynx and 22.75% in the oral cavity.

Table 1 Basic Characteristics of the Participants

The basic information and MAFs of candidate SNPs are listed in Table 2. All of the SNPs were consistent with HWE (p > 0.05). We found that four SNPs had a significant allelic frequency distribution between the case and control groups. The MAF of rs11264799 was lower in cases than in controls, making it a protective variant against HNC risk (OR = 0.761, 95% CI: 0.6150.943, p = 0.012). In contrast, the MAF of rs7528684 in HNC patients was more prominent than in healthy donors, hinting that rs7528684-G might be a risk allele for HNC (OR = 1.260, 95% CI: 1.0351.533, p = 0.021). Additionally, rs35829419-A (OR = 1.632, 95% CI: 1.1522.311, p = 0.005) and rs6822844-T (OR = 1.600, 95% CI: 1.1262.275, p = 0.008) were both risk alleles for HNC.

Table 2 Allele Frequency Distributions Among HNC Cases and Healthy Controls

The genotypic frequencies of candidate SNPs were also compared between cases and controls (Table 3). The frequency of rs11264799-TT in HNC cases was lower; thus, rs11264799-TT was correlated with a reduced risk of HNC (OR = 0.54, 95% CI: 0.330.89, p = 0.031), while rs7528684-GG (OR = 1.63, 95% CI: 1.102.43, p = 0.044) and rs6822844-TG (OR = 1.75, 95% CI: 1.182.60, p = 0.010) were found to be more prominent in HNC cases than in controls, which made them associated with an elevated risk of HNC.

Table 3 Genotype Frequency Distributions Among HNC Cases and Healthy Controls

Three classic genetic models were used to evaluate associations between SNPs and disease (Table 4). One protective variant and three risk variants were identified in different models. rs11264799 was correlated with a declining risk of HNC in all three models (p < 0.05). In contrast, rs7528684 exhibited an elevated risk of HNC in recessive and additive models, and rs35829419 and rs6822844 were associated with an increased risk of disease in dominant and additive models (p < 0.05).

Table 4 Associations Between Candidate SNPs and HNC Risk in Three Genetic Models

Finally, the interactions of four polymorphisms and tobacco and alcohol consumption were evaluated using a stratification analysis (Table 5). The effects of four SNPs on the risk of HNC were not affected by smoking status (p < 0.05). However, when participants were stratified by drinking status, the four SNPs had associations with HNC risk only in drinkers (p < 0.05).

Table 5 Associations of Candidate SNPs with HNC Risk in Four Subgroups

Identification of genetic and environmental risk factors is not only helpful for us to better understand the pathogenesis of HNC but also beneficial to decrease the incidence of disease from the original. Immune-related genes have been extensively investigated in association studies on cancer. In this study, we genotyped six SNPs in the immune-related genes FCRL3, NLRP3 and IL2 and found that rs11264799 was a protective factor against HNC risk, while rs7528684, rs35829419, and rs6822844 were associated with an increased HNC risk.

FCRL3 is an immunoglobulin receptor and has specific immunoreceptor-tyrosine activation/inhibitor motifs in its cytoplasmic domain, affecting the modulation of the immune response.15 Genetic variation in FCRL3 has been associated with a wide range of diseases in different samples, including allergic rhinitis,16 sudden sensorineural hearing loss,17 autoimmune thyroid disease,18 rheumatoid arthritis,19 and multiple sclerosis.20 rs11264799 and rs7528684 in FCRL3 have been investigated in many association studies, and a meta-analysis has verified a significant association between these two SNPs and human autoimmune diseases.21 In the present study, we demonstrated novel correlations between rs11264799 and rs7528684 and HNC risk: rs11264799-T may protect carriers from HNC risk, while rs7528684-G contributes to an elevated risk of disease. rs11264799 and rs7528684 are located in the 5 UTR and upstream transcript region of FCRL3, respectively, meaning that their polymorphisms may change the expression levels of FCRL3 and other related downstream genes. Thus, we speculated that rs11264799 and rs7528684 may exert an influence on the predisposition to HNC by changing the molecular function of FCRL3 in HNC patients; however, this hypothesis still needs to be further confirmed.

NLRP3 is a pyrin-like protein that can interact with the cell apoptosis-related protein PYCARD/ASC and from the NALP3 inflammasome complex (an upstream inducer of NF-kappaB signaling) with other proteins.22 Therefore, NLRP3 plays important roles in cell apoptosis and the immune response. Polymorphisms of NLRP3 have been associated with a diversity of diseases, such as Parkinsons disease,23 Alzheimers disease,24 insulin resistance,25 ischemic stroke26 and other autoimmune and inflammatory diseases.27 rs35829419 is a missense variant (Q705K) in NLRP3 and has been identified as a susceptible risk factor for multiple human diseases.28 However, little evidence is available to determine its role in HNC. Our study demonstrated a significant correlation between rs35829419 and HNC risk by a comprehensive evaluation (allele, genotype frequency, and genetic model analysis). We suggested that carriers with the rs35829419-A allele should focus on their health: keeping away from tobacco and alcohol, maintaining a balanced diet and exercise, and having periodic physical examinations will reduce the risk of HNC.

IL2 is a secreted cytokine that is mainly produced by T cells. IL2 can promote the proliferation and activation of T, B and NK cells, consequently participating in the immune response. The effects of IL2 polymorphisms on the risk of cancer have been extensively investigated, including esophageal, gastric, hepatocellular, breast and bladder cancers.29 A recent study revealed that rs6822844 in IL2 was associated with plasma IL2 levels and might be used as a blood-based biomarker in the evaluation of immune status among breast cancer patients.14 Our study found that rs6822844-T contributed to a 1.6-fold increased risk of HNC, suggesting that rs6822844-T may also alter the expression of IL2 and impair the normal function of the immune system of HNC patients. However, the detailed mechanism needs to be explored in further studies.

Given that smoking and drinking are certain risk factors for HNC, we verified the associations between rs11264799, rs7528684, rs35829419, rs6822844 and HNC risk by stratification analysis. The associations were significant in both smokers and nonsmokers, suggesting that these SNPs are independent protective/risk factors for HNC that are not affected by smoking. However, although four SNPs had effects on the risk of disease in drinkers, no significant correlation was observed in nondrinkers. We speculated that there might be an interaction between these SNPs and drinking in the development of HNC.

In conclusion, we found that rs11264799 contributed to a lower HNC risk, while rs7528684, rs35829419, rs6822844 were associated with an increased HNC risk. The results expand our knowledge on immune-related gene polymorphisms in HNC and provide clues for further functional study on the pathogenesis of HNC.

All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, agreed to the submitted journal, and agree to be accountable for all aspects of the work.

The authors declare that they have no conflicts of interest.

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Original post:
Genetic polymorphisms and the risk of head and neck cancer | PGPM - Dove Medical Press

PALO ALTO, Calif. & SHANGHAI & PRINCETON, N.J.--(BUSINESS WIRE)--LianBio, a biotechnology company dedicated to bringing paradigm-shifting medicines to patients in China and other major Asian markets, and BridgeBio Pharma, Inc. (Nasdaq: BBIO) today announced the first patient has been treated in a Phase 2a clinical trial of infigratinib in patients with locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma with fibroblast growth factor receptor-2 (FGFR2) gene amplification and other advanced solid tumors with FGFR genomic alterations.

Infigratinib is a potent and selective FGFR inhibitor that has demonstrated compelling clinical activity across multiple tumor types with FGFR alterations, said Yizhe Wang, Ph.D., chief executive officer of LianBio. Given the disproportionately high prevalence rate of gastric cancer in China, LianBio is pursuing a region-specific development strategy focused on this area of great unmet need. This study marks LianBios first trial initiation and demonstrates our continued progress in delivering potentially transformational medicines to patients in Asia.

TRUSELTIQ (infigratinib) is an oral selective inhibitor of FGFR1-3 that is approved in the United States for the treatment of patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement as detected by an FDA-approved test. It is also being further evaluated in clinical trials based on demonstration of clinical activity in patients with advanced urothelial carcinoma with FGFR3 genomic alterations. LianBio in-licensed rights from BridgeBio for infigratinib for development and commercialization in Mainland China, Hong Kong and Macau.

The Phase 2a trial is a multicenter, open-label, single-arm study in China designed to evaluate the safety and efficacy of infigratinib in patients with locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma with FGFR2 gene amplification and other advanced solid tumors with FGFR alterations. The primary endpoint is objective response rate (ORR). Secondary endpoints include duration of response, safety, disease control rate, progression-free survival and overall survival.

Preclinical data have demonstrated the potential infigratinib may have for patients with gastric cancer. These results, published in Cancer Discovery, demonstrated tumor regression in multiple in vivo FGFR2 amplified gastric models.1

We believe that infigratinib could have a meaningful impact for people living with gastric cancer as well as many other cancers with FGFR alterations, and are pleased LianBio is initiating this clinical trial in China where more therapeutic options are needed to match the growing diagnosis rate, said BridgeBio founder and chief executive officer Neil Kumar, Ph.D. On the heels of TRUSELTIQ recently obtaining accelerated approval in the United States, we are hopeful that this trial will yield pivotal results in another subset of cancer patients as we continue to build our portfolio of oncology indications with the aim of reaching as many people in need as possible.

About TRUSELTIQ (infigratinib)

TRUSELTIQ (infigratinib) is an orally administered, ATP-competitive, tyrosine kinase inhibitor of fibroblast growth factor receptor (FGFR) that received accelerated approval from the FDA in the United States for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test. TRUSELTIQ targets the FGFR protein, blocking downstream activity. In clinical studies, TRUSELTIQ demonstrated a clinically meaningful rate of tumor shrinkage (overall response rate) and duration of response. TRUSELTIQ is not FDA-approved for any other indication in the United States and is not approved for use by any other health authority, including any Chinese or other Asian health authority. It is currently being evaluated in clinical studies for first-line cholangiocarcinoma, urothelial carcinoma (bladder cancer), locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma, and other advanced solid tumors with FGFR genomic alterations.

About BridgeBio Pharma, Inc.

BridgeBio is a biopharmaceutical company founded to discover, create, test and deliver transformative medicines to treat patients who suffer from genetic diseases and cancers with clear genetic drivers. BridgeBios pipeline of over 30 development programs ranges from early science to advanced clinical trials and its commercial organization is focused on delivering the companys first two approved therapies. BridgeBio was founded in 2015 and its team of experienced drug discoverers, developers and innovators are committed to applying advances in genetic medicine to help patients as quickly as possible. For more information visit bridgebio.com.

About LianBio

LianBios mission is to catalyze the development and accelerate availability of paradigm-shifting medicines to patients in China and other major Asian markets, through partnerships that provide access to innovative therapeutic discoveries with a strong scientific basis and compelling clinical data. LianBio collaborates with world-class partners across a diverse array of therapeutic and geographic areas to build out a broad and clinically validated pipeline with the potential to impact patients with unmet medical needs. For more information, please visit http://www.lianbio.com.

About the LianBio and BridgeBio Pharma, Inc. Strategic Alliance

In August 2020, LianBio entered into a strategic alliance with BridgeBio, a commercial-stage biopharmaceutical company focused on genetic diseases and cancers with clear genetic drivers, to develop and commercialize BridgeBios programs in China and other major Asian markets. This strategic relationship initially focuses on two of BridgeBios targeted oncology drug candidates: FGFR inhibitor infigratinib, for the treatment of FGFR-driven tumors, and SHP2 inhibitor BBP-398, in development for tumors driven by MAPK pathway mutations. The agreement also provides LianBio with preferential future access in China and certain other major Asian markets to more than 20 drug development candidates currently owned or controlled by BridgeBio. This collaboration is designed to advance and accelerate BridgeBios programs in China and other major Asian markets, allowing BridgeBio and LianBio to potentially bring innovation to large numbers of patients with high unmet need.

BridgeBio Pharma, Inc. Forward-Looking Statements

This press release contains forward-looking statements. Statements we make in this press release may include statements that are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended (the Securities Act), and Section 21E of the Securities Exchange Act of 1934, as amended (the Exchange Act), which are usually identified by the use of words such as anticipates, believes, estimates, expects, intends, may, plans, projects, seeks, should, will, and variations of such words or similar expressions. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Exchange Act, and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements, including statements relating to: the timing and success of the Phase 2a clinical trial of infigratinib in patients with locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma with fibroblast growth factor receptor-2 (FGFR2) gene amplification, and other advanced solid tumors with FGFR genomic alterations; the planned approval of infigratinib by foreign regulatory authorities in China and the necessary clinical trial results, and timing and completion of regulatory submissions related thereto; and the competitive environment and clinical and therapeutic potential of infigratinib; reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations, strategies and prospects as reflected in or suggested by those forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a variety of risks and factors that are beyond our control including, without limitation: the safety, tolerability and efficacy profile of infigratinib observed to date may change adversely in ex-U.S. clinical trials, ongoing analyses of trial data or subsequent to commercialization; foreign regulatory agencies may not agree with our regulatory approval strategies, components of our filings, such as clinical trial designs, conduct and methodologies, or the sufficiency of data submitted; the continuing success of the BridgeBio and LianBio strategic alliance; and potential adverse impacts due to the global COVID-19 pandemic such as delays in regulatory review, manufacturing and clinical trials, supply chain interruptions, adverse effects on healthcare systems and disruption of the global economy; as well as those set forth in the Risk Factors section of BridgeBio Pharma, Inc.s most recent Annual Report on Form 10-K filed with the U.S. Securities and Exchange Commission (SEC) and in subsequent SEC filings, which are available on the SECs website at http://www.sec.gov. Except as required by law, each of BridgeBio and QED disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release in the event of new information, future developments or otherwise. Moreover, BridgeBio and QED operate in a very competitive environment in which new risks emerge from time to time. These forward-looking statements are based on each of BridgeBios and QEDs current expectations, and speak only as of the date hereof.

1 Guagnano, V., Kauffman, A., Wrle, S., et al. FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor. Cancer Discovery 2 (2012): 1118-1133.

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BridgeBio Pharma and LianBio Announce First Patient Treated in Phase 2a Trial of Infigratinib in Patients with Gastric Cancer and Other Advanced Solid...

A team of scientists from Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU) played a vital role in supporting Dubais response to COVID-19 through crucial viral genomic surveillance research Image Credit: WAM

Dubai: A team of scientists from Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU) played a vital role in supporting Dubais response to COVID-19 through crucial viral genomic surveillance research. The result of these studies have now been published in several international peer-reviewed journals, providing crucial reference material to the academic and medical community.

Commenting on the impact of the study, Dr Ahmad Abou Tayoun, Director of Genomics Centre, Al Jalila Childrens Specialty Hospital and Associate Professor of Genetics, MBRU, said: This research was instrumental in tracing the origins of the virus early on in the UAE, identifying problem areas and providing vital inputs on the scale, intensity and scope of the response to the pandemic. Given Dubais geographic position and role as a bridge between the East and West, the findings of our research have also helped calibrate and tweak frontline strategies in the global response to the pandemic.

Tracking the COVID-19 fingerprint

Scientists from MBRU collaborated with scientists from Dubai Health Authority (DHA) and the Genomic Center at Al Jalila Childrens Specialty Hospital (Al Jalila Childrens) to understand how the virus mutates when passed from person to person over weeks and months and examined its genomic fingerprint to track the origin, spread and possible mutations within a population. The studies contributed to shaping Dubais data-driven approach to managing the pandemic.

Cost-effective virus surveillance

The team developed a scalable, cost-effective method for large-scale genomic surveillance of the virus, which demonstrated high accuracy in identifying the origin and distinguishing modes of transmission in Dubai and the UAE. The team also mapped the origin and timing of the start of the COVID-19 infection during the early stage of the pandemic, including early geographical clusters. The study also shed light on how factors such as age, gender and underlying health conditions combined with specific mutations of the virus to decide disease severity.

Additionally, the research team also identified how cells function in patients with severe COVID-19, that can be used to predict disease outcomes in those patients and allow health-care professionals to tailor the intensity of treatment.

Virus genome sequenced fully

Full genome sequencing of the virus from Dubai was shared with the global scientific community, delivering critical insights to assist the worlds battle with the disease, providing particularly crucial information on the spread of the virus globally and specifically in Europe.

Laudable scientific research

Professor Alawi Alsheikh-Ali, Deputy Director General, DHA, and Chair of the Scientific Advisory Group for Dubai COVID-19 Command and Control Centre, and Member of MBRUs Board of Trustees, said: Scientific research is a highly prized resource that has informed and guided Dubais measured and balanced response to the pandemic. Collaboration with leading academic and medical institutions in Dubai was the key, highlighting the value of an integrated academic health system.

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How UAE scientists tracked the COVID-19 virus gene - Gulf News

Gene therapy is a promising new method for treating non-small cell lung cancer (NSCLC). It allows doctors to target specific genes to prevent cancerous cells from growing and spreading.

NSCLC is a common form of cancer. It causes cancerous cells to form in the tissues of the lung. NSCLC is a serious condition. However, many people receive treatment and survive for years.

Treating NSCLC typically involves interacting with multiple specialists and receiving a combination of therapies. Specific treatment plans depend on factors that include the tumor size, type of NSCLC, and the extent of its spread to other organs.

Surgery, radiation or chemotherapy, and immunotherapy are examples of key techniques that doctors use to treat NSCLC.

Gene therapy is another promising treatment for NSCLC, which targets genes that contribute to the tumor.

There are two main approaches to using gene therapy to treat cancer:

This article focuses on the second approach to NSCLC gene therapy. Read on to learn more.

Getting genes into cells requires making vectors, which are vehicles that scientists engineer to deliver genetic materials. For example, viruses have a natural ability to deliver genetic material into cells and can act as vectors.

Scientists can deactivate parts of the virus that cause infectious diseases. They can then modify the virus to carry genetic material into cancerous cells.

One type of gene therapy for NSCLC targets tumor-suppressor genes, which are the most common gene mutation that contributes to the disease. Another approach involves restoring specific proteins to prevent disease progression.

Other possible applications include inserting genes that:

NSCLC gene therapy is a new form of treatment. However, early results are promising.

A 2017 review suggests that restoring a functional tumor-suppressing gene could slow the growth of cancer cells. Clinical trials have found that inserting tumor-suppressing genes into people who had not responded to other treatments reduced tumor size by up to 50%.

Another review in 2016 suggests that the treatment is more effective when combining NSCLC gene therapy with other therapies, such as chemotherapy or immunotherapy.

According to the American Cancer Society, doctors typically use gene therapy for advanced cancer cases.

NSCLC gene therapy is a new technique. However, it still has to meet rigorous Food and Drug Administration (FDA) standards for safety and effectiveness before a doctor can recommend it.

Gene therapies that the FDA approves are safe. However, they can have side effects, such as:

According to the FDA, gene therapies can transform medicine and provide options for people with illnesses that were previously without a cure. However, every treatment has limitations to its effectiveness.

Some limitations to gene therapy include:

Doctors will typically develop a treatment plan with people who have NSCLC depending on their health, age, and other relevant factors. Some common forms of NSCLC treatment include:

Doctors may combine these treatments to maximize their effectiveness. This will involve undergoing multiple treatments at once or back-to-back treatments, or both.

For example, doctors may use a therapy to treat cancer in one part of the body and another therapy to treat where it is spreading.

Doctors typically describe the outlook for people with cancer using the percentage of people alive at least 5 years after their diagnosis. This is the 5-year survival rate. They may further break down 5-year survival rates according to specific NSCLC diagnoses.

According to the American Cancer Society, the 5-year survival rate for people with NSCLC are:

NSCLC is a common form of lung cancer in the United States. Gene therapy for people with NSCLC is a promising new treatment that targets specific genes that contribute to disease progression. There is evidence that gene therapy can slow the growth of tumors in people with NSCLC.

Gene therapy is new, but has the potential to change the way doctors can treat cancer. Scientists and doctors must first overcome limitations, including finding reliable methods to deliver gene therapy.

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NSCLC gene therapy: Success rate, other options, and more - Medical News Today

When oncologists talk about cancer targets, theyre usually referring to mutated genes that can be thwarted with drugs. Researchers at the University of Pennsylvania used gene-editing technology CRISPR to elucidate a different sort of target in acute myeloid leukemia (AML)and to uncover a way to target it with drugs.

A team at Penns medical school discovered that an epigenetic regulatory protein called ZMYND8 governs the expression of genes that are critical for the growth and survival of AML cells. Inhibiting ZMYND8 in mouse models shrank tumors. The researchers also found a biomarker that they believe could predict which patients are likely to respond to ZMYND8 inhibition, they reported in the journal Molecular Cell.

AML is one of the hardest leukemias to treat, with a five-year survival rate of about 27% in adults. The Penn team had been searching for precision medicine approaches that could improve the prognosis for adults with AML, and they turned to CRISPR for help.

ZMYND8 is known as a histone reader in cancer that can recognize epigenetic changes and influence gene expression involved in metastasis.

Using CRISPR, the Penn team disrupted various functions of proteins in cancer cells and mapped their functions on a molecular level. When they blocked the epigenetic reader function of ZMYND8 in mouse models, it not only caused tumors to shrink, but also improved survival, they said in a statement. With CRISPR, they were able to pinpoint a pocket on ZMYND8 that they believe could be targeted with drugs.

RELATED: Novartis-backed Penn study proposes boosting CAR-T responses in CLL by waking up 'war weary' T cells

Several efforts to develop new treatments for AML have hit roadblocks of late. The FDA placed a hold on trials of Aprea Therapeutics eprenetapopt in AML after worrisome side effects appeared in a trial of the drug in myelodysplastic syndrome. Amgen had been developing a bispecific antibody for AML, AMG 427, but stopped a phase 1 trial after some patients developed the dangerous side effect cytokine release syndrome. The company is now investigating ways to optimize the treatment approach, a spokesperson said earlier this month.

Several immuno-oncology approaches to AML are under development, including engineered natural killer cell therapies, and researchers are investigating a range of targeted approaches such as combining MDM2 and BET blockers.

The Penn researchers wanted to see whether they could predict how sensitive AML cells might be to ZMYND8 inhibition, so they turned to blood samples from patients treated at Penn Medicine. They found that high expression of a particular gene in those cells, IRF8, could serve as a biomarker of response to ZMYND8 inhibition.

CRISPR revealed here, for the time, an unexpected epigenetic-linked molecular circuity that AML is dependent on, and one that we can potentially manipulate, said co-author Shelley Berger, Ph.D., professor at the Perelman School of Medicine and director of the Penn Epigenetics Institute, in the statement. It opens a new door toward better treatments for these patients using next-generation epigenetic inhibitors.

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CRISPR pinpoints new leukemia target and a 'pocket' that could make it druggable - FierceBiotech