scholarly journals An interview with Swathi Arur

Development ◽  
2021 ◽  
Vol 148 (2) ◽  
pp. dev199366
Author(s):  
Alex Eve
Keyword(s):  
American Association ◽  
Associate Professor ◽  
Cancer Center ◽  
Germline Development ◽  
Faculty Mentor ◽  
C Elegans ◽  
Distinguished Research ◽  
Md Anderson ◽  
Female Germline ◽  
Research Faculty

Swathi Arur is an Associate Professor for the Department of Genetics at the MD Anderson Cancer Center, USA, where she uses multidisciplinary approaches to understand female germline development and fertility. She has received numerous accolades, including the MD Anderson Distinguished Research Faculty Mentor Award in 2017. In 2020, she was elected to the American Association for the Advancement of Science (AAAS). Swathi joined the team at Development as an Academic Editor in 2020, and we met with her over Zoom to hear more about her life, her career and her love for C. elegans.

scholarly journals Tissue- and sex-specific small RNAomes reveal sex differences in response to the environment

2018 ◽  
Author(s):  
Alexandra Bezler ◽  
Fabian Braukmann ◽  
Sean West ◽  
Arthur Duplan ◽  
Raffaella Conconi ◽  
...  
Keyword(s):  
Sex Differences ◽  
High Throughput Sequencing ◽  
Transmission Efficiency ◽  
Germline Development ◽  
Specific Expression ◽  
C Elegans ◽  
Male Germline ◽  
Somatic Gonad ◽  
Underlying Mechanisms ◽  
Female Germline

ABSTRACTBackgroundRNA interference (RNAi) related pathways are essential for germline development and fertility in metazoa and can contribute to inter-and trans-generational inheritance. In the nematode Caenorhabditis elegans environmental double-stranded RNA provided by feeding can lead to heritable changes in phenotype and gene expression. Notably, transmission efficiency differs between the male and female germline, yet the underlying mechanisms remain elusive.ResultsHere we use high-throughput sequencing of dissected gonads to quantify sex-specific endogenous piRNAs, miRNAs and siRNAs in the C. elegans germline and the somatic gonad. We identify genes with exceptionally high levels of 22G RNAs that are associated with low mRNA expression, a signature compatible with silencing. We further demonstrate that contrary to the hermaphrodite germline, the male germline, but not male soma, is resistant to environmental RNAi triggers provided by feeding. This sex-difference in silencing efficacy is associated with lower levels of gonadal RNAi amplification products. Moreover, this tissue-and sex-specific RNAi resistance is regulated by the germline, since mutant males with a feminized germline are RNAi sensitive.ConclusionThis study provides important sex-and tissue-specific expression data of miRNA, piRNA and siRNA as well as mechanistic insights into sex-differences of gene regulation in response to environmental cues.

Inhibition of DMRTA2 impairs human female germline development in xeno-grafted ovaries

2014 ◽  
Author(s):  
Marine Poulain ◽  
Sophie Tourpin ◽  
Vincent Muczynski ◽  
Sebastien Messiaen ◽  
Delphine Moison ◽  
...  
Keyword(s):  
Human Female ◽  
Germline Development ◽  
Female Germline

657 Interleukin-6 receptor blockade for management of immune checkpoint inhibitor related adverse events in patients with melanoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A694-A694
Author(s):  
Chantal Saberian ◽  
Faisal Fa’ak ◽  
Jean Tayar ◽  
Maryam Buni ◽  
Sang Kim ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Activity ◽  
Median Time ◽  
Interleukin 6 ◽  
Immune Checkpoint ◽  
Activity Index ◽  
Critical Role ◽  
Cancer Center ◽  
Interleukin 6 Receptor ◽  
Md Anderson

BackgroundManagement of certain immune mediated adverse events (irAEs) can be challenging and may require prolonged/chronic immune suppression with corticosteroids or other immunosuppressant which could compromise and even reverse the efficacy of immune checkpoint inhibitors (ICI). While the exact immunobiology of irAEs is not fully understood there is enough evidence that IL-6 induced Th-17 that may play critical role in the pathogenesis. Herein, we describe our clinical experience using interleukin-6 receptor (IL-6R) blockade in management of irAEs in melanoma patients.MethodsWe searched MD Anderson databases to identify cancer patients who had received ICIs between January 2004 and March 2020. Of 11,391 ICI-treated patients, 21 patients with melanoma who received IL-6R blockade after ICI infusion were identified and their medical records were reviewed.ResultsMedian age was 61 years (41–82), 52% were females, 90% received anti-programmed cell death-1 antibodies. Fourteen patients (67%) had de novo onset irAEs (11 had arthritis, and 1 each with polymyalgia rheumatica, oral mucositis, and CNS vasculitis), and 7 patients (33%) had flare of their pre-existing autoimmune diseases (5 had had rheumatoid arthritis, and 1 each with myasthenia gravis and Crohn’s disease). Median time from ICI initiation to irAEs was 91 days (range, 1–496) and to initiation of IL-6R blockade was 6.6 months (range, 0.6–24.3). Median number of IL-6R blockade was 12 (range, 1–35), and 16 patients (76%) were concomitantly receiving corticosteroids of median dose of 10 mg (range, 5–20 mg). Of the 21 patients, irAEs improved in 14 (67%) (95% CI: 46%-87%). Of 13 evaluable patients with arthritis, 11 (85%) achieved remission or minimal disease activity as defined by the clinical disease activity index. Median time from initiation of IL-6R blockade till improvement of irAEs was 2.9 months (range, 1.5–36.9). Nineteen patients tolerated well IL-6R blockade, while two patients stopped treatment due to abdominal pain and sinus tachycardia. The median CRP levels at irAEs was 84 mg/L (0.6–187) and decreased to 1.9 mg/L (0.56–12) at 10 weeks after initiation of IL-6R blockade (P=0.02). Of the 17 evaluable patients, the overall tumor response rate by RECIST-1.1 criteria was similar before and after IL-6R blockade initiation (41% vs. 53%).ConclusionsOur data demonstrated that IL-6R blockade could be an effective therapy for irAEs management without dampening the efficacy of ICIs. Prospective clinical trials with longitudinal blood, tumor, and inflamed tissue biopsies are planned to accurately validate these findings and better study the immunobiology of irAEs.Ethics ApprovalThe study was approved by The University of Texas MD Anderson Cancer Center intuition’s Ethics Board, approval number PA19-0089

Frequent Germline Mutations and Somatic Repeat Instability in DNA Mismatch-Repair-Deficient Caenorhabditis elegans

Genetics ◽  
2002 ◽  
Vol 161 (2) ◽  
pp. 651-660
Author(s):  
Marcel Tijsterman ◽  
Joris Pothof ◽  
Ronald H A Plasterk
Keyword(s):  
Caenorhabditis Elegans ◽  
Mismatch Repair ◽  
Large Scale ◽  
Somatic Tissue ◽  
Repeat Instability ◽  
Dna Mismatch ◽  
C Elegans ◽  
Colon Cancers ◽  
Dna Repeat ◽  
Female Germline

Abstract Mismatch-repair-deficient mutants were initially recognized as mutation-prone derivatives of bacteria, and later mismatch repair deficiency was found to predispose humans to colon cancers (HNPCC). We generated mismatch-repair-deficient Caenorhabditis elegans by deleting the msh-6 gene and analyzed the fidelity of transmission of genetic information to subsequent generations. msh-6-defective animals show an elevated level of spontaneous mutants in both the male and female germline; also repeated DNA tracts are unstable. To monitor DNA repeat instability in somatic tissue, we developed a sensitive system, making use of heat-shock promoter-driven lacZ transgenes, but with a repeat that puts this reporter gene out of frame. In genetic msh-6-deficient animals lacZ+ patches are observed as a result of somatic repeat instability. RNA interference by feeding wild-type animals dsRNA homologous to msh-2 or msh-6 also resulted in somatic DNA instability, as well as in germline mutagenesis, indicating that one can use C. elegans as a model system to discover genes involved in maintaining DNA stability by large-scale RNAi screens.

scholarly journals The Mammalian Ovary from Genesis to Revelation

2009 ◽  
Vol 30 (6) ◽  
pp. 624-712 ◽  
Author(s):  
Mark A. Edson ◽  
Ankur K. Nagaraja ◽  
Martin M. Matzuk
Keyword(s):  
Germ Cells ◽  
Ovarian Function ◽  
Primordial Germ Cells ◽  
Bioactive Molecules ◽  
Sex Characteristics ◽  
Germline Development ◽  
Peptide Growth Factors ◽  
Development And Differentiation ◽  
Common Destiny ◽  
Female Germline

Abstract Two major functions of the mammalian ovary are the production of germ cells (oocytes), which allow continuation of the species, and the generation of bioactive molecules, primarily steroids (mainly estrogens and progestins) and peptide growth factors, which are critical for ovarian function, regulation of the hypothalamic-pituitary-ovarian axis, and development of secondary sex characteristics. The female germline is created during embryogenesis when the precursors of primordial germ cells differentiate from somatic lineages of the embryo and take a unique route to reach the urogenital ridge. This undifferentiated gonad will differentiate along a female pathway, and the newly formed oocytes will proliferate and subsequently enter meiosis. At this point, the oocyte has two alternative fates: die, a common destiny of millions of oocytes, or be fertilized, a fate of at most approximately 100 oocytes, depending on the species. At every step from germline development and ovary formation to oogenesis and ovarian development and differentiation, there are coordinated interactions of hundreds of proteins and small RNAs. These studies have helped reproductive biologists to understand not only the normal functioning of the ovary but also the pathophysiology and genetics of diseases such as infertility and ovarian cancer. Over the last two decades, parallel progress has been made in the assisted reproductive technology clinic including better hormonal preparations, prenatal genetic testing, and optimal oocyte and embryo analysis and cryopreservation. Clearly, we have learned much about the mammalian ovary and manipulating its most important cargo, the oocyte, since the birth of Louise Brown over 30 yr ago.

scholarly journals 236 Predictors of ICI renal toxicity: a pathological approach

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A252-A252
Author(s):  
Ala Abudayyeh ◽  
Liye Suo ◽  
Heather Lin ◽  
Omar Mamlouk ◽  
Cassian Yee ◽  
...  
Keyword(s):  
Overall Survival ◽  
Renal Toxicity ◽  
Checkpoint Inhibitors ◽  
Interstitial Fibrosis ◽  
Transplant Rejection ◽  
Categorical Variables ◽  
Rank Test ◽  
Cancer Center ◽  
Renal Response ◽  
Md Anderson

BackgroundInflammatory response in unintended tissues and organs associated with the use of immune checkpoint inhibitors also known as immune related adverse events (irAEs) is a management challenge, and renal irAEs are associated with increased patient morbidity and mortality. The most common renal toxicity is acute interstitial nephritis (AIN), characterized by infiltration of renal tissue with immune cells, and may be analogous to kidney transplant rejection. Using both clinical variables and tissue findings we evaluated a large cohort of ICI cases to determine predictors of renal response and overall survival.MethodsWe retrospectively reviewed all patients treated with ICI (August 2007 to August 2020) at MD Anderson Cancer Center. A total of 38 patients with biopsy confirmed AIN and available tissue were identified. All slides were reviewed by two board certified renal pathologists and the severity of inflammation and chronicity was graded using transplant rejection BANFF criteria. Patients were categorized as renal responders if creatinine improved or returned to baseline after treatment and non-responders if it did not. Fisher’s exact tests for categorical variables and t-test/ANOVA or the counterparts of the non-parametric approaches (Wilcoxon rank-sum or Kruskal-Wallis) for continuous variables were used to compare patient‘s characteristics between groups. The distribution of overall survival (OS) was estimated by the Kaplan-Meier method. Log-rank test was performed to test the difference in survival between groups.ResultsBased on the detailed pathological findings, patients with increased interstitial fibrosis were less likely to have renal response with treatment compared to patients with less fibrosis, (p < 0.05). Inflammation, tubulitis, number of eosinophils and neutrophils had no impact on renal response. Patients with response within 3 months of AKI treatment had a superior OS in comparison to patients who responded late (12-month OS rate: 77% vs 27%, p < 0.05). Notably, patients who received concurrent ICI and achieved renal response within 3 months had the best OS while those who did not receive concurrent ICI nor achieved renal response had worst OS (12-month OS rate: 100% (renal response and concurrent ICI) vs 72% ( renal response with no concurrent ICI), vs 27% ( no renal response and nonconcurrent ICI) (p < 0.05).ConclusionsThis is the first analysis of ICI induced nephritis where a detailed pathological and clinical evaluation was performed to predict renal response. Our findings highlight the importance of early diagnosis and treatment of ICI-AIN while continuing concurrent ICI therapy.Ethics ApprovalThis retrospective study was approved by the institutional review board at The University of Texas MD Anderson Cancer Center, and the procedures followed were in accordance with the principles of the Declaration of Helsinki.

scholarly journals Pituitary carcinoma: The University of Texas MD Anderson Cancer Center experience

2018 ◽  
Author(s):  
Fernando Santos-Pinheiro ◽  
Marta Penas-Prado ◽  
Carlos Kamiya-Matsuoka ◽  
Steven G Waguespack ◽  
Anita Mahajan ◽  
...  
Keyword(s):  
Survival Rate ◽  
Disease Control ◽  
Survival Rates ◽  
Pituitary Carcinoma ◽  
Cancer Center ◽  
Ki 67 ◽  
Entire Cohort ◽  
University Of Texas ◽  
Single Center Experience ◽  
Md Anderson

AbstractBackground: Pituitary carcinoma (PC) is an aggressive neuroendocrine tumor diagnosed when a pituitary adenoma (PA) becomes metastatic. PCs are typically resistant to therapy and frequently recur. Recently, treatment with temozolomide (TMZ) has shown promising results, although the lack of prospective trials limits accurate assessment. Methods: We describe a single-center experience in managing PC over a 22-year period and review previously published PC series. Results: 17 patients were identified. Median age at PC diagnosis was 44 years (range 16-82), and the median PA-to-PC conversion time was 5 years (range 1-29). Median follow-up was 28 months (range 8-158) with 7 deaths. Most PC were hormone-positive based on immunohistochemistry (n=12): ACTH (n=5), PRL (n=4), LH/FSH (n=2), GH (n=1). All patients underwent at least one resection and one course of radiation after PC diagnosis. Immunohistochemistry showed high Ki-67 labeling index (>3%) in 10/15 cases. Eight patients (47%) had metastases only to the CNS, and 6 (35%) had combined CNS and systemic metastases. The most commonly used chemotherapy was TMZ, and TMZ-based therapy was associated with the longest period of disease control in 12 (71%) cases, as well as the longest period from PC diagnosis to first progression in 8 (47%) cases. The 2, 3 and 5-year survival rate of the entire cohort was 71%, 59% and 35%, respectively. All patients surviving >5 years were treated with TMZ-based therapy. Conclusions: PC treatment requires a multidisciplinary approach and multimodality therapy including surgery, radiation and chemotherapy. TMZ-based therapy was associated with higher survival rates and longer disease control.PrecisWe describe 17 PC patients who were diagnosed and treated at MDACC over a 22-year period. We have found that TMZ-based therapy correlated with longer disease control and higher survival rate.

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