tbuckley/cabot-search huggingface dataset:
Genomic characterization of bladder cancer with variant histology.
Authors: Andrew Thomas Lenis, Timothy Nguyen Clinton, Wenhuo Hu, Nima Almassi, Peter Reisz, Hong Truong, Jasmine Thomas, Karan Nagar, Alvin Goh, Eugene K. Cha, Timothy F. Donahue, Bernard H. Bochner, Eugene J. Pietzak, Kwanghee Kim, Gopa Iyer, David B. Solit, Hikmat A Al-Ahmadie
Journal: Journal of Clinical Oncology (2021)

470 Background: Up to 25% of tumors are of pure variant or mixed urothelial and variant histology. The presence of variant histology may be associated with more advanced stage at presentation and a poorer response to systemic therapy. While histomorphologic assessment provides important prognostic information, genomic analysis of tumors can provide important insight into the biology of disease and inform treatment. In this analysis we performed genomic sequencing of tumors from patients with bladder cancer with variant histology. Methods: Our prospectively generated institutional cohort of molecularly profiled bladder and upper tract tumors contains over 2,000 samples including nearly 300 primary bladder tumor samples from patients with variant histology. Targeted sequencing with MSK-IMPACT was used to identify alterations in cancer-associated genes and to describe trends across variant subtypes. To explore and compare tumor and immune cell heterogeneity, single-cell RNA sequencing (scRNA-seq) was performed on a subset of specimens. Results: Our cohort included patients with pure urothelial carcinoma not otherwise specified (NOS), as well as squamous, small cell, pure adenocarcinoma and urothelial carcinoma with glandular differentiation, micropapillary, nested, and plasmacytoid variants. Compared with urothelial carcinoma NOS, nearly all small cell tumors had mutations in TP53, RB1, and TERT. Squamous tumors had similar mutational frequencies as urothelial carcinoma NOS. Pure adenocarcinoma had frequent mutations in TP53, KRAS, and PIK3CA, resembling colorectal adenocarcinomas, while urothelial carcinoma with glandular differentiation resembled NOS. Micropapillary variant commonly had ERBB2 amplifications. Nested variant was more commonly found to have RHOA mutations and FOXA1 amplifications. Finally, nearly all plasmacytoid variants had pathognomonic alterations in CDH1. To further explore heterogeneity in tumor and immune cell populations, scRNA-seq was performed on four samples from patients with urothelial carcinoma NOS, squamous, micropapillary, and nested variants, showing distinct tumor cell clusters and varying contributions of immune cells from each variant. Conclusions: While the distribution of oncogenic mutations differed among distinct histologic variants, a pathognomonic DNA alteration was not found for most variant histologic subtypes. Within the context of a larger effort to characterize bladder cancer with variant histology, scRNA-seq may reveal differences in immune cell population infiltrates. Further efforts will aim to characterize these cohorts with whole exome sequencing and mutational signatures, and increase the number of samples per histology and representation of variant histologies for scRNA-seq.
Severe-COVID-19 and mortality among patients (pts) with prostate cancer (PCa) receiving androgen deprivation therapy (ADT).
Authors: Matthew D Tucker, Andrew Lachlan Schmidt, Chih-Yuan Hsu, Yu Shyr, Andrew J. Armstrong, Ziad Bakouny, Christina Hunter Chapman, Scott Dawsey, Benjamin Adam Gartrell, Susan Halabi, Monika Joshi, Ali Raza Khaki, Harry Menon, Matthew Puc, Nima Sharifi, Justin Shaya, Elizabeth Marie Wulff-Burchfield, Tian Zhang, Shilpa Gupta, Rana R. McKay
Journal: Journal of Clinical Oncology (2021)

39 Background: The presence of progressing cancer, male sex and advanced age have been shown to increase the severity of coronavirus disease 2019 (COVID-19). Given that the androgen regulated gene TMPRSS2 has been implicated in SARS-CoV-2 viral entry, we hypothesized that ADT may improve COVID-19 outcomes. This analysis evaluated clinical outcomes of pts with PCa with concurrent SARS-CoV-2 infection and investigated the impact of ADT on occurrence of severe-COVID-19 and mortality. Methods: Data was obtained via the COVID-19 and Cancer Consortium (CCC19), a multicenter registry including &gt;120 cancer centers with de-identified data from pts with COVID-19 and cancer. Men with confirmed SARS-CoV-2 infection and a primary diagnosis of prostate cancer were included: data cutoff of July 31, 2020. The primary endpoint was the development of severe-COVID-19 (death, ICU admission, or mechanical ventilation) among pts on ADT vs. those not on ADT at time of COVID-19 infection. Secondary endpoints included 30-day mortality based on ADT use. Mortality and development of severe-COVID-19 were assessed in Pts grouped by therapy: 1st generation androgen receptor inhibitor (ARI-1), 2nd generation ARI (darolutamide, enzalutamide, apalutamide, ARI-2), abiraterone/prednisone, and chemotherapy. Propensity score matching was utilized. Logistic regression was utilized to adjust for age, ECOG PS, comorbidities, and race. Results: 589 pts were included; median follow-up was 42 days (IQR 25-90) and 62% (363/589) were hospitalized. Severe-COVID-19 developed in 28% of pts and the all-cause 30-day mortality rate was 19%. There was no significant difference in the development of severe-COVID-19 or 30-day mortality between Pts on ADT vs not on ADT, whether using descriptive statistics with the entire population or using the propensity score matched population (Table). Among the descriptive population, the numerical rates of severe-COVID-19 and mortality were lowest in Pts receiving ARI-2, but sample size was low. Conclusions: The overall 30-day mortality rate and percentage developing severe-COVID-19 were high. There was no statistical difference in the development of severe-COVID-19 or mortality based on receipt of ADT; however, this analysis is limited by the retrospective nature and small N after propensity-matching. [Table: see text]
Broad neutralization of H1 and H3 viruses by adjuvanted influenza HA stem vaccines in nonhuman primates
Authors: Nicole Darricarrère, Yu Qiu, Masaru Kanekiyo, Adrian Creanga, Rebecca A. Gillespie, Syed M. Moin, Jacqueline Saleh, Jose Sancho, Te-Hui Chou, Yanfeng Zhou, Ruijun Zhang, Shujia Dai, Anthony Moody, Kevin O. Saunders, Michelle C. Crank, John R. Mascola, Barney S. Graham, Chih-Jen Wei, Gary J. Nabel
Journal: Science Translational Medicine (2021)

Nonhuman primates immunized with adjuvanted stabilized headless HA stem nanoparticles generated influenza-specific broadly neutralizing antibodies.
This Is a Title in Chidamide, a Novel HDAC Inhibitor, Is Effective for Treating Leukemia Relapse Post Allogeneic Stem Cell Transplantation and Results in Th1 Polarization in AML Patients with AML1-ETO
Authors: Xi Yang, Xiaobing Huang, Hong Zheng, Chenglong Li, Jingying Dai, Rong Zhang, Xiaodong Wang, Chunsen Wang
Journal: Blood (2017)
Abstract 14496: Frailty is Associated With Increased Cardiovascular Mortality in 2,837,152 United States Veterans Aged 65 and Older
Authors: William Shrauner, Emily Lord, Xuan-Mai T Nguyen, Rebecca J Song, Ashley Galloway, David Gagnon, Jane Driver, John M Gaziano, Peter Wilson, Luc Djousse, Kelly Cho, Ariela R Orkaby
Journal: Circulation (2020)

Introduction: Frailty has been associated with an increased risk of all-cause mortality and CV events. There are limited data from the modern era of CV prevention to examine the relationship between frailty and CV mortality. We hypothesized that frailty would be associated with with increased risk of CV mortality. Methods: All Veterans ≥65 who were regular users of VA care from 2002–2014 were included. Index date was the last visit date in the year of cohort entry. Data were queried biennially, with frailty &amp; outcomes queried each period. Frailty was defined using a 31-item previously validated frailty index, ranging from 0-1. Degrees of frailty were defined as: not frail (FI &lt;0.1), pre-frail (FI &gt;0.1-≤0.2), mild frailty (FI &gt;0.2-≤0.3), moderate frailty (FI &gt;0.3-≤0.4), and severe frailty (FI &gt;0.4). Variables were extracted from national VA administrative data linked to Medicare and Medicaid. The primary outcome was CV mortality. Survival analysis was performed. Models were adjusted for age, sex, race/ethnicity, geographic region, smoking status, hyperlipidemia, statin use, and blood-pressure medication use. Results: There were 2,837,152 Veterans included in the analysis. In 2002 mean age was 74+/- 5.8 years and in 2012 was 76+/- 8.1 years, 98% were male, 88.8% were white. In 2002, the median frailty score was 0.16 (IQR= 0.13). This increased and then stabilized to 0.19 for 2006 to 2012 (IQR= ranging 0.19 to 0.23). Overall frailty became more prevalent over time (prevalence increased from 31.9% in 2002 to 46.5% in 2012). The presence of frailty was associated with increased risk of CVD mortality at every degree of frailty and year, as shown in the Table. Discussion: Frailty is highly prevalent in the VA population, and both the presence and severity of frailty are tightly correlated with CV death. This study is the largest and most contemporary evaluation of the relationship between frailty and CV mortality to date. Further work is needed to understand how this risk can be diminished.
Accelerated antimicrobial discovery via deep generative models and molecular dynamics simulations
Authors: Payel Das, Tom Sercu, Kahini Wadhawan, Inkit Padhi, Sebastian Gehrmann, Flaviu Cipcigan, Vijil Chenthamarakshan, Hendrik Strobelt, Cicero dos Santos, Pin-Yu Chen, Yi Yan Yang, Jeremy P. K. Tan, James Hedrick, Jason Crain, Aleksandra Mojsilovic
Journal: Nature Biomedical Engineering (2021)
Abstract 10448: Proteomic Profiling and Risk of New-Onset Atrial Fibrillation - Framingham Heart Study
Authors: Darae Ko, Mark D Benson, Debby Ngo, Qiong Yang, Martin G Larson, Thomas J Wang, Ludovic Trinquart, David D McManus, Steven A Lubitz, Patrick T Ellinor, Ramachandran S Vasan, Robert E Gerszten, Emelia J Benjamin, Honghuang Lin
Journal: Circulation (2018)

Background: Prior proteomics analyses on the risk of incident AF screened for limited numbers of proteins. We report the use of single-stranded DNA-based aptamers as affinity agents to screen for 1...
Implementation of clinician-facing prostate cancer therapeutic clinical trial decision tool at a comprehensive cancer center.
Authors: Hala Borno, Patricia Li, Sylvia Zhang, Dame Idossa, Arpita Desai, Tammy J. Rodvelt, Rohit Bose, Vadim S Koshkin, Jonathon Chou, Terence W. Friedlander, Franklin W. Huang, Eric Jay Small, Rahul Raj Aggarwal
Journal: Journal of Clinical Oncology (2021)

19 Background: The conventional model for clinical trial (CT) recruitment relies on clinicians to identify potential CTs for patients. Internet technology can be leveraged as a decision tool to enhance the CT recruitment process. Methods: An internet-based, clinician-facing decision tool was developed in genitourinary medical oncology clinic at a Comprehensive Cancer Center (CCC). The tool provided access to a real-time, tailored list of treatment CTs actively recruiting patients with PCa at the CCC based on clinical characteristics inputted by user. The clinical data was summarized. All clinicians (n = 9) with access to the decision tool completed a survey to assess effectiveness and satisfaction. Results: During a 9-month pilot period, user engagement increased from a baseline of 36 to 136 cases per month, with a total of 644 cases overall. Among cases, 525 had metastatic disease, 436 of which were metastatic castration resistant PCa (mCRPC). Overall, 145 cases were classified as having oligo-metastatic ( &lt; = 3) PCa, 93 of whom were also mCRPC. Prior treatments received included abiraterone in hormone-sensitive PCa (HSPC 19.3%, CRPC 48.7%); enzalutamide (HSPC 3.7%, CRPC 34.9%) apalutamide (HSPC 1.3%, CRPC 6.9%), taxane (HSPC 17.2%, CRPC 27.8%), radium-223 (6.1%), sipuleucel-T (18.3%), parp inhibitors (4%), or check-point inhibitors (6%). Clinician-inputted genomics of cases included CDK12 (20.9%), MSI-high disease (13.6%), BRCA1/2 (32.7%), ARID1a (7.3%), ATM (21.8%), FANCA (4.5%), or CHEK2 (6.4%) and HDAC2 (0.9%). Among survey respondents, use of tool in clinic was reported sometimes (22%), often/always (78%). Results of decision tool were reported to inform treatment sometimes (22%) or often/always (78%). Respondents confidence in often/always knowing all available CTs increased from a baseline of 0% to 89%, and 89% of users reported very/complete satisfaction with decision tool. Conclusions: An internet-based CT decision tool for provides detailed clinical characteristics of patients for whom CTs are being considered at a CCC. Clinicians using the decision tool report high levels of satisfaction. The tool was effective in increasing confidence in knowledge of current available CTs. Data gathered in the decision tool may inform future CT development. Future research with expanded use of decision tool among referring clinicians will assess its impact in promoting diversity among CT participants.
The role of cardiopulmonary exercise test in identifying pulmonary veno-occlusive disease
Authors: Carmen Pérez-Olivares, Teresa Segura de la Cal, Ángela Flox-Camacho, Jorge Nuche, Jair Tenorio, Amaya Martínez Meñaca, Alejandro Cruz-Utrilla, Javier de la Cruz-Bertolo, Marte Pérez Núñez, Spanish PAH Consortium, Fernando Arribas-Ynsaurriaga, Pilar Escribano Subías
Journal: European Respiratory Journal (2021)

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension that shares some clinical and haemodynamic features with idiopathic pulmonary arterial hypertension (PAH). However, suspicion of PVOD is crucial, considering that PAH-specific treatment may precipitate life-threatening pulmonary oedema and lung transplant should be considered from diagnosis [1, 2]. Cardiopulmonary exercise tests provide additional data for the noninvasive diagnosis of pulmonary veno-occlusive disease <https://bit.ly/3p6Dzc5>
Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity
Authors: Matan Sorek, Walaa Oweis, Malka Nissim-Rafinia, Moria Maman, Shahar Simon, Cynthia C. Hession, Xian Adiconis, Sean K. Simmons, Neville E. Sanjana, Xi Shi, Congyi Lu, Jen Q. Pan, Xiaohong Xu, Mahmoud A. Pouladi, Lisa M. Ellerby, Feng Zhang, Joshua Z. Levin, Eran Meshorer
Journal: Genome biology (2021)

Abstract Background Many neurodegenerative diseases develop only later in life, when cells in the nervous system lose their structure or function. In many forms of neurodegenerative diseases, this late-onset phenomenon remains largely unexplained. Results Analyzing single-cell RNA sequencing from Alzheimer’s disease (AD) and Huntington’s disease (HD) patients, we find increased transcriptional heterogeneity in disease-state neurons. We hypothesize that transcriptional heterogeneity precedes neurodegenerative disease pathologies. To test this idea experimentally, we use juvenile forms (72Q; 180Q) of HD iPSCs, differentiate them into committed neuronal progenitors, and obtain single-cell expression profiles. We show a global increase in gene expression variability in HD. Autophagy genes become more stable, while energy and actin-related genes become more variable in the mutant cells. Knocking down several differentially variable genes results in increased aggregate formation, a pathology associated with HD. We further validate the increased transcriptional heterogeneity in CHD8+/− cells, a model for autism spectrum disorder. Conclusions Overall, our results suggest that although neurodegenerative diseases develop over time, transcriptional regulation imbalance is present already at very early developmental stages. Therefore, an intervention aimed at this early phenotype may be of high diagnostic value.
Parenting as a full time job: The experience of secular middle-class Jewish parents of transgender emerging adults in Israel
Authors: Yochay Nadan
Journal: International Journal of Transgender Health (2021)

Emerging adulthood is a developmental period that encompasses individuals from their late teens through at least their mid-twenties, causing parents to be engaged in "parenting" activities longer than in the past. The present study aims to explore the parenting experience and its ascribed meaning among parents of trans emerging adults in Israel.Perceptions and perspectives of 18 Israeli parents of trans emerging adults regarding their parenting experiences were explored using in-depth, semi-structured interviews. All interviews were audiotaped, fully transcribed verbatim, and thematically analyzed.Analysis of the interviews yielded three main themes. The first pertains to parental worries; the second pertains to parental support practices, including accompanying and supporting their child in different arenas and serving as their companions and advocates; and the third pertains to parental coping skills.Participants portrayed the parenting of trans emerging adults as a demanding, challenging, and complex experience which they described as a "full time job." Their parenting experiences revolved around the tension between responding to the special needs of their trans children by helping them navigate this period of experimentation and exploration, and the need to give them autonomy and help them develop the independence they want and need. This tension should be understood in light of the specific situation and the stage of the child's transition, the parent-child relationship, and the family situation, in addition to the wider societal context, which is often hostile and transphobic.
Abstract PO-060: Individualized prediction of meningioma recurrence risk over prolonged time periods
Authors: Yasin Mamatjan, Farshad Nassiri, Mira Salih, Kenneth Aldape, Gelareh Zadeh
Journal: Clinical Cancer Research (2021)

Abstract Rationale and purpose: Meningiomas are benign tumors, but significant number of meningiomas display risk of early tumor recurrence. The inter-observer variability among pathologists for grading and some indistinguishable features of meningioma under the microscope prevent accurate prediction of recurrence risk that critically limits appropriate treatment and management of patients who may benefit from adjuvant radiation therapy. We aim to develop individualized prediction of meningioma recurrence risk over prolonged time periods using DNA methylation signatures and other associated clinical factors. Method: The recurrence risk predictor is based on continuous survival random-forest modelling to calculate the probabilities of a recurrence for each meningioma patient over various prolonged time frames. We processed over 500 meningioma samples using our machine-learning model that predicts probability of tumor recurrence based on methylation data. We used Random Forest based Rangers package as the survival model that returns the probabilities of a recurrence not happening over various prolonged time frames. Result: Methylation-based predictor distinguishes high-low risk groups over prolonged time periods. The predictor was validated using external validation cohort based on the selected probes and original training model. We found that methylation based predictor has potential to identify in patients with grade II meningiomas especially, while it also can identify grade I patients with higher recurrence risk over prolonged time periods. Conclusion: There were limitations of standard of care classifications in meningioma especially for Grade 2 patients due to significant intra- and inter-observer variability for grading and selection of patients for treatment. The individualized risk predictor can help determining the decisions regarding adjuvant radiation treatment versus observation along for each meningioma patient in the clinic. Citation Format: Yasin Mamatjan, Farshad Nassiri, Mira Salih, Kenneth Aldape, Gelareh Zadeh. Individualized prediction of meningioma recurrence risk over prolonged time periods [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-060.
Efficacy of cabozantinib in advanced MiT family translocation renal cell carcinomas (TRCC).
Authors: Jonathan Thouvenin, Omar Alhalabi, Laure Hirsch, Elshad Hasanov, Philippe Barthelemy, Dylan J. Martini, Lucas Campedel, Karim Amrane, Delphine Borchiellini, Jad Chahoud, Ziad Bakouny, Praful Ravi, Srinivas Raghavan Viswanathan, Mehmet Asim Bilen, Toni K. Choueiri, Nizar M. Tannir, Gabriel G. Malouf
Journal: Journal of Clinical Oncology (2021)

274 Background: MiT family translocation renal cell carcinomas (TRCC) represent a rare and aggressive subgroup of RCC harboring high expression of c-MET. While response rates of VEGF receptor-tyrosine kinase inhibitor and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a TKI that inhibits VEGFR, MET, and AXL) in this subgroup is unclear. Methods: We performed a multicentre, retrospective, international cohort study of patients with TRCC treated with cabozantinib regardless the line of treatment at 7 centers (3 in France and 4 in the US). The main objectives were to estimate response rate according to RECIST criteria, and to analyze progression-free survival (PFS) and overall survival (OS). Results: Among 31 metastatic patients treated in the participating centers, 24 were evaluable for response and were included in this study (21 with TFE3 and 3 with TFEB translocations). Median age at diagnosis was 43.5 years (range, 22–70). Most frequent metastatic sites at diagnosis were lungs (62.5%), retroperitoneal lymph nodes (45.8%) and bone (37.5%). Patient’s IMDC risk group at diagnosis was favourable (20,8%), intermediate (62,5%) and poor (16,7%). Seven (29%) patients received cabozantinib at first line, 9 (37.5%) at second line and 8 (33%) at third line and beyond. The proportion of patients who achieved an objective response was 16.6%, including 1 complete response and 3 partial responses. For 11 (45.8%) patients, stable disease was the best response. With a median follow-up of 14 months (IQR 5-23), median PFS was 8.4 months (range, 1-34+) and median OS was 17 months (range, 2-43). No PFS difference was detected overall or in any subgroup except in patients with bone metastasis which harbored a median PFS of 3.6 months as compared to 9.1 months for those without (p=0.03). Conclusions: This real-world study provides evidence supporting activity of cabozantinib in TRCC, with more durable responses to therapy than those observed with of VEGF receptor-tyrosine kinase inhibitor and immune checkpoint inhibitors. International collaborations and prospective studies are necessary to identifies efficacious therapies for this rare disease that lacks evidence-based treatment options.
Interpreting the RAPIDO trial: factors to consider – Authors' reply
Authors: Renu R Bahadoer, Esmée A Dijkstra, Boudewijn van Etten, Corrie A M Marijnen, Hein Putter, Elma Meershoek-Klein Kranenbarg, Per J Nilsson, Bengt Glimelius, Cornelis J H van de Velde, Geke A P Hospers
Journal: The Lancet Oncology (2021)
Antisense oligonucleotide therapy in a humanized mouse model of <i>MECP2</i> duplication syndrome
Authors: Yingyao Shao, Yehezkel Sztainberg, Qi Wang, Sameer S. Bajikar, Alexander J. Trostle, Ying-Wooi Wan, Paymaan Jafar-nejad, Frank Rigo, Zhandong Liu, Jianrong Tang, Huda Y. Zoghbi
Journal: Science Translational Medicine (2021)

Antisense oligonucleotides are efficacious and safe in a humanized mouse model of MECP2 duplication syndrome.
Virus-inducible IGFALS facilitates innate immune responses by mediating IRAK1 and TRAF6 activation
Authors: Gang Xu, Feiyan Deng, Qi Zuo, Lin Liu, Kaiwen Dou, Zhikui Cheng, Wei Cao, Chuanjin Luo, Chen Yu, Shi Liu, Ying Zhu
Journal: Cellular and Molecular Immunology (2021)