tbuckley/cabot-search huggingface dataset:
The contribution of germline DNA damage response mutations on prostate cancer risk and prognosis: A UK Biobank whole-exome analysis.
Authors: Niedzica Camacho, Athena Matakidou
Journal: Journal of Clinical Oncology (2021)

67 Background: Germline mutations in DNA Damage Response (DDR) genes such as BRCA2 and ATM have been associated with prostate cancer risk and aggressiveness. These associations are largely based on studies that ascertain for cancer diagnosis and family history and provide risk estimates with limited population-level accuracy. Here we evaluate the clinical significance of germline pathogenic variants in 20 DDR genes and a high-risk susceptibility coding variant in HOXB13 using whole exome sequences from (1) the UK Biobank (UKBB), a population-based cohort (300,000 participants) and (2) patients recruited in AZ clinical trials. Methods: Whole exomes from 6,987 prostate cancer patients (5,921 UKBB and 1,066 AZ) and 88,499 cancer-free males were analysed. Known and novel pathogenic variants were identified and associations with disease risk, age of onset, family history, response to hormonal therapy and overall survival were estimated (multiplicity corrected P value &lt; 0.005). Results: HOXB13 G48E (1.36%), ATM (1.03%) and BRCA2 (0.99%) were the largest contributors to prostate cancer risk, each conferring an increase of ~4-fold, followed by CHEK2 with a moderate contribution (0.46%). No significant contributions to prostate cancer risk were observed for any of the other genes analysed. Family history of prostate cancer was not significantly enriched in any of the gene subpopulations of prostate cancer carriers and compared with non-carriers, there was no significant difference in the median age of disease onset. Analysis of clinical outcomes showed that BRCA2 carriers had a 4-fold increased risk of death (Cox PH HR p = 4.11E-12) and poorer overall survival (Log-Rank p = 4.60E-14), with 88% dying from prostate cancer compared to 49% of non- BRCA2 carriers (UKBB analysis). BRCA2 pathogenic mutations were also associated with early failure to hormonal therapy (Cox PH HR 2.38; p = 9.48E-04; AZ cohort analysis). HOXB13, ATM and CHEK2 mutations were not significantly associated with clinical outcomes. Conclusions: This is the largest study to date providing population-based estimates of prostate cancer risk and prognosis, highlighting BRCA2 carriers as a population in clinical need of early identification and targeted intervention. Updated analyses with data from the full 450,000 UKBB participants (9,000 prostate cancers) will be presented.
The Severe Respiratory Insufficiency Application (SRI App): a pilot randomised controlled trial
Authors: Daniel Sebastian Majorski, Sarah Bettina Schwarz, Friederike Sophie Magnet, Rebar Ahmad, Tim Mathes, Wolfram Windisch
Journal: Thorax (2021)

An application (app) for the Severe Respiratory Insufficiency Questionnaire (SRI) has been designed and developed for mobile devices. In a randomised controlled trial comprising 60 patients with chronic respiratory failure, the app was compared with the classic paper SRI. Thereby, it was shown that the SRI app is a practical tool that is well accepted. Missing values can be completely avoided by using the SRI app. Finally, reliability, convergent and discriminant validities were established. Accordingly, for the individual SRI subscales, Cronbach’s alpha ranged between 0.56 and 0.81 (app) and between 0.54 and 0.83 (paper), respectively. The multilingual SRI app is accessible free of charge for non-profit research purposes.
Abstract 9800: Natural History and Clinical Outcomes of Inappropriate Sinus Tachycardia: The Mayo Clinic Experience
Authors: Samuel A Shabtaie, Chance M Witt, Samuel J Asirvatham
Journal: Circulation (2019)

Introduction: Very limited data is known regarding the demographics, disease associations and long-term prognosis of patients with inappropriate sinus tachycardia (IST). Methods: We retrospectively...
Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals
Authors: Emily K. Sims, Brian N. Bundy, Kenneth Stier, Elisavet Serti, Noha Lim, S. Alice Long, Susan M. Geyer, Antoinette Moran, Carla J. Greenbaum, Carmella Evans-Molina, Kevan C. Herold, Linda A. DiMeglio, Stephen E. Gitelman, Peter A. Gottlieb, Jennifer B. Marks, Wayne Moore, Henry Rodriguez, William E. Russell, Desmond Schatz, Eva Tsalikian, Diane K. Wherrett, Anette-Gabriele Ziegler
Journal: Science Translational Medicine (2021)

Teplizumab treatment of nondiabetic relatives at high risk for T1D induces partially exhausted CD8 + T cells and improves beta cell function.
Impact of early hypothalamic-pituitary-gonadal axis maturation on prostate cancer:Cross-sectional analysis of a Veterans Affairs cohort.
Authors: Rimaz M. Khadir, Rashid K. Sayyid, Martha K. Terris
Journal: Journal of Clinical Oncology (2021)

255 Background: Early onset of puberty, resulting in more prolonged exposure to higher androgen levels, has been hypothesized to be a risk factor for more aggressive prostate cancer (PCa) later in life. We sought to determine whether earlier age of first shave and height, as surrogates of pubertal onset, were associated with worsening PCa characteristics. Methods: A prospectively collected registry of patients presenting for a prostate biopsy at the Charlie Norwood Veterans Affairs Medical Center in Augusta, GA between July 1995 and June 2016 was utilized. Age of first shave and height were compared to the risk of cancer on prostate biopsy, high grade cancer (i.e. Gleason score 8 or higher), and high volume disease (i.e. at least 50% of total cores were positive) using univariable and multivariable logistic regression analysis, controlling for patient age, race, prostate specific antigen, percent free prostate specific antigen, clinical stage, prostate volume, body mass index, family history. Statistical significance was set at p &lt; 0.05 and all statistical analyses were performed using R version 3.6.1. Results: Of the 1,176 patients analyzed, 599 (50.9%) had a cancer on prostate biopsy, of which 141 (23.5%) and 194 (32.4%) had high grade and volume disease, respectively. Median age of first shave was 17.0 years (interquartile range 16.0-19.0) and height was 177.8 cm (172.7-182.9). On multivariable analysis, later age of first shave was significantly associated with increased odds of a positive prostate biopsy (odds ratio for &gt; 18 years versus &lt; 16 years: 5.36, p = 0.03) and taller patients had significantly increased odds of high-grade cancer (odds ratio for 175-180 cm versus &lt; 175 cm 7.41, p = 0.038). Conclusions: Among patients presenting for a prostate biopsy, those with a later age of first shave and taller height had an increased risk of a positive prostate biopsy and high-grade PCa, respectively. This suggests that patients with later age of puberty, and thus later testosterone surges, are at increased risk of overall and high-grade PCa. [Table: see text]
Renal sarcomas: Epidemiology, treatment and outcomes.
Authors: Johannes Uhlig, Annemarie Uhlig, Hari Anant Deshpande, Michael E. Hurwitz, Peter Humphrey, Kevin Kim
Journal: Journal of Clinical Oncology (2021)

362 Background: Renal sarcomas are a rare malignancy in adults and have been inadequately evaluated on a US national level regarding epidemiology, treatment, and outcomes. Methods: The 2004-2016 NCDB and SEER databases were queried for adult patients diagnosed with sarcomas of renal origin. Age-adjusted incidence rates were derived from the SEER database. Overall survival (OS) was assessed using multivariable Cox proportional hazards models adjusting for demographics, tumor and treatment variables. Results: 1,279 renal sarcomas comprising 39 subtypes were reported from 2004-2016, contributing 0.3% of all NCDB renal malignancies. As shown in the table below, the most common subtypes were leiomyosarcoma (LMS), angiosarcoma (AS), malignant rhabdoid tumor (MRT), dedifferentiated liposarcoma (DL) and primitive neuroectodermal tumors (PNET). Over the study period, renal sarcoma incidence rates remained constant at 0.5 cases / 1 million citizens. Sex-specific incidence differences were evident with female predominance for LMS, and male predominance for AS. Age at diagnosis and tumor diameter varied according to sarcoma subtypes: for example, median age in LMS was 62y compared to 30y in Ewing sarcoma patients; median tumor diameter was 18cm for solitary fibrous tumors and 7.5cm for synovial sarcoma. Renal sarcoma was staged as T3 in 33.3% and T4 in 14.2%, while distant metastases were evident in 29.1% of cases at diagnosis. Most T1-T3 stage renal sarcomas underwent surgical resection (992/1098, 84%), compared to 71% for T4 renal sarcomas (128/181). Systemic therapy was administered in 32.1% of renal sarcoma cases (23.5% combined with surgical resection). Renal sarcoma 1-,2-, and 5-year OS rates were 48%, 24%, and 13%. OS was worse for T4 vs T1-3 sarcomas (HR=1.6, p&lt;0.001), and cases with distant metastases vs none (HR=3.2, p&lt;0.001). As summarized in the table, OS varied according to sarcoma subtypes with worse OS for AS compared to PNET (HR=1.5, p=0.04). Conclusions: Accounting for 0.3% of renal malignancies in adults, renal sarcomas include 39 different histological subtypes with distinct demographics, tumor parameters and outcomes. Renal sarcomas commonly present with advanced T stage at diagnosis and are treated with surgical resection with or without systemic therapy. [Table: see text]
Recent advances in the development of nanomedicines for the treatment of ischemic stroke
Authors: Xing Tian, Taojian Fan, Wentian Zhao, Ghulam Abbas, Bo Han, Ke Zhang, Nan Li, Ning Liu, Weiyuan Liang, Hao Huang, Wen Chen, Bing Wang, Zhongjian Xie
Journal: Bioactive Materials (2021)

Ischemic stroke is still a serious threat to human life and health, but there are few therapeutic options available to treat stroke because of limited blood-brain penetration. The development of nanotechnology may overcome some of the problems related to traditional drug development. In this review, we focus on the potential applications of nanotechnology in stroke. First, we will discuss the main molecular pathological mechanisms of ischemic stroke to develop a targeted strategy. Second, considering the important role of the blood-brain barrier in stroke treatment, we also delve mechanisms by which the blood-brain barrier protects the brain, and the reasons why the therapeutics must pass through the blood-brain barrier to achieve efficacy. Lastly, we provide a comprehensive review related to the application of nanomaterials to treat stroke, including liposomes, polymers, metal nanoparticles, carbon nanotubes, graphene, black phosphorus, hydrogels and dendrimers. To conclude, we will summarize the challenges and future prospects of nanomedicine-based stroke treatments.
Differential gene expression in human pancreatic cell lines L3.6pl (metastatic) and FG (non-metastatic).
Authors: Peter Camaj, Martin Luckner, Michael Bruckel, Helmut Blum, Susanne Schmidt, Karl-Walter Jauch, Christiane Bruns
Journal: Cancer Research (2007)

4706  Background: Our experimental model consists of two pancreatic cancer cell lines: parental FG cells and metastatic L3.6pl cells generated from FG via three cycles of in vivo selection in nude mice.  Methods: Nude mice were injected orthotopically with 1x106 human pancreatic tumor cells L3.6pl or FG, respectively. Tumor volume and body weight was continuously monitored. In vitro production of VEGF was determined by ELISA and cell proliferation by MTT-Assay. RNA from 3 biological replicates of the both cell lines was hybridized with human gene chips (Affymetrix). The results were validated by RT-PCR and by western blotting. Expression of the chosen genes was investigated in pancreatic cancer tissues isolated from patients and compared with healthy tissue from the same pancreas using RT-PCR and immunohistochemistry. Protein-protein interactions were investigated by immunoprecipitation and Western blotting.  Results: The volume of L3.6pl-tumors at day 37 after injection was 15-fold larger than the volume of FG-tumors. The body weight of L3.6pl-injected mice was 71% of the body weight of FG-injected mice. Primary L3.6pl-tumors were very well vascularized and liver metastases were detectable at the time of sacrifice. In vitro, we measured 9-fold more VEGF protein content in conditioned media of L3.6pl cells as compared to conditioned media of FG cells. The proliferation rate of L3.6pl cells was 1,5-fold higher as compared to FG cells. The analysis of differential gene expression has revealed 38 genes transcriptional upregulated in L3.6pl cells. Interestingly, one part of the genes belongs to the interferon signalling cascade such as the receptor (IFNAR), signal transducers (STAT1, NFkB) or targets of the interferon regulation (IFIT3, G1P2). Furthermore, Affymetrix analysis demonstrated a very strong upregulation of uPA transcripts important for metastasis development. Primarily, we have chosen for further investigations the 6,4-fold upregulated EFEMP1 gene (EGF-containing fibulin-like extracellular matrix protein 1). By RT-PCR we confirmed the upregulation of the following transcripts in L3.6pl cells: IFNAR1, NFkB, IFIT3, EFEMP1 and PLAU. Interestingly, L3.6pl cells did not only express a higher amount of total NFκB, but also a higher amount of the phosphorylated protein.  We have immunoprecipitated EFEMP1 protein using anti-EGFR antibody. The yield of this immunoprecipitation was inversely proportional to concentration of EGF in cell culture.  Conclusion: So far we can conclude that the upregulation of IFNAR1, NFκB, IFIT3, EFEMP1 and PLAU in L3.6pl is associated to a metastatic and angiogenic phenotype in pancreatic cancer. We have demonstrated that the EGF-homologous protein EFEMP1 binds to EGF-receptor and therefore might activate EGF-signalling and influence proliferation and metastasis of pancreatic cancer cells. (Supported by KFO128/1-1, TP3, Bruns DFG).
Gluconeogenic enzyme PCK1 deficiency promotes CHK2 O-GlcNAcylation and hepatocellular carcinoma growth upon glucose deprivation
Authors: Jin Xiang, Chang Chen, Rui Liu, Dongmei Gou, Lei Chang, Haijun Deng, Qingzhu Gao, Wanjun Zhang, Lin Tuo, Xuanming Pan, Li Liang, Jie Xia, Luyi Huang, Ke Yao, Bohong Wang, Zeping Hu, Ailong Huang, Kai Wang, Ni Tang
Journal: Journal of Clinical Investigation (2021)

Although cancer cells are frequently faced with a nutrient- and oxygen-poor microenvironment, elevated hexosamine-biosynthesis pathway (HBP) activity and protein O-GlcNAcylation (a nutrient sensor) contribute to rapid growth of tumor and are emerging hallmarks of cancer. Inhibiting O-GlcNAcylation could be a promising anticancer strategy. The gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) is downregulated in hepatocellular carcinoma (HCC). However, little is known about the potential role of PCK1 in enhanced HBP activity and HCC carcinogenesis under glucose-limited conditions. In this study, PCK1 knockout markedly enhanced the global O-GlcNAcylation levels under low-glucose conditions. Mechanistically, metabolic reprogramming in PCK1-loss hepatoma cells led to oxaloacetate accumulation and increased de novo uridine triphosphate synthesis contributing to uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis. Meanwhile, deletion of PCK1 also resulted in AMPK-GFAT1 axis inactivation, promoting UDP-GlcNAc synthesis for elevated O-GlcNAcylation. Notably, lower expression of PCK1 promoted CHK2 threonine 378 O-GlcNAcylation, counteracting its stability and dimer formation, increasing CHK2-dependent Rb phosphorylation and HCC cell proliferation. Moreover, aminooxyacetic acid hemihydrochloride and 6-diazo-5-oxo-L-norleucine blocked HBP-mediated O-GlcNAcylation and suppressed tumor progression in liver-specific Pck1-knockout mice. We reveal a link between PCK1 depletion and hyper-O-GlcNAcylation that underlies HCC oncogenesis and suggest therapeutic targets for HCC that act by inhibiting O-GlcNAcylation.
Five-Year Outcomes of PFO Closure or Antiplatelet Therapy for Cryptogenic Stroke
Authors: Scott E. Kasner, John F. Rhodes, Grethe Andersen, Helle K. Iversen, Jens E. Nielsen-Kudsk, Magnus Settergren, Christina Sjöstrand, Risto O. Roine, David Hildick-Smith, J. David Spence, Lars Søndergaard
Journal: New England Journal of Medicine (2021)

Extended 5-Year Follow-up of the PFO Closure Trial In the initial report of the Gore REDUCE trial of patent foramen ovale closure, with a median follow-up of 3.2 years, 18 patients had stroke recur...
School reopening without robust COVID-19 mitigation risks accelerating the pandemic
Authors: Deepti Gurdasani, Nisreen A Alwan, Trisha Greenhalgh, Zoë Hyde, Luke Johnson, Martin McKee, Susan Michie, Kimberly A Prather, Sarah D Rasmussen, Stephen Reicher, Paul Roderick, Hisham Ziauddeen
Journal: The Lancet (2021)
Combinatorial biomarkers to predict responses to immune checkpoint therapy in metastatic urothelial cancer.
Authors: Sangeeta Goswami, Yulong Chen, Swetha Anandhan, Peter M Szabo, Sreyashi Basu, Jorge M Blando, Wenbin Liu, Jan Zhang, Seanu Natarajan, Liangwen Xiong, Baoxiang Guan, Shalini Singh, Abdel Saci, James Patrick Allison, Matt D. Galsky, Padmanee Sharma
Journal: Journal of Clinical Oncology (2021)

488 Background: Immune checkpoint therapy can produce durable anti-tumor responses in metastatic urothelial carcinoma (mUCC); however, the responses are not universal. Despite multiple approvals of immune checkpoint therapy in mUCC, we lack predictive biomarkers to guide patient selection. Therefore, there is a critical need to develop clinically useful biomarkers to refine patient selection. The single biomarker studies either focused on tumor mutations or immune response biomarkers, which may limit predictive power due to lack of integration between cancer cell biology and immune cell responses. The identification of biomarkers may require interrogation of both the tumor mutational status and the immune microenvironment. Methods: We performed retrospective multi-platform immuno-genomic analyses of pre-treatment tumor tissues in a discovery cohort (n = 31). Next, we tested the clinical relevance of ARID1A mutation and pre-treatment CXCL13 expression in two independent confirmatory cohorts (CheckMate275 and IMvigor210). Additionally, we performed reverse translational studies using murine model of bladder cancer to demonstrate direct association of the biomarkers in anti-PD-(L)-1 mediated anti-tumor immunity. Results: We identified genomic mutation of AT-rich interactive domain-containing protein 1A ( ARID1A) in tumor cells and expression of immune cytokine CXCL13 in the pre-treatment tumor tissues as two predictors of clinical responses. We found that ARID1A mutation and expression of CXCL13 in the baseline tumor tissues correlated with improved overall survival (OS) in both confirmatory cohorts (CheckMate275, CXCL13 data, n = 217; ARID1A data, n = 139, and IMvigor210, CXCL13 data, n = 348; ARID1A data, n = 275). Further, reverse translational studies revealed that CXCL13 −/− tumor-bearing mice were resistant to immune checkpoint therapy whereas ARID1A knockdown enhanced sensitivity to immune checkpoint therapy in a murine model of bladder cancer. We then interrogated CXCL13 expression plus ARID1A mutation as a combination biomarker in predicting response to immune checkpoint therapy in CheckMate275 and IMvigor210. Combination of the 2 biomarkers in baseline tumor tissues showed improved OS compared to either single biomarker. Conclusions: Cumulatively, this study revealed that the combination of CXCL13 plus ARID1A mutation may improve patient selection in mUCC for immune checkpoint therapy.
Stereotactic radiotherapy and pembrolizumab for oligometastatic renal tumors: The RAPPORT trial.
Authors: Shankar Siva, Mathias Bressel, Simon Wood, Mark Shaw, Sherene Loi, Shahneen Kaur Sandhu, Ben Tran, Arun Azad, Jeremy Howard Lewin, Katharine Cuff, Nitika Neha, Duncan Colyer, Paul J. Neeson, Howard Liu, Sarat Chander, Daniel Moon, Jeremy Goad, Declan G. Murphy, Nathan Lawrentschuk, David Pryor
Journal: Journal of Clinical Oncology (2021)

277 Background: Pembrolizumab monotherapy, whilst not standard of care, has demonstrated efficacy in clear cell renal cell carcinoma (ccRCC). The first-line KEYNOTE-427 study demonstrated an overall response rate (ORR) of 34%, and a median progression-free survival (PFS) of 7.1 mo (McDermott D et al. J Clin Oncol 2020; 38:S15; 5069-5069). Stereotactic ablative body radiotherapy (SABR) is an option for oligometastatic ccRCC, but patients often develop distant progression or relapse within irradiated sites. The RAPPORT study (NCT02855203) was a multi-institutional single arm, phase I/II study evaluating safety and efficacy of SABR and pembrolizumab. Methods: Patients with up to 2 lines of prior systemic therapy with 1-5 oligometastases from ccRCC were eligible. A single fraction of 20Gy SABR to all metastatic sites was given (or 10 fractions of 3 Gy of conventional radiotherapy [CRT] if SABR was not feasible), followed by pembrolizumab 200mg administered Q3W for 8 cycles. The primary objective was safety (CTCAEv4.03), with secondary key objectives of efficacy (RECIST1.1) by disease control rate (DCR), defined as complete response (CR), partial response (PR) or stable disease for at least 6 months, ORR, PFS and overall survival (OS). Results: Thirty patients were enrolled and received protocol treatment. The median follow-up was was 2.3 years. The median age was 62 (range 47-80) years, 23 patients (77%) were male. Twenty-three patients (77%) were treatment naïve, 1 patient (3%) had a prior interleukin-2 therapy and 6 patients (20%) had a prior tyrosine kinase inhibitor. Nine patients (30%) had prior metastasectomy. Eighty-three oligometastases were treated (median of 3 per patient), of which 64 (77%) received SABR, and 19 (23%) received CRT. There were 8 adrenal, 11 bone, 43 lung, 12 lymph node and 9 soft tissue metastases irradiated. Four patients (13% [95%CI: 4-31%]) had one or more grade 3 treatment-related AE: Pneumonitis (n=2), dyspnoea (n=1) and elevated ALP/ALT (n=1). There were no grade 4 or 5 AEs. All eight cycles of pembrolizumab were completed by 24 (80%) patients. DCR was 83% (95%CI: 65-94%). ORRs are tabulated below. Median PFS was 15.6 mo. Estimated 1 and 2-year OS was 90% (95%CI: 72-97%) and 74% (95%CI: 53-87%), respectively, while PFS was 60% (95%CI: 40-75%) and 45% (95%CI: 27-62%), respectively. Freedom from local progression at 2-years was 92% (95%CI: 80-97%). Conclusions: The combination of SABR and pembrolizumab in oligometastatic renal cell carcinoma is well tolerated with excellent local control. Durable responses and encouraging PFS were observed with this approach, which warrants further investigation. Clinical trial information: NCT02855203 . [Table: see text]