tbuckley/cabot-search huggingface dataset:
Intratumoral TIGIT<sup>+</sup> CD8<sup>+</sup> T-cell infiltration determines poor prognosis and immune evasion in patients with muscle-invasive bladder cancer
Authors: Zhaopei Liu, Quan Zhou, Zewei Wang, Hongyu Zhang, Han Zeng, Qiuren Huang, Yifan Chen, Wenbin Jiang, Zhiyuan Lin, Yang Qu, Ying Xiong, Qi Bai, Yu Xia, Yiwei Wang, Li Liu, Yu Zhu, Le Xu, Bo Dai, Jianming Guo, Jiajun Wang, Yuan Chang, Weijuan Zhang
Journal: Journal for ImmunoTherapy of Cancer (2020)

T-cell immunoglobulin and ITIM domain (TIGIT) is identified as a novel checkpoint receptor that can facilitate immune escape via mediating T-cell exhaustion in tumors. However, the clinical significance and immune contexture correlation of intratumoral TIGIT+ CD8+ T-cells remain to be further explored in muscle-invasive bladder cancer (MIBC).259 patients with MIBC from two clinical centers (Zhongshan Hospital, n=141; Shanghai Cancer Center, n=118) were analyzed to evaluate the prognostic value and immune contexture association of TIGIT+ CD8+ T-cells through immunohistochemistry. Fresh tumor tissue samples from 26 patients with MIBC were examined to discover the phenotype of this CD8 subpopulation by flow cytometry.High infiltration of intratumoral TIGIT+ CD8+ T-cells predicted poor overall survival (OS) and recurrence-free survival (RFS) in MIBC. For patients with stage II MIBC with low infiltration of TIGIT+ CD8+ cells, adjuvant chemotherapy (ACT) could significantly prolong their OS and RFS. Intratumoral TIGIT+ CD8+ T-cell abundance was correlated with impaired CD8+ T-cell cytotoxicity and exhibited production of immunosuppressive cytokine IL-10. Further analysis of tumor-infiltrating immune cell landscape revealed TIGIT+ CD8+ T-cells were associated with suppressive immune contexture, including Th2 cells, regulatory T-cells, mast cells and neutrophils.Intratumoral TIGIT+ CD8+ T-cell abundance could serve as an independent prognosticator for clinical outcome and a predictive biomarker for inferior ACT responsiveness. Intratumoral TIGIT+ CD8+ T-cell abundance correlated with dampened CD8+ T-cell antitumor immunity and immunosuppressive contexture abundance, highlighting a tumor-promoting role of TIGIT+ CD8+ T-cells.
Re: Andrew Vickers, Sigrid V. Carlsson, Matthew Cooperberg. Routine Use of Magnetic Resonance Imaging for Early Detection of Prostate Cancer Is Not Justified by the Clinical Trial Evidence. Eur Urol 2020;78:304–6
Authors: Roderick C.N. van den Bergh, Olivier Rouvière, Theodorus van der Kwast, Erik Briers, Thomas Van den Broeck, Philip Cornford, Marcus G. Cumberbatch, Maria De Santis, Stefano Fanti, Nicola Fossati, Giorgio Gandaglia, Nikolaos Grivas, Jeremy Grummet, Thomas B. Lam, Michael Lardas, Matthew Liew, Lisa Moris, Malcolm D. Mason, Nicolas Mottet, Daniela E. Oprea-Lager, Guillaume Ploussard, Ivo G. Schoots, Derya Tilki, Henk G. van der Poel, Thomas Wiegel, Peter-Paul M. Willemse
Journal: European Urology (2020)
Abstract A09: Photoimmunotherapy (PIT) for treatment of bladder cancer
Authors: Reema Railkar, Mohammad Rashid Siddiqui, Thomas Sanford, Hisataka Kobayashi, Peter L. Choyke, Piyush K. Agarwal
Journal: Clinical Cancer Research (2020)

Abstract Introduction: The use of light as a means of therapy for bladder cancer (BC) has a long history but has been hampered by a lack of tumor specificity and therefore, damage to the normal bladder mucosa. Here, we describe a targeted form of phototherapy called photoimmunotherapy (PIT). To begin with, anti-EGFR antibody panitumumab (pan) was labeled with the photo-absorber (PA), IRDye 700Dx (IR700), to create pan IR700, an antibody-PA conjugate that is activated by near-infrared radiation (NIR). However, PIT may be less effective when a tumor lacks “overwhelming” expression of a single target such as EGFR. Hence, a combinatorial PIT approach for targeting BC expressing EGFR and HER2, using PA-labeled pan and trastuzumab (tra), respectively. Methods: Human BC tissue microarray (TMAs) and BC cell lines were analyzed for expression of EGFR and HER2. Mechanism of PIT-induced cell death was studied using proliferation assays, transmission electron microscopy (TEM), and production of reactive and singlet oxygen species (ROS/SOS). Finally, efficacy of PA-labeled antibodies singly and in combination was analyzed in vitro and in vivo. Results: Most BC tissues have some expression of EGFR, but squamous cell carcinoma (SCC) of bladder has maximum EGFR expression. About 45% of BC tissues stain for both EGFR and HER2. Pan IR700 activated by NIR light rapidly killed UMUC-5 cells, a bladder SCC line. Pan alone, pan IR700 without NIR, or NIR alone had no effect on cells. TEM demonstrated that cell death is due to necrosis. Singlet oxygen species (SOS) had a substantially larger contribution towards cell death than reactive oxygen species (ROS). NIR-PIT with pan IR700 demonstrated reduced growth compared to only pan IR700-treated UMUC-5 xenograft tumors. In non-SCC BCs we used a combinatorial PIT approach using pan IR700 and tra IR700 to target EGFR and HER2, respectively. In vitro, PIT in the presence of combination pan IR700 and tra IR700 was more efficacious than either agent alone with lethal dose 50 (LD50) of 28.66 J/cm2 for combination PIT compared to 71.55 J/cm2 for the PanIR700 alone. In vivo, tumor xenografts treated with combination PIT showed significant tumor growth retardation compared to single-agent therapy. Conclusion: PIT is a new targeted treatment for BC. Our data demonstrate that pan IR700-induced PIT selectively kills EGFR-expressing bladder cancer. Combination PIT is a promising approach for treating BC by selectively inducing death in BC cells with low/moderate expression of surface receptors. Citation Format: Reema Railkar, Mohammad Rashid Siddiqui, Thomas Sanford, Hisataka Kobayashi, Peter L. Choyke, Piyush K. Agarwal. Photoimmunotherapy (PIT) for treatment of bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A09.
A cocktail of antibodies for COVID-19 therapy
Authors: Dean B. Matthews
Journal: Nature reviews. Immunology (2020)

role of HDAC3 as a transcriptional repressor.A machine-learning approach revealed DNA sequences associated with DA-independent and DA-dependent genomic regions bound by HDAC3 that could predict transcriptional outcome.In particular, binding of the co-factor ATF2 was associated with DA-independent sites whereas ATF3 binding was associated with DA-dependent sites.In keeping with this, LPS stimulated the transcription of a DA-independent reporter gene containing the ATF2 motif in the presence of ATF2 and inactive HDAC3, whereas LPS-mediated repression of a DA-dependent reporter gene with
New-Onset Type 1 Diabetes in Children During COVID-19: Multicenter Regional Findings in the U.K.
Authors: Rebecca Unsworth, Susan Wallace, Nick S. Oliver, Shunmay Yeung, Archana Kshirsagar, Harshini Naidu, Ruth Min Wai Kwong, Priya Kumar, Karen M. Logan
Journal: Diabetes Care (2020)

Data on new-onset type 1 diabetes during the coronavirus disease 2019 (COVID-19) pandemic, particularly in children, are limited. A recent U.S. multicenter study reported outcomes in 64 adults and children with type 1 diabetes, and confirmed or suspected COVID-19. However, only six patients presented with new-onset type 1 diabetes (1).

We report multicenter regional data from North West London (NWL) of new-onset type 1 diabetes and diabetic ketoacidosis (DKA) in children up to the age of 16 years during the peak of the COVID-19 pandemic. We collected data from five inpatient units (four National Health Service [NHS] Trusts) comprising the NWL Pediatric Diabetes Network between 23 March (coinciding with the commencement of the U.K. Government lockdown) and 4 June 2020.

Thirty children aged 23 months to 16.8 years presented with new-onset type 1 diabetes (Table 1). We observed an apparent increase in two units, with 10 cases each (versus typically 2 and 4 cases, respectively, for April/May combined in the previous 5 years). Rates in the other three units were similar to previous years. A high proportion of children (21/30, 70%) presented with DKA, …
Abstract 10626: Temporal Changes in Statin Prescription, Intensity at Discharge, and Impact on Outcomes in Patients With Newly Diagnosed Atherosclerotic Peripheral Arterial Disease (PAD). A Real-World Experience Within a Large Integrated Health Care System: The IMPRES Study
Authors: Jeffrey L Anderson, Kirk U Knowlton, Heidi T May, Tami L Bair, Viet T Le, Donald L Lappe, Joseph B Muhlestein
Journal: Circulation (2019)

Introduction: Statins are indicated for atherosclerotic cardiovascular disease (ASCVD) with high intensity dosing generally recommended. At both highest risk for ASCVD and treatment benefit are pat...
Abstract 6378: CDC20 is a novel therapeutic target in triple-negative breast cancer
Authors: Jayesh K. Sharma, Prasanna Alluri, Nashir Udden
Journal: Cancer Research (2020)

Abstract Background: Approximately 15% of breast cancers lack expression of Estrogen Receptor (ER), Progesterone Receptor (PR) and Human Epidermal Growth Factor Receptor 2 (HER-2), and are referred to as Triple-Negative Breast Cancer (TNBC). Due to a lack of targeted therapies, clinical outcomes in patients with TNBC continue to be poor. Likewise, due to the inherently aggressive biology of the disease, patients are forced to deal with the toughest breast cancer while having the least treatment options. In this study, we identified Cell Division Cycle protein 20 (CDC20), a key regulatory protein that mediates sister chromatid separation in mitosis, as a novel therapeutic target in TNBC. Methods: To uncover new drivers of TNBC, we nominated genes that are significantly overexpressed in patients with TNBC, compared to non-TNBCs. After identifying CDC20 as a top hit in this analysis, we used RNAseq analyses, expression microarrays, and Western blotting to assess CDC20 expression levels in breast cancer patients and cell lines. Kaplan-Meier analyses were formed to study the correlation between clinical outcomes and CDC20 expression levels, including recurrence-free survival, metastasis-free survival and overall survival. shRNA and siRNA-mediated knockdown of CDC20 in TNBC cell lines were employed to study the role of CDC20 in TNBC proliferation, invasion, and migration. Results: CDC20 was significantly overexpressed in TNBCs (compared to non-TNBCs) patients and is a predictor of poor clinical outcomes and radiation resistance. CDC20 expression was also significantly higher in TNBC cell lines compared to non-TNBC cell lines, reflecting what is seen in clinical data sets, such as in The Cancer Genome Atlas. Sh and siRNA-mediated knockdown of CDC20 expression resulted in decreased proliferation, invasion and migration in TNBC cell lines. Conclusions and future directions: Our findings support the development of pharmacologic strategies to inhibit CDC20 function as a potential targeted therapy against TNBC. Efforts are underway to validate our findings in vivo in xenograft models of TNBC in mice. Citation Format: Jayesh K. Sharma, Prasanna Alluri, Nashir Udden. CDC20 is a novel therapeutic target in triple-negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6378.
AB0638 THE EFFECT OF VITAMIN D ON QUALITY OF LIFE AND SEVERITY OF PAIN IN PATIENTS WITH ANKYLOSING SPONDYLITE
Authors: E. Komarova, I. Blaginina, N. Bludova, P. Bakhtoyarov, I. Pokryshka
Journal: Annals of the Rheumatic Diseases (2020)

Background: The high incidence of ankylosing spondylite (AS) in people of working age, as well as the negative impact of the disease on the quality of life of patients, determine the need for adjuvants to reduce the severity of pain and thereby achieve the physical, psychological and emotional well-being of patients. Objectives: To study the effect of vitamin D (colecalciferol) on the quality of life and the severity of pain in patients with ankylosing spondylite. Methods: The study included 69 patients with AS, who studied the quality of life indicators according to the Medical Outcomes Study Short Form (SF-36); pain syndrome and stiffness in the spine were assessed by a visual analogue scale by patients, and by a physician - by counting the number of painful joints (NPJ), the disease activity index (BASDAI) and the Functional Index (BASFI). All patients were receiving a basic therapy in a stable dose for at least 10 months. They were divided into 2 groups, comparable in age, disease activity; Group 1 (n = 33) additionally received colecalciferol 1500 МЕ during 6 months of observation. Results: At the end of the observation period when evaluating data on SF-36: in the 1st group, the physical health component has improved - the increase in physical functioning (PF) and bodily pain (BP) by 51.4% and 37.8% from the baseline; vital activity, psychological health, and social functioning due to emotional state have also increased by 37.6%, 33.4% and 42.5%, respectively. In the 2nd group above mentioned parameters have not changed. In the 1st group the indexes of BASDAI and BASFI have decreased by 16% and 22% (p = 0.0079, p = 0.0022, respectively), and their dynamics in the 2nd group were less significant (p = 0.013, p = 0.017, respectively) Also, in patients of the 1st group have decreased the severity of morning stiffness and the pain in the spine a highly reliable (p &lt; 0.001), and in the 2nd group they were less significant (p = 0.043, p = 0.016, respectively). Positive dynamics of NPJ in the 1st group was more significant (p = 0.003) than it was in the 2nd group (p = 0.033). Conclusion: In the group of patients treated with colecalciferol was noted improvement in indicators of quality of life (the parameters of the physical component of health, vitality and social functioning) and also more significant decrease of the intensity of pain and of morning stiffness duration, of NPJ, than in not received to colecalciferol patients. Inclusion of vitamin D in the comprehensive AS therapy promotes not only reduction the severity of the chronic pain manifestations, but also improves the quality of life of patients with this pathology. Disclosure of Interests: None declared
Abstract A27: Fidelity of a PDX-CR model for bladder cancer
Authors: Abdul M. Mondal, Ai-Hong Ma, Guangzhao Li, Ewa Krawczyk, Lu Jie, Richard Schlegel, Chong-Xian Pan, Xuefeng Liu
Journal: Clinical Cancer Research (2020)

Abstract Current efforts for cancer drug discovery have predominantly been deterred by the lack of appropriate preclinical cancer models that recapitulate the characteristics of this complex disease. Patient-derived xenografts (PDXs) are widely recognized as a more physiologically relevant preclinical model than organoids and standard cell lines, and often resemble the original tumor histology, genetic profile, and gene-expression patterns. Despite these benefits, PDX models are limited by their variable engraftment rate, lack of sustained growth in vitro, low throughput for drug screening, lower amenability to experimental manipulation, and high cost. In this study, we utilized conditional reprogramming (CR) technology to generate four CR cell (CRC) lines from bladder cancer PDXs. The CR cells were then employed to evaluate the genetic status and drug sensitivity and compared with the parental PDX tumors. All the established CRC lines maintained parental mutations and allele frequencies without clonal drift. Moreover, the drug responses of the parental PDX tumors in vivo were retained in the established CRC lines in vitro. Altogether, CR technology offers the ability to generate cell lines and expand PDX cells without compromising fundamental biologic properties of the model, thereby allowing for in vitro use to reduce animal usage, variability, and study cost. Perhaps more importantly, the CR cell lines established here can be used for personalized high-throughput drug screening as well as for studying drug-resistance mechanisms. Citation Format: Abdul M. Mondal, Ai-Hong Ma, Guangzhao Li, Ewa Krawczyk, Lu Jie, Richard Schlegel, Chong-Xian Pan, Xuefeng Liu. Fidelity of a PDX-CR model for bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A27.
Abstract 16937: Incidence of New Onset Atrial Fibrillation in Lung Cancer Patients
Authors: Bharat Marwaha, Jay Shah, Khalid Changal, Maen Al Dabbas, Zainulabedin A Waqar, Heminder Singh, Mohammad Taleb
Journal: Circulation (2018)

Introduction: Atrial fibrillation (Afib) is the most common sustained arrhythmia with prevalence of 5.2 million cases and predicted up to 12.1 million cases in United States by 2030. Recent studies have reported higher incidence of Afib among cancer patients with multiple confounding factors. Hypothesis: It is postulated that inflammation is a common denominator for both cancer patients and Afib. Afib may represent inflammatory complication of cancer and correlate with disease burden of lung cancer. Methods: Retrospective study. Included were adult (&gt;18 years) newly diagnosed lung cancer patients admitted to 3 Mercy hospitals in the Toledo, Ohio area between May 1, 2013 and December 31st, 2016. Excluded were patients with history of A fib (out of window period), severe MR and MS. N ew onset of A fib was defined by new onset paroxysmal or persistent A fib rhythm on 12 lead EKG or rhythm strip diagnosed 6 months before or after the new diagnosis of the lung cancer. Results: One hundred sixty newly diagnosed lung cancer patients were included in the study. Of these 160 patients, 37 had new onset A fib (23%, 95% CI: 17% to 30%) and 53 (38%) died within 1 year. Among the A fib patients 4 (11%) had stage 1 cancer, 7 (19%) stage 2, 7 (19%) stage 3 and 17 (46%) stage 4 (2 missing data). Ten of the A fib patients had systolic CHF. Conclusions: Our data suggests that about one quarter of newly diagnosed lung cancer patients also have new onset A fib.The incidence of A fib may be higher but is not picked up on routine EKG because of paroxysmal nature. Future studies need to address potential correlation between A fib and pathological type, stage of lung cancer and the role of regular screening for A fib in cancer patients.
AB0229 Influence of rheumatologist in primary care
Authors: MC García Gómez, C Galisteo, MP Lisbona, M Sanmartí, M Castellanos, N Navarro, C Alegre
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To study if there are differences between the type and frequency of pathologies visited in a surgery of rheumatology hospital before and after the presence of rheumatologist in primary care (PC). <h3>Methods</h3> Descriptive and retrospective study in the urban medium from Barcelona. We revised the historial clinic from first six months period in 1995 (without rheumatologist in PC) and 2000 (when the rheumatologist goes once per week to the primary care centre). We analysed the variables age, sex and principal diagnosis from all the first visits attended. We assembled the diagnosis in 10 groups: infectious arthritis (1), connective tissue disorders (2), crystal-related arthropathies (3), inflammatories arhropaties (4), osteoarthritis and related disorders (5), regional pain problems and soft tissue (6), muscular diseases (7), tumours and paraneoplastic syndromes in the musculoskeletal system (9) and others pathologies (10). For the statistic test we use the chi-squared test to contrast of proportions and the Fisher´s exact test when the expected effectives were lower than 5. <h3>Results</h3> In 1995 we have done 779 first visits (with 2.3% of loses the fact is not to have the historial clinic) and from 2000, 411 (11% of loses caused by the same matter). In 1995 the average age was 55 years (3–86), the distribution per sex was: 185 men (24%) and 594 women (76%), and per pathology: group 1, 2(0.2%), group 2, 45 (5.72%), group 3, 18(2.3%), group 4, 23 (2.9%), group 5, 453(58.1%), group 6, 152(19.5%), group 7, 1(0.12%), group 8, 55(7%), group 9, 4(0.5%), group 10, 26(3.3%). In 2000 the average age was 55 years (5–87), the distribution per sex was:126 men (30%) and 285 women (70%), and per pathology: group 1, 1(0.2%), group 2, 38(9.2%), group 3, 14 (3.4%), group 4,21 (5.1%), group 5, 200 (48.6%), group 6 89 (21.6%), group 7, 0, group 8, 31(7.5%), group 9, 3 (0.73%), group 10, 14(3.4%). We found significant difference between both years in the groups 2 (p = 0.025) and 5 (p = 0.0002). <h3>Conclusion</h3> The total numbers of first visits in the hospital done in 2000 were half less than in 1995 (above all in degeneration pahology), without being geographic and demographic variations. The incorporation of the rheumatologist in PC would improve the quality assistance in the hospital and also allow an early diagnosis from many rheumatic illness that would benefit from it.
The mechanism by which prostate specific membrane antigen (PSMA) may induce prostate carcinogenesis and growth
Authors: Veronica Yao, Dean J. Bacich
Journal: Cancer Research (2005)

3940   Prostate specific membrane antigen (PSMA) is of intense interest as a prostate cancer marker and for its potential as a diagnostic and therapeutic target in humans. This protein is a type II transmembrane glycoprotein that is predominantly expressed in prostate cancers, whereas normal and benign prostate tissues mainly express a shorter alternatively spliced variant, designated PSM’. Mice that express human PSMA in their prostates have been shown to develop precancerous lesions whereas mice that express human PSM’ do not develop such lesions. PSMA has a unique folate hydrolase activity whereas PSM’ exists in the cell cytoplasm and has no enzymatic activity. These findings suggest that PSMA plays a role in prostate carcinogenesis and that the enzymatic activity and/or the extracellular location of PSMA are important. A mechanism by which PSMA might be involved in prostate carcinogenesis is via its folate hydrolase activity. It is thought that this membrane folate hydrolase could give prostate cancer cells expressing PSMA a growth advantage in a low folate tumor microenvironment by allowing these cells to capture extracellular folates and deglutamate poly-γ-glutamated folates released by surrounding dead and dying cells. Folate taken up by these cells is an essential nutrient for growth and replication. Other researchers who have investigated if PSMA confers a growth advantage have found no such effect. However, their studies were flawed as they were carried out in standard tissue culture media which contain folate at a concentration 100 times greater than the folate concentration in human sera. The purpose of this study was firstly to examine whether PSMA gives a human prostate cancer cell line expressing PSMA a growth advantage in physiologically relevant folate level in the presence of poly-γ-glutamated folates. Secondly, by using a folate hydrolase inhibitor we examined if the folate hydrolase activity of PSMA is the mechanism by which it give cells a growth advantage. The proliferation rates of LNCaP and DU-145 cells were assessed when grown in RPMI 1640 media containing either low ( in vitro , PSMA expression confers a growth advantage in  physiological  folate level in the presence of penta-γ-glutamated folate via the folate hydrolase activity of PSMA. This study will provide a better understanding of the molecular events that underlie prostate carcinogenesis which may be useful in designing therapies that target PSMA.