tbuckley/cabot-search huggingface dataset:
Modes of Regulated Cell Death in Cancer
Authors: Elle Koren, Yaron Fuchs
Journal: Cancer Discovery (2021)

Cell suicide pathways, termed regulated cell death (RCD), play a critical role in organismal development, homeostasis, and pathogenesis. Here, we provide an overview of key RCD modalities, namely apoptosis, entosis, necroptosis, pyroptosis, and ferroptosis. We explore how various RCD modules serve as a defense mechanism against the emergence of cancer as well as the manner in which they can be exploited to drive oncogenesis. Furthermore, we outline current therapeutic agents that activate RCD and consider novel RCD-based strategies for tumor elimination. SIGNIFICANCE: A variety of antitumor therapeutics eliminate cancer cells by harnessing the devastating potential of cellular suicide pathways, emphasizing the critical importance of RCD in battling cancer. This review supplies a mechanistic perspective of distinct RCD modalities and explores the important role they play in tumorigenesis. We discuss how RCD modules serve as a double-edged sword as well as novel approaches aimed at selectively manipulating RCD for tumor eradication.
Access to innovative cancer medicines in gastrointestinal oncology: 2010 through 2020.
Authors: David Edward O Reilly, Ronan Andrew McLaughlin, Cian Ronayne, Anne-Marie DeFrein, Bojan Macanovic, Richard Martin Bambury, Derek Gerard Power, Seamus O'Reilly, Dearbhaile Catherine Collins
Journal: Journal of Clinical Oncology (2021)

469 Background: There are significant disparities in patient access to innovative cancer medicines internationally. We sought to describe global drug licensing developments in gastrointestinal (GI) oncology from 2010 – 2020. We compared US, European, UK and Irish patient access to these drugs, their cost and associated efficacy. Methods: Data was collected from public sources online including the FDA, European Medicines Agency (EMA), the UK National Institute of Clinical Excellence (NICE) and the Irish National Cancer Control Programme (NCCP). Anti-cancer compounds approved for GI malignancies between January 1, 2010 and September 1, 2020 were recorded. Approval publications and updated survival analysis outcomes were included to assess for demonstrable overall survival (OS) and/or progression free survival (PFS) benefit. Results: There were 26 regimens approved by the FDA for GI malignancies between 2010 and 2020. Slightly over half (n=15, 57.7%) of these regimens were approved by the EMA. The median time from FDA to EMA approval was 3 months (mo) +/- 5 mo. Only a small minority of these regimens were funded for patients in the UK (including the Cancer Drugs Fund, 9 regimens, 31%) or Ireland (IRL) (7 regimens, 27%). The median time from EMA approval to patient access was short in both of these countries (3.5 mo (UK) and 0.5 m (IRL)). However, the range in these countries was large (2 - 73 mo (UK) &amp; 0-24 mo (IRL)). More than half of regimens (15, 57.7%) demonstrated an OS benefit. Of the remaining 11 regimens, a further 6 drugs (23%) demonstrated a PFS benefit. The median OS benefit (if present) was 2.3 mo +/- 3 mo. The median price of these regimens in the USA (list price) was $13,758 per month +/- $5,152. Regimens which demonstrated an OS benefit were not more expensive than those that did not (median $13,065 versus $13,758 respectively, p &lt; 0.05). For regimens with an OS benefit, there was no statistically significant correlation between the length of OS benefit and drug cost (Pearson’s correlation = 0.32, p = 0.07). Conclusions: Less than one third of patients in the UK and Ireland have access to medicines approved by the FDA for GI malignancies between 2010 – 2020. Overall survival benefits are often modest, or absent. The cost of regimens in the USA commonly exceeds $100,000/year irrespective of OS benefit. Our work highlights the necessity to develop a value based-pricing system in GI oncology.
Incidence of and Risk Factors for Colorectal Strictures in Ulcerative Colitis: A Multicenter Study
Authors: Pierre-Antoine Laurain, Lucas Guillo, Ferdinando D’Amico, Patrick Netter, Silvio Danese, Cédric Baumann, Amandine Luc, Isabelle Clerc-Urmes, Spyridon Sofos, Laurent Peyrin-Biroulet
Journal: Clinical Gastroenterology and Hepatology (2021)
OP0051 Synovitis predicts the arthroscopic progression of medial tibiofemoral knee osteoarthritis (oa)
Authors: X Ayral, EH Pickering, TG Woodworth, N Mackillop, L Loose, M Dougados
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To evaluate the prevalence of synovitis in painful medial tibiofemoral knee OA and to evaluate correlations between such synovitis and the structural severity of medial knee OA. <h3>Methods</h3> Multicenter, prospective, one year duration study; primary painful knee OA (ACR criteria) of the medial compartment; medial joint space width &gt; or = 2 mm; at least 10% of one cartilage surface of the medial compartment affected by superficial fibrillation or worse. Arthroscopy under local anaesthesia performed and videorecorded at entry and after one year; medial chondropathy scored by using SFA score (0–100) and reader's overall assessment (VAS score 100 mm); medial perimeniscal synovial scored as normal (few villi, fine vascular network), reactive (proliferation of opaque villi), inflammatory (hypervascularization and/or proliferation of hypertrophic and hyperemic villi). Progression of medial chondropathy defined by an increase in SFA and VAS scores of at least 4.5 and 8.0 after one year, respectively, as previously reported;<sup>1</sup> assessment of severity of chondropathy by a single reader blind to chronology of paired videotapes. <h3>Results</h3> 506 patients were enrolled and 498 completed the one year longitudinal study (mean age: 61.2 ± 7.7 years, female sex: 58.9%, BMI: 30.4 ± 4.7, mean disease duration: 3.8 ± 2.9 years). The Table 1 summarises cross-sectional and longitudinal correlations between synovitis and chondropathy. <h3>Conclusion</h3> This study suggests that synovitis is a common feature of painful knee OA, associated with more severe chondropathy, but it also suggests that synovitis could be considered as a predictive factor of subsequent chondrolysis. <h3>Reference</h3> Ayral X, <i>et al</i>. Arthroscopic evaluation of chondropathy in osteoarthritis of the knee. J Rheumatol. 1996;23:698–706
Building the European Antimicrobial Resistance Surveillance network in veterinary medicine (EARS-Vet)
Authors: Rodolphe Mader, Peter Damborg, Jean-Philippe Amat, Björn Bengtsson, Clémence Bourély, Els M Broens, Luca Busani, Paloma Crespo-Robledo, Maria-Eleni Filippitzi, William Fitzgerald, Heike Kaspar, Cristina Muñoz Madero, Madelaine Norström, Suvi Nykäsenoja, Karl Pedersen, Lucie Pokludova, Anne Margrete Urdahl, Alkiviadis Vatopoulos, Christos Zafeiridis, Jean-Yves Madec
Journal: Eurosurveillance (2021)

Antimicrobial resistance (AMR) should be tackled through a One Health approach, as stated in the World Health Organization Global Action Plan on AMR. We describe the landscape of AMR surveillance in the European Union/European Economic Area (EU/EEA) and underline a gap regarding veterinary medicine. Current AMR surveillance efforts are of limited help to veterinary practitioners and policymakers seeking to improve antimicrobial stewardship in animal health. We propose to establish the European Antimicrobial Resistance Surveillance network in Veterinary medicine (EARS-Vet) to report on the AMR situation, follow AMR trends and detect emerging AMR in selected bacterial pathogens of animals. This information could be useful to advise policymakers, explore efficacy of interventions, support antimicrobial stewardship initiatives, (re-)evaluate marketing authorisations of antimicrobials, generate epidemiological cut-off values, assess risk of zoonotic AMR transmission and evaluate the burden of AMR in animal health. EARS-Vet could be integrated with other AMR monitoring systems in the animal and medical sectors to ensure a One Health approach. Herein, we present a strategy to establish EARS-Vet as a network of national surveillance systems and highlight challenges of data harmonisation and bias. Strong political commitment at national and EU/EEA levels is required for the success of EARS-Vet.
Abstract 15654: The Hypoxia-induced Long Non-coding RNA Hyp_up_3 Regulates Alternative Splicing and Controls Angiogenesis of Endothelial Cells
Authors: Philipp Neumann, Youssef Fouani, Nicolas Jaé, Andrea Knau, David John, Shizuka Uchida, Juliana Heidler, Ilka Wittig, Stefanie Dimmeler
Journal: Circulation (2016)

RNA deep sequencing revealed that the human genome is pervasively transcribed, however, the vast majority are non-coding transcripts and belong to the class of long non-coding RNAs (lncRNAs). LncRN...
Nanoparticle T-cell engagers as a modular platform for cancer immunotherapy
Authors: Kinan Alhallak, Jennifer Sun, Katherine Wasden, Nicole Guenthner, Julie O’Neal, Barbara Muz, Justin King, Daniel Kohnen, Ravi Vij, Samuel Achilefu, John F. DiPersio, Abdel Kareem Azab
Journal: Leukemia (2021)

T-cell-based immunotherapy, such as CAR-T cells and bispecific T-cell engagers (BiTEs), has shown promising clinical outcomes in many cancers; however, these therapies have significant limitations, such as poor pharmacokinetics and the ability to target only one antigen on the cancer cells. In multiclonal diseases, these therapies confer the development of antigen-less clones, causing tumor escape and relapse. In this study, we developed nanoparticle-based bispecific T-cell engagers (nanoBiTEs), which are liposomes decorated with anti-CD3 monoclonal antibodies (mAbs) targeting T cells, and mAbs targeting the cancer antigen. We also developed a nanoparticle that targets multiple cancer antigens by conjugating multiple mAbs against multiple cancer antigens for T-cell engagement (nanoMuTEs). NanoBiTEs and nanoMuTEs have a long half-life of about 60 h, which enables once-a-week administration instead of continuous infusion, while maintaining efficacy in vitro and in vivo. NanoMuTEs targeting multiple cancer antigens showed greater efficacy in myeloma cells in vitro and in vivo, compared to nanoBiTEs targeting only one cancer antigen. Unlike nanoBiTEs, treatment with nanoMuTEs did not cause downregulation (or loss) of a single antigen, and prevented the development of antigen-less tumor escape. Our nanoparticle-based immuno-engaging technology provides a solution for the major limitations of current immunotherapy technologies.
Differential gene expression patterns in HER2 positive metastatic breast cancer patients according to hormone receptor status
Authors: C. Omarini, S. Kaleci, G. Guaitoli, S. Bettelli, C. Caprera, S. Manfredini, F. Caggia, M.C. Baschieri, L. Moscetti, A. Maiorana, S. Cascinu, F. Piacentini
Journal: Annals of Oncology (2017)
The Membrane Interactions of Synuclein: Physiology and Pathology
Authors: Gautam Runwal, Robert H. Edwards
Journal: Annual Review of Pathology Mechanisms of Disease (2021)

Specific proteins accumulate in neurodegenerative disease, and human genetics has indicated a causative role for many. In most cases, however, the mechanisms remain poorly understood. Degeneration is thought to involve a gain of abnormal function, although we do not know the normal function of many proteins implicated. The protein α-synuclein accumulates in the Lewy pathology of Parkinson's disease and related disorders, and mutations in α-synuclein cause degeneration, but we have not known its normal function or how it triggers disease. α-Synuclein localizes to presynaptic boutons and interacts with membranes in vitro. Overexpression slows synaptic vesicle exocytosis, and recent data suggest a normal role for the endogenous synucleins in dilation of the exocytic fusion pore. Disrupted membranes also appear surprisingly prominent in Lewy pathology. Synuclein thus interacts with membranes under both physiological and pathological conditions, suggesting that the normal function of synuclein may illuminate its role in degeneration.
AB0003 Lack of association between rheumatoid arthritis and vitamin d receptor polymorphisms in koreans
Authors: J Choe, CG Kim, YH Song, SG Kim, CH Jeon, OD Kim
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To determine whether 1) the frequency of vitamin D receptor (VDR) polymorphisms in the rheumatoid arthritis (RA) patient group is different from that of the control group; and 2) there is a relationship between VDR genotypes vs the radiographic severity of RA and bone mineral density (BMD) in RA patients in Korea. <h3>Methods</h3> The VDR genotype was determined by using polymerase chain reaction and by digestion with three restriction enzymes<i> Taq I</i> and <i>Bsm I</i> in elderly female controls (n = 78) and RA patients (n = 97). Hand X-rays were scored by Larsen's method and femoral neck BMD was measured by dual energy X-ray absorptiometry in RA patients. <h3>Results</h3> VDR genotypic distributions in Koreans were much different from those of Caucasians in both the control and RA group. In particular, "tt" and "BB" alleles were very rare, unlike the distribution in Caucasian population. No significant differences in VDR genotypic frequency were observed between the control group and the RA group. In addition, no significant relationship was found between the VDR genotypes and radiographic scores of RA, nor between the VDR genotypes and BMD in RA patients. <h3>Conclusion</h3> The distribution of VDR polymorphisms in RA patients is not different from that of the controls. The VDR polymorphisms do not significantly correlate with the radiographic severity of RA, nor with BMD in Korean RA patients.
Extracorporeal Membrane Oxygenation and Coronavirus Disease 2019
Authors: Kiran Shekar, Elliott Worku, Daniel Brodie
Journal: JAMA Surgery (2021)

Asif K. Mustafa, MD, PhD; Philip J. Alexander, MD; Devang J. Joshi, MD; Deborah R. Tabachnick, MD; Chadrick A. Cross, MD; Pat S. Pappas, MD; Antone J. Tatooles, MD
Immunity against diphtheria among children aged 5–17 years in India, 2017–18: a cross-sectional, population-based serosurvey
Authors: Manoj V Murhekar, Pattabi Kamaraj, Muthusamy Santhosh Kumar, Siraj Ahmed Khan, Ramesh Reddy Allam, Pradip V Barde, Bhagirathi Dwibedi, Suman Kanungo, Uday Mohan, Suman Sundar Mohanty, Subarna Roy, Vivek Sagar, Deepali Savargaonkar, Babasaheb V Tandale, Roshan Kamal Topno, C P Girish Kumar, Ramasamy Sabarinathan, Sailaja Bitragunta, Gagandeep Singh Grover, P V M Lakshmi, Chandra Mauli Mishra, Provash Sadhukhan, Prakash Kumar Sahoo, Shivendra Kumar Singh, Chander Prakash Yadav, Rajesh Kumar, Shanta Dutta, G S Toteja, Nivedita Gupta, Sanjay M Mehendale, T Karunakaran, C Govindhasamy, T Daniel Rajasekar, A Jeyakumar, A Suresh, D Augustine, P Ashok Kumar, Annamma Jose, R Sivakumar, JW Banerjee John
Journal: The Lancet Infectious Diseases (2021)
Abstract 13244: Is Early Statin Treatment Justified Before Formation of Atherosclerotic Plaques?
Authors: Yuxin Li, Akira Onishi, Mitsumasa Sudo, Hironori Haruta, Qing-Fei Lin, Tadateru Takayama, Shunichi Suzuki, Daiichiro Fuchimoto, Shoichiro Sembon, Masaki Iwamoto, Michiko Hashimoto, Shunichi Yoda, Satoshi Kunimoto, Takafumi Hiro, Taro Matsumoto, Masako Mitsumata, Masahiko Sugitani, Satoshi Saito, Atsushi Hirayama
Journal: Circulation (2015)

Objective: Although statin is recommended for secondary prevention of acute coronary syndrome regardless of the baseline LDL-cholesterol level, statin administration in the pre-intervention phase has not been established as a routine strategy because of lack of sufficient evidence. We conducted an animal study comparing the results of early statin administration vs. no such administration in pigs susceptible to atherosclerosis. Methods and Results: Three-month-old LDL receptor knockout (LDLR-/-) pigs with no atherosclerosis were divided into two groups: those fed an atherosclerotic diet consisting of 15% fat and 1.5% cholesterol for 4 months (control group) and those fed the same diet but given oral pitavastatin (40 mg/day) (early treatment group). Human-like unstable plaques developed in the coronary arteries of the control pigs. After in vivo intravascular ultrasound (IVUS) examination, pigs’ coronary arteries were harvested and cut into 1-cm sections for pathological analyses. Blood cholesterol levels (mg/dL) did not differ significantly between the control group and early treatment group: total cholesterol, 931±45 vs 881±81; VLDL, 539±26 vs 514±59; LDL, 277±35 vs 245±36; HDL, 89±3 vs 95 ± 6, respectively). IVUS and pathological examination revealed similar lumen areas but a significant reduction in plaque and vessel volume in the early treatment group. The proportion of atherosclerotic lesions was 80% in the control group and 67% in the early treatment group (P=0.01). Most lesions (87%) in the early treatment group were early-stage lesions (Stary types I-III), whereas 45% of lesions in the control group were early-stage lesions (P&lt;0.01). Only 1% of lesions were considered unstable plaques (Stary type VI lesions) in the early treatment group (vs 10% in the control group) (P&lt;0.01). With respect to instability, thin-cap fibroatheroma was 40% in the control group vs. 8% in the early treatment group (P&lt;0.01), intraplaque hemorrhage was 11% vs 1% (P&lt;0.01), and calcification was 22% vs 1% (P&lt;0.01). Conclusions: Our large-animal experiment provides support for early statin treatment before occurrence of atherosclerosis. Early statin treatment appears to retard development of coronary artery atherosclerosis and maintain lesion stability.
SAT0033 Enrichment of cd8<sup>+</sup>cd28- cytotoxic t cells in circulating lymphocytes of patients with ankylosing spondylitis
Authors: M Schirmer, C Goldberger, C Duftner, J Clausen, A Falkenbach
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> In patients with ankylosing spondylitis (AS), HLA-B27 restricted cytotoxic T lymphocytes (CTLs) exist with specificity for arthritogenic bacteria, viral peptides or autoantigens. These MHC-class I restricted CTLs could maintain the inflammatory process even after the bacterial pathogen itself had been eradicated by antibacterial immune responses and thus be directly involved in the pathogenesis of spondylarthropathies. Phenotypically they are characterised by the distinct expression of CD28-CD57<sup>+</sup>CD11ahigh. <h3>Objectives</h3> This study was performed to directly compare the relative number of CD8<sup>+</sup> CTLs from AS patients with age-matched healthy controls. Until now only few data are available for the incidence of CD8<sup>+</sup>CD28- T cells in autoimmune diseases. <h3>Methods</h3> AS patients were recruited and examined at the Gasteiner Heilstollen Hospital. Controls were preselected by evaluating the proband?s history and physical examination excluding an inflammatory or autoimmune diseases. Peripheral blood mononuclear cells were isolated by Ficoll density gradient centrifugation, triple-stained for CD3, CD4, and CD28-antigens and analysed on a FACScan flow cytometer. <h3>Results</h3> Peripheral blood was analysed from 95 AS patients and 53 age? matched healthy controls (49,1 ± 11,4 and 48.0 ± 14.0 years old, respectively). In AS patients CD8<sup>+</sup>CD28- T cells are expanded more than in the age-matched population (41,2 ± 17,7% and 18,6 ± 7,6% (p &lt; 0,0001), with regression lines y = 0,23x + 29,85 (R2 = 0,02) and y = 0,03x + 17,03 (R2 = 0,004), respectively). The percentage of CD8<sup>+</sup>CD28- T cells does not increase over the decades in healthy controls. Trends are described for increased percentages of CD8<sup>+</sup>CD28- T cells in patients with severe disease. <h3>Conclusion</h3> These data suggest that the fraction of CD8<sup>+</sup>CD28- T cells is not only increased in certain infectious diseases but also in patients diagnosed with AS. Increased percentages of CD8<sup>+</sup>CD28- T cells during ageing might be an artificial effect of undiagnosed infectious or autoimmune diseases. This finding further supports the hypothesis that increased levels of CD8<sup>+</sup>CD28- T cells can be considered pathogenic, comparable to benign monoclonal gammopathy.
Stronger induction of trained immunity by mucosal BCG or MTBVAC vaccination compared to standard intradermal vaccination
Authors: Michel P.M. Vierboom, Karin Dijkman, Claudia C. Sombroek, Sam O. Hofman, Charelle Boot, Richard A.W. Vervenne, Krista G. Haanstra, Maarten van der Sande, Liesbeth van Emst, Jorge Domínguez-Andrés, Simone J.C.F.M. Moorlag, Clemens H.M. Kocken, Jelle Thole, Esteban Rodríguez, Eugenia Puentes, Joost H.A. Martens, Reinout van Crevel, Mihai G. Netea, Nacho Aguilo, Carlos Martin, Frank A.W. Verreck
Journal: Cell Reports Medicine (2021)

BCG vaccination can strengthen protection against pathogens through the induction of epigenetic and metabolic reprogramming of innate immune cells, a process called trained immunity. We and others recently demonstrated that mucosal or intravenous BCG better protects rhesus macaques from Mycobacterium tuberculosis infection and TB disease than standard intradermal vaccination, correlating with local adaptive immune signatures. In line with prior mouse data, here, we show in rhesus macaques that intravenous BCG enhances innate cytokine production associated with changes in H3K27 acetylation typical of trained immunity. Alternative delivery of BCG does not alter the cytokine production of unfractionated bronchial lavage cells. However, mucosal but not intradermal vaccination, either with BCG or the M. tuberculosis-derived candidate MTBVAC, enhances innate cytokine production by blood- and bone marrow-derived monocytes associated with metabolic rewiring, typical of trained immunity. These results provide support to strategies for improving TB vaccination and, more broadly, modulating innate immunity via mucosal surfaces.