tbuckley/cabot-search huggingface dataset:
Immune Activation Induces Telomeric DNA Damage and Promotes Short‐Lived Effector T Cell Differentiation in Chronic HCV Infection
Authors: Lam Nhat Nguyen, Lam Ngoc Thao Nguyen, Juan Zhao, Madison Schank, Xindi Dang, Dechao Cao, Sushant Khanal, Bal Krishna Chand Thakuri, Jinyu Zhang, Zeyuan Lu, Xiao Y. Wu, Mohamed El Gazzar, Shunbin Ning, Ling Wang, Jonathan P. Moorman, Zhi Q. Yao
Journal: Hepatology (2021)

Background and Aims Hepatitis C virus (HCV) leads to a high rate of chronic infection and T cell dysfunction. Although it is well known that chronic antigenic stimulation is a driving force for impaired T cell functions, the precise mechanisms underlying immune activation–induced T cell dysfunctions during HCV infection remain elusive. Approach and Results Here, we demonstrated that circulating CD4 + T cells from patients who are chronically HCV‐infected exhibit an immune activation status, as evidenced by the overexpression of cell activation markers human leukocyte antigen‐antigen D‐related, glucose transporter 1, granzyme B, and the short‐lived effector marker CD127 ‐ killer cell lectin‐like receptor G1 + . In contrast, the expression of stem cell–like transcription factor T cell factor 1 and telomeric repeat‐binding factor 2 (TRF2) are significantly reduced in CD4 + T cells from patients who are chronically HCV‐infected compared with healthy participants (HP). Mechanistic studies revealed that CD4 + T cells from participants with HCV exhibit phosphoinositide 3‐kinase/Akt/mammalian target of rapamycin signaling hyperactivation on T cell receptor stimulation, promoting proinflammatory effector cell differentiation, telomeric DNA damage, and cellular apoptosis. Inhibition of Akt signaling during T cell activation preserved the precursor memory cell population and prevented inflammatory effector cell expansion, DNA damage, and apoptotic death. Moreover, knockdown of TRF2 reduced HP T cell stemness and triggered telomeric DNA damage and cellular apoptosis, whereas overexpression of TRF2 in CD4 T cells prevented telomeric DNA damage. Conclusions These results suggest that modulation of immune activation through inhibiting Akt signaling and protecting telomeres through enhancing TRF2 expression may open therapeutic strategies to fine tune the adaptive immune responses in the setting of persistent immune activation and inflammation during chronic HCV infection.
Chitin-derived polymer deacetylation regulates mitochondrial reactive oxygen species dependent cGAS-STING and NLRP3 inflammasome activation
Authors: Joanna L. Turley, Hannah B.T. Moran, Craig P. McEntee, Katie O'Grady, Natalia Muñoz-Wolf, Lei Jin, Frank Follmann, Peter Andersen, Mats Andersson, Ed C. Lavelle
Journal: Biomaterials (2021)

Chitosan is a cationic polysaccharide that has been evaluated as an adjuvant due to its biocompatible and biodegradable nature. The polysaccharide can enhance antibody responses and cell-mediated immunity following vaccination by injection or mucosal routes. However, the optimal polymer characteristics for activation of dendritic cells (DCs) and induction of antigen-specific cellular immune responses have not been resolved. Here, we demonstrate that only chitin-derived polymers with a high degree of deacetylation (DDA) enhance generation of mitochondrial reactive oxygen species (mtROS), leading to cGAS-STING mediated induction of type I IFN. Additionally, the capacity of the polymers to activate the NLRP3 inflammasome was strictly dependent on the degree and pattern of deacetylation and mtROS generation. Polymers with a DDA below 80% are poor adjuvants while a fully deacetylated polyglucosamine polymer is most effective as a vaccine adjuvant. Furthermore, this polyglucosamine polymer enhanced antigen-specific Th1 responses in a NLRP3 and STING-type I IFN-dependent manner. Overall these results indicate that the degree of chitin deacetylation, the acetylation pattern and its regulation of mitochondrial ROS are the key determinants of its immune enhancing effects.
Anti-PITPNM3 small molecular compounds reverse breast cancer metastasis by targeting PITPNM3.
Authors: Chang Gong, Zihao Liu, Qun Lin, Yu Shi, Qing Luo, Yinghuan Cen, Juanmei Li, Xiaolin Fang, Wenguo Jiang
Journal: Journal of Clinical Oncology (2021)

e15005 Background: Recent studies highlight the fundamental roles of PITPNM3 in breast cancer metastasis. PITPNM3 is identified as the functional receptor of CCL18 and promotes breast cancer cell invasion and metastasis by binding with CCL18. Since anti-CCL18 neutralized antibodies shows medium binding affinity which restricts their clinical application, small molecular inhibitors targeting PITPNM3 are needed to be further investigated. Therefore, we identified several first in class small molecular inhibitors potentially targeting PITPNM3 and can inhibit breast cancer metastasis conducted by PITPNM3 activation. Methods: We performed computer-assisted drug design by constructing PITPNM3 homology model, characterizing potential binding pockets and docking preselected high diversity structured small molecule compounds into the static PITPNM3 model. Top 100 small molecules in silico scores were selected and screened through basic experiments. After screening, the anti-metastasis effects of selected compounds were tested through transwell migration and invasion assay. Immunofluorescence and qPCR were applied to confirm the expression of vimentin and CDH1. Western blot were used to clarify the inhibition effects of selected compounds on PITPNM3 signaling pathways. Results: By using homology remodeling, we successfully constructed the PITPNM3(680-920aa) protein model. The PITPNM3(680-920aa) domain is responsible for interacting with PYK2 and phosphorylating PYK2. The phosphorylation of PYK2 conducted by PITPNM3 signaling pathway will lead to metastasis and epithelial-mesenchymal transition (EMT) of breast cancer cells. We then characterized the potential binding pockets of this static model and a druggable site was founded. More than 50K molecules with high diversity were docked into this druggable site and scored through their docking performance. Finally, top 100 scored small molecules were selected. In addition, through 1 rounds of toxicity screening, 1 round of transwell migration assay screening and 1 round of transwell invasion assay screening, 4 small molecules with higher bioactivity is identified and 1 compound with the highest bioactivity as well as docking performance among 50K small molecules is chose. This compound can inhibit CCL18 treatment as well as tumor associated macrophage co-culture mediated migration and invasion. Besides, it can also inhibit the phophorylation of PYK2 and Src without inhibition the expression of PITPNM3. Conclusions: Our findings identify the first-in-class anti-PITPNM3 small molecule inhibitors. These compounds can inhibit PITPNM3 signaling pathway and reverse breast cancer metastasis.
PRESYNAPTIC IONOTROPIC RECEPTORS AND THE CONTROL OF TRANSMITTER RELEASE
Authors: Amy B. MacDermott, Lorna W. Role, Steven A. Siegelbaum
Journal: Annual Review of Neuroscience (1999)

▪ Abstract The quantity of neurotransmitter released into the synaptic cleft, the reliability with which it is released, and the response of the postsynaptic cell to that transmitter all contribute to the strength of a synaptic connection. The presynaptic nerve terminal is a major regulatory site for activity-dependent changes in synaptic function. Ionotropic receptors for the inhibitory amino acid GABA, expressed on the presynaptic terminals of crustacean motor axons and vertebrate sensory neurons, were the first well-defined mechanism for the heterosynaptic transmitter-mediated regulation of transmitter release. Recently, presynaptic ionotropic receptors for a large range of transmitters have been found to be widespread throughout the central and peripheral nervous systems. In this review, we first consider some general theoretical issues regarding whether and how presynaptic ionotropic receptors are important regulators of presynaptic function. We consider the criteria that should be met to identify a presynaptic ionotropic receptor and its regulatory function and review several examples of presynaptic receptors that meet at least some of those criteria. We summarize the classic studies of presynaptic inhibition mediated by GABA-gated Cl channels and then focus on presynaptic nicotinic ACh receptors and presynaptic glutamate receptors. Finally, we briefly discuss evidence for other types of presynaptic ionotropic receptors.
Covid-19: Aspirin does not improve survival for patients admitted to hospital, trial reports
Authors: Gareth Iacobucci
Journal: BMJ (2021)

Covid-19: Aspirin does not improve survival for patients admitted to hospital, trial reports Gareth IacobucciAspirin does not improve survival for patients in hospital with covid-19, the UK Recovery trial 1 has reported.1 Recovery Trial.www.recoverytrial.net. 2Recovery trial finds aspirin does not improve survival for patients hospitalised with covid-19.8 June 2021.www.recoverytrial.net/news/recovery-trial-finds-aspirin-does-not-improve-survival-for-patients-hospitalised-with-covid-19.
Quality of life analysis of HPV-positive oropharyngeal cancer patients in a randomized trial of reduced-dose (rdCRT) versus standard (sdCRT) chemoradiotherapy: Five-year follow-up.
Authors: Mai Takahashi, Michael Hwang, Krzysztof Misiukiewicz, Richard Lorne Bakst, Brett A. Miles, Vishal Gupta, Marcelo Raul Bonomi, Sonam Sharma, John Botzler, Eric Michael Genden, Erin Moshier, Isaiah Selkridge, Marshall R. Posner
Journal: Journal of Clinical Oncology (2021)

6062 Background: Human papillomavirus-positive oropharyngeal cancer (HPV OPC) portends a more favorable prognosis compared to HPV-negative cases. To prevent overtreatment, long-term morbidity and deterioration in functionality and quality of life (QoL), multiple studies have focused on de-intensification techniques for HPV OPC treatment. To this end, we prospectively assessed differences in patient reported QoL in locally advanced HPV OPC patients receiving rdCRTversus sdCRT)in a randomized trial using a sequential therapy plan. Methods: Patients were enrolled between December 2012 and February 2016; received 3 cycles of induction docetaxel, cisplatin, and 5-FU; and were randomized to sdCRT (70 Gy) or rdCRT (56 Gy) with weekly carboplatin. Patients were followed for Progression Free Survival (PFS), Overall Survival (OS), and changes in QoL as assessed by the MD Anderson Dysphagia Inventory (MDADI), MD Anderson Symptom Inventory (MDASI Head and Neck), Xerostomia Questionnaire (XQ), and the European Organization for Research and Treatment of Cancer Questionnaire (EORTC QLQ-C30) with the head and neck module (EORTC HN). A mixed model ANOVA was used to estimate changes from baseline QoL to that at each follow-up timepoint and to compare the difference in QoL changes between the treatment arms. Results: We randomized 20 HPV+ locally advanced (LA) patients (median age: 56.5 yrs) to rdCRT (12 subjects) or sdCRT (8 subjects). 70% had high risk features. At a median follow-up of 81.5 mos, PFS and OS were 87.5% and 83.3% for sdCRT and rdCRT, respectively with a median OS of 76 mos in both arms. One patient in the sdCRT arm developed an HPV negative retromolar trigone squamous cell cancer in the radiation field 7 yrs after therapy. Baseline QoL was identical in the 15 patients who completed the QoL modules. Patients receiving rdCRT hadsignificantly lower declines in QoL scores at 3-6 month follow-up. At 5 yrs, differences in QoL changes all favored the rdCRT arm (Table) and two QoL scales reached statistical significance (P&lt;0.05). Conclusions: In HPV OPC patients, rdCRT resulted in comparable long-term survival and greater improvement in specific domains of QoL when compared to sdCRT. Our results support the need for a larger, long-term Phase 3 study in LA HPVOPC to assess these two treatments with respect to survival, QoL, and safety. Clinical trial information: NCT02945631. [Table: see text]
CAcTUS: A parallel arm, biomarker driven, phase II feasibility trial to determine the role of circulating tumor DNA in guiding a switch between targeted therapy and immune therapy in patients with advanced cutaneous melanoma.
Authors: Rebecca Lee, Dominic G. Rothwell, Shien Chow, Heather May Shaw, Samra Turajlic, Nigel Smith, Alexandra Clipson, Harry Clarke, Noel Kelso, Jackie Mitchell, Chris Sutton, Gema Sylvestre, Paul D. Nathan, James Larkin, Philippa Gail Corrie, Elizabeth Ruth Plummer, Richard Marais, Caroline Dive, Paul Lorigan
Journal: Journal of Clinical Oncology (2021)

TPS9587 Background: Circulating tumor DNA (ctDNA; the tumour derived fraction of circulating free DNA in the blood) has been shown to be a biomarker of tumor burden/progression in many cancers. We recently accurately monitored treatment response and resistance in stage IV melanoma by ctDNA analysis in serial peripheral blood samples. Pre-clinical data has previously revealed that BRAF inhibition provokes a micro-environment with increased T cell infiltration, improved T cell recognition of melanoma associated antigens and reduced production of immunosuppressive cytokines that could enhance immune responses. We aimed to test the hypothesis that ctDNA could be implemented as a personalised, real-time liquid biopsy to identify when tumours are responding to targeted therapy in order optimise a switch to immunotherapy. Methods: We validated the ctDNA assays for BRAF mutation calling as a primary trial endpoint. We designed a phase II multicenter, parallel arm study across 6 UK sites, to assess primary objectives of i). Whether a ctDNA result can be turned around within 7 days and actioned in a clinically relevant timeframe ii). to assess whether a decrease in ctDNA levels of mutant BRAF by ≥80% from baseline on targeted therapy is an appropriate ‘cut off’ to instruct switching to immunotherapy. Secondary endpoints include Overall Response Rate (ORR) to immunotherapy, radiological/clinical and ctDNA determined progression free survival (PFS) on each treatment. Forty patients are planned based on inclusion criteria of stage IV or stage III unresectable cutaneous BRAF mutant melanoma, baseline ctDNA BRAF variant allele frequency (VAF) ≥1.5%, ECOG 0/1/2, no symptomatic brain metastases, no prior adjuvant nivolumab plus ipilimumab (N+I). Prior adjuvant dabrafinib + trametinib (D+T) is allowed as long as recurrence is &gt;6 months from completion. Patients are randomised 1:1 to either standard Arm A; investigator choice of either D+T (150mg BD +2mg OD respectively) or N+I (1 mg/kg N +3 mg/kg I q3 wkly, then N 480mg q4 wkly) first line, then switch on progression to the other treatment. In the experimental Arm B; all patients start on D+T and have BRAF ctDNA monitored q2 wkly for 4 wks then q4 wkly. When ≥80% decrease vs. baseline in ctDNA BRAF VAF occurs, patients switch to N+I. If patients subsequently progress on N+I, they will resume D+T. The study is open with 9 patients enrolled at time of submission. Clinical trial information: NCT03808441.
Temporal and spatial topography of cell proliferation in cancer.
Authors: Sheheryar Kairas Kabraji, Giorgio Gaglia, Danae Argyropoulou, Yang Dai, Shu Wang, Johann Bergholz, Shannon Coy, Jia-Ren Lin, Rinath Jeselsohn, Otto Metzger, Eric P. Winer, Deborah Dillon, Jean Zhao, Peter Sorger, Sandro Santagata
Journal: Journal of Clinical Oncology (2021)

3122 Background: Tumors are complex ecosystems where exogenous and endogenous cues are integrated to either stimulate or inhibit cancer cell proliferation. However, the nature of these complex cell cycle states, their spatial organization, response to perturbation, and implications for clinical outcomes, are poorly characterized in tumor tissues. Methods: We used multiplexed tissue imaging to develop a robust classifier of proliferation, the multivariate proliferation index (MPI), using 513 unique tumors across five cancer types. Next, we used dimensionality reduction analysis to assess how the patterns of cell cycle protein expression in tumors were altered in response to perturbation. Results: The MPI outperforms single markers, like Ki67, when classifying proliferative index across diverse tumor types and reveals the proliferative architecture of tumors in situ. We find that proliferative and non-proliferative cancer cells are organized across microscopic (cell-to-cell) and macroscopic (tissue-level) scales. Both domains are reshaped by therapy, and local clusters of proliferative and non-proliferative tumor cells preferentially neighbor distinct tumor-infiltrating immune cells. We further phenotyped non-proliferating cancer cells using markers of quiescent cancer cells, cancer stem cells, and dormant cancer cells. We found that these types of non-proliferating cancer cells can occupy distinct regions within the same primary tumor. In high-dimensional marker space, populations of proliferative cancer cells express canonical patterns of cell cycle protein markers, a property we refer to as “cell cycle coherence”. Untreated tumors exist in a continuum of coherence states, ranging from optimal coherence, akin to freely cycling cells in culture, to reduced coherence characterized by either cell cycle polarization or non-canonical marker expression. Coherence can be stereotypically altered by induction and abrogation of mitogen signaling in a HER2-driven model of breast cancer. Cell cycle coherence is modulated by neoadjuvant therapy in patients with localized breast cancer, and coherence is associated with disease-free survival after adjuvant therapy in patients with colorectal cancer, mesothelioma and glioblastoma. Conclusions: The MPI robustly defines proliferating and non-proliferating cells in tissues, with immediate implications for clinical practice and research. The coherence metrics capture the diversity of post-treatment cell cycle states directly in clinical samples, a fundamental step in advancing precision medicine. More broadly, replacing binary metrics with multivariate traits provides a quantitative framework to study temporal processes from fixed static images and to investigate the rich spatial biology of human cancers.
Development and validation of a new prognostic score for hepatitis B virus-related acute-on-chronic liver failure
Authors: Jiaqi Li, Xi Liang, Shaoli You, Tingting Feng, Xin Zhou, Bing Zhu, Jinjin Luo, Jiaojiao Xin, Jing Jiang, Dongyan Shi, Yingyan Lu, Keke Ren, Tianzhou Wu, Lingling Yang, Jiang Li, Tan Li, Qun Cai, Suwan Sun, Beibei Guo, Xingping Zhou, Jiaxian Chen, Lulu He, Peng Li, Hui Yang, Wen Hu, Zhanglu An, Xiaojun Jin, Jin Tian, Baoju Wang, Xin Chen, Shaojie Xin, Jun Li
Journal: Journal of Hepatology (2021)

Early determination of the prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is important to guide clinical management and decrease mortality. The aim of this study was to develop a new simplified prognostic score to accurately predict outcomes in patients with HBV-ACLF.Prospective clinical data from 2,409 hospitalized patients with acute deterioration of HBV-related chronic liver disease were used to develop a new prognostic score that was validated in an external group.A total of 954 enrolled patients with HBV-ACLF were diagnosed based on the Chinese Group on the Study of Severe Hepatitis B-ACLF (COSSH-ACLF) criteria. Six predictive factors were significantly related to 28-day mortality and constituted a new prognostic score (=1.649×ln(international normalized ratio)+0.457×hepatic encephalopathy score+0.425×ln(neutrophil)+0.396×ln(total bilirubin)+0.576×ln(serum urea)+0.033×age). The C-indices of the new score for 28-/90-day mortality (0.826/0.809) were significantly higher than those of 4 other scores (COSSH-ACLF, 0.793/0.784; CLIF-C ACLF, 0.792/0.770; MELD, 0.731/0.727; MELD-Na, 0.730/0.726; all p <0.05). The prediction error rates of the new score for 28-day mortality were significantly lower than those of the 4 other scores: COSSH-ACLF (15.9%), CLIF-C ACLF (16.3%), MELD (35.3%) and MELD-Na (35.6%). The probability density function evaluation and risk stratification of the new score also showed the highest predictive values for mortality. These results were then validated in an external cohort.A new prognostic score based on 6 predictors, without an assessment of organ failure, can accurately predict short-term mortality in patients with HBV-ACLF and might be used to guide clinical management.Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a complex syndrome that is associated with a high short-term mortality rate. We developed a simplified prognostic score for patients suffering from this condition based on a prospective multicentre cohort. This new score had better predictive ability than 4 other commonly used scores.
Expression of B Cell Maturation Antigen (BCMA) and Transmembrane Activator and Caml Interactor (TACI) Are Correlated and Can be Targeted at Multiple Points during the Course of Multiple Myeloma
Authors: Allison O. Taylor, Matthew J. Frigault, Felipe Bedoya, Michelle E. DeLelys, Alexandra J. Shay, Rachel T. Nicholson, Noopur Raje, Fredric I. Preffer, Timothy A. Graubert, Marcela V. Maus
Journal: Blood (2017)
High-Intensity Strength Training, Knee Pain, and Knee Joint Compressive Forces in Adults With Knee Osteoarthritis
Authors: Bedri Karaismailoglu
Journal: JAMA (2021)

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