tbuckley/cabot-search huggingface dataset:
P14.27 Exploring end-of-life care in the GlioCova national brain tumour patient cohort
Authors: R Mauricaite, K Le Calvez, J Droney, M Caldano, M Alam, M Williams
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Brain tumours are the leading cause of cancer deaths in the under-40s. Research on end-of-life care, especially in brain tumour patients is rare, yet important to patients and carers. The GlioCova project holds data on all adult brain tumour patients in England diagnosed between 2013 and 2018. Using this linked data set, we performed preliminary analysis on end-of-life care, focusing on treatment close to death and place of death. MATERIAL AND METHODS We used data from the English National Cancer Registry and identified all patients with a primary CNS tumour (ICD-10: C70, C71, C72) who were diagnosed between 2013 - 2018. We examined demographics, tumour morphology and grade, primary cause of death, treatment received within the last 3 and 1 month of life, and the location of death. For patients with unclear location of death (‘unknown’, ‘other’, ‘NA’), we looked at their final destination of discharge recorded in their last inpatient admission. RESULTS We identified 26,239 brain tumour patients of whom 20,715 had died. 41.7% were female and median age was 68 (IQR=19). Most patients had a malignant neoplasm of brain (98.6%), followed by meninges (0.7%) and spinal cord, cranial nerves and other parts of central nervous system (0.7%). The most common primary cause of death was malignant neoplasm (70%). Of the 10,021(48.4%) patients who received radiotherapy at any time between diagnosis and death, 1,341 (6.5%) received it within the last three months of life and 254 (1.3%) received it within the last month of life. Of the 5,957 (28.8%) patients who received chemotherapy, 1,358 (6.6%) started a chemotherapy regimen 3 months and 200 (0.97%) 1 month before death. 36.0% of all patients died at home, 23.8% at hospital, 14.7% in a hospice and 8.8% in a nursing home. For 16.7% of patients with an unclear location of death, the most common destination of discharge during their last hospital admission was usual place of residence (54.5%), non-NHS run Care Home (13.9%), NHS run Care Home (11.2%). CONCLUSION To the best of our knowledge, this is the first national analysis of end-of-life care in brain tumour patients. Active treatment towards the end of life and in a hospital deaths appear lower in brain tumour patients than in studies of other cancer groups.
The transcription factor CREB1 is a mechanistic driver of immunogenicity and reduced HIV-1 acquisition following ALVAC vaccination
Authors: Jeffrey Alan Tomalka, Adam Nicolas Pelletier, Slim Fourati, Muhammad Bilal Latif, Ashish Sharma, Kathryn Furr, Kevin Carlson, Michelle Lifton, Ana Gonzalez, Peter Wilkinson, Genoveffa Franchini, Robert Parks, Norman Letvin, Nicole Yates, Kelly Seaton, Georgia Tomaras, Jim Tartaglia, Merlin L. Robb, Nelson L. Michael, Richard Koup, Barton Haynes, Sampa Santra, Rafick Pierre Sekaly
Journal: Nature Immunology (2021)
PD-L1P146R is prognostic and a negative predictor of response to immunotherapy in gastric cancer
Authors: Qing Li, Zhi-Wei Zhou, Jia Lu, Hao Luo, Shu-Nan Wang, Yu Peng, Meng-Sheng Deng, Guan-Bin Song, Jian-Min Wang, Xi Wei, Dong Wang, Kenneth D. Westover, Cheng-Xiong Xu
Journal: Molecular Therapy (2021)

Cancer cells evade immune detection via programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) interactions that inactivate T cells. PD-1/PD-L1 blockade has become an important therapy in the anti-cancer armamentarium. However, some patients do not benefit from PD-1/PD-L1 blockade despite expressing PD-L1. Here, we screened 101 gastric cancer (GC) patients at diagnosis and 141 healthy control subjects and reported one such subpopulation of GC patients with rs17718883 polymorphism in PD-L1, resulting in a nonsense P146R mutation. We detected rs17718883 in 44% of healthy control subjects, and rs17718883 was associated with a low susceptibility to GC and better prognosis in GC patients. Structural analysis suggests that the mutation weakens the PD-1:PD-L1 interaction. This was supported by co-culture experiments of T cells, with GC cells showing that the P146R substitution results in interferon (IFN)-γ secretion by T cells and enables T cells to suppress GC cell growth. Similar results with animal gastric tumor models were obtained in vivo. PD-1 monoclonal antibody treatment did not enhance the inhibitory effect of T cells on GC cells expressing PD-L1P146R in vitro or in vivo. This study suggests that rs17718883 is common and may be used as a biomarker for exclusion from PD-1/PD-L1 blockade therapy. Cancer cells evade immune detection via programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) interactions that inactivate T cells. PD-1/PD-L1 blockade has become an important therapy in the anti-cancer armamentarium. However, some patients do not benefit from PD-1/PD-L1 blockade despite expressing PD-L1. Here, we screened 101 gastric cancer (GC) patients at diagnosis and 141 healthy control subjects and reported one such subpopulation of GC patients with rs17718883 polymorphism in PD-L1, resulting in a nonsense P146R mutation. We detected rs17718883 in 44% of healthy control subjects, and rs17718883 was associated with a low susceptibility to GC and better prognosis in GC patients. Structural analysis suggests that the mutation weakens the PD-1:PD-L1 interaction. This was supported by co-culture experiments of T cells, with GC cells showing that the P146R substitution results in interferon (IFN)-γ secretion by T cells and enables T cells to suppress GC cell growth. Similar results with animal gastric tumor models were obtained in vivo. PD-1 monoclonal antibody treatment did not enhance the inhibitory effect of T cells on GC cells expressing PD-L1P146R in vitro or in vivo. This study suggests that rs17718883 is common and may be used as a biomarker for exclusion from PD-1/PD-L1 blockade therapy.
BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity
Authors: Zsófia Agnes Bittner, Xiao Liu, Maria Mateo Tortola, Ana Tapia-Abellán, Sangeetha Shankar, Liudmila Andreeva, Matthew Mangan, Marianne Spalinger, Hubert Kalbacher, Peter Düwell, Marta Lovotti, Karlotta Bosch, Sabine Dickhöfer, Ana Marcu, Stefan Stevanović, Franziska Herster, Yamel Cardona Gloria, Tzu-Hsuan Chang, Francesca Bork, Carsten L. Greve, Markus W. Löffler, Olaf-Oliver Wolz, Nadine A. Schilling, Jasmin B. Kümmerle-Deschner, Samuel Wagner, Anita Delor, Bodo Grimbacher, Oliver Hantschel, Michael Scharl, Hao Wu, Eicke Latz, Alexander N.R. Weber
Journal: The Journal of Experimental Medicine (2021)

Activity of the NLRP3 inflammasome, a critical mediator of inflammation, is controlled by accessory proteins, posttranslational modifications, cellular localization, and oligomerization. How these factors relate is unclear. We show that a well-established drug target, Bruton’s tyrosine kinase (BTK), affects several levels of NLRP3 regulation. BTK directly interacts with NLRP3 in immune cells and phosphorylates four conserved tyrosine residues upon inflammasome activation, in vitro and in vivo. Furthermore, BTK promotes NLRP3 relocalization, oligomerization, ASC polymerization, and full inflammasome assembly, probably by charge neutralization, upon modification of a polybasic linker known to direct NLRP3 Golgi association and inflammasome nucleation. As NLRP3 tyrosine modification by BTK also positively regulates IL-1β release, we propose BTK as a multifunctional positive regulator of NLRP3 regulation and BTK phosphorylation of NLRP3 as a novel and therapeutically tractable step in the control of inflammation.
Integrated Molecular and Immune Phenotype of HER2-Positive Breast Cancer and Response to Neoadjuvant Therapy: A NeoALTTO Exploratory Analysis
Authors: Sara Pizzamiglio, Chiara Maura Ciniselli, Tiziana Triulzi, Chiara Gargiuli, Loris De Cecco, Evandro de Azambuja, Debora Fumagalli, Christos Sotiriou, Nadia Harbeck, Miguel Izquierdo, Paolo Nuciforo, Jens Huober, Vera Cappelletti, Saverio Cinieri, Martine Piccart, Maria Grazia Daidone, Giancarlo Pruneri, Mario Paolo Colombo, Elda Tagliabue, Paolo Verderio, Serena Di Cosimo
Journal: Clinical Cancer Research (2021)

Little is known about the efficacy of HER2-targeted therapy in patients with breast cancer showing different HER2-pathway dependence and immune phenotypes. Herein, we report a NeoALTTO exploratory analysis evaluating the clinical value of 22 types of tumor-infiltrating immune cells by CIBERSORT and 5 immune-related metagenes in the overall patient population, and in subgroups defined by the TRAR classifier as HER2-addicted (TRAR-low) or not (TRAR-high).Association of baseline TRAR, immune-related metagenes, and CIBERSORT data with pathologic complete response (pCR) and event-free survival (EFS) were assessed using logistic and Cox regression models. Corrections for multiple testing were performed by the Bonferroni method.A total of 226 patients were analyzed: 80 (35%) achieved a pCR, and 64 (28%) experienced a relapse with a median follow-up of 6.7 (interquartile range 6.1-6.8) years; 108 cases were classified as TRAR-low, and 118 TRAR-high. Overall, γδ T-cell fraction [OR = 2.69; 95% confidence interval (CI), 1.40-5.18], and no immune-related metagenes were predictive of pCR. Notably, lymphocyte-specific kinase (LCK) predicted pCR to combination (OR = 2.53; 95% CI, 1.12-5.69), but not to single-agent trastuzumab or lapatinib [OR = 0.74; 95% CI, 0.45-1.22 (Pinteraction = 0.01)]. Integrating LCK with γδ T cells in a multivariate model added to the discriminatory capability of clinical and molecular variables with a shift in AUC from 0.80 (95% CI, 0.74-0.86) to 0.83 (95% CI, 0.78-0.89). In TRAR-low cases, activated mast cells, IFN and MHCII were reduced, and STAT1, HCK1, and γδ T cells were associated with pCR. STAT1 was broadly associated with improved EFS regardless of pCR, and nodal status in overall (HR = 0.68; 95% CI, 0.49-0.94) and in TRAR-low cases (HR = 0.50; 95% CI, 0.30-0.86).Immuno-phenotyping holds the promise to complement current predictive models in HER2-positive breast cancer and to assist in new therapeutic development.
포스터전시 : 간내 담관암과 유사하게 나타난 간경화성 혈관종
Authors: 한형준, 최새별, 김완배, 정은석, 정영걸, 김지훈, 송태진, 연종은, 변관수, 최상룡
Journal: Clinical and Molecular Hepatology (2009)
P13.01 Neuronal activity drives distinct invasion modes of glioma cells
Authors: Y Yang, V Venkataramani, M Schubert, C Beretta, M Botz, L Fankhauser, W Wick, T Kuner, F Winkler
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Gliomas are incurable brain tumors characterized by their infiltrative growth which makes them a whole-brain disease. Previously we described membrane protrusions called tumor microtubes (TMs), and glutamatergic synapses between neurons and glioma cells, as mechanisms contributing to glioma cell invasion and tumor progression. However, the interrelation of the two, and the exact mechanisms of glioma cell dynamics over time was unknown. Therefore, we investigate neuronal synaptic input on TM-associated glioma cell motility. MATERIAL AND METHODS Here we established a novel workflow for analyzing single glioma cell dynamics over several hours with in-vivo two-photon microscopy. First, a membranous fluorescent marking of patient-derived glioma cells was established to reliably track membrane changes. Secondly, augmented microscopy based on deep- and machine-learning algorithms was used to track glioma cells. Neuronal activity was manipulated with different doses of isoflurane anesthesia, and used to study its effects on glioma cell dynamics. RESULTS This novel method revealed that motility of glioma cells can be described by the displacement of whole glioma cell somata (somatokinesis) and TM dynamics. TM motility in turn could be sub-categorized into protrusion, retraction and branching. Next, we describe three different invasion modes, all with similarities to different cell types involved in CNS development. Lastly, the effects of neuronal activity on glioma cell invasion were investigated. With the application of high anesthesia and subsequently reduced neuronal activity, TM turnover, branching events and as a result glioma cell invasion were inhibited, but in a heterogeneous manner. CONCLUSION The novel workflow allowed to comprehensively characterize glioma cell invasion over several hours. Its application demonstrates novel, hitherto unknown cellular mechanisms of glioma cell invasion, and provides a link between TM biology and neuron-glioma communication. Finally, neuronal input drives distinct subtypes of glioma cell motility patterns.All in all, this work presents an important first step in understanding mechanisms that lead to the whole- brain colonization of glioma cells making these brain tumors incurable. A further characterization of the exact molecular mechanisms that drive neuronal activity-dependent glioma cell motility is warranted.
Seasonality of Respiratory Viruses at Northern Latitudes
Authors: Michael T. Hawkes, Bonita E. Lee, Jamil N. Kanji, Nathan Zelyas, Kerry Wong, Michelle Barton, Shamir Mukhi, Joan L. Robinson
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Every year, respiratory viruses exact a heavy burden on Canadian hospitals during winter months. Generalizable seasonal patterns of respiratory virus transmission may estimate the evolution of SARS-CoV-2 or other emerging pathogens. <h3>Objective</h3> To describe the annual and biennial variation in respiratory virus seasonality in a northern climate. <h3>Design, Setting, and Participants</h3> This cohort study is an epidemiological assessment using population-based surveillance of patients with medically attended respiratory tract infection from 2005 through 2017 in Alberta, Canada. Incident cases of respiratory virus infection and infant respiratory syncytial virus (RSV) hospitalizations in Alberta were extracted from the Data Integration for Alberta Laboratories platform and Alberta Health Services Discharge Abstract Database, respectively. A deterministic susceptible-infected-recovered-susceptible mathematical model with seasonal forcing function was fitted to the data for each virus. The possible future seasonal course of SARS-CoV-2 in northern latitudes was modeled on the basis of these observations. The analysis was conducted between December 15, 2020, and February 10, 2021. <h3>Exposures</h3> Seasonal respiratory pathogens. <h3>Main Outcomes and Measures</h3> Incidence (temporal pattern) of respiratory virus infections and RSV hospitalizations. <h3>Results</h3> A total of 37 719 incident infections with RSV, human metapneumovirus, or human coronaviruses 229E, NL63, OC43, or HKU1 among 35 375 patients (18 069 [51.1%] male; median [interquartile range], 1.29 [0.42-12.2] years) were documented. A susceptible-infected-recovered-susceptible model mirrored the epidemiological data, including a striking biennial variation with alternating severe and mild winter peaks. Qualitative description of the model and numerical simulations showed that strong seasonal contact rate and temporary immunity lasting 6 to 12 months were sufficient to explain biennial seasonality in these various respiratory viruses. The seasonality of 10 212 hospitalizations among children younger than 5 years with RSV was also explored. The median (interquartile range) rate of hospitalizations per 1000 live births was 18.6 (17.6-19.9) and 11.0 (10.4-11.7) in alternating even (severe) and odd (less-severe) seasons, respectively (<i>P</i> = .001). The hazard of admission was higher for children born in severe (even) seasons compared with those born in less-severe (odd) seasons (hazard ratio, 1.68; 95% CI, 1.61-1.75;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> In this modeling study of respiratory viruses in Alberta, Canada, the seasonality followed a pattern estimated by simple mathematical models, which may be informative for anticipating future waves of pandemic SARS-CoV-2.
Characteristics, treatment patterns, and economic burden of patients with metastatic cervical cancer receiving systemic anticancer therapy.
Authors: Xiaoyun Pan, Lincy S. Lal, John White, Seyed Hamidreza Mahmoudpour, Christian Valencia
Journal: Journal of Clinical Oncology (2021)

51 Background: In 2021, 14,480 patients are estimated to be diagnosed with cervical cancer in the US; 16% of patients are expected to have metastatic disease for whom the 5-year survival rate is 17.6% per SEER estimates. Patients with metastatic cervical cancer (mCC) are treated mainly with systemic therapy. This study aims to describe the clinical characteristics, demographics, treatment patterns, and economic burden of patients with mCC receiving systemic therapy. Methods: Eligible women had been diagnosed with cervical cancer, as evidenced by &gt;2 outpatient or &gt;1 inpatient claim in the Optum Research Database from January 2014 through January 2020. Patients were included if they had metastasis within 6 months before or after cervical cancer diagnosis, with evidence of systemic treatment on or after the latter of a claim date for cervical cancer disease or metastatic disease. The index date was the first-line treatment initiation date. Patients were required to have ≥6 months of pre-index continuous enrollment. The top 3 treatment regimens and median treatment duration by line of therapy were described. All-cause per-patient-per-month (PPPM) costs (2019 US dollars), including plan and patient paid amounts, were reported for full follow-up period from first-line and second-line therapy initiation. Results: The study sample consisted of 778 patients (mean age, 59 years; commercial, 58%; Medicare Advantage, 42%). The mean (median) follow-up period was 14 (9) months. Top baseline comorbidities were diseases of the urinary system (71%) and diseases of the female genital organs (70%), and the median Charlson comorbidity index was 7. In the first line, 80% of patients received platinum-based therapy and 23% received bevacizumab (bev). Of 778 patients, only 294 (38%) received second-line therapy, with 34% receiving bev. Top first-line treatment regimens were carboplatin + paclitaxel (27%), cisplatin (21%), and bev + carboplatin + paclitaxel (10%); the median (95% CI) duration of treatment was 3.4 (3.1-3.7) months. Top second-line treatment regimens were bev + carboplatin + paclitaxel (13%), carboplatin + paclitaxel (11%), and pembrolizumab (6%); the median duration of treatment was 3.8 (3.1-4.2) months. Mean all-cause total PPPM costs were $19,519 from first-line and $22,660 second-line therapy initiation (table). Conclusions: This study indicates that real-world mCC patients have short treatment durations and significant economic burden with first-line and second-line therapy. Novel therapies associated with greater clinical benefits in patients with mCC may provide economic benefit.[Table: see text]
Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction in Patients With Chronic Immune-Mediated Inflammatory Diseases
Authors: Konstantinos Papamichael, Marla C. Dubinsky, Adam S. Cheifetz
Journal: JAMA (2021)

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Experimental study of a 3D printed permanent implantable porous Ta-coated bone plate for fracture fixation
Authors: Baoyi Liu, Zhijie Ma, Junlei Li, Hui Xie, Xiaowei Wei, Benjie Wang, Simiao Tian, Jiahui Yang, Lei Yang, Liangliang Cheng, Lu Li, Dewei Zhao
Journal: Bioactive Materials (2021)

Metal plates have always been the gold standard in the clinic for internal fracture fixation due to their high strength advantages. However, high elastic modulus can cause stress shielding and lead to bone embrittlement. This study used an electron beam melting method to prepare personalized porous Ti6Al4V (pTi) bone plates. Then, chemical vapor deposition (CVD) technology coats tantalum (Ta) metal on the pTi bone plates. The prepared porous Ta-coated bone plate has an elastic modulus similar to cortical bone, and no stress shielding occurred. In vitro experiments showed that compared with pTi plates, Ta coating significantly enhances the attachment and proliferation of cells on the surface of the scaffold. To better evaluate the function of the Ta-coated bone plate, animal experiments were conducted using a coat tibia fracture model. Our results showed that the Ta-coated bone plate could effectively fix the fracture. Both imaging and histological analysis showed that the Ta-coated bone plate had prominent indirect binding of callus formation. Histological results showed that new bone grew at the interface and formed good osseointegration with the host bone. Therefore, this study provides an alternative to bio-functional Ta-coated bone plates with improved osseointegration and osteogenic functions for orthopaedic applications.
Traditional Chinese medicine in COVID-19
Authors: Ming Lyu, Guanwei Fan, Guangxu Xiao, Taiyi Wang, Dong Xu, Jie Gao, Shaoqin Ge, Qingling Li, Yuling Ma, Han Zhang, Jigang Wang, Yuanlu Cui, Junhua Zhang, Yan Zhu, Boli Zhang
Journal: Acta Pharmaceutica Sinica B (2021)

COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread across the globe, posing an enormous threat to public health and safety. Traditional Chinese medicine (TCM), in combination with Western medicine (WM), has made important and lasting contributions in the battle against COVID-19. In this review, updated clinical effects and potential mechanisms of TCM, presented in newly recognized three distinct phases of the disease, are summarized and discussed. By integrating the available clinical and preclinical evidence, the efficacies and underlying mechanisms of TCM on COVID-19, including the highly recommended three Chinese patent medicines and three Chinese medicine formulas, are described in a panorama. We hope that this comprehensive review not only provides a reference for health care professionals and the public to recognize the significant contributions of TCM for COVID-19, but also serves as an evidence-based in-depth summary and analysis to facilitate understanding the true scientific value of TCM.