tbuckley/cabot-search huggingface dataset:
Risk Factors for Development of Hypocalcemia in Patients With Cancer Treated With Bone-Modifying Agents
Authors: Paul S. White, Michael Dennis, Eric A. Jones, Janice M. Weinberg, Shayna Sarosiek
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background: This retrospective analysis describes the prevalence of and risk factors associated with the development of hypocalcemia in patients with cancer receiving bone-modifying agents (BMAs) as supportive care. Patients and Methods: Patients with cancer treated with an intravenous or subcutaneous BMA, including pamidronate, zoledronic acid, or denosumab, at a tertiary care/safety net hospital in 2005 through 2015 were included in this retrospective review. We reviewed the medical records for predictive clinical and laboratory parameters and for patient outcomes. Results: A total of 835 patients with cancer received at least one dose of a BMA during the specified time frame; 205 patients (25%) developed hypocalcemia of CTCAE grade ≥1 within 8 weeks of BMA initiation, 18 of whom (8.8%) had grade ≥3, and 3 patients died as a result. Multivariate analysis showed that patients with hematologic malignancy (odds ratio [OR], 1.956; P =.025), bone metastases (OR, 2.443; P =.017), inpatient status (OR, 2.592; P &lt;.001), and deficient baseline vitamin D levels (OR, 2.546; P &lt;.023) were more likely to develop hypocalcemia. Hypercalcemia before BMA administration (OR, 0.474; P =.032) was protective. Conclusions: Certain patient populations, including those with hematologic malignancies and/or bone metastases, warrant closer monitoring of calcium levels while receiving BMAs because of the high rate of hypocalcemia. Low pretreatment vitamin D levels are associated with the development of hypocalcemia. These data support close monitoring of calcium levels in patients with cancer receiving BMAs, in addition to adequate repletion of vitamin D before initiation of BMAs when possible.
Rapid Expansion of Highly Functional Antigen-Specific T Cells from Patients with Melanoma by Nanoscale Artificial Antigen-Presenting Cells
Authors: Junya Ichikawa, Tatsuya Yoshida, Ariel Isser, Andressa S. Laino, Melinda Vassallo, David Woods, Sojung Kim, Mathias Oelke, Kristi Jones, Jonathan P. Schneck, Jeffrey S. Weber
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Generation of antigen-specific T cells from patients with cancer employs large numbers of peripheral blood cells and/or tumor-infiltrating cells to generate antigen-presenting and effector cells commonly requiring multiple rounds of restimulation ex vivo. We used a novel paramagnetic, nanoparticle-based artificial antigen-presenting cell (nano-aAPC) that combines anti-CD28 costimulatory and human MHC class I molecules that are loaded with antigenic peptides to rapidly expand tumor antigen–specific T cells from patients with melanoma. Experimental Design: Nano-aAPC–expressing HLA-A*0201 molecules and costimulatory anti-CD28 antibody and HLA-A*0201 molecules loaded with MART-1 or gp100 class I–restricted peptides were used to stimulate CD8 T cells purified from the peripheral blood of treatment-naïve or PD-1 antibody–treated patients with stage IV melanoma. Expanded cells were restimulated with fresh peptide-pulsed nano-aAPC at day 7. Phenotype analysis and functional assays including cytokine release, cytolysis, and measurement of avidity were conducted. Results: MART-1–specific CD8 T cells rapidly expanded up to 1,000-fold by day 14 after exposure to peptide-pulsed nano-aAPC. Expanded T cells had a predominantly stem cell memory CD45RA+/CD62L+/CD95+ phenotype; expressed ICOS, PD-1, Tim3, and LAG3; and lacked CD28. Cells from patients with melanoma were polyfunctional; highly avid; expressed IL2, IFNγ, and TNFα; and exhibited cytolytic activity against tumor cell lines. They expanded 2- to 3-fold after exposure to PD-1 antibody in vivo, and expressed a highly diverse T-cell receptor V beta repertoire. Conclusions: Peptide-pulsed nano-aAPC rapidly expanded polyfunctional antigen-specific CD8 T cells with high avidity, potent lytic function, and a stem cell memory phenotype from patients with melanoma.
IRE1α Disruption in Triple-Negative Breast Cancer Cooperates with Antiangiogenic Therapy by Reversing ER Stress Adaptation and Remodeling the Tumor Microenvironment
Authors: Jonathan M. Harnoss, Adrien Le Thomas, Mike Reichelt, Ofer Guttman, Thomas D. Wu, Scot A. Marsters, Anna Shemorry, David A. Lawrence, David Kan, Ehud Segal, Mark Merchant, Klara Totpal, Lisa M. Crocker, Kathryn Mesh, Monika Dohse, Margaret Solon, Zora Modrusan, Joachim Rudolph, Hartmut Koeppen, Peter Walter, Avi Ashkenazi
Journal: Cancer Research (2020)

Cancer cells exploit the unfolded protein response (UPR) to mitigate endoplasmic reticulum (ER) stress caused by cellular oncogene activation and a hostile tumor microenvironment (TME). The key UPR sensor IRE1α resides in the ER and deploys a cytoplasmic kinase-endoribonuclease module to activate the transcription factor XBP1s, which facilitates ER-mediated protein folding. Studies of triple-negative breast cancer (TNBC)-a highly aggressive malignancy with a dismal posttreatment prognosis-implicate XBP1s in promoting tumor vascularization and progression. However, it remains unknown whether IRE1α adapts the ER in TNBC cells and modulates their TME, and whether IRE1α inhibition can enhance antiangiogenic therapy-previously found to be ineffective in patients with TNBC. To gauge IRE1α function, we defined an XBP1s-dependent gene signature, which revealed significant IRE1α pathway activation in multiple solid cancers, including TNBC. IRE1α knockout in TNBC cells markedly reversed substantial ultrastructural expansion of their ER upon growth in vivo. IRE1α disruption also led to significant remodeling of the cellular TME, increasing pericyte numbers while decreasing cancer-associated fibroblasts and myeloid-derived suppressor cells. Pharmacologic IRE1α kinase inhibition strongly attenuated growth of cell line-based and patient-derived TNBC xenografts in mice and synergized with anti-VEGFA treatment to cause tumor stasis or regression. Thus, TNBC cells critically rely on IRE1α to adapt their ER to in vivo stress and to adjust the TME to facilitate malignant growth. TNBC reliance on IRE1α is an important vulnerability that can be uniquely exploited in combination with antiangiogenic therapy as a promising new biologic approach to combat this lethal disease. SIGNIFICANCE: Pharmacologic IRE1α kinase inhibition reverses ultrastructural distension of the ER, normalizes the tumor vasculature, and remodels the cellular TME, attenuating TNBC growth in mice.
Molecular alterations underlying colitis-related colorectal carcinogenesis in a mouse model of induced colitis
Authors: Renata Coudry, Cynthia Spittle, Rita Michielli, Harry S. Cooper, Wen-Chi Chang, Monique Gary, Margie L. Clapper
Journal: Cancer Research (2005)

6066  Ulcerative colitis (UC) is a diffuse inflammatory disease of the colorectum, which is often accompanied by the development of colon cancer from dysplastic precursor lesions. Development and progression of UC-associated colorectal cancer (CRC) involves multiple genetic alterations that appear to be different from those of sporadic cancer. Aberrations in the adenomatous polyposis coli (APC) and K-ras genes, hallmarks of sporadic colon cancer, are less frequently found in neoplasms arising in a background of inflammation. Mutation of β-catenin, a key component of both Wnt signaling and cadherin-mediated cell-cell adhesion, is rare while nuclear translocation of β-catenin is observed frequently in both sporadic and UC-associated colorectal neoplasms. Previous studies by this group have demonstrated that administration of dextran sulfate sodium (DSS) to Swiss Webster mice in combination with azoxymethane (AOM) results in the induction of flat and polypoid colonic dysplasias and cancers similar, both clinically and histopathologically, to those seen in UC patients. Based upon the observed ability of select chemopreventive agents to preferentially inhibit flat or polypoid lesions in this model, the present study was initiated to characterize and compare the molecular events that accompany the development of flat and polypoid dysplasias in the AOM/DSS model. Polypoid (N=28) and flat (N=21) lesions with high grade dysplasia were laser capture microdissected (PixCell II, Arcturus) to obtain a pure population of dysplastic colonic epithelial cells and DNA was isolated for mutational analysis. Neither mutation of K-ras nor p53 was detected in flat or polypoid precursor lesions by pyrosequencing or direct sequence analysis, respectively. The same colonic lesions were negative for p53 expression as assessed by immunohistochemistry. Although sequence analysis of the full-length β-catenin gene failed to reveal mutations in any of the lesions, nuclear translocation of β-catenin was observed in 100% of the polypoid and 92% of the flat dysplasias; a common feature of human UC-associated colonic dysplasias. Loss of heterozygosity of the APC gene was not detected. No significant difference in the mutational status of p53, K-ras or β-catenin was observed in flat and polypoid dysplasias. A better understanding of the pathogenesis of CRC in the setting of chronic inflammation is required before surveillance programs that are currently failing to accurately detect UC-related dysplasias/cancers can be optimized and efficacious chemopreventive regimens can be established for UC patients at high risk for colorectal cancer. (Supported by a grant from the AHEPA Cancer Research Foundation, Inc.)
Adverse skin reactions among healthcare workers during the coronavirus disease 2019 outbreak: a survey in Wuhan and its surrounding regions
Authors: P. Lin, S. Zhu, Y. Huang, L. Li, J. Tao, T. Lei, J. Song, D. Liu, L. Chen, Y. Shi, S. Jiang, Q. Liu, J. Xie, H. Chen, Y. Duan, Y. Xia, Y. Zhou, Y. Mei, X. Zhou, J. Wu, M. Fang, Z. Meng, H. Li
Journal: British Journal of Dermatology (2020)

Adverse skin reactions among healthcare workers during the coronavirus disease 2019 outbreak: a survey in Wuhan and its surrounding regions
Disruption of the RNA modifications that target the ribosome translation machinery in human cancer
Authors: Maxime Janin, Laia Coll-SanMartin, Manel Esteller
Journal: Molecular Cancer (2020)

Genetic and epigenetic changes deregulate RNA and protein expression in cancer cells. In this regard, tumors exhibit an abnormal proteome in comparison to the corresponding normal tissues. Translation control is a crucial step in the regulation of gene expression regulation under normal and pathological conditions that ultimately determines cellular fate. In this context, evidence shows that transfer and ribosomal RNA (tRNA and rRNA) modifications affect the efficacy and fidelity of translation. The number of RNA modifications increases with the complexity of organisms, suggesting an evolutionary diversification of the possibilities for fine-tuning the functions of coding and non-coding RNAs. In this review, we focus on alterations of modifications of transfer and ribosomal RNA that affect translation in human cancer. This variation in the RNA modification status can be the result of altered modifier expression (writers, readers or erasers), but also due to components of the machineries (C/D or H/ACA boxes) or alterations of proteins involved in modifier expression. Broadening our understanding of the mechanisms by which site-specific modifications modulate ribosome activity in the context of tumorigenesis will enable us to enrich our knowledge about how ribosomes can influence cell fate and form the basis of new therapeutic opportunities.
Visual Field Outcomes from the Multicenter, Randomized Controlled Laser in Glaucoma and Ocular Hypertension Trial (LiGHT)
Authors: David M. Wright, Evgenia Konstantakopoulou, Giovanni Montesano, Neil Nathwani, Anurag Garg, David Garway-Heath, David P. Crabb, Gus Gazzard, Mariam Adeleke, Gareth Ambler, Keith Barton, Rupert Bourne, David Broadway, Catey Bunce, Marta Buszewicz, David Crabb, Amanda Davis, Anurag Garg, David Garway-Heath, Gus Gazzard, Daniel Hornan, Rachael Hunter, Hari Jayaram, Yuzhen Jiang, Evgenia Konstantakopoulou, Sheng Lim, Joanna Liput, Timothy Manners, Giovanni Montesano, Stephen Morris, Neil Nathwani, Giovanni Ometto, Gary Rubin, Nicholas Strouthidis, Victoria Vickerstaff, Sarah Wilson, Richard Wormald, David Wright, Haogang Zhu
Journal: Ophthalmology (2020)
Pediatric Mental Health Care Must Be Family Mental Health Care
Authors: Matthew G. Biel, Michael H. Tang, Barry Zuckerman
Journal: JAMA Pediatrics (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Mesenchymal folliculin is required for alveolar development: implications for cystic lung disease in Birt-Hogg-Dubé syndrome
Authors: Ling Chu, Yongfeng Luo, Hui Chen, Qing Miao, Larry Wang, Rex Moats, Tiansheng Wang, John C Kennedy, Elizabeth P Henske, Wei Shi
Journal: Thorax (2020)

Pulmonary cysts and spontaneous pneumothorax are presented in most patients with Birt-Hogg-Dubé (BHD) syndrome, which is caused by loss of function mutations in the folliculin (FLCN) gene. The pathogenic mechanisms underlying the cystic lung disease in BHD are poorly understood.Mesenchymal Flcn was specifically deleted in mice or in cultured lung mesenchymal progenitor cells using a Cre/loxP approach. Dynamic changes in lung structure, cellular and molecular phenotypes and signalling were measured by histology, immunofluorescence staining and immunoblotting.Deletion of Flcn in mesoderm-derived mesenchymal cells results in significant reduction of postnatal alveolar growth and subsequent alveolar destruction, leading to cystic lesions. Cell proliferation and alveolar myofibroblast differentiation are inhibited in the Flcn knockout lungs, and expression of the extracellular matrix proteins Col3a1 and elastin are downregulated. Signalling pathways including mTORC1, AMP-activated protein kinase, ERK1/2 and Wnt-β-catenin are differentially affected at different developmental stages. All the above changes have statistical significance (p<0.05).Mesenchymal Flcn is an essential regulator during alveolar development and maintenance, through multiple cellular and molecular mechanisms. The mesenchymal Flcn knockout mouse model provides the first in vivo disease model that may recapitulate the stages of cyst development in human BHD. These findings elucidate the developmental origins and mechanisms of lung disease in BHD.
A comparison of daily physical activity profiles between adults with severe asthma and healthy controls
Authors: Jill Neale, Mark W. Orme, Sally Majd, Stacey Chantrell, Sally J. Singh, Peter Bradding, Ruth H. Green, Rachael A. Evans
Journal: European Respiratory Journal (2020)

<b>Compared to controls, adults with severe #asthma attain fewer daily steps and reduced sustained moderate–vigorous #physicalactivity which are associated with worse quality of life. Physical activity and #exercise interventions are needed for severe asthma.</b>http://bit.ly/2W8c7Qa
Identification of Deleterious<i>NOTCH</i>Mutation as Novel Predictor to Efficacious Immunotherapy in NSCLC
Authors: Kai Zhang, Xiaohua Hong, Zhengbo Song, Yu Xu, Chengcheng Li, Guoqiang Wang, Yuzi Zhang, Xiaochen Zhao, Zhengyi Zhao, Jing Zhao, Mengli Huang, Depei Huang, Chuang Qi, Chan Gao, Shangli Cai, Feifei Gu, Yue Hu, Chunwei Xu, Wenxian Wang, Zhenkun Lou, Yong Zhang, Li Liu
Journal: Clinical Cancer Research (2020)

NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in non-small cell lung cancer (NSCLC), indicating its association with the clinical benefit of immune checkpoint inhibitors (ICI). We hypothesized that NOTCH mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy.Multiple-dimensional data including genomic, transcriptomic, and clinical data from cohorts of NSCLC internal and public cohorts involving immunotherapeutic patients were analyzed. Polymorphism Phenotyping v2 (PolyPhen-2) system was performed to determine deleterious NOTCH mutation (del-NOTCHmut). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis.Our 3DMed cohort (n = 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; n = 1,499) uncovered marked correlation between NOTCH1/2/3 mutation and better ICI outcomes in EGFR/ALKWT population, including objective response rate (2.20-fold, P = 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46-0.81; P = 0.001], and overall survival (HR, 0.56; 95% CI, 0.32-0.96; P = 0.035). Del-NOTCHmut exhibited better predictive function than non-deleterious NOTCH mutation, potentially via greater transcription of genes related to DNA damage response and immune activation. Del-NOTCHmut was not linked with prognosis in TCGA cohorts and chemotherapeutic response, but was independently associated with immunotherapeutic benefit, delineating the predictive, but not prognostic, utility of del-NOTCHmut.This work distinguishes del-NOTCHmut as a potential predictor to favorable ICI response in NSCLC, highlighting the importance of genomic profiling in immunotherapy. More importantly, our results unravel a possibility of personalized combination immunotherapy as adding NOTCH inhibitor to ICI regimen in NSCLC, for the optimization of ICI treatment in clinical practice.
Gynaecologist is suspended for 12 months after sexual advances were reported in wake of #MeToo
Authors: Clare Dyer
Journal: BMJ (2020)

A leading obstetrician and gynaecologist has been suspended from the UK medical register for 12 months after a tribunal found that he had made inappropriate sexual advances to female colleagues.

Khalid Khan was at the time of the incidents a professor of women’s health and clinical epidemiology at Queen Mary University of London and editor in chief of the British Journal of Obstetrics and Gynaecology . At a medical practitioners tribunal hearing, which heard sharply different accounts of events, he was accused by four women of making unwanted and improper advances.

Allegations by two of the four women were found not proved. In rebutting the accounts of the two women whose allegations were ultimately found proved, Khan denied having been present at the times and places described, bringing alibi witnesses. However, the two, a gynaecologist and a research assistant, had witnesses who …
Gene Expression Profiling of Mediastinal Gray Zone Lymphoma and Its Relationship to Primary Mediastinal B-cell Lymphoma and Classical Hodgkin Lymphoma
Authors: Stefania Pittaluga, Alina Nicolae, George W. Wright, Christopher Melani, Mark Roschewski, Seth Steinberg, DaWei Huang, Louis M. Staudt, Elaine S. Jaffe, Wyndham H. Wilson
Journal: Blood Cancer Discovery (2020)

Abstract Mediastinal gray zone lymphoma (MGZL) has immunopathologic features between classical Hodgkin lymphoma (cHL) and primary mediastinal thymic B-cell lymphoma (PMBL), leading to uncertainty regarding its biological relationship to these entities. We performed gene expression profiling from patients with MGZL (20), cHL (18), and PMBL (17) and show MGZL clusters between cHL and PMBL. Expression signatures reveal germinal B-cell and IFN regulatory factor 4 (IRF4) signatures were relatively low in MGZL and cHL compared with PMBL, indicating downregulation of the B-cell program in MGZL, a hallmark of cHL. T-cell and macrophage signatures were higher in MGZL and cHL compared with PMBL, consistent with infiltrating immune cells, which are found in cHL. The NFκB signature was higher in MGZL than PMBL, and like cHL, MGZL and PMBL express NFκB inducing kinase (NIK), indicating noncanonical signaling. These findings indicate that while MGZL has distinctive clustering, it is biologically closer to cHL. Significance: We performed comparative gene expression analysis of MGZL, cHL, and PMBL and show most MGZL cases are biologically closer to cHL. MGZL has significantly higher tumor cell density than cHL and greater NFκB activation compared with PMBL, which may explain its greater treatment resistance compared with cHL and PMBL. This article is highlighted in the In This Issue feature, p. 127
Germline <i>MBD4</i> Mutations and Predisposition to Uveal Melanoma
Authors: Anne-Céline Derrien, Manuel Rodrigues, Alexandre Eeckhoutte, Stéphane Dayot, Alexandre Houy, Lenha Mobuchon, Sophie Gardrat, Delphine Lequin, Stelly Ballet, Gaëlle Pierron, Samar Alsafadi, Odette Mariani, Ahmed El-Marjou, Alexandre Matet, Chrystelle Colas, Nathalie Cassoux, Marc-Henri Stern
Journal: JNCI Journal of the National Cancer Institute (2020)

Uveal melanoma (UM) arises from malignant transformation of melanocytes in the uveal tract of the eye. This rare tumor has a poor outcome with frequent chemo-resistant liver metastases. BAP1 is the only known predisposing gene for UM. UMs are generally characterized by low tumor mutation burden, but some UMs display a high level of CpG>TpG mutations associated with MBD4 inactivation. Here, we explored the incidence of germline MBD4 variants in a consecutive series of 1093 primary UM case patients and a series of 192 UM tumors with monosomy 3 (M3).We performed MBD4 targeted sequencing on pooled germline (n = 1093) and tumor (n = 192) DNA samples of UM patients. MBD4 variants (n = 28) were validated by Sanger sequencing. We performed whole-exome sequencing on available tumor samples harboring MBD4 variants (n = 9). Variants of unknown pathogenicity were further functionally assessed.We identified 8 deleterious MBD4 mutations in the consecutive UM series, a 9.15-fold (95% confidence interval = 4.24-fold to 19.73-fold) increased incidence compared with the general population (Fisher exact test, P = 2.00 × 10-5, 2-sided), and 4 additional deleterious MBD4 mutations in the M3 cohort, including 3 germline and 1 somatic mutations. Tumors carrying deleterious MBD4 mutations were all associated with high tumor mutation burden and a CpG>TpG hypermutator phenotype.We demonstrate that MBD4 is a new predisposing gene for UM associated with hypermutated M3 tumors. The tumor spectrum of this predisposing condition will likely expand with the addition of MBD4 to diagnostic panels. Tumors arising in such a context should be recognized because they may respond to immunotherapy.
Abstract 15123: Estimation of Stroke Outcomes in Atrial Fibrillation Using Continuous Clinical and Implantable Device Data From the Treat-AF Study: A Comparison With CHA2DS2-VASc Score
Authors: Jason P Bentley, Mariam Askari, Jun Fan, Paul A Heidenreich, Kenneth W Mahaffey, Manisha Desai, David Scheinker, Mintu P Turakhia
Journal: Circulation (2018)

Introduction: In atrial fibrillation (AF), the CHA2DS2-VASc score is widely used for risk stratification but has consistently shown modest discrimination at best. The addition of time-varying healt...