tbuckley/cabot-search huggingface dataset:
Recent advances in the design of choline kinase α inhibitors and the molecular basis of their inhibition
Authors: Belén Rubio‐Ruiz, Lucía Serrán‐Aguilera, Ramón Hurtado‐Guerrero, Ana Conejo‐García
Journal: Medicinal Research Reviews (2020)

Abstract Upregulated choline metabolism, characterized by an increase in phosphocholine (PCho), is a hallmark of oncogenesis and tumor progression. Choline kinase (ChoK), the enzyme responsible for PCho synthesis, has consequently become a promising drug target for cancer therapy and as such a significant number of ChoK inhibitors have been developed over the last few decades. More recently, due to the role of this enzyme in other pathologies, ChoK inhibitors have also been used in new therapeutic approaches against malaria and rheumatoid arthritis. Here, we review research results in the field of ChoKα inhibitors from their synthesis to the molecular basis of their binding mode. Strategies for the development of inhibitors and their selectivity on ChoKα over ChoKβ, the plasticity of the choline‐binding site, the discovery of new exploitable binding sites, and the allosteric properties of this enzyme are highlighted. The outcomes summarized in this review will be a useful guide to develop new multifunctional potent drugs for the treatment of various human diseases.
Appraisal and revalidation for UK doctors: the profession should determine any requirements
Authors: Paul Thornton
Journal: BMJ (2020)

The analysis by Tzortziou Brown and colleagues says it all1—the proposal to reintroduce appraisal and revalidation is ill timed, wholly mistaken, and should be withdrawn. If the General Medical Council seeks credibility, then a turnaround is required.

Clarity of purpose should be the …
Incidental Finding of Endobronchial Metastasis by 18F-FDG PET/CT Leads to Change in Management in a Patient With Rectal Adenocarcinoma
Authors: Matthias P. Fabritius, Adrien Holzgreve, Thomas Knösel, Reinhold Tiling, Johannes Rübenthaler
Journal: Clinical Nuclear Medicine (2020)

Abstract A 58-year-old man with history of resected rectal adenocarcinoma and synchronous unifocal pulmonary metastasis showed a solitary pulmonary relapse in follow-up CT after 3 years of complete remission. Resection was planned. Preoperative 18 F-FDG PET/CT detected a high focal 18 F-FDG uptake in the left main bronchus. Bronchoscopy showed a papillary endobronchial lesion that was biopsied. Histology confirmed distant colorectal metastasis. The initial treatment plan changed, and the recommendation for systemic therapy was made by a multidisciplinary oncology team. Endobronchial metastases are rare and difficult to detect in conventional CT. PET/CT is useful to uncover endobronchial metastasis, which may change patient management.
Manufacturers Get Advice on Preventing Nitrosamine Impurities
Authors: Mary Chris Jaklevic
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Impact of COVID-19 on patients with rheumatic complications of cancer immunotherapy: results of a registry survey
Authors: Nilasha Ghosh, Aidan Tirpack, Karmela K Chan, Anne R Bass
Journal: Journal for ImmunoTherapy of Cancer (2020)

Immune checkpoint inhibitors (ICI) block negative regulatory molecules, such as CTLA-4, PD-1 and PD-L1, in order to mount an antitumor response. T cells are important for antiviral defense, but it is not known whether patients with cancer treated with ICI are more or less vulnerable to viral infections such as COVID-19. Furthermore, immunosuppressive treatment of immune-related adverse events (irAE) may also impact infection risk. Rheumatic irAEs are often persistent, and can require long-term treatment with immunosuppressive agents. The aim of this study was to determine the incidence of COVID-19 infection and assess changes in ICI and immunosuppressive medication use among patients enrolled in a prospective rheumatic irAE registry during the height of the COVID-19 pandemic. On April 16 2020, following the ‘surge’ of COVID-19 infections in the New York Tri-State area, we sent a 23-question survey to 88 living patients enrolled in a single institutional registry of patients with rheumatic irAE. Questions addressed current cancer and rheumatic irAE status, ICI and immunosuppressant medication use, history of COVID-19 symptoms and/or diagnosed infection. A follow-up survey was sent out 6 weeks later. Sixty-five (74%) patients completed the survey. Mean age was 63 years, 59% were female, 70% had received anti-PD-(L)1 monotherapy and 80% had had an irAE affecting their joints. Six patients (10%) had definite or probable COVID-19, but all recovered uneventfully, including two still on ICI and on low-to-moderate dose prednisone. Of the 25 on ICI within the last 6 months, seven (28%) had their ICI held due to the pandemic. In patients on immunosuppression for irAE, none had changes made to those medications as a result of the pandemic. The incidence of COVID-19 was no higher in patients still on ICI. Ten percent of rheumatic irAE patients developed COVID-19 during the NY Tri-state ‘surge’ of March–April 2020. Oncologists held ICI in a quarter of the patients still on them, particularly women, those on anti-PD-(L)1 monotherapy, and those who had had a good cancer response. The incidence of COVID-19 was no higher on patients still on ICI. None of the patients on disease-modifying antirheumatic drugs or biological immunosuppressive medications developed COVID-19.
Epithelial-Derived Reactive Oxygen Species Enable AppBCX-Mediated Aerobic Respiration of Escherichia coli during Intestinal Inflammation
Authors: Rachael B. Chanin, Maria G. Winter, Luisella Spiga, Elizabeth R. Hughes, Wenhan Zhu, Savannah J. Taylor, Alexandre Arenales, Caroline C. Gillis, Lisa Büttner, Angel G. Jimenez, Madeline P. Smoot, Renato L. Santos, Sebastian E. Winter
Journal: Cell Host & Microbe (2020)
Abstract 11878: The Role of Coronary Artery Calcium as a Risk Enhancer to Personalize Treatment in Stage 1 Hypertension - The Multi-ethnic Study of Atherosclerosis
Authors: Amal Abdellatif, Mohamed Elshazly, Soha Dargham, Renato Quispe, Miguel Cainzos-Achirica, Seth S Martin, Joseph Yeboah, Bruce M Psaty, Wendy S Post, Khurram Nasir, Matthew J Budoff, Roger S Blumenthal, Michael J Blaha, John W McEvoy
Journal: Circulation (2019)

Background: The 2017 ACC/AHA multi-society High Blood Pressure (BP) guidelines recommend risk-based BP treatment goals in stage 1 hypertension. We sought to establish whether coronary artery calciu...
In adults exposed to COVID-19, hydroxychloroquine did not reduce confirmed or probable COVID-19; trial stopped for futility
Authors: Ameeta Singh, Ashlesha Sonpar
Journal: Annals of Internal Medicine (2020)

Source CitationBoulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19. N Engl J Med. 2020;383:517-25. https://pubmed.ncbi.nlm.nih.gov/32492293/AbstractClinical Impact RatingsGIM/FP/GP: Emergency Med: Hospitalists: Infectious Disease: Public Health:
MMR variants & HNPCC susceptibility
Authors: Sheron Perera, Bharati Bapat
Journal: Cancer Research (2006)

3343  Germline mutations in the mismatch repair (MMR) genes predispose to a common form of colorectal cancer known as hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch Syndrome. Approximately 25% of sequence alterations in the MMR genes are of uncertain pathogenic relevance, which poses difficulties for predictive testing programs offered to familial colorectal cancer patients. We hypothesize that missense alterations in distinct domains of the MMR proteins likely affect their function(s) to varying degrees and this likely contributes to the variable disease phenotype observed in HNPCC. Hence this project aims to characterize the pathogenicity associated with a panel of variants of unknown functional significance, and to elucidate the mechanisms by which they exert their effects. We have selected a panel of unclassified variants identified in HNPCC patients based on their presence in functional domains, evolutionary status and pathogenicity as predicted by computational databases. The variants chosen in hMLH1 include: I19F, A128S, R265C, K618A and L749Q. These variants were created in plasmids containing wild type MLH1 cDNA by site-directed mutagenesis, verified by sequencing and transiently transfected into the colon cancer cell line HCT116, which is deficient for hMLH1. Western blotting assays were carried out to ascertain the expression levels of the proteins. Coimmunoprecipitation experiments were performed to determine if these putative mutations disrupt interactions with partner proteins. In order to differentiate between endogenous and transfected mRNA, we have sub-cloned the wild type and variant MLH1 cDNAs into tagged expression constructs, which will be used in mRNA stability assays following Actinomycin D treatment. Cyto-nuclear fractionation experiments are in progress to ascertain if the variants affect the localization of the MMR proteins. Results indicate that the variants R265C and K618A significantly decrease the overall expression of MLH1 compared to the wild type vector. I19F, A128S and L749Q however, affect the temporal expression profile of MLH1, indicating a possible decrease in the stability of the protein. Coimmunoprecipitation experiments indicate that the ability of the MLH1 L749Q variant to interact with its cognate partner PMS2 is compromised. This is an interesting observation as this variant is located just adjacent to the previously defined PMS2 interaction domain. Preliminary results from cyto-nuclear fractionation studies show no difference between the localization of the variants R265C, L749Q and wild type MLH1. Our results indicate that the majority of unclassified variants investigated in this study perturb the expression and/ or interaction of the MMR proteins. In addition to its clinical utility, these studies will also provide a better understanding of the MMR proteins and the manner in which they contribute to colorectal cancer progression.
Management of a patient with mantle cell lymphoma who developed severe neurotoxicity after chimeric antigen receptor T-cell therapy in ZUMA-2
Authors: Michael Wang, Preetesh Jain, T Linda Chi, Sheree E Chen, Amy Heimberger, Shiao-Pei Weathers, Lianqing Zheng, Arati V Rao, John M Rossi
Journal: Journal for ImmunoTherapy of Cancer (2020)

Cerebral edema following chimeric antigen receptor (CAR) T-cell therapy can be fatal. ZUMA-2 is a pivotal phase 2, multicenter study evaluating KTE-X19, an autologous anti-CD19 CAR T-cell therapy, in relapsed/refractory mantle cell lymphoma. We describe a 65-year-old patient in ZUMA-2 who developed cerebral edema following CAR T-cell therapy and had complete recovery after multimodality clinical intervention including rabbit antithymocyte globulin (ATG). Biomarker results show early and robust CAR T-cell expansion and related induction of inflammatory cytokines, followed by rapid declines in CAR T-cell and proinflammatory cytokine levels after ATG administration. This clinical profile highlights a potential relevance of ATG in treating severe CAR T-cell-related neurotoxicity.
<i>In situ</i>immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy
Authors: Yinwen Cheng, Caitlin D Lemke-Miltner, Wattawan Wongpattaraworakul, Zhaoming Wang, Carlos H F Chan, Aliasger K Salem, George J Weiner, Andrean L Simons
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background CMP-001 is a novel Toll-like receptor-9 agonist that consists of an unmethylated CpG-A motif-rich G10 oligodeoxynucleotide (ODN) encapsulated in virus-like particles. In situ vaccination of CMP-001 is believed to activate local tumor-associated plasmacytoid dendritic cells (pDCs) leading to type I interferon secretion and tumor antigen presentation to T cells and systemic antitumor T cell responses. This study is designed to investigate if CMP-001 would enhance head and neck squamous cell carcinoma (HNSCC) tumor response to anti-programmed cell death protein-1 (anti-PD-1) therapy in a human papilloma virus-positive (HPV+) tumor mouse model. Methods Immune cell activation in response to CMP-001±anti-Qβ was performed using co-cultures of peripheral blood mononuclear cells and HPV+/HPV- HNSCC cells and then analyzed by flow cytometry. In situ vaccination with CMP-001 alone and in combination with anti-PD-1 was investigated in C57BL/6 mice-bearing mEERL HNSCC tumors and analyzed for anti-Qβ development, antitumor response, survival and immune cell recruitment. The role of antitumor immune response due to CMP-001+anti-PD-1 treatment was investigated by the depletion of natural killer (NK), CD4 + T, and CD8 + T cells. Results Results showed that the activity of CMP-001 on immune cell (pDCs, monocytes, CD4+/CD8+ T cells and NK cells) activation depends on the presence of anti-Qβ. A 2-week ‘priming’ period after subcutaneous administration of CMP-001 was required for robust anti-Qβ development in mice. In situ vaccination of CMP-001 was superior to unencapsulated G10 CpG-A ODN at suppressing both injected and uninjected (distant) tumors. In situ vaccination of CMP-001 in combination with anti-PD-1 therapy induced durable tumor regression at injected and distant tumors and significantly prolonged mouse survival compared with anti-PD-1 therapy alone. The antitumor effect of CMP-001+anti-PD-1 was accompanied by increased interferon gamma (IFNγ) + CD4 + /CD8 + T cells compared with control-treated mice. The therapeutic and abscopal effect of CMP-001+ anti-PD-1 therapy was completely abrogated by CD8 + T cell depletion. Conclusions These results demonstrate that in situ vaccination with CMP-001 can induce both local and abscopal antitumor immune responses. Additionally, the antitumor efficacy of CMP-001 combined with α-PD-1 therapy warrants further study as a novel immunotherapeutic strategy for the treatment of HNSCC.
COVID-19 in Italian patients with rheumatic autoimmune systemic diseases
Authors: Clodoveo Ferri, Dilia Giuggioli, Vincenzo Raimondo, Poupak Fallahi, Alessandro Antonelli
Journal: Annals of the Rheumatic Diseases (2020)

We followed with great interest the numerous reports published by the Annals 1–9 as regards the impact of the COVID-19 pandemic on different rheumatic autoimmune systemic diseases (ASD), including the survey study by Costa et al 9 that underlined the usefulness of telerheumatology in the management of patients with psoriatic arthritis in COVID-19 era. On the same topic, the world literature encompasses a large number of anecdotal observations, cohort studies and telephone surveys.1–15 Overall, the observed prevalence of symptomatic COVID-19, usually as mild-moderate disease, in patients with chronic arthritis was comparable to that found in the general population, while worse outcomes represented almost rare events.1–15 Conversely, increased percentages of symptomatic COVID-19 were observed in patient cohorts with connective tissue diseases, especially systemic lupus or systemic vasculitis.6 7 Of note, in ASD complicated by COVID-19, the baseline use of immune modifiers, namely, conventional synthetic (csDMARD), biological (bDMARD) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARD), was not associated with worse COVID-19 disease outcomes.3–5 9 10 Almost invariably these monocentre studies focused on ASD patients’ populations from limited geographical areas.1–15 Given the heterogeneous distribution of pandemic infection within the same country, we investigated the impact of COVID-19 in ASD patients’ populations from three distinct regions of Italy (northern, Emilia Romagna; central, Tuscany; and southern, Calabria), characterised by different spread of the COVID-19 pandemic, prevalent in northern Italy with a marked gradient north-south.16 Our 6-week multicentre telephone survey of 1641 unselected patients with ASD confirmed the quite benign clinical course of COVID-19 in ASD, along with the safety of baseline use of either …
Association of Medicaid-Focused or Commercial Medicaid Managed Care Plan Type With Outpatient and Acute Care
Authors: Shailender Swaminathan, Chima D. Ndumele, Sarah H. Gordon, Yoojin Lee, Amal N. Trivedi
Journal: JAMA Internal Medicine (2020)

Enrollment in Medicaid managed care plans has increased rapidly, particularly in national commercial insurance plans. Whether the type of managed care plan is associated with the use of health services for Medicaid beneficiaries is unknown. To compare the use of outpatient and acute care between Medicaid enrollees randomly assigned to a national commercial managed care plan or a local Medicaid-focused managed care plan. This natural experiment of a cohort of Medicaid enrollees randomly assigned to 2 managed care plans in a Northeastern US state was conducted from June 30, 2009, to June 30, 2013. Statistical analysis was performed from September 1, 2019, to August 30, 2020. Assignment to a Medicaid-focused insurance plan or a commercial managed care plan. Outpatient visits, emergency department visits, and total inpatient and ambulatory care-sensitive hospitalizations. A total of 8010 patients were included in the analysis: 4737 were assigned to a Medicaid-focused plan (2795 female [59.0%]; mean [SD] age, 17.8 [3.2] years) and 3273 to a commercial managed care plan (1915 female [58.5%]; mean [SD] age, 17.9 [3.3] years). Those randomly assigned to the Medicaid-focused plan had a mean (SD) of 6.67 (9.18) annual outpatient visits per person, and those assigned to the commercial plan had a mean (SD) of 8.36 (11.77) annual outpatient visits per person (adjusted absolute difference, 1.72 [95% CI, 1.31-2.13]; 22% relative difference). The increased use of outpatient visits in the commercial plan was associated with an increase in specialty care visits (mean [SD], 2.34 [6.31] visits in Medicaid-focused plan vs 3.75 [9.32] visits in commerical plan; adjusted absolute difference, 1.43 visits [95% CI, 1.25-1.56 visits]; 61% relative difference). Mean (SD) annual emergency department visits were 0.49 (1.39) per person in the Medicaid-focused plan and 0.51 (1.40) in the commercial plan (adjusted absolute difference, 0.02 [95% CI, -0.02 to 0.05]). Mean (SD) annual inpatient admissions were 0.067 (0.45) per person in the Medicaid-focused plan and 0.069 (0.53) in the commercial plan (adjusted absolute difference, 0.003 [95% CI, -0.01 to 0.02]). Plan assignment was not significantly associated with ambulatory care-sensitive admissions. Results were consistent in instrumental variables analyses that accounted for disenrollment and switching. Compared with Medicaid managed care enrollees assigned to a Medicaid-focused plan, those assigned to a commercial plan had more outpatient visits, particularly for specialty care, but had similar rates of emergency department visits and hospitalizations. These findings suggest that the type of managed care plan may be associated with health services use and spending among Medicaid beneficiaries and that random assignment may help states understand how well different plans perform for enrollees.
EULAR recommendations for a core data set for pregnancy registries in rheumatology
Authors: Yvette Meissner, Rebecca Fischer-Betz, Laura Andreoli, Nathalie Costedoat-Chalumeau, Diederik De Cock, Radboud J E M Dolhain, Frauke Forger, Doreen Goll, Anna Molto, Catherine Nelson-Piercy, Rebecca Özdemir, Luigi Raio, Sebastian Cruz Rodríguez-García, Savino Sciascia, Marianne Wallenius, Astrid Zbinden, Angela Zink, Anja Strangfeld
Journal: Annals of the Rheumatic Diseases (2020)

There is an urgent need for robust data on the trajectories and outcomes of pregnancies in women with inflammatory rheumatic diseases (IRD). In particular when rare outcomes or rare diseases are to be investigated, collaborative approaches are required. However, joint data analyses are often limited by the heterogeneity of the different data sources.To facilitate future research collaboration, a European League Against Rheumatism (EULAR) Task Force defined a core data set with a minimum of items to be collected by pregnancy registries in rheumatology covering the period of pregnancy and the 28-day neonatal phase in women with any underlying IRD.A stepwise process included a two-round Delphi survey and a face-to-face meeting to achieve consensus about relevant items.A total of 64 multidisciplinary stakeholders from 14 different countries participated in the two rounds of the Delphi process. During the following face-to-face meeting of the EULAR Task Force, consensus was reached on 51 main items covering 'maternal information', 'pregnancy' and 'treatment'. Generic instruments for assessment are recommended for every item. Furthermore, for the five most frequent IRDs rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, systemic lupus erythematosus and other connective tissue diseases, disease-specific laboratory markers and disease activity measurements are proposed.This is the first consensus-based core data set for prospective pregnancy registries in rheumatology. Its purpose is to stimulate and facilitate multinational collaborations that aim to increase the knowledge about pregnancy course and safety of treatment in women with IRDs during pregnancy.
Specificity and positive predictive value of SARS-CoV-2 nucleic acid amplification testing in a low-prevalence setting
Authors: Jordan P. Skittrall, Michael Wilson, Anna A. Smielewska, Surendra Parmar, Mary D. Fortune, Dominic Sparkes, Martin D. Curran, Hongyi Zhang, Hamid Jalal
Journal: Clinical Microbiology and Infection (2020)