tbuckley/cabot-search huggingface dataset:
<i>TP53</i>, a gene for colorectal cancer predisposition in the absence of Li-Fraumeni-associated phenotypes
Authors: Mariona Terradas, Pilar Mur, Sami Belhadj, Emma R Woodward, George J Burghel, Pau M Munoz-Torres, Isabel Quintana, Matilde Navarro, Joan Brunet, Conxi Lazaro, Marta Pineda, Victor Moreno, Gabriel Capella, D Gareth R Evans, Laura Valle
Journal: Gut (2020)

Germline TP53 pathogenic (P) variants cause Li-Fraumeni syndrome (LFS), an aggressive multitumor-predisposing condition. Due to the implementation of multigene panel testing, TP53 variants have been detected in individuals without LFS suspicion, for example, patients with colorectal cancer (CRC). We aimed to decipher whether these findings are the result of detecting the background population prevalence or the aetiological basis of CRC.We analysed TP53 in 473 familial/early-onset CRC cases and evaluated the results together with five additional studies performed in patients with CRC (total n=6200). Control population and LFS data were obtained from Genome Aggregation Database (gnomAD V.2.1.1) and the International Agency for Research on Cancer (IARC) TP53 database, respectively. All variants were reclassified according to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), following the ClinGen TP53 Expert Panel specifications.P or likely pathogenic (LP) variants were identified in 0.05% of controls (n=27/59 095) and 0.26% of patients with CRC (n=16/6200) (p<0.0001) (OR=5.7, 95% CI 2.8 to 10.9), none of whom fulfilled the clinical criteria established for TP53 testing. This association was still detected when patients with CRC diagnosed at more advanced ages (>50 and>60 years) were excluded from the analysis to minimise the inclusion of variants caused by clonal haematopoiesis. Loss-of-function and missense variants were strongly associated with CRC as compared with controls (OR=25.44, 95% CI 6.10 to 149.03, for loss of function and splice-site alleles, and OR=3.58, 95% CI 1.46 to 7.98, for missense P or LP variants).TP53 P variants should not be unequivocally associated with LFS. Prospective follow-up of carriers of germline TP53 P variants in the absence of LFS phenotypes will define how surveillance and clinical management of these individuals should be performed.
COVID-19 in patients with cirrhosis: understanding adverse impact
Authors: Sanchit Sharma, Anshuman Elhence, Manas Vaishnav, Ramesh Kumar, None Shalimar
Journal: Gut (2020)

We read with great interest the article by Bajaj et al 1 comparing the outcomes of hospitalised patients with COVID-19+cirrhosis with that of patients with cirrhosis alone and COVID-19 alone. The authors found that the risk of mortality in patients with COVID-19+cirrhosis was not significantly higher than in patients with cirrhosis alone, though it was higher than patients with COVID-19 alone. The findings of the current study add to the existing understanding of the effects of COVID-19 in patients with cirrhosis;2–5 however, interpretation of such results must be mindful of two facts: first, the study subjects were not properly matched with regard to the severity of cirrhosis; and second, small and unbalanced sample size comparisons may lead to erroneous conclusions.

Model for end-stage liver disease (MELD) score is a reliable marker of severity of liver disease and predictor of mortality in patients with cirrhosis. In this study, patients with COVID-19+cirrhosis had …
Efficacy of Selpercatinib in <i>RET</i>-Altered Thyroid Cancers
Authors: Lori J. Wirth, Eric Sherman, Bruce Robinson, Benjamin Solomon, Hyunseok Kang, Jochen Lorch, Francis Worden, Marcia Brose, Jyoti Patel, Sophie Leboulleux, Yann Godbert, Fabrice Barlesi, John C. Morris, Taofeek K. Owonikoko, Daniel S.W. Tan, Oliver Gautschi, Jared Weiss, Christelle de la Fouchardière, Mark E. Burkard, Janessa Laskin, Matthew H. Taylor, Matthias Kroiss, Jacques Medioni, Jonathan W. Goldman, Todd M. Bauer, Benjamin Levy, Viola W. Zhu, Nehal Lakhani, Victor Moreno, Kevin Ebata, Michele Nguyen, Dana Heirich, Edward Y. Zhu, Xin Huang, Luxi Yang, Jennifer Kherani, S. Michael Rothenberg, Alexander Drilon, Vivek Subbiah, Manisha H. Shah, Maria E. Cabanillas
Journal: New England Journal of Medicine (2020)

RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown.
THU0164 Is soluble cd44 isoform variant 5 useful as predicting factor and as parameter for long-term observation in rheumatoid arthritis?
Authors: M Skoumal, G Kolarz, A Wottawa
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> CD44 is a widely expressed adhesion molecule responsible for cell-cell, cell-matrix interaction and binds hyaluronan and other extracellular matrix and cell surface proteins. Binding of CD44 leads to immune mediated inflammation, target lysis and tumour dissemination. Except this constant membrane bound form a variety of isoforms are expressed. Soluble CD44 variant isoform 5 (sCD44v5) is associated with a high rate of cell division and is elevated in patients with erosive IgM rheumatoid factor positive Rheumatoid Arthritis (RA+). <h3>Objectives</h3> To examine whether sCD44v5 correlates with inflammation and/or joint destruction in a long-term treatment of patients with RA. <h3>Methods</h3> Serum levels of sCD44v5 were measured in 73 patients with RA according to the criteria of ACR treated in intervals in our department in the duration of 10 years using a commercially available ELISA-test, developed by Bender-Med-Systems-Vienna. The results of sCD44v5 were compared with Disease Activity Score (DAS), 28 Joint Count (28JC), 30 Swollen Joint Count (30SJC), Ritchie Index, Proximal Interphalangeal Score (PIP), Stoke Index, Larson Score, Steinbrocker Stage, C- Reactive- Protein (CRP), Erythrocyte Sedimentation Rate (ESR), rheumatoid factor (RF) and DMARD therapy. <h3>Results</h3> We detected elevated serum levels of sCD44v5 in 50/356 measurements, with a range from 58,4 to 312,9. The mean sCD44v5 was 42,3 ng/ml. The results showed a significant correlation with RF (mean 299,4 U/ml, p &lt; 0,001) and a weak correlation with ESR(mean 31,9 mm HG, p &lt; 0,03)), but no correlation with CRP (mean 21,1 mg/l), DAS (mean 3,54) and other clinical scores. Furthermore we found no significant difference of sCD44v5 with different DMARD therapies. <h3>Conclusion</h3> In our cohort sCD44v5 does not prove to be useful as predicting factor or indicator for a long-term treatment observation. Although sCD44v5 is known to be elevated in patients with rheumatoid flare such a correlation could not be shown in our study with weak to moderate inflamed patients. Soluble CD44v5 therefore seems to be elevated only in severe inflammation. <h3>References</h3> Haberhauer G, Kittel EM. Soluble CD44-Isoform variant 5 (sCD44v5): a new serum marker in rheumatoid arthritis? J Rheumatol. 1998;25(7):1442–4 Haberhauer G, Skoumal M, Kittel EM, Bauer K, Feyertag J, Dunky A. Soluble CD44-isoform variant -5 (sCD44v5) in psoriatic arthritis. Clin Exp Rheumatol. 1998;16(6):766–7 Feyertag J, Haberhauer G, Skoumal M, Kittl EM, Bauer K, Dunky A. Serumspiegel löslicher CD 44-Isoform-Variante 5 von Patienten mit seropositiver Rheumatoid-Arthritis unter Cyclosporin-A-Therapie. Acta Medica Austriaca 2000;27(5):156–9
Cytokine-directed therapy with tocilizumab for immune checkpoint inhibitor-related hemophagocytic lymphohistiocytosis
Authors: B.C. Özdemir, S. Latifyan, M. Perreau, C. Fenwick, L. Alberio, G. Waeber, F. Spertini, L. de Leval, O. Michielin, M. Obeid
Journal: Annals of Oncology (2020)
DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives
Authors: Lukas Perkhofer, Johann Gout, Elodie Roger, Fernando Kude de Almeida, Carolina Baptista Simões, Lisa Wiesmüller, Thomas Seufferlein, Alexander Kleger
Journal: Gut (2020)

Complex rearrangement patterns and mitotic errors are hallmarks of most pancreatic ductal adenocarcinomas (PDAC), a disease with dismal prognosis despite some therapeutic advances in recent years. DNA double-strand breaks (DSB) bear the greatest risk of provoking genomic instability, and DNA damage repair (DDR) pathways are crucial in preserving genomic integrity following a plethora of damage types. Two major repair pathways dominate DSB repair for safeguarding the genome integrity: non-homologous end joining and homologous recombination (HR). Defective HR, but also alterations in other DDR pathways, such as BRCA1 , BRCA2 , ATM and PALB2, occur frequently in both inherited and sporadic PDAC. Personalised treatment of pancreatic cancer is still in its infancy and predictive biomarkers are lacking. DDR deficiency might render a PDAC vulnerable to a potential new therapeutic intervention that increases the DNA damage load beyond a tolerable threshold, as for example, induced by poly (ADP-ribose) polymerase inhibitors. The Pancreas Cancer Olaparib Ongoing (POLO) trial, in which olaparib as a maintenance treatment improved progression-free survival compared with placebo after platinum-based induction chemotherapy in patients with PDAC and germline BRCA1/2 mutations, raised great hopes of a substantially improved outcome for this patient subgroup. This review summarises the relationship between DDR and PDAC, the prevalence and characteristics of DNA repair mutations and options for the clinical management of patients with PDAC and DNA repair deficiency.
An inflammatory cytokine signature predicts COVID-19 severity and survival
Authors: Diane Marie Del Valle, Seunghee Kim-Schulze, Hsin-Hui Huang, Noam D. Beckmann, Sharon Nirenberg, Bo Wang, Yonit Lavin, Talia H. Swartz, Deepu Madduri, Aryeh Stock, Thomas U. Marron, Hui Xie, Manishkumar Patel, Kevin Tuballes, Oliver Van Oekelen, Adeeb Rahman, Patricia Kovatch, Judith A. Aberg, Eric Schadt, Sundar Jagannath, Madhu Mazumdar, Alexander W. Charney, Adolfo Firpo-Betancourt, Damodara Rao Mendu, Jeffrey Jhang, David Reich, Keith Sigel, Carlos Cordon-Cardo, Marc Feldmann, Samir Parekh, Miriam Merad, Sacha Gnjatic
Journal: Nature Medicine (2020)
Changes in Reoperation After Publication of Consensus Guidelines on Margins for Breast-Conserving Surgery
Authors: M. Luke Marinovich, Naomi Noguchi, Monica Morrow, Nehmat Houssami
Journal: JAMA Surgery (2020)

The 2014 publication of the Society of Surgical Oncology-American Society for Radiation Oncology (SSO-ASTRO) Consensus Guideline on Margins for Breast-Conserving Surgery recommended a negative margin definition of no ink on tumor. Adoption of this guideline would represent a major change in surgical practice that could lower the rates of reoperation.To assess changes in reoperation rates after publication of the SSO-ASTRO guideline.A systematic search of Embase, PREMEDLINE, Evidence-Based Medicine Reviews, Scopus, and Web of Science for biomedical literature published from January 2014 to July 2019 was performed. This search was supplemented by web searches and manual searching of conference abstracts.Included studies compared the reoperation rates in preguideline vs postguideline cohorts (actual change), retrospectively applied the SSO-ASTRO guideline to a preguideline cohort (projected change), or described the economic outcomes of the guideline.Study characteristics and reoperation rates were extracted independently by 2 reviewers. Odds ratios (ORs) were pooled by random effects meta-analysis. Analyses were stratified by study setting (institutional or population) and preguideline accepted margins. The economic outcomes of the guideline were summarized narratively. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed.Odds ratios for postguideline vs preguideline reoperation rates.From 1114 citations, 30 studies (with 599 016 participants) reported changes in reoperation rates. Studies included a median (range) of 487 (100-521 578) participants, and 20 studies were undertaken in the US, 6 in the UK, 3 in Canada, and 1 in Australia. Among 21 studies of actual changes, pooled ORs showed a statistically significant reduction in reoperation, with an OR lower in institution-based studies than in population-based studies (OR, 0.62 [95% CI, 0.52-0.74] vs 0.76 [95% CI, 0.72-0.80]; P = .04 for subgroup differences). Among 9 studies of projected changes, the pooled OR was lower for preguideline margin thresholds of 2 mm or more compared with 1 mm (OR, 0.47 [95% CI, 0.40-0.56] vs 0.85 [95% CI, 0.79-0.91; P < .001 for subgroup differences). Projected changes were likely to overestimate actual changes. Six studies that estimated the postguideline economic outcome found the guideline to be potentially cost saving, with a median (range) saving of US $3540 ($1800-$25 650) per woman avoiding reoperation.This study found a decrease in reoperation rates after the publication of the SSO-ASTRO guideline; this reduction was greater at an institutional level than a population level, the latter reflecting the differences in guideline adoption between centers. These early outcomes may be conservative estimates of longer-term implications.
Midwives, paramedics, and physiotherapists could deliver covid and flu vaccines under government plan
Authors: Elisabeth Mahase
Journal: BMJ (2020)

A wider range of healthcare professionals, including midwives, paramedics, physiotherapists, and pharmacists, will be asked to administer covid-19 and flu vaccines under changes proposed by the government.1

The government is consulting on changes to the Human Medicine Regulations with the aim of enabling the safe deployment of a covid-19 vaccine as soon as one is available. The changes include allowing the Medicines and Healthcare Products Regulatory Agency to grant temporary authorisation for a covid-19 vaccine that has not yet been licensed …
Recent developments on PET radiotracers for TSPO and their applications in neuroimaging
Authors: Lingling Zhang, Kuan Hu, Tuo Shao, Lu Hou, Shaojuan Zhang, Weijian Ye, Lee Josephson, Jeffrey H. Meyer, Ming-Rong Zhang, Neil Vasdev, Jinghao Wang, Hao Xu, Lu Wang, Steven H. Liang
Journal: Acta Pharmaceutica Sinica B (2020)

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.
Abstract 15570: A Telemedicine-Based Program Covers Millions of Patients and Flattens Disparities in AMI Care
Authors: Sameer Mehta, Roberto Botelho, Jamil Cade, Marco Perin, Mauricio Prudente, Francisco Fernandez, Ricardo Cavalcanti, Rodolfo Cardoso, Fredy Bojanini, Nabil Hamdan, Cesar Dusilek, Marco Alcocer, Juan Carlos Perez Alva, Alfredo Estrada, Manuel Odin De Los Rios, Alejandra Frauenfelder, Daniel Vieira, Mariana Ceschim, Rodrigo Jacobucci, Lorena Pisana, Jorge Mazzini, Maria Angelica Marin, Camila Funatsu, Isabella Vallenilla, Akhil Vaid
Journal: Circulation (2019)

Introduction: Global health trends reveal vast number of AMI patients that do not get reperfused, in particular, in developing countries. Latin America Telemedicine Infarct Network (LATIN) is a tel...
Involuntary Groaning Induced by Levodopa Therapy in a Patient With Progressive Supranuclear Palsy
Authors: Jung E. Park
Journal: JAMA Neurology (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 Neurology 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 Neurology journal
A phase I study of MK-2206, an oral potent allosteric Akt inhibitor (Akti), in patients (pts) with advanced solid tumor (ST)
Authors: A. W. Tolcher, T. A. Yap, I. Fearen, A. Taylor, C. Carpenter, A. T. Brunetto, M. Beeram, K. Papadopoulos, L. Yan, J. de Bono
Journal: Journal of Clinical Oncology (2009)

3503 Background: Akt facilitates cell proliferation/survival and is a suspected driver of progression in ST. MK-2206, a highly selective non-ATP competitive allosteric Akti, has nM IC 50 and broad preclinical antitumor activity. Methods: Safety and tolerability of MK-2206 administered QOD in 28-day cycles (cy) was assessed. Doses evaluated: 30, 60, 90 mg, and 75 mg. Main eligibility criteria: ≥18 yo, evaluable advanced ST, ECOG ≤1, HbA1c ≤8% or fasting glucose ≤110% upper limit of normal. PK and phosphorylated Akt (pAkt) in whole blood by meso-scale ELISA were measured. Sequential tumor biopsies were performed in a subset of pts. Results: Dose escalation occurred in 19 pts (8 female/11 male; median age 57 yo; ECOG 0/1: 5/14) and 37 cy of therapy with no DLTs at 30 and 60 mg. CTCAE G3/4 skin rash and CTCAE G3 mucositis were observed at 90 mg in 4/7 pts. After further accrual at 60 mg confirmed safety at this dose, 75 mg was explored; however, 2/3 pts experienced DLT of rash. Dose escalation is complete; the MTD of MK-2206 is 60 mg QOD. Common drug-related AEs included skin (47.1%), gastrointestinal (41.2%), and general disorders (29.4%). AUC 0–48hr and C max were dose proportional up to 60 mg. Median T max is 6 hrs and mean t 1/2 ranged from 63 to 76 hr. MK-2206 concentrations exceeding a preliminary, statistically determined PK target of approximately 50–65 nM for significant pAkti in blood were maintained over the entire dosing interval in all patients in the 60 mg cohort. Evidence of PD activity included decreases in whole blood pAkt at all dose levels, reversible CTCAE G1/2 hyperglycemia and CTCAE G1 insulin c-peptide elevations. RECIST stable disease following 2 cycles of therapy was observed in 1 pt at 30 mg and 5 pts at 60 mg. Observed clinical activity included: central tumor necrosis, decreased ascites and peripheral edema, reduction in index lesions, normalization of LFTs, and decreased CA-125. Conclusions: MK-2206 is generally well tolerated at doses up to 60 mg QOD with plasma concentrations that portend activity in preclinical models. PK/PD data suggest a substantial and maintained target inhibition at 60 mg. [Table: see text]
MILO/ENGOT-ov11: Binimetinib Versus Physician’s Choice Chemotherapy in Recurrent or Persistent Low-Grade Serous Carcinomas of the Ovary, Fallopian Tube, or Primary Peritoneum
Authors: Bradley J. Monk, Rachel N. Grisham, Susana Banerjee, Elsa Kalbacher, Mansoor Raza Mirza, Ignacio Romero, Peter Vuylsteke, Robert L. Coleman, Felix Hilpert, Amit M. Oza, Anneke Westermann, Martin K. Oehler, Sandro Pignata, Carol Aghajanian, Nicoletta Colombo, Esther Drill, David Cibula, Kathleen N. Moore, Janna Christy-Bittel, Josep M. del Campo, Regina Berger, Christian Marth, Jalid Sehouli, David M. O’Malley, Cristina Churruca, Adam P. Boyd, Gunnar Kristensen, Andrew Clamp, Isabelle Ray-Coquard, Ignace Vergote
Journal: Journal of Clinical Oncology (2020)

PURPOSE Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC. METHODS This was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician’s choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ≥ 1 prior platinum-based chemotherapy but ≤ 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety. RESULTS A total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ≥ 12.0 months) versus 6.7 months (0.03 to ≥ 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ≥ 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent. CONCLUSION Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib.
Abstract 13979: Pharmacological Blockade of C-C Chemokine Receptor 4 Exacerbates Atherosclerosis in Apolipoprotein E-Deficient Mice
Authors: Hilman Z Amin, Naoto Sasaki, Sayo Horibe, Shoji Kawauchi, Kazuhiko Matsuo, Takashi Nakayama, Yoshiyuki Rikitake, Ken-Ichi Hirata
Journal: Circulation (2019)

Background: Regulatory T cells (Tregs) play a critical role in preventing the development of atherosclerosis. However, their sites of action in atherosclerosis are poorly defined. Although C-C chem...