tbuckley/cabot-search huggingface dataset:
Characterization of <i>Kcnk3</i> -Mutated Rat, a Novel Model of Pulmonary Hypertension
Authors: Mélanie Lambert, Véronique Capuano, Angèle Boet, Laurent Tesson, Thomas Bertero, Morad K. Nakhleh, Séverine Remy, Ignacio Anegon, Christine Pechoux, Aurélie Hautefort, Catherine Rucker-Martin, Boris Manoury, Valérie Domergue, Olaf Mercier, Barbara Girerd, David Montani, Frédéric Perros, Marc Humbert, Fabrice Antigny
Journal: Circulation Research (2019)

Rationale: Pulmonary arterial hypertension is a severe lethal cardiopulmonary disease. Loss of function mutations in KCNK3 (potassium channel subfamily K member 3) gene, which encodes an outward rectifier K + channel, have been identified in pulmonary arterial hypertension patients. Objective: We have demonstrated that KCNK3 dysfunction is common to heritable and nonheritable pulmonary arterial hypertension and to experimental pulmonary hypertension (PH). Finally, KCNK3 is not functional in mouse pulmonary vasculature. Methods and Results: Using CRISPR/Cas9 technology, we generated a 94 bp out of frame deletion in exon 1 of Kcnk3 gene and characterized these rats at the electrophysiological, echocardiographic, hemodynamic, morphological, cellular, and molecular levels to decipher the cellular mechanisms associated with loss of KCNK3. Using patch-clamp technique, we validated our transgenic strategy by demonstrating the absence of KCNK3 current in freshly isolated pulmonary arterial smooth muscle cells from Kcnk3 -mutated rats. At 4 months of age, echocardiographic parameters revealed shortening of the pulmonary artery acceleration time associated with elevation of the right ventricular systolic pressure. Kcnk3 -mutated rats developed more severe PH than wild-type rats after monocrotaline exposure or chronic hypoxia exposure. Kcnk3 -mutation induced a lung distal neomuscularization and perivascular extracellular matrix activation. Lungs of Kcnk3 -mutated rats were characterized by overactivation of ERK1/2 (extracellular signal–regulated kinase1-/2), AKT (protein kinase B), SRC, and overexpression of HIF1-α (hypoxia-inducible factor-1 α), survivin, and VWF (Von Willebrand factor). Linked with plasma membrane depolarization, reduced endothelial-NOS expression and desensitization of endothelial-derived hyperpolarizing factor, Kcnk3 -mutated rats presented predisposition to vasoconstriction of pulmonary arteries and a severe loss of sildenafil-induced pulmonary arteries relaxation. Moreover, we showed strong alteration of right ventricular cardiomyocyte excitability. Finally, Kcnk3 -mutated rats developed age-dependent PH associated with low serum-albumin concentration. Conclusions: We established the first Kcnk3 -mutated rat model of PH. Our results confirm that KCNK3 loss of function is a key event in pulmonary arterial hypertension pathogenesis. This model presents new opportunities for understanding the initiating mechanisms of PH and testing biologically relevant therapeutic molecules in the context of PH.
(Inverse) Agonists of Retinoic Acid–Related Orphan Receptor γ: Regulation of Immune Responses, Inflammation, and Autoimmune Disease
Authors: Anton M. Jetten, Donald N. Cook
Journal: The Annual Review of Pharmacology and Toxicology (2019)

Retinoic acid-related orphan receptor γt (RORγt) functions as a ligand-dependent transcription factor that regulates multiple proinflammatory genes and plays a critical role in several inflammatory and autoimmune diseases. Various endogenous and synthetic RORγ (inverse) agonists have been identified that regulate RORγ transcriptional activity, including many cholesterol intermediates and oxysterols. Changes in cholesterol biosynthesis and metabolism can therefore have a significant impact on the generation of oxysterol RORγ ligands and, consequently, can control RORγt activity and inflammation. These observations contribute to a growing literature that connects cholesterol metabolism to the regulation of immune responses and autoimmune disease. Loss of RORγ function in knockout mice and in mice treated with RORγ inverse agonists results in reduced production of proinflammatory cytokines, such as IL-17A/F, and increased resistance to autoimmune disease in several experimental rodent models. Thus, RORγt inverse agonists might provide an attractive therapeutic approach to treat a variety of autoimmune diseases.
Psychotherapy for adjustment disorder in oncological patients: A systematic review.
Authors: Pablo Lopez, Daniela Gercovich, Diego Bortolato, Patricia Margiolakis, Mirta Morgenfeld, Laura Rosell, Silvina Laura Musini, Ernesto Gil Deza
Journal: Journal of Clinical Oncology (2013)

e20504 Background: Many previous studies argue that the Adjustment Disorder is the most prevalent mental syndrome in patients with cancer. However the research about the psychological treatment for this disorder is scarce. The aim of this study was to evaluate the efficacy of psychological treatments in Adjustment Disorder for oncological patients. We systematically reviewed the randomized controlled trials of psychological interventions for this specific population. Previous related reviews include less specific studies in terms of patients and interventions selected. Methods: Electronic searches were carried out. To identify randomized studies that were published up to 2012, we have searched in the following databases: PubMed, PsycINFO and the Cochrane Central Register of Controlled Trials. The search strategy included the following terms: cancer, adjustment disorder, oncology, psychotherapy, psychosocial interventions and stress. Additionally, we have searched in Scholar Google to find gray literature. The study designs, participants, treatments and outcome characteristics of the studies were coded and evaluated by two independent researchers, following the established selection and inclusion criteria. Results: Following the criteria, we found only one randomized study about the efficacy of psychological treatment for Adjustment Disorder in cancer patients, published in 1998. Conclusions: Considering that the Adjustment Disorder is the most prevalent mental illness in cancer patients, the lack of evidence about the efficacy of psychological treatment represents a significant public health issue. This review reveals that such lack of evidence exists, indicating a serious need of increasing studies about psychological treatments for this specific population.
A statistical and biological response to an informatics appraisal of healthy aging gene signatures
Authors: James A. Timmons, Iain J. Gallagher, Sanjana Sood, Bethan Phillips, Hannah Crossland, Robert Howard, William E. Kraus, Philip J. Atherton
Journal: Genome biology (2019)

Jacob and Speed did not identify even a single example of a ‘150-gene-set’ that was statistically significant at classifying Alzheimer’s disease (AD) samples, or age in independent studies. We attempt to clarify the various misunderstandings, below.
Role of miRNAs in tumor and endothelial cell interactions during tumor progression
Authors: Francesca Orso, Lorena Quirico, Daniela Dettori, Roberto Coppo, Federico Virga, Livia C Ferreira, Camilla Paoletti, Désirée Baruffaldi, Elisa Penna, Daniela Taverna
Journal: Seminars in Cancer Biology (2019)
Endocytic Profiling of Cancer Cell Models Reveals Critical Factors Influencing LNP-Mediated mRNA Delivery and Protein Expression
Authors: Edward J. Sayers, Samantha E. Peel, Anna Schantz, Richard M. England, Maya Beano, Stephanie M. Bates, Arpan S. Desai, Sanyogitta Puri, Marianne B. Ashford, Arwyn T. Jones
Journal: Molecular Therapy (2019)
Activity of small molecule inhibitors of the epidermal growth factor receptor (EGFR) kinase, on EGFR kinase domain mutants
Authors: Jacqueline Doody, Robin Rolser, Sheetal Patel, Cindy Wang, Cindy Chiang, Kun Hu, Leon Smith, Sabina Burdzovic-Wizmann, Larry Witte, Peter Bohlen, Daniel J. Hicklin, Paul Kussie, Yaron R. Hadari
Journal: Cancer Research (2005)

5288  It was recently suggested that epidermal growth factor receptor (EGFR) mutations may predict sensitivity to small molecule tyrosine kinase inhibitors (TKIs), as several somatic mutations in the EGFR gene have been identified in certain patients with non-small-cell lung cancer (NSCLC). We characterized the activation state of four different EGFR receptors bearing mutations in the kinase domain (G719C, L858R, L861Q, del747-753) and studied their sensitivity to small molecule TKIs. We found two mutants (L858R, L861Q) to be ligand-independent, constitutively activate kinases. Activation of the G719 mutant was found to be ligand-dependent, and the deletion mutant (del747-753) exhibited reduced kinase activity (20-fold less as compare to wild type EGFR). In the present study we determined the inhibitory activity of gefitinib and IM092214 against three EGFR mutants (G719C, L858R, L861Q) and wild type EGFR using enzymatic and cell-based phosphorylation assays. IM092214 is a structurally novel benzoxazepine that potently inhibits the EGFR kinase activity (cell-based IC50 = 60 nM). We found that gefitinib and IM092214 inhibited wild-type and mutant EGFR activity to similar extent in both the enzymatic assay (gefitinib IC50 = 15 nM, IM092214 IC50 = 60 nM) and the cell-based phosphorylation assay (gefitinib IC50 = 20 nM, IM092214 IC50 = 50 nM). Importantly, we did not observe hypersensitivity of any of the tested mutants to gefitinib or IM092214. Our data suggest that there may be other mechanisms responsible for the observed favorable response of certain lung cancer patients with EGFR mutations to TKIs.
Value of postoperative adjuvant chemotherapy (ac) for patients with completely resected hepatic (hm) and/or pulmonary metastases (pm) from colorectal cancer (crc): retrospective analysis of 146 patients
Authors: A. Muñoz, R. Barceló, A. Gil-Negrete, S. Carrera, G. López-Argumedo, A. Ruiz de Lobera, I. Diaz de Corcuera, I. Rubio, A. Viteri, G. López-Vivanco
Journal: Journal of Clinical Oncology (2006)

13509 Background: AC is indicated for stage III and high risk stage II colon cancer, as well as for stages II-III rectal cancers combined with RT. Moreover, chemotherapy improves survival in metastatic disease. There are no randomised trials evaluating the role of systemic AC after resection of metastases from CRC. Methods: We retrospectively reviewed patients with completely (R0) removed HM and/or PM from CRC, analysing prognostic factors for overall survival, including AC. Kaplan-Meier method with log rank test was used to assess and compare survival curves. Cox regression model was applied for multivariate analysis. Results: From Jan 1993 to Jun 2004, 146 patients were identified: 98 (67%) with HM, 39 with PM (27%) and 9 (6%) with both HM and PM. Gender (M/F): 102/44. Median age: 65.5 y-o (39.3–82.6). Primary CRC: rectum 62 (42.5%), pN+ 87 (60%), stage IV at diagnosis 57 (39%). Number of metastatic nodules resected: mean 2.25 (1–10). Size of the largest metastasis: mean 4 cm (0.5–18). Mean serum CEA value before surgery 20.6 (0–332): normal 73 (50%), increased 45 (31%), missing data 28 (19%). Ninety seven patients (66.5%) received postoperative AC (5FU/LV: 81, CPT11: 15, FOLFOX 1), 10 patients were not treated because of postoperative death (1) or early progression (9), and 39 due to several causes: not referred, medical contraindication or patient refusal. Median overall survival was 46.4 m, with a 3, 5 and 7-year survival probability of 59%, 35% and 22%. At univariate analysis, number (2 vs &gt;2) of metastases resected (60.1 vs 38.3m, p=0.0004) and AC (54.3 vs 31.2m, p=0.0001) were significant prognostic factors. Increased CEA (p=0.088), involved nodes in the primary (p=0.0618) and PM+HM (p=0.0538) showed a trend towards worse survival. In multivariate analysis (excluding patients with early death/progression) AC was associated with longer survival probability (HR 2.049, 95%CI 1.149–3.656, p=0.015). Conclusions: In our retrospective series AC seems to improve survival after resection of liver and/or lung metastases from CRC. The best use of chemotherapy (adjuvant, neoadjuvant or both) in patients with resectable metastatic CRC should be evaluated in a randomised fashion. No significant financial relationships to disclose.
Women in India face “extensive gender discrimination” in healthcare access
Authors: Elisabeth Mahase
Journal: BMJ (2019)

India’s women face “extensive gender discrimination” in access to healthcare, and the worst affected are those under 30, over 60, or living far from a hospital, a study has found.1

Researchers from India and the US analysed more than two million outpatient clinic appointments for any gender differences in access and to see whether age or distance from the hospital might also have an effect. In response to the findings the research team called for “systemic societal and governmental action to correct this gender discrimination.”

The …
Arterial stiffness to predict hypertensive response to antiangiogenic drugs.
Authors: Julie Giroux, Maureen Alivon, Marie Briet, Pascaline Boudou-Rouquette, Stanislas Ropert, Anatole Cessot, Jean-Philippe Durand, Pierre Boutouyrie, Stephane Laurent, Francois Goldwasser
Journal: Journal of Clinical Oncology (2013)

e13589 Background: Targeting angiogenesis with anti-VEGF receptors is a new approach for cancer treatment. The most common side effect is arterial hypertension. We hypothesize that pre-existing large artery remodeling with increased arterial stiffness is a determinant of blood pressure (BP) increase under antiangiogenic (AAD) and that AAD may alter mechanical properties of large arteries independently of BP increase. Methods: 49 patients (mean age=57[15] years, mean bSBP=128[22] mmHg and mean DBP=75[11] mmHg; treated for a cancer with an indication to start AAD (Sorafenib, Sunitinib or Bevacizumab) were included in this longitudinal study. Arterial evaluation was assessed at baseline (BL) before the introduction of AAD and every two weeks for 2 months (V1 to V4) with aortic stiffness (PWV) and central BP measurements by aplanation tonometry (SphygmoCor), carotid distensibility with high resolution echotracking system (ArtLab). Results: 43% of the patients developed hypertension between BL and V1. Using linear mixed model analysis with random effects, PWV significantly increased between BL and V1 (BL-V1, adjusted slope 0.89 m/s, F value=6.8, p=0.04) after adjustment to age and mean BP, carotid distensibility decreased significantly during follow-up (BL-V1, adjusted slope= -4.4, p=0.04; BL-V2, adjusted slope= -5.23, p=0.001) after adjustment to age and mean BP. The determinants of BP increase were studied between BL and V1 since anti-hypertensive drugs were introduced after V1. Using multivariate analysis, BL PWV was an independent determinant of the delta brachial SBP (β= -1.36 [-2.61; 0.11], p=0.034) with age (β=0.25 [0.04; 0.47], p=0.02). Conclusions: AAD induce functional alterations of large arteries, increasing arterial stiffness, independently of BP increase. In addition, pre-AAD administration arterial properties influence the hypertensive response to AAD.
Weighing the Risks and Rewards of Peanut Oral Immunotherapy
Authors: Jennifer Abbasi
Journal: JAMA (2019)

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
MiR-126 Promotes Leukemogenesis in Inv(16) Acute Myeloid Leukemia
Authors: Casey J Brewer, Guerry Jeanne Cook, Bin Zhang, Le Xuan Truong Nguyen, Jing Qi, Wei-Kai Hua, Qi Cai, Emily Carnahan, Ayelet Marom, Ling Li, Marcin Kortylewski, Guido Marcucci, Ya-Huei Kuo
Journal: Blood (2017)
Antitumor activity of cabozantinib (XL184) in a cohort of patients (pts) with differentiated thyroid cancer (DTC).
Authors: Maria E. Cabanillas, Marcia S. Brose, David A. Ramies, Yihua Lee, Dale Miles, Steven I. Sherman
Journal: Journal of Clinical Oncology (2012)

5547 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET, VEGFR2, and RET that is currently undergoing evaluation in several oncology indications. Differentiated thyroid cancer (DTC) pts were included in this study based on involvement of the MET, VEGFR, and RET signaling pathways in this disease. The primary objective of this study is to determine the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone (rosi). Anti-tumor activity and safety were also evaluated. Methods: Metastatic DTC pts who were enrolled to this study were required to be RAI-refractory, have progressed on standard therapies and have measurable disease. Cabo was given daily at a dose of 140 mg free base (equivalent to 175mg salt form) starting at Day 2. Rosi (4mg) was given Day 1 and Day 22 to complete PK assessment for drug-drug interaction (DDI). Cabo was continued until PD. On Day 57 and every 8 weeks thereafter subjects underwent tumor assessments by mRECIST. Results: 15 DTC pts were enrolled. Median number of prior regimens was 2 (11/15 pts had at least 1 prior VEGFR inhibitor). 8/15 pts (53%) had confirmed PRs including 1 pt with marked improvement of a bone infiltrating lesion; 6 (40%) had best response of SD; all 14 pts with ≥1 post-baseline scan experienced tumor regression (range: -9 to -55%). Disease control rate (PR + SD): 80% at 16 weeks; 10/15 (67%) remain on cabo with a median follow-up of 7.3 months. Median PFS and OS have not been reached. Most common Gr 3/4 AEs were: diarrhea (20%), lipase increased (20%), hypertension (13%) and palmar-plantar erythrodyesthesia (13%); one related Gr 5 event reported: hemoptysis due to aorto-trachael fistula in a pt with history of prior mediastinal XRT and extensive neck surgeries. PK data suggest that clinically relevant doses of cabo do not alter the C max or AUC 0-24h of rosi, consistent with no inhibition of CYP2C8. Conclusions: In pts with DTC, cabo treatment resulted in substantial anti-tumor activity. The safety profile of cabo was comparable to that seen with other VEGFR TKIs. PK data suggest no DDI between cabo and rosi (CYP2C8 substrate).
Emotional reactions of children and adolescents to the advanced oncologic disease of the parents: Preliminary results.
Authors: Anna Rodriguez-Morera, Joaquin T. Limonero, Sonia del Barco, Rut Porta
Journal: Journal of Clinical Oncology (2012)

e19542 Background: To describe perceptions of children and adolescents on advanced or terminal oncological disease of their parents, and some factors affecting these perceptions. Methods: Sample of 30 children and adolescents, aged between 5 to 18 years old, whose parents were in treatment or follow-up for advanced oncological disease. We used a semi-structured interview, reflecting the perceptions of ill parents, healthy parents and children. Also, parents were asked for the information they thought their children had about the disease. All participants older than 12 years old, gave Informed Consent to participate in the study. Results: Children and adolescents, described the disease of their parents mixing objetivable data (88.9%) and subjective perceptions (66.7%) with the expression of wishes (44.4%). Up to 76.7 % of ill parents and 82.6% of healthy parents, tended to minimize the capacity of understanding of the disease by their children. The perception that the patient and the healthy parent had of the information of the children correlates positively and significantly (r=0.59; p&lt;0.01) and (r=0.53, p&lt;0.01) respectively with the minimization or maximization of the capabilities of coping that the parents had of their children. There was a significant correlation (r=0.50, p&lt;0.05), between the perceptions from the patient and his partner regarding the information and knowledge that their children have from the disease. Mothers, were the ones usually to decide the type, quality and quantity of information to provide to their children. Conclusions: Most parents and patients tend to underestimate the capacity of understanding of the children and teenagers, being mothers the ones to decide, in most cases, the amount and quality/quantity of the information given to their children about the illness. It would be necessary to attend from the beginning of the disease, the needs of parents with minor children, as well as the needs of their children, in order to help the adaptation to the serious illness from one of their parents, and detect and treat if necessary, cases of psychological vulnerability that can develop psychopathology symptoms.
Gene Expression Profiling and Cellularity of Bone Marrow CD34+/Lin- Cells of Patients with Chronic-Phase Chronic Myeloid Leukemia at Diagnosis Vs. 12 Months of First-Line Nilotinib Treatment
Authors: Alessandra Trojani, Ester Pungolino, Giuseppe Rossi, Mariella D'Adda, Milena Lodola, Barbara Di Camillo, Alessandra Perego, Mauro Turrini, Ester Maria Orlandi, Lorenza Maria Borin, Alessandra Iurlo, Simona Malato, Francesco Spina, Maria Luisa Latargia, Francesco Lanza, Salvatore Artale, Michela Anghilieri, Carraro Maria Cristina, Cristina Bucelli, Gabriella De Canal, Enrica Morra, Roberto Cairoli
Journal: Blood (2017)
Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes
Authors: Michael Song, Xiaoyu Yang, Xingjie Ren, Lenka Maliskova, Bingkun Li, Ian R. Jones, Chao Wang, Fadi Jacob, Kenneth Wu, Michela Traglia, Tsz Wai Tam, Kirsty Jamieson, Si-Yao Lu, Guo-Li Ming, Yun Li, Jun Yao, Lauren A. Weiss, Jesse R. Dixon, Luke M. Judge, Bruce R. Conklin, Hongjun Song, Li Gan, Yin Shen
Journal: Nature Genetics (2019)
Mapping Interactions of Microbial Metabolites with Human G-Protein-Coupled Receptors
Authors: Dominic A. Colosimo, Jeffrey A. Kohn, Peter M. Luo, Frank J. Piscotta, Sun M. Han, Amanda J. Pickard, Arka Rao, Justin R. Cross, Louis J. Cohen, Sean F. Brady
Journal: Cell Host & Microbe (2019)

Despite evidence linking the human microbiome to health and disease, how the microbiota affects human physiology remains largely unknown. Microbiota-encoded metabolites are expected to play an integral role in human health. Therefore, assigning function to these metabolites is critical to understanding these complex interactions and developing microbiota-inspired therapies. Here, we use large-scale functional screening of molecules produced by individual members of a simplified human microbiota to identify bacterial metabolites that agonize G-protein-coupled receptors (GPCRs). Multiple metabolites, including phenylpropanoic acid, cadaverine, 9-10-methylenehexadecanoic acid, and 12-methyltetradecanoic acid, were found to interact with GPCRs associated with diverse functions within the nervous and immune systems, among others. Collectively, these metabolite-receptor pairs indicate that diverse aspects of human health are potentially modulated by structurally simple metabolites arising from primary bacterial metabolism.