tbuckley/cabot-search huggingface dataset:
Safety and reproducibility of nasal allergen challenge
Authors: Ibon Eguiluz‐Gracia, Almudena Testera‐Montes, Miguel González, Natalia Pérez‐Sánchez, Adriana Ariza, María Salas, Carmen Moreno‐Aguilar, Paloma Campo, María José Torres, Carmen Rondon
Journal: Allergy (2019)

Abstract Background The nasal allergen challenge ( NAC ) is a useful tool for the diagnosis of allergic rhinitis ( AR ) and local allergic rhinitis ( LAR ) and might serve to design and monitor allergen immunotherapy. Nevertheless, data about its safety and reproducibility are scarce. Objective To investigate the safety and reproducibility of NAC in pediatric and adult rhinitis patients with/without asthmatic symptoms, and in healthy controls. Methods A retrospective evaluation of the NAC s conducted in our Unit for 2005‐2017 and monitored by acoustic rhinometry and nasal‐ocular symptoms was performed to analyze the safety of two methods for allergen application (metered spray &amp; micropipette) and NAC protocols ( NAC with single or multiple allergens/session [ NAC ‐S &amp; NAC ‐M]). The adverse events ( AE s), spirometry values, and rescue medication required for AE were recorded. The reproducibility was examined by a prospective analysis of three repeated NAC ‐S performed at 1‐2‐month interval in AR , LAR and nonallergic rhinitis patients, and in healthy controls. Results A total of 11 499 NAC s were performed in 518 children and 5830 adults. Only four local AE occurred, and 99.97% of NAC s were well tolerated. The reproducibility and positive and negative predictive values of three consecutive NAC ‐S performed in 710 subjects were 97.32%, 100%, and 92.91%, respectively. There were no false‐positive results in the 710 analyzed subjects. Safety and reproducibility were comparable between the methods of allergen application and the rhinitis phenotypes. Conclusion The NAC is a safe and highly reproducible diagnostic test ready to be used in the clinical practice in both children and adults with or without asthma.
MLL-Fusion Leukemia Dependence on MBNL1 Is Associated with Alternative Splicing of Oncogenic Proteins
Authors: Arun Gurunathan, Lana S Itskovich, Jason Clark, Matthew Burwinkel, Nathan Salomonis, Meenakshi Venkatasubramanian, Kashish Chetal, Lynn Lee, Ashish R Kumar
Journal: Blood (2018)
Publisher Correction: Cannabinoid CB1 receptors in the amygdalar cholecystokinin glutamatergic afferents to nucleus accumbens modulate depressive-like behavior
Authors: Chen-Jie Shen, Di Zheng, Ke-Xin Li, Jian-Ming Yang, Hao-Qi Pan, Xiao-Dan Yu, Jia-Yu Fu, Yi Zhu, Qi-Xin Sun, Meng-Yu Tang, Ying Zhang, Peng Sun, Yi Xie, Shumin Duan, Hailan Hu, Xiao-Ming Li
Journal: Nature Medicine (2019)
An essential role for the Zn2+ transporter ZIP7 in B cell development
Authors: Consuelo Anzilotti, David J. Swan, Bertrand Boisson, Mukta Deobagkar-Lele, Catarina Oliveira, Pauline Chabosseau, Karin R. Engelhardt, Xijin Xu, Rui Chen, Luis Alvarez, Rolando Berlinguer-Palmini, Katherine R. Bull, Eleanor Cawthorne, Adam P. Cribbs, Tanya L. Crockford, Tarana Singh Dang, Amy Fearn, Emma J. Fenech, Sarah J. de Jong, B. Christoffer Lagerholm, Cindy S. Ma, David Sims, Bert van den Berg, Yaobo Xu, Andrew J. Cant, Gary Kleiner, T. Ronan Leahy, M. Teresa de la Morena, Jennifer M. Puck, Ralph S. Shapiro, Mirjam van der Burg, J. Ross Chapman, John C. Christianson, Benjamin Davies, John A. McGrath, Stefan Przyborski, Mauro Santibanez Koref, Stuart G. Tangye, Andreas Werner, Guy A. Rutter, Sergi Padilla-Parra, Jean-Laurent Casanova, Richard J. Cornall, Mary Ellen Conley, Sophie Hambleton
Journal: Nature Immunology (2019)
NK Cell Infiltrates and HLA Class I Expression in Primary HER2+ Breast Cancer Predict and Uncouple Pathological Response and Disease-free Survival
Authors: Aura Muntasell, Federico Rojo, Sonia Servitja, Carlota Rubio-Perez, Mariona Cabo, David Tamborero, Marcel Costa-García, María Martínez-Garcia, Sílvia Menéndez, Ivonne Vazquez, Ana Lluch, Abel Gonzalez-Perez, Ana Rovira, Miguel López-Botet, Joan Albanell
Journal: Clinical Cancer Research (2019)

We investigated the value of tumor-infiltrating NK (TI-NK) cells and HLA class I tumor expression as biomarkers of response to neoadjuvant anti-HER2 antibody-based treatment in breast cancer.TI-NK cells and HLA-I were determined by IHC in pretreatment tumor biopsies from two cohorts of patients with HER2-positive breast cancer [discovery cohort (n = 42) and validation cohort (n = 71)]. Tumor-infiltrating lymphocytes (TIL) were scored according to international guidelines. Biomarker association with pathologic complete response (pCR) and disease-free survival (DFS) was adjusted for prognostic factors. Gene set variation analysis was used for determining immune cell populations concomitant to NK-cell enrichment in HER2-positive tumors from the Cancer Genome Atlas (n = 190).TI-NK cells were significantly associated with pCR in the discovery cohort as well as in the validation cohort (P < 0.0001), independently of clinicopathologic factors. A ≥3 TI-NK cells/50x high-power field (HPF) cutoff predicted pCR in the discovery and validation cohort [OR, 188 (11-3154); OR, 19.5 (5.3-71.8)]. Presence of TI-NK cells associated with prolonged DFS in both patient cohorts [HR, 0.07 (0.01-0.6); P = 0.01; HR, 0.3 (0.08-1.3); P = 0.1]. NK-, activated dendritic- and CD8 T-cell gene expression signatures positively correlated in HER2-positive tumors, supporting the value of NK cells as surrogates of effective antitumor immunity. Stratification of patients by tumor HLA-I expression identified patients with low and high relapse risk independently of pCR.This study identifies baseline TI-NK cells as an independent biomarker with great predictive value for pCR to anti-HER2 antibody-based treatment and points to the complementary value of tumor HLA-I status for defining patient prognosis independently of pCR.
Abstract 16089: Functional Coupling of SK Channels and L-type Calcium Channels in Cardiomyocytes
Authors: Xiao-Dong Zhang, Wei Chun Chen, Jeong-Han Lee, Zhong Jian, Leighton Izu, Ye-Chen Izu, Nipavan Chiamvimonvat
Journal: Circulation (2015)

Background. Small conductance Ca 2+ -activated K + (SK) channels play significant roles in regulating the excitability of cardiomyocytes (CMs). SK channels are unique in that they are gated solely by intracellular Ca 2+ and hence, function to integrate intracellular Ca 2+ and membrane potentials on a beat-to-beat basis in the heart. Our previous studies revealed that cardiac SK2 channels coupled with L-type Ca 2+ channels (LTCCs) through a physical bridge, α-actinin2, suggesting that LTCCs may be functionally coupled with SK2 channels by providing local Ca 2+ domain to activate the SK channels. However, a recent study suggested that sarcoplasmic reticulum (SR) Ca 2+ release is necessary and sufficient for the activation of cardiac SK channels. The objective of the study is to examine the mechanisms of SK channel activation in native CMs. Methods and Results. By using a voltage-clamp protocol in rabbit CMs to activate LTCCs followed immediately by a test voltage to monitor the SK currents, we recorded apamin-sensitive SK currents in response to the Ca 2+ influx. By altering the duration of activation of LTCCs, the activation of SK currents as a function of the increasing Ca 2+ influx was quantified. EGTA or BAPTA were then used to test the intracellular Ca 2+ domain necessary for SK channel activation. BAPTA but not EGTA completely disengaged the coupling between LTCCs and SK channels. SK currents coupled with Ca 2+ influx via LTCCs continued to be elicited after application of caffeine, ryanodine or thapsigargin to deplete SR Ca 2+ store, suggesting that LTCCs provide the immediate Ca 2+ microdomain for the activation of SK channels in CMs. Super-resolution imaging of SK2, Ca v 1.2, and ryanodine receptor 2 (RyR2) using stimulated emission depletion (STED) microscopy was performed to directly quantify the distance among SK, LTCC and RyR2 in CMs. Conclusion. Ca 2+ influx through LTCCs provides the immediate and efficient Ca 2+ microdomain for the activation of SK channels. Furthermore, changes in SK channel activation kinetics following SR Ca 2+ depletion suggest both LTCC-mediated Ca 2+ influx and SR Ca 2+ release are necessary for the activation of cardiac SK channels. Funded by NIH (R01 HL085727 and R01 HL085844 to NC), VA (I01 BX000576 to NC) and AHA (14BGIA18870087 to XZ).
Abstract 471: Kinase-independent Function of PI3Kγ Enables ERK Activation
Authors: Maradumane L Mohan, Arunachal Chatterjee, Swetha Ganapathy, Sromona Mukherjee, Sathyamangla V Naga Prasad
Journal: Circulation Research (2017)

Phosphoinositide 3-kinase (PI3K) enzymes are critical in many cellular processes including cell survival. PI3Kγ, a member of the PI3K family, is activated in response to G-protein coupled receptor (GPCR) stimulation leading to extracellular regulated kinase (ERK) signal transduction cascade, a cell survival pathway. However, less is known about the underlying mechanisms of PI3Kγ-directed ERK activation. Knockdown of PI3Kγ showed that PI3Kγ not only regulates ERK phosphorylation in response to GPCR stimulation but also to receptor tyrosine kinase activation in HEK 293 cells. The key role of PI3Kγ in ERK activation was further validated by loss of insulin-stimulated ERK phosphorylation in PI3Kγ-knockout (KO) mouse embryonic fibroblasts (MEFs). Surprisingly, ERK activation in KO MEFs post-insulin stimulation was completely rescued by expression of kinase-dead PI3Kγ mutant in KO MEFs demonstrating a kinase-independent role of PI3Kγ in regulating ERK function. Mechanistic studies showed that PI3Kγ regulates ERK activation by inhibiting ERK dephosphorylation following stimulation thereby, sustaining ERK phosphorylation and activation. Critically, PI3Kγ regulates ERK dephosphorylating phosphatase PP2A by interacting and sequestering PP2A from ERK maintaining ERK phosphorylation, which is evidenced by increased PP2A association with ERK in KO MEFs. Consistently, ERK activation was completely abolished in KO MEFs following carvedilol or insulin suggesting an essential role for PI3Kγ in ERK activation pathway. Correspondingly, primary cardiac fibroblasts isolated from KO mice showed complete loss of insulin-stimulated ERK phosphorylation compared to WT mice. This is intriguing given that GSK3 phosphorylation and not ERK phosphorylation is regulated by inhibition of PP2A through kinase-independent mechanism of PI3Kγ in the total cardiac lysates. Even though GSK3 and ERK are substrates for PP2A, our findings that ERK is regulated by kinase-independent function PI3Kγ suggest the existence of this unique regulation in fibroblasts and not in cardiomyocytes. Thus, kinase activity of PI3Kγ may contribute to cardiac-pathology while kinase-independent function could be beneficial and will be discussed in presentation.
Intratumor DNA methylation heterogeneity in glioblastoma: implications for DNA methylation-based classification
Authors: Anna Wenger, Sandra Ferreyra Vega, Teresia Kling, Thomas Olsson Bontell, Asgeir Store Jakola, Helena Carén
Journal: Neuro-Oncology (2019)

A feature of glioblastoma (GBM) is cellular and molecular heterogeneity, both within and between tumors. This variability causes a risk for sampling bias and potential tumor escape from future targeted therapy. Heterogeneous intratumor gene expression in GBM is well documented, but little is known regarding the epigenetic heterogeneity. Variability in DNA methylation within tumors would have implications for diagnostics, as methylation can be used for tumor classification, subtyping, and determination of the clinically used biomarker O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. We therefore aimed to profile the intratumor DNA methylation heterogeneity in GBM and its effect on diagnostic properties.Three to 4 spatially separated biopsies per tumor were collected from 12 GBM patients. We performed genome-wide DNA methylation analysis and investigated intratumor variation.All samples were classified as GBM isocitrate dehydrogenase (IDH) wild type (wt)/mutated by methylation profiling, but the subclass differed within 5 tumors. Some GBM samples exhibited higher DNA methylation differences within tumors than between, and many cytosine-phosphate-guanine (CpG) sites (mean: 17 000) had different methylation levels within the tumors. MGMT methylation status differed in IDH mutated patients (1/1).We demonstrated that intratumor DNA methylation heterogeneity is a feature of GBM. Although all biopsies were classified as GBM IDH wt/mutated by methylation analysis, the assigned subclass differed in samples from the same patient. The observed heterogeneity within tumors is important to consider for methylation-based biomarkers and future improvements in stratification of GBM patients.
The BRUCE‐ATR Signaling Axis Is Required for Accurate DNA Replication and Suppression of Liver Cancer Development
Authors: Chunmin Ge, Chrystelle L. Vilfranc, Lixiao Che, Raj K. Pandita, Shashank Hambarde, Paul R. Andreassen, Liang Niu, Olugbenga Olowokure, Shimul Shah, Susan E. Waltz, Lee Zou, Jiang Wang, Tej K. Pandita, Chunying Du
Journal: Hepatology (2019)

Replication fork stability during DNA replication is vital for maintenance of genomic stability and suppression of cancer development in mammals. ATR (ataxia‐telangiectasia mutated [ATM] and RAD3‐related) is a master regulatory kinase that activates the replication stress response to overcome replication barriers. Although many downstream effectors of ATR have been established, the upstream regulators of ATR and the effect of such regulation on liver cancer remain unclear. The ubiquitin conjugase BRUCE (BIR R epeat containing U biquitin‐Conjugating E nzyme) is a guardian of chromosome integrity and activator of ATM signaling, which promotes DNA double‐strand break repair through homologous recombination. Here we demonstrate the functions for BRUCE in ATR activation in vitro and liver tumor suppression in vivo . BRUCE is recruited to induced DNA damage sites. Depletion of BRUCE inhibited multiple ATR‐dependent signaling events during replication stress, including activation of ATR itself, phosphorylation of its downstream targets CHK1 and RPA, and the mono‐ubiquitination of FANCD2. Consequently, BRUCE deficiency resulted in stalled DNA replication forks and increased firing of new replication origins. The in vivo impact of BRUCE loss on liver tumorigenesis was determined using the hepatocellular carcinoma model induced by genotoxin diethylnitrosamine. Liver‐specific knockout of murine Bruce impaired ATR activation and exacerbated inflammation, fibrosis and hepatocellular carcinoma, which exhibited a trabecular architecture, closely resembling human hepatocellular carcinoma (HCC). In humans, the clinical relevance of BRUCE down‐regulation in liver disease was found in hepatitis, cirrhosis, and HCC specimens, and deleterious somatic mutations of the Bruce gene was found in human hepatocellular carcinoma in the Cancer Genome Atlas database. Conclusion: These findings establish a BRUCE‐ATR signaling axis in accurate DNA replication and suppression of liver cancer in mice and humans and provides a clinically relevant HCC mouse model.
Reframing the Suicide Prevention Message for Military Personnel
Authors: Murray B. Stein, Ronald C. Kessler, Robert J. Ursano
Journal: JAMA Psychiatry (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 Psychiatry 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 Psychiatry journal
Disease-free survival as a surrogate for overall survival in patients with HER2-positive, early breast cancer in trials of adjuvant trastuzumab for up to 1 year: a systematic review and meta-analysis
Authors: Everardo D Saad, Pierre Squifflet, Tomasz Burzykowski, Emmanuel Quinaux, Suzette Delaloge, Dimitris Mavroudis, Edith Perez, Martine Piccart-Gebhart, Bryan P Schneider, Dennis Slamon, Norman Wolmark, Marc Buyse
Journal: The Lancet Oncology (2019)
Tislelizumab in combination with chemotherapy in Chinese patients with advanced gastric or gastroesophageal junction (G/GEJ) cancer: Results from one cohort of an ongoing phase 2 study.
Authors: Yu-Xian Bai, En Xiao Li, Buhai Wang, Xianglin Yuan, Nong Xu, Yunxin Chen, Xiang Li, Huanli Wang, Jianming Xu
Journal: Journal of Clinical Oncology (2019)

11 Background: Tislelizumab, a humanized IgG4 mAb with high affinity and specificity for PD-1, was specifically engineered to minimize FcγR binding on macrophages, thus abrogating antibody-dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy. This phase 2 study (NCT03469557) evaluated safety, tolerability, and antitumor activity of first-line tislelizumab plus chemotherapy in Chinese pts with advanced G/GEJ or esophageal cancer; data from the G/GEJ cohort are presented here. Methods: Adult pts with histologically or cytologically confirmed HER2 negative G/GEJ were treated with tislelizumab (200 mg IV Q3W) + oxaliplatin (130 mg/m² IV Q3W for up to 6 cycles) + capecitabine (1000 mg/m² BID, Days 1–14 Q3W). AEs were assessed per CTCAE v4.03; tumor responses were assessed every 9 wks. Results: As of 13 June 2018, 15 G/GEJ pts (median age, 59 yr; M/F, 11/4) were enrolled; median treatment duration was 171 days (range 21-251). AEs in &gt; 2 pts considered related to chemotherapy and/or tislelizumab are detailed in the Table. No fatal AEs occurred. Three pts discontinued treatment due to ascites or increased ALT, AST, or total bilirubin. With a median follow up of 181 days, 46.7% (n = 7) had confirmed PR, 20% (n = 3) had SD, 13.3% (n = 2) with non-target disease only at baseline had non-CR/non-PD, 6.7% (n = 1) had PD, and 13.3% (n = 2) did not have evaluable disease. ORR and DCR were 46.7% (n = 7/15) and 80% (n = 12/15), respectively. Conclusions: First-line tislelizumab plus chemotherapy was generally well tolerated and antitumor activity was observed in pts with advanced G/GEJ cancer. Clinical trial information: NCT03469557. [Table: see text]
Telomere Damage Maintains Hematopoietic Stem Cells (HSCs) in an Activated Metabolic State, Which Compromises Their Self-Renewal Capability
Authors: Andrea Santoni, Elena Fiorini, Fides D Lay, Matteo Marchesini, Yamini Ogoti, Christopher Jackson, Ashley Rose, Karen Clise-Dwyer, Irene Ganan-Gomez, Guillermo Garcia-Manero, Simona Colla
Journal: Blood (2018)
Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration
Authors: Rinki Ratnapriya, Olukayode A. Sosina, Margaret R. Starostik, Madeline Kwicklis, Rebecca J. Kapphahn, Lars G. Fritsche, Ashley Walton, Marios Arvanitis, Linn Gieser, Alexandra Pietraszkiewicz, Sandra R. Montezuma, Emily Y. Chew, Alexis Battle, Gonçalo R. Abecasis, Deborah A. Ferrington, Nilanjan Chatterjee, Anand Swaroop
Journal: Nature Genetics (2019)
Helen Salisbury: The inverse care law in the digital age
Authors: Helen Salisbury
Journal: BMJ (2019)

A GP friend of mine has a relative in a distant city who is affected by a severe, long term mental health condition. He has evening carers who visit to make sure that he eats at least one good meal a day. They require parking permits, which have to be ordered from the city council. Here the problems begin.

The process is online only and involves filling in a form and attaching multiple documents. My friend asked the council, “What happens if this person doesn’t use the internet?”

“That’s OK—they can get help with that at the library or Citizens Advice.”

“And if they’re housebound?” …
Abstract 15749: Retail Soda Purchases Decrease After Two Years of a Community Campaign Promoting Better Beverage Choices
Authors: Marlene B Schwartz, Glenn E Schneider, Xun Li, Jennifer Harris, Tatiana Andreyeva, Maia Hyary, Nicolette Highsmith Vernick, Lawrence J Appel
Journal: Circulation (2016)

Introduction: Sugary drink consumption is a major risk factor for excess weight gain. In 2013, a mid-Atlantic county launched a multi-component, multi-year public health campaign to decrease sugary...
Selective tissue targeting of synthetic nucleic acid drugs
Authors: Punit P. Seth, Michael Tanowitz, C. Frank Bennett
Journal: Journal of Clinical Investigation (2019)

Antisense oligonucleotides (ASOs) are chemically synthesized nucleic acid analogs designed to bind to RNA by Watson-Crick base pairing. Following binding to the targeted RNA, the ASO perturbs RNA function by promoting selective degradation of the targeted RNA, altering RNA intermediary metabolism, or disrupting function of the RNA. Most antisense drugs are chemically modified to enhance their pharmacological properties and for passive targeting of the tissues of therapeutic interest. Recent advances in selective tissue targeting have resulted in a newer generation of ASO drugs that are more potent and better tolerated than previous generations, spawning renewed interest in identifying selective ligands that enhance targeted delivery of ASOs to tissues.