tbuckley/cabot-search huggingface dataset:
LTP at Hilar Mossy Cell-Dentate Granule Cell Synapses Modulates Dentate Gyrus Output by Increasing Excitation/Inhibition Balance
Authors: Yuki Hashimotodani, Kaoutsar Nasrallah, Kyle R. Jensen, Andrés E. Chávez, Daniel Carrera, Pablo E. Castillo
Journal: Neuron (2017)

Excitatory hilar mossy cells (MCs) in the dentate gyrus receive inputs from dentate granule cells (GCs) and project back to GCs locally, contralaterally, and along the longitudinal axis of the hippocampus, thereby establishing an associative positive-feedback loop and connecting functionally diverse hippocampal areas. MCs also synapse with GABAergic interneurons that mediate feed-forward inhibition onto GCs. Surprisingly, although these circuits have been implicated in both memory formation (e.g., pattern separation) and temporal lobe epilepsy, little is known about activity-dependent plasticity of their synaptic connections. Here, we report that MC-GC synapses undergo a presynaptic, NMDA-receptor-independent form of long-term potentiation (LTP) that requires postsynaptic brain-derived neurotrophic factor (BDNF)/TrkB and presynaptic cyclic AMP (cAMP)/PKA signaling. This LTP is input specific and selectively expressed at MC-GC synapses, but not at the disynaptic inhibitory loop. By increasing the excitation/inhibition balance, MC-GC LTP enhances GC output at the associative MC-GC recurrent circuit and may contribute to dentate-dependent forms of learning and epilepsy.
Drug Development at the Portfolio Level Is Important for Policy, Care Decisions and Human Protections
Authors: Jonathan Kimmelman, Benjamin Carlisle, Mithat Gönen
Journal: JAMA (2017)

This Viewpoint discusses the drug development portfolio—a family of trials assessing a drug for different indications or in different combinations with other drugs—and summarizes some of the challenges drug portfolios pose for policy, care, and human protections.
Alveolar Recruitment Strategies After Cardiac Surgery
Authors: Jayshil J. Patel, Kurt Pfeifer
Journal: JAMA (2017)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Ultrasensitive mutation detection identifies rare residual cells causing acute myelogenous leukemia relapse
Authors: Brian Parkin, Angelina Londoño-Joshi, Qing Kang, Muneesh Tewari, Andrew D. Rhim, Sami N. Malek
Journal: Journal of Clinical Investigation (2017)

Acute myelogenous leukemia (AML) frequently relapses after complete remission (CR), necessitating improved detection and phenotypic characterization of treatment-resistant residual disease. In this work, we have optimized droplet digital PCR to broadly measure mutated alleles of recurrently mutated genes in CR marrows of AML patients at levels as low as 0.002% variant allele frequency. Most gene mutations persisted in CR, albeit at highly variable and gene-dependent levels. The majority of AML cases demonstrated residual aberrant oligoclonal hematopoiesis. Importantly, we detected very rare cells (as few as 1 in 15,000) that were genomically similar to the dominant blast populations at diagnosis and were fully clonally represented at relapse, identifying these rare cells as one common source of AML relapse. Clinically, the mutant allele burden was associated with overall survival in AML, and our findings narrow the repertoire of gene mutations useful in minimal residual disease-based prognostication in AML. Overall, this work delineates rare cell populations that cause AML relapse, with direct implications for AML research directions and strategies to improve AML therapies and outcome.
Cardiotoxicity associated with carfilzomib: Systematic review and meta-analysis.
Authors: Chintan Shah, Rohit Bishnoi, Harini Bejjanki, Ankur Jain, Subhankar Samal, Jan Moreb
Journal: Journal of Clinical Oncology (2017)

e21674 Background: Carfilzomib (Carf)is a novel proteasome inhibitor (PI) that is approved for patients with relapsed multiple myeloma (RMM) who have failed ≥ 1 prior lines of therapy. The incidence and seriousness of Carf associated cardiotoxicity (CT) is not well defined. We hypothesize that CT is more frequent than that seen with other PIs. We performed systematic review of Carf literature with meta-analysis to determine its incidence and overall risk. Methods: Initial search of literature led to a total of 175 Carf related articles. However, we used 29 publicatons; phase I/II, phase II and phase III (n = 3) clinical trials in which Carf was used as monotherapy or in combination with other chemo agents. We excluded phase I studies and studies without CT data. Incidence rates and odds ratios (OR) were calculated with either fixed effect or random effect model based on the heterogeneity of included studies. Toxicity was reported according to CTCAE v4.0. Results: A total of 4560 patients with various hematological and solid malignancies were included. Incidence of all grades and high grades (≥ 3) CT (including arrhythmias, CHF with LVEF drop, and coronary syndrome) were 7.8% and 4.72%, respectively. When compared to control group taken from phase III clinical trials, the risk of developing CT due to Carf was significantly higher with OR of 1.90 and 2.03 (P &lt; 0.01) for all grades and high grades, respectively. Moreover, incidence of CT was significantly higher in Carf combination therapy (9.85%) compared to Carf monotherapy (5.40%) (P = 0.01). Furthermore, incidence of high grade CT was 7.5% and 5% with and without concomitant immunomodulatory agent (IMiD), respectively (P = 0.004). There was no variation in the incidence of CT among newly diagnosed versus RMM (P = 0.6), and no Carf dose effect. Mortality rate associated with cardiotoxicity was 1.5%. Conclusions: Overall incidence of Carf related CT seems to be higher than that reported with other PIs. Although, the pathophysiology is poorly understood, this trend could potentially be secondary to irreversible nature of proteasome inhibition by Carf. There seems to be a significant increase in CT with combination of Carf and an IMiD. Prior therapies and higher Carf doses have no effect on CT incidence.
Abstract P255: Protein Arginine Methyltransferase 5 and Methylosome Protein 50, Novel Components of P300/gata4 Complex, Suppress Hypertrophic Gene Transcriptions in Cardiomyocytes
Authors: Yasufumi Katanasaka, Yukiko Nakagawa, Yoichi Sunagawa, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
Journal: Circulation Research (2011)

Introduction: One of intrinsic histone acetyltransferases (HAT), p300, serves as a coactivator of hypertrophy-responsive transcriptional factors such as a cardiac zinc finger protein GATA4 and is involved in its hypertrophic stimulus-induced acetylation and DNA binding. Disruption of this complex results in the inhibition of hypertrophic responses in cardiomyocytes. By tandem affinity purification and mass spectrometric analyses, we identified protein arginine methyltransferase 5 (PRMT5) and methylosome protein 50 (MEP50), an activator of PRMT5, as novel p300/GATA4-binding partners. However, the precise functional relationships among p300/GATA4, PRMT5 and MEP50 remain unknown. Methods and Results: To confirm the binding of GATA4 with PRMT5, expression plasmids encoding GATA4 and PRMT5 were co-transfected into HEK293 cells. Nuclear extracts from these cells were subjected to immunoprecipitation, followed by western blotting. We observed that GATA4 formed a complex with p300, PRMT5 and MEP50 in HEK293 cells. Next, to investigate whether PRMT5 is required for p300-mediated activation of the GATA4-dependent promoter activities, we performed reporter assays in HEK293 cells. While overexpression of either PRMT5 or MEP50 inhibited p300/GATA4-induced atrial natriuretic factors (ANF) and endotheline-1 (ET-1) promoter activities, knockdown of PRMT5 by RNAi enhanced these promoter activities in HEK293 cells. Immunoprecipitation followed by western blotting demonstrated that PRMT5 repressed p300-induced acetylation of GATA4 in HEK293T cells. Finally, PRMT5 or MEP50 repressed phenylephrine-induced promoter activation of the ANF and ET-1 in cardiomyocytes. Conclusion: These findings demonstrate that PRMT5 and MEP50 form a functional protein complex with GATA4/p300 and regulated hypertrophic responses in cardiomyocytes.
Incentivizing Transradial Access for Primary Percutaneous Coronary Intervention While Maintaining Timely Reperfusion
Authors: Robert W. Yeh, Ajay J. Kirtane, Sunil V. Rao
Journal: JAMA Cardiology (2017)

This Viewpoint discusses a proposal to incentivize adopting transradial rather than transfemoral access for primary percutaneous coronary intervention to improve processes of care in patients with ST-segment elevation myocardial infarction.
リツキシマブ含有化学療法(R‐Chemo)で前処理されている再発性もしくは耐性の無痛性B細胞非ホジキンスリンパ腫(B‐NHL)に対して非常に効果的であるY‐90イブリツモマブチウキセタン(Y2B8、ゼヴァリン(R))放射免疫療法(RIT):日本多施設第II相試験
Authors: Ogura M, Morishima Y, Watanabe T, Hotta T, Ishizawa K, Itoh K, Okamoto S, Taniwaki M, Endo K, Tobinai K
Journal: Blood (2006)
Abstract 12632: Impact of Systolic Pressure Response on Measurement of Fractional Flow Reserve
Authors: Tomoyuki Ikeda, Masafumi Ueno, Shinichiro Ikuta, Kosuke Fujita, Masakazu Yasuda, Takashi Nakamura, Kazuhiro Kobuke, Yositaka Iwanaga, Shunichi Miyazaki
Journal: Circulation (2015)

Background: Fractional flow reserve (FFR) is calculated as the ratio between distal coronary pressure(Pd)and aortic pressure(Pa)during whole cardiac cycle at stable hyperemia. In clinical practice, we experience various Pd wave pattern during hyperemia, such as decreasing equally in systolic and diastolic phase, or mainly decreasing in diastolic phase. Purpose: The aim of the study was to evaluate the impact of systolic and diastolic pressure response during hyperemia in patients with coronary stenosis and an FFR of less than 0.8. Methods: A total of 35 patients (40 stenosis)had FFR of less than 0.8 were enrolled. FFR measurements were performed using a standard technique. Based on Pa and Pd wave forms, the decreasing area in systolic and diastolic were calculated by integrating Pa-Pd pressure gradient during hyperemia using the RadiView2.2 software. %Sys value was defined as the percentage of delta systolic area during the whole cardiac cycle (Figure). The results of %Sys values were divided into tertiles to evaluate the most significant factors for systolic pressure response. Results: Vessel distribution was as follows: LAD (60%), CX (20%) and RCA (20%). There was a significant difference of vessel distribution in coronary arteries in the upper tertile compared with the other two tertiles of %Sys values (p=0.028). However, the other factors such as FFR value, lesion length and severity, history of diabetes mellitus and previous myocardial infraction were not affected by the %Sys values. In addition, there was a significant difference of %Sys values among three major coronary arteries (LAD 49.4±18.5%, CX 81.5±38.7%, RCA 67.5±20.2%, p=0.006). %Sys values were significantly higher in non-LAD lesions compared with LAD lesions (74.5±30.7% vs 49.4±18.5%, p=0.003). Conclusions: There was a significant difference of decreasing pattern of Pd wave during hyperemia among the three coronary arteries. These findings suggest that iFR might not be accurate in non-LAD lesion.
血管攣縮性狭心症患者における外膜vasa vasorum形成亢進‐光周波数領域イメージングによる評価‐
Authors: Nishimiya Kensuke, Matsumoto Yasuharu, Takahashi Jun, Uzuka Hironori, Wang Hongxin, Tsuburaya Ryuji, Hao Kiyotaka, Ohyama Kazuma, Odaka Yuji, Miyata Satoshi, Ito Kenta, Shimokawa Hiroaki
Journal: Circulation (2016)
Anti-PD-1 to enhance NK-cell cytotoxicity towards CD30+ Hodgkin lymphoma induced by CD30/CD16A TandAb AFM13.
Authors: Martin Treder, Xing Zhao, Narendiran Rajasekaran, Uwe Reusch, Jens-Peter Marschner, Holbrook Edwin Kohrt
Journal: Journal of Clinical Oncology (2016)

e14012 Background: AFM13 is an NK-cell engaging TandAb in Ph. 2 development in Hodgkin Lymphoma (HL) and CD30+ malignancies. As immune checkpoint modulators have demonstrated clinical efficacy in a various cancers we were prompted to investigate the combination of AFM13 with several immunomodulatory antibodies. In previous experiments, we demonstrated higher efficacy of AFM13 than such antibodies and strong synergy between AFM13 and an anti-PD1 antibody in vitro, and in vivo PDX models with human HL tumors. Methods: To further investigate the immunological mechanisms we used an autologous PDX mouse model with donor-matched tumors and PBMCs from HL patients. Animals were treated with AFM13 and in combination with anti-PD1. Tumor size, tumor-infiltrating human lymphoid cells, myeloid cells and intra-tumoral cytokines were evaluated at several time-points after treatment start. Results: While monotherapy with AFM13 was reproducibly more potent than anti-PD1 in controlling tumor growth, significant synergy was observed when both agents were combined. We observed a strong correlation between tumor growth inhibition and levels of tumor-infiltrating NK-cells, T-cells, myeloid cells and intra-tumoral cytokines. In contrast to anti-PD1 monotherapy, which only induced T-cell infiltration, AFM13 monotherapy was able to induce infiltration of both NK- and T-cells, which was further enhanced by the combination of both agents. Tumor analyses at earlier time-points showed that the initial immune response is characterized by infiltration of macrophages and activated NK-cells, whilst the adaptive immune response by T-cells and dendritic cells occurred later. These findings strongly support AFM13-mediated cross-talk between innate and adaptive immunity and a concerted role in tumor eradication. Conclusions: Our data support strong synergistic anti-tumor efficacy when AFM13 is combined with anti-PD1 checkpoint, mediated by tumor-infiltrating lymphoid and myeloid cells, providing strong evidence for cross-talk between innate and adaptive immunity induced by AFM13-recruited human NK-cells. A clinical study in r/r HL patients of AFM13 in combination with KEYTRUDA is currently in preparation.
Honokiol reduces drug resistance by inhibition of P-glycoprotein expression in multidrug resistant (MDR) squamous cell carcinoma of the head and neck (SCCHN)
Authors: Xu Wang, kwang Cho, Zhuo Chen, Jack Arbiser, Dong Shin
Journal: Cancer Research (2007)

2776  Head and neck squamous cell carcinoma (SCCHN) frequently develops resistance to chemotherapy shortly after the treatment. Overexpression of the multidrug resistance 1 (MDR1) gene in SCCHN during progression is one of the involved mechanisms. MDR1 gene encodes a transmembrane, permeability glycoprotein (P-gp) that antagonizes intracellular accumulation of cytotoxic agents. Targeting P-gp expression and function, by small molecular drugs, may sensitize SCCHN cells to chemotherapy, thereby serving as novel therapeutic agents for chemoresistant SCCHN. Honokiol (HNK) is a small molecule purified from Magnolia officinalis, which has been demonstrated to suppress tumor growth through apoptosis and inhibition of angiogenesis. In this study, we investigated the effects of HNK on human MDR SCCHN cells and underlying mechanism of HNK in reducing drug resistance. The cytotoxic effects of HNK on the drug sensitive cell line, KB-3-1, and MDR SCCHN cell lines, KB-8-5, KB-C1, and KB-V1 which have different levels of P-gp, were evaluated by in vitro cell proliferation assay. HNK-induced cell cycle arrest and apoptosis were analyzed using fluorescence activated cell sorting (FACS). Western blotting was performed to study the changes in P-gp expression, apoptosis markers (cleaved caspase-9 and PARP), and the involvement of survival signals (the PI-3K/AKT pathway and myeloid cell leukemia factor 1 (Mcl-1), a survival factor implicated in SCCHN progression. HNK effectively inhibited proliferation and induced apoptosis in all four cell lines. The IC50 of HNK is 5.0±0.4, 5.3±0.4, 5.0±0.7, and 4.5±0.5 μg/ml, in KB-3-1, KB-8-5, KB-C1, and KB-V1 cells, respectively. Those data indicate that regardless of the differential expression levels of P-gp in four cell lines, they showed similar sensitivities to HNK. FACS analysis showed that HNK rapidly induce cell cycle arrest after 24 h of treatment. The expression of caspase-9 and PARP were decreased by HNK treatment. Interestingly, expression of Mcl-1 was inhibited by HNK treatment. The PI3-K/AkT survival pathway may mediate HNK effects on Mcl-1 down-regulation, as revealed by western blotting. The mechanism of HNK mediated reduction of P-gp expression is being investigated. Using the MDR SCCHN cell model, we demonstrated that HNK may minimize chemoresistance by reducing P-gp expression. Blockade of survival signals (such as the PI3K/Akt, and Mcl-1) by HNK treatment may initiate apoptosis, as well as arrest in cell cycle. The combination of HNK and taxol synergistically inhibited growth of MDR cell, KB-C1, in vitro. These results suggest that HNK may be a promising drug in sensitizing chemoresistant SCCHN. Targeting MDR SCCHN using HNK in combination with conventional chemotherapy, may provide novel therapeutic opportunity. (Supported by GCC Distinguished Cancer Scholar and R01 CA 112643 to Dong M. Shin)
Neurodevelopmental Outcome in Relation to Treatment of Patent Ductus Arteriosus—Reply
Authors: Dany E. Weisz, Lucia Mirea, Prakesh S. Shah
Journal: JAMA Pediatrics (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Changes in intestinal microbiota and their effects on allogeneic stem cell transplantation
Authors: Rory M. Shallis, Christopher M. Terry, Seah H. Lim
Journal: American Journal of Hematology (2017)

Abstract The human intestinal microbiota is essential for microbial homeostasis, regulation of metabolism, and intestinal immune tolerance. Rapidly evolving understanding of the importance of the microbiota implicates changes in the composition and function of intestinal microbial communities in an assortment of systemic conditions. Complications following allogeneic stem cell transplant now join the ever‐expanding list of pathologic states regulated by intestinal microbiota. Dysbiosis, or disruption of the normal ecology of this microbiome, has been directly implicated in the pathogenesis of entities such as Clostridium difficile infections, graft‐versus‐host disease (GVHD), and most recently disease relapse, all of which are major causes of morbidity and mortality in patients undergoing allogeneic stem cell transplant. In this review, we elucidate the key origins of microbiotic alterations and discuss how dysbiosis influences complications following allogeneic stem cell transplant. Our emerging understanding of the importance of a balanced and diverse intestinal microbiota is prompting investigation into the appropriate treatment of dysbiosis, reliable and early detection of such, and ultimately its prevention in patients to improve the outcome following allogeneic hematopoietic stem cell transplant.
グルタチオンS-トランスフェラーゼP1遺伝子の多形性と,Barrett食道および食道癌の発症感受性との関連性
Authors: Van Lieshout E M M, Roelofs H M J, Dekker S, Mulder C J J, Wobbes T, Jansen J B M J, Peters W H M
Journal: Cancer Research (1999)
Long-term Peripheral Neuropathy in Breast Cancer Patients Treated With Adjuvant Chemotherapy: NRG Oncology/NSABP B-30
Authors: Hanna Bandos, Joy Melnikow, Donna R. Rivera, Sandra M. Swain, Keren Sturtz, Louis Fehrenbacher, James L. Wade, Adam M. Brufsky, Thomas B. Julian, Richard G. Margolese, Edward C. McCarron, Patricia A. Ganz
Journal: JNCI Journal of the National Cancer Institute (2017)

The long-term effects of chemotherapy are sparsely reported. Peripheral neuropathy (PN) is one of the most frequent toxicities associated with taxane use for the treatment of early-stage breast cancer. We investigated the impact of the three different docetaxel-based regimens and patient characteristics on long-term, patient-reported outcomes of PN and the impact of PN on long-term quality of life (QOL).