tbuckley/cabot-search huggingface dataset:
Abstract 19322: Cardiac Function and Beta-Adrenergic Response in Mice with Genetic Ablation of Two Major Phosphorylation Sites in the Cardiac Ryanodine Receptor
Authors: Emmanuel Camors, Randall Loaiza, Francisco Alvarado, Patricia Powers, Héctor H Valdivia
Journal: Circulation (2012)

Despite intensive research, the functional consequences of cardiac ryanodine receptor (RyR2) phosphorylation remain highly controversial. Two major phosphorylation sites, S2808 and S2814, are respective targets for PKA and CaMKII and form a RyR2 “phosphorylation hot spot”. We previously showed that genetic ablation of S2808 has no structural or functional consequences for cardiac function. Here we generated a novel double knock-in mouse with genetic ablation of S2808 and S2814 (S2808A/S2814A) and tested the hypothesis that preventing the “hot spot” phosphorylation has discernible impact in cardiac function. Echocardiography and intraventricular pressure measurements revealed that, under basal conditions, S2808A/S2814A mice have higher heart rate (553±33 vs. 460±28 bpm, p &lt;0.05, n= 8/group) and decreased ejection fraction (55±3 vs. 65±2%, p &lt;0.05, n=12/group) compared to WT. In addition, ventricular myocytes isolated from the S2808A/S2814A hearts displayed a significant increase in Ca 2+ transient amplitude (357±27 vs. 257±31 nM, p &lt;0.05, n=13 cells/group), a trend towards higher Ca 2+ spark frequency (0.51±0.14 vs. 0.30±0.17 sparks.100 μm -1 .sec -1 , n=7 cells/group) while the sarcoplasmic reticulum (SR) Ca 2+ load was comparable to that of WT cells (107±7 vs. 97±4 μmol/L cytosol). Surprisingly, β-adrenergic stimulation eliminated the differences between the two groups: Langerdorff-perfused hearts displayed a robust increase in the amplitude of contraction in response to 200 nM isoprenaline (51±4 vs. 62±14% above control in double knock-in and WT mice, respectively; n=5/group) and in isolated ventricular myocytes, 100 nM isoproterenol significantly increased the Ca 2+ transient amplitude (1.99±0.18 vs. 1.47±0.15 μM, n= 7 cells/group) and SR Ca 2+ load (175±12 vs. 183±14 μmol/L cytosol) in double knock-in and WT mice, respectively. Thus, ablation of the “phosphorylation hot spot” has discernible effects on cardiac function at baseline, but under β-adrenergic stimulation other RyR2 phosphorylation sites appear to normalize Ca 2+ transient and cardiac contraction. This is compatible with a multi-phosphorylation site model of RyR2 where the β-adrenergic stimulation response is dictated by a complex interplay of phosphorylations.
Lead Exposure as a Confounding Factor in the Association of Air Pollution Exposure and Psychotic Experiences—Reply
Authors: Joanne B. Newbury, Aaron Reuben, Helen L. Fisher
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
A cholesterol derivative (oxysterol; 24-ethyl-cholestane-3β, 5α, 6α-triol) with high antitumor activity against a variety of sarcomas.
Authors: Nabil Habib, Hamid Elia Daaboul, Georges Hage, Abdo Jabbour, Riad Khalife, Nader Kassem
Journal: Journal of Clinical Oncology (2012)

e20500 Background: Oxygenated derivatives of cholesterol, oxysterols, have different physicochemical properties acting on cell membranes. Agents belonging to this class of compounds have been found to induce apoptosis and to harbor antitumor activity demonstrated in vitro and in vivo. 24-ethyl-cholestane- 3β, 5α, and 6α-triol is a new oxysterol developed in our lab. Unlike other derivatives, it is, to our knowledge, the first tested in the clinic. Methods: We have previously reported encouraging and rapid results observed in patients suffering from a variety of solid tumors with an improvement of their quality-of- life and without side- effects. We have treated eight patients suffering from different types of sarcomas on a compassionate basis because we did not have any ongoing trial in sarcomas. Furthermore, most of these patients would not have been eligible for a clinical trial because of their bad performance-status. Three patients were suffering from carcinosarcomas, one from angiosarcoma, one from osteosarcoma, one from chondrosarcoma, one from undifferentiated sarcoma and one from Ewing sarcoma. Most of them were pretreated with chemotherapy and radiotherapy and most of them were in bad clinical conditions. Seven patients were females and one male with ages ranging from 21 to 82 (median age 55y). Results: None of these 8 patients experienced any side-effect despite the fact that one of them was taking a mild chemotherapy in association with oxysterol. This patient was excluded from the evaluation of the response to therapy. Among the 7 patients evaluable for response, we observed 4 complete responses (one of them confirmed by PET scan), two stable diseases and one progressive disease. The complete responses were observed in one osteosarcoma, one Ewing sarcoma, one angiosarcoma and one carcinosarcoma. As with our previous experience with this drug, no clinical or biological side-effect was observed and symptom control was achieved rapidly in all 6 symptomatic patients. Conclusions: We believe that this new compound deserves to be tested in phase II trials in patients suffering from sarcomas.
Overall survival (OS) with oral selinexor plus low dose dexamethasone (Sd) in patients with triple class refractory-multiple myeloma (TCR-MM).
Authors: Paul G. Richardson, Sundar Jagannath, Ajai Chari, Dan T. Vogl, Meletios A. Dimopoulos, Philippe Moreau, David Dingli, L J Wei, Lingling Li, Shijie Tang, William Reichman, Michael G. Kauffman, Jatin J. Shah, Sharon Shacham, Sagar Lonial
Journal: Journal of Clinical Oncology (2019)

8014 Background: TCR-MM is defined as being refractory to immunomodulatory agents, proteasome inhibitors, and anti-CD38 mAbs, representing an urgent unmet medical need with a median OS of 3-5 months( Pick M et al, Eur J Haem 2018; Gandhi U et al, ASH 2018). Sd has shown a 26.2% overall response rate (ORR) in 122 patients (pts) with TCR-MM in the Phase 2b STORM study ( Chari A et al, ASH 2018). Here, we evaluate the OS of pts in the STORM study with Sd and in pts with bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab (“penta”)-exposed, TCR-MM from an observational cohort not receiving Sd. Methods: Data were drawn from STORM and a retrospective cohort from the nationally representative Flatiron Health Analytic Database (FHAD). All pts from both sources had penta-exposed TCR-MM. In order to align study populations, OS was evaluated in pts in STORM whose first therapy after their MM reached TCR status was Sd and in pts in the FHAD who received ≥1 therapy after their MM reached TCR status. The index date for this evaluation was the start date of treatment after their MM reached TCR status. A Cox proportional hazards regression model was performed to assess the survival impact of Sd. In STORM, ORR was assessed by an Independent Review Committee based on IMWG criteria. Results: In the FHAD, 69 pts with TCR-MM were identified. Characteristics of the two groups of pts were similar, except that pts in STORM were more heavily pretreated, had a higher frequency of high-risk MM, a longer time since initial diagnosis of MM, and higher baseline hemoglobin and platelet values. Among the 122 pts in STORM, 64 received Sd as their first therapy after their MM became TCR, and ORR was 32.8%. Among the 69 pts from FHAD, 37 received ≥1 therapy after their MM became TCR. Median OS (N = 64) was 10.4 months for pts receiving Sd in STORM and 5.2 months (N = 37) for pts not receiving Sd in FHAD (HR = 0.49, p = 0.0241). Conclusions: The prognosis of TCR-MM in the real-world population appears very poor. Within the limits of this analysis, median OS of pts receiving Sd as their first therapy after their MM becomes TCR is significantly better than those not receiving Sd, suggesting that Sd may be associated with an OS benefit in pts with TCR-MM. Clinical trial information: NCT02336815.
VOLTAGE: Investigator-initiated clinical trial of nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable locally advanced rectal cancer
Authors: T. Yoshino, H. Bando, Y. Tsukada, K. Inamori, S. Yuki, Y. Komatsu, S. Homma, M. Uemura, T. Kato, D. Kotani, S. Fukuoka, T. Sasaki, Y. Nishizawa, N. Nakamura, M. Wakabayashi, M. Kojima, Y. Togashi, A. Sato, H. Nishikawa, M. Ito
Journal: Annals of Oncology (2019)
DNA–SWCNT Biosensors Allow Real-Time Monitoring of Therapeutic Responses in Pancreatic Ductal Adenocarcinoma
Authors: Santanu Bhattacharya, Xun Gong, Enfeng Wang, Shamit K. Dutta, Joseph R. Caplette, Manki Son, Freddy T. Nguyen, Michael S. Strano, Debabrata Mukhopadhyay
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic cancer with limited treatment options. There is an urgent need for tools that monitor therapeutic responses in real time. Drugs such as gemcitabine and irinotecan elicit their therapeutic effect in cancer cells by producing hydrogen peroxide (H2O2). In this study, specific DNA-wrapped single-walled carbon nanotubes (SWCNT), which precisely monitor H2O2, were used to determine the therapeutic response of PDAC cells in vitro and tumors in vivo. Drug therapeutic efficacy was evaluated in vitro by monitoring H2O2 differences in situ using reversible alteration of Raman G-bands from the nanotubes. Implantation of the DNA–SWCNT probe inside the PDAC tumor resulted in approximately 50% reduction of Raman G-band intensity when treated with gemcitabine versus the pretreated tumor; the Raman G-band intensity reversed to its pretreatment level upon treatment withdrawal. In summary, using highly specific and sensitive DNA-SWCNT nanosensors, which can determine dynamic alteration of hydrogen peroxide in tumor, can evaluate the effectiveness of chemotherapeutics. Significance: A novel biosensor is used to detect intratumoral hydrogen peroxide, allowing real-time monitoring of responses to chemotherapeutic drugs.
Sequential chemotherapy with dose-dense docetaxel, cisplatin, folinic acid and 5-fluorouracil (TCF-dd) followed by oxaliplatin, folinic acid, 5-fluorouracil, and irinotecan (COFFI) in locally advanced or metastatic gastric cancer (MGC).
Authors: Gianluca Tomasello, Wanda Liguigli, Rossana Poli, Federica Negri, Matteo Brighenti, Laura Toppo, Alessandra Curti, Silvia Lazzarelli, Stefano Panni, Maddalena Donini, Mariangela Maltese, Margherita Ratti, Rodolfo Passalacqua
Journal: Journal of Clinical Oncology (2012)

4097 Background: MGC is a chemosensitive tumour. According to the Norton-Simon hypothesis, a reduction of tumor burden could best be achieved by shortening the interval between the cycles, and the resistance might be overcome by switching from initial chemotherapy to a new, non cross-resistant one. We previously reported on the high efficacy of a new strategy using 2 sequential, non cross-resistant chemotherapy regimens in MGC (Cancer Chemother Pharmacol 11 Jan; 67 (1): 41-8). Aim of this study is to evaluate this therapeutic approach in a larger case series. Methods: 43 patients (pts) treated at our centre from November 04 to April 11 were included. All pts were chemo-naïve and received 4 cycles of TCF-dd (see reference above for doses) every 2 weeks. Subsequently and irrespective of their response, they received 4 cycles of COFFI (see reference above ) every 2 weeks. In both regimens pegfilgrastim 6 mg sc on day 3 was included. Results: Median age: 63; 74% male. PS 0-1. After the first regimen (TCF-dd) 43 pts were evaluable for response.We registered 3 CR, 27 PR, 7 SD, 5 PD and 1 not evaluable for an ORR at ITT of 70% (95% CI, 58-85). All pts proceeded to the second regimen (COFFI) and 40 pts were evaluable for response. The 3 CR observed after TCF-dd were maintained. Among the 27 pts with PR after TCF-dd, 2 achieved CR, 14 improved the response, 6 maintained PR, 3 progressed. Among the 7 pts with SD after TCF-dd, 1 achieved CR, 3 achieved PR, 2 progressed and 1 is not valuable. Among the 5 pts with PD after TCF-dd, 1 achieved CR, 4 achieved RP. After COFFI we observed 5 CR, 21 PR, 9 SD and 5 PD. The ORR in the 40 pts was 60% (95% CI, 50-80). Considering both regimen ORR was 93%. mTTP was 12.1 months (95% CI, 8,1-16,2). mOS was 16.1 months (95% CI, 12.7-21.6). At Dec '11, 4 out of 8 pts who achieved CR are alive and disease free. Most frequent G3-4 toxicities were: astenia (32%), neutropenia (35%), anemia (14%), neurotoxicity (21%). Conclusions: The study confirms that a sequential dose-dense strategy using TCF-dd followed by COFFI is feasible and highly effective and deserves to be tested in a randomized study which is on going.
Peroral Endoscopic Myotomy (POEM) vs Pneumatic Dilation
Authors: Brian C. Jacobson, David R. Lichtenstein
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 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
Variabilities in Childhood Cardiovascular Risk Factors and Incident Diabetes in Adulthood: The Bogalusa Heart Study
Authors: Tingting Du, Camilo Fernandez, Rupert Barshop, Vivian Fonseca, Wei Chen, Lydia A. Bazzano
Journal: Diabetes Care (2019)

Although emerging evidence indicates that increased variability in cardiovascular risk factors (CVRFs) among populations at midlife or later is a reliable predictor of adverse health outcomes, it is unknown whether intraindividual CVRF variability during childhood or adolescence is an independent predictor of later-life diabetes. We aimed to examine the association of CVRF variability during childhood with diabetes in later life.
Quadruple versus triple combination antiretroviral therapies for treatment naive people with HIV: systematic review and meta-analysis of randomised controlled trials
Authors: Qi Feng, Aoshuang Zhou, Huachun Zou, Suzanne Ingle, Margaret T May, Weiping Cai, Chien-Yu Cheng, Zuyao Yang, Jinling Tang
Journal: BMJ (2019)

To evaluate the effects of four drug (quadruple) versus three drug (triple) combination antiretroviral therapies in treatment naive people with HIV, and explore the implications of existing trials for clinical practice and research.Systematic review and meta-analysis of randomised controlled trials.PubMed, EMBASE, CENTRAL, Web of Science, and the Cumulative Index to Nursing and Allied Health Literature from March 2001 to December 2016 (updated search in PubMed and EMBASE up to June 2018); and reference lists of eligible studies and related reviews.Randomised controlled trials comparing quadruple with triple combination antiretroviral therapies in treatment naive people with HIV and evaluating at least one effectiveness or safety outcome.Outcomes of interest included undetectable HIV-1 RNA, CD4 T cell count, virological failure, new AIDS defining events, death, and severe adverse effects. Random effects meta-analyses were conducted.Twelve trials (including 4251 people with HIV) were eligible. Quadruple and triple combination antiretroviral therapies had similar effects on all relevant effectiveness and safety outcomes, with no point estimates favouring quadruple therapy. With the triple therapy as the reference group, the risk ratio was 0.99 (95% confidence interval 0.93 to 1.05) for undetectable HIV-1 RNA, 1.00 (0.90 to 1.11) for virological failure, 1.17 (0.84 to 1.63) for new AIDS defining events, 1.23 (0.74 to 2.05) for death, and 1.09 (0.89 to 1.33) for severe adverse effects. The mean difference in CD4 T cell count increase between the two groups was -19.55 cells/μL (-43.02 to 3.92). In general, the results were similar, regardless of the specific regimens of combination antiretroviral therapies, and were robust in all subgroup and sensitivity analyses.In this study, effects of quadruple combination antiretroviral therapy were not better than triple combination antiretroviral therapy in treatment naive people with HIV. This finding lends support to current guidelines recommending the triple regimen as first line treatment. Further trials on this topic should be conducted only when new research is justified by adequate systematic reviews of the existing evidence. However, this study cannot exclude the possibility that quadruple cART would be better than triple cART when new classes of antiretroviral drugs are made available.
Efficacy and safety of dolutegravir–rilpivirine for maintenance of virological suppression in adults with HIV-1: 100-week data from the randomised, open-label, phase 3 SWORD-1 and SWORD-2 studies
Authors: Michael Aboud, Chloe Orkin, Daniel Podzamczer, Johannes R Bogner, David Baker, Marie-Aude Khuong-Josses, David Parks, Konstantinos Angelis, Lesley P Kahl, Elizabeth A Blair, Kimberly Adkison, Mark Underwood, Jessica E Matthews, Brian Wynne, Kati Vandermeulen, Martin Gartland, Kimberly Smith
Journal: The Lancet HIV (2019)
Clinical Utility of 18F-Florbetaben PET for Detecting Amyloidosis Associated With Multiple Myeloma
Authors: Minjung Seo, Hee Jeong Cha, Misung Kim, Sang Hyuk Park, Ji Hun Lim, Yunsuk Choi, Yoo Jin Lee, Seol Hoon Park, Jae-Cheol Jo
Journal: Clinical Nuclear Medicine (2019)

Purpose The aims of this study were to evaluate the diagnostic performance of 18 F-florbetaben PET/CT for detecting amyloid deposits in patients with multiple myeloma (MM) and to identify the optimal PET analysis method. Methods Fourteen patients with MM were prospectively enrolled (6 with amyloidosis, 8 control subjects). Dynamic imaging of the kidneys was performed for 20 minutes, and the retention ratio was obtained. At 90 minutes after injection, PET was performed. All images were assessed qualitatively and quantitatively, and the SUVmax, SUVmean, and SUVratio were obtained. Variables were compared between the amyloidosis group and the control group. Amyloid deposition was confirmed according to international consensus guidelines. Results Tracer uptake was abnormal in all patients with amyloidosis. The visual detection rate was excellent (100%) in the heart, stomach, and tongue but limited in the kidneys (50%) and poor (0%) in the esophagus, liver, and colon. 18 F-florbetaben PET/CT identified 13 unexpected cases of abnormal uptake, confirming further amyloid deposition. Both spherical and manual volumes of interest showed similar diagnostic performance when evaluating amyloidosis in target organs. There was no significant difference in diagnostic performance between the SUVmax, SUVmean, and SUVratio. Conclusions 18 F-florbetaben PET/CT can accurately detect systemic amyloid deposits in patients with MM. 18 F-florbetaben PET/CT was particularly useful in the heart, stomach, and tongue but of limited value in the esophagus, liver, and colon. 18 F-florbetaben PET/CT can provide clinical information on organ involvement and could replace pathologic examination for diagnosis of amyloidosis in the future.
Automated flow cytometric profiling of tumor heterogeneity, tumor-infiltrating leukocyte (TIL) exhaustion, and coexpression of checkpoint receptors/ligands in patient-derived carcinomas.
Authors: Konstantin Salojin, Christine Hauther, Dai Liu, Santosh Putta, Norman Purvis, Matt Westfall
Journal: Journal of Clinical Oncology (2019)

28 Background: Clinical benefits of immune checkpoint receptor (ICP-R) blockade in cancer patients can be predicted using various biomarkers such as Immune Index. However, traditional IHC approaches are lacking in sensitivity and in addressing the heterogeneity of the tumor microenvironment (TME), TIL functional status, expression of targetable ICP-R and their ligands (ICP-L), and detection of rare immune subsets within the TME. Methods: We developed a flow cytometry platform (ImmunoINTEL™) that delivers quantitative, clinically relevant information by merging these aspects of tumor biology into a single automated HTP assay comprised of multi-parameter Ab panels and automated sample/data processing procedures for immunophenotyping of blood and tissue specimens from patients with lung, breast, renal, and colorectal carcinomas. Results: Analysis of tumor specimens revealed distinct immune profiles characterized by variations in TIL makeup, differential expression of ICP-R and ICP-L (PD1/PDL1, TIGIT/CD112&amp;CD155, Tim-3/Galectin-9, SIRPa/CD47), and changes in the functional/exhaustion status of TILs. We observed several discrete carcinoma profiles characterized by (1) an elevated Treg : CD8+GZMB+ T cell ratio, (2) high expression of ICP-L on epithelial cells and myeloid TILs, (3) enrichment for M1 macrophages (Mφ), M2 Mφ, and mixed M1/M2 phenotype Mφ (4) elevated levels of myeloid cells with suppressive phenotypes (MDSCs), (5) significant presence of myeloid and plasmacytoid dendritic cells, and (6) enrichment for mesenchymal cells. The elevated expression of several ICP-Ls on TILs and ICPs on epithelial cells suggested tumor- and TIL-intrinsic mechanisms modulating checkpoint interactions. Conclusions: The heterogeneity of TILs and ICP-R/ICP-L expression profiles across cell and tumor types can be explored in proof-of-mechanism studies and clinical trials to provide a rational for targeting distinct ICP-R/ICP-L interactions and TIL exhaustion mechanisms with immunotherapeutics, and for more refined selection of potential responders to ICP inhibitors.