tbuckley/cabot-search huggingface dataset:
Abstract 336: Conservation of Cardiac L-type Ca2+ Channels and Their Modulation in Drosophila: a Novel Genetically Pliable Channelopathic Model
Authors: Worawan B Limpitikul, Meera C Viswanathan, Anthony Cammarato, David T Yue
Journal: Circulation Research (2015)

Misregulation of L-type Ca 2+ channels (LTCCs) underlies numerous cardiac pathologies. For example, heart failure features blunted protein kinase A (PKA) upregulation of the LTCCs. However, studying LTCC regulation in mammalian systems is challenging due to complex physiology and lack of genetic manipulability while recombinant channels expressed in heterologous systems, which lack key auxiliary elements, poorly represent the native context. Drosophila , however, has a simple heart with many conserved genes and is genetically pliable. Thus, we pinpointed the signature of Ca 2+ channels (CCs) in the fly cardiac tubes. First, RNAi-mediated selective knockdown of Dmca1D, homologous to the human LTCCs, abolished cardiac contraction (B, as compared to ctrl in A), establishing this channel isoform as the primary CC in fly hearts. Second, we successfully isolated viable single fly cardiomyocytes (C, inset) and recorded robust Ca 2+ currents using patch clamp electrophysiology (C), a feat never before accomplished for the fly cardiac system. Moreover, recording Ca 2+ currents in distinct hypomorphic CC lines, we confirmed the CC type in the fly heart. We also observed pharmacological responses of the CCs that were strikingly similar to those seen in humans. Current through Dmca1D is blocked by a dihydropiridine, nifedipine (C), and is readily upregulated by forskolin, a downstream activator of the PKA pathway (C). In all, we have established the existence of a conserved compendium of cardiac CCs in fly heart tubes, suggesting that Drosophila may serve as a robust and effective platform to study the pathophysiology of diseases involving cardiac CCs and to devise therapeutic strategies.
Individualized screening trial of innovative glioblastoma therapy (INSIGhT).
Authors: Brian Michael Alexander, Lorenzo Trippa, Sarah C. Gaffey, Isabel Arrillaga, Eudocia Quant Lee, Shyam Kumar Tanguturi, Manmeet Singh Ahluwalia, Howard Colman, Evanthia Galanis, John Frederick De Groot, Jan Drappatz, Andrew B. Lassman, Louis B. Nabors, David A. Reardon, David Schiff, Mary Roberta Welch, Keith L. Ligon, Patrick Y. Wen
Journal: Journal of Clinical Oncology (2017)

TPS2079 Background: Patient with glioblastoma (GBM) with unmethylated MGMT promoters derive limited benefit from temozolomide (TMZ) and have dismal outcome. Prioritizing the numerous available therapies and biomarkers for late stage testing requires an efficient clinical testing platform. INSIGhT (NCT02977780) is a biomarker-based, Bayesian adaptively randomized, multi-arm phase II platform screening trial for patients with newly diagnosed GBM and unmethylated MGMT promoters. Methods: INSIGhT compares experimental arms to a common control of standard concurrent TMZ and radiation therapy (RT) followed by adjuvant TMZ. The primary endpoint is overall survival (OS). Patients with newly diagnosed, unmethylated GBM that are IDH R132H mutation negative, and with genomic data available or who consent to whole exome sequencing through the ALLELE companion study for biomarker grouping are eligible. Two experimental arms consist of concurrent RT/TMZ followed by adjuvant neratinib (EGFR, HER2, and HER4 inhibitor) or abemaciclib CDK 4/6 inhibitor), respectively, in place of TMZ. The other experimental arm is CC-115 (TORC1/2 and DNA PK inhibitor), which replaces TMZ in both the concurrent and adjuvant phases. Biomarker groups include: EGFR + patients with EGFR amplification/mutation; PI3K + patients with PIK3CA mutation/amplification, PIK3R1 mutation, AKT3amplification, PIK3C2B &gt; 1 copy gain, or PTEN dual loss; CDK: + patients with wild-type RB1 and CDK4 amplification, CDK6 amplification, or CDKN2A &gt; 1 copy loss. Given the lack of pretrial biomarker data and the anticipated overlap of the groups, randomization will initially be equal. As the trial progresses, randomization probabilities will be adapted based on the Bayesian estimation of the probability of treatment impact on progression-free survival (PFS). These randomization probabilities can vary among the biomarker groups so predictive biomarkers will be identified and utilized if present. Treatment arms may drop due to low probability of treatment impact on OS, and new arms may be added. Experimental arms are compared only with control and should be thought of as discrete experimental questions, with INSIGhT being open to new investigators with proposed therapeutic hypotheses. Clinical trial information: NCT02977780.
Abstract 062: Mitoubiquinone Decreases Reactive Oxygen Species Production and Improves Cardiac Efficiency in Chronic Volume Overload
Authors: Danielle M Yancey, James D Gladden, Jason L Guichard, Victor M Darley-Usmar, Louis J Dell’Italia, LuFang Zhou
Journal: Circulation Research (2013)

Background: The hemodynamic stress of left ventricular (LV) volume overload (VO) produces LV dysfunction accompanied by mitochondrial and cytoskeletal disruption in cardiomyocytes. Because mitochondria are both a source and target of reactive oxygen species (ROS), we hypothesize myocyte damage and LV dysfunction are mediated by mitochondrially produced ROS and can be attenuated by the mitochondrially targeted antioxidant, mitoubiquinone (MitoQ). Methods: Aortocaval fistula (ACF) was induced for 8 weeks in adult rats ± MitoQ. Echocardiography and high-fidelity LV pressure catheter recordings were used to study the LV end-systolic pressure-volume relationship and cardiac efficiency. Isolated cardiomyocytes were loaded with Carboxy-H2DFFDA (CM-DCF) and tetramethylrhodamine (TMRM) to measure mitochondrial ROS production and membrane potential. Results: Isolated cardiomyocyte studies demonstrated increased ROS production and decreased mitochondrial membrane potential in VO animals, both of which were attenuated with MitoQ. Treatment with MitoQ demonstrated a strong trend toward improvement in LV contractility, as cardiac efficiency improved significantly in MitoQ-treated VO animals. Untreated VO animals exhibited mitochondrial swelling and myofibrillar disruption that was prevented by MitoQ. Conclusion: These studies suggest an early interplay between mitochondrial-derived ROS production and cardiac ultrastructure and function.
High-Risk Subtype of Ph-like Acute Lymphoblastic Leukemia (ALL) in Adults: Dismal Outcomes of CRLF2+ ALL Patients Treated with Intensive Chemotherapy
Authors: Nitin Jain, Kathryn G. Roberts, Elias J. Jabbour, Keyur Patel, Karina Eterovic, Gloria Fawcett, Patrick Zweidler-McKay, Xinyan Lu, Sa Wang, Sergej Konoplev, Richard C Harvey, I-Ming L. Chen, Debbie Payne-Turner, Marcus Valentine, Deborah A Thomas, Guillermo Garcia-Manero, Farhad Ravandi, Jorge E. Cortes, Steven M. Kornblau, Susan M. O'Brien, Sherry Pierce, Jeffrey L. Jorgensen, Kenna Shaw, Cheryl L. Willman, Charles Mullighan, Hagop M. Kantarjian, Marina Konopleva
Journal: Blood (2016)
Full-length mRNA sequencing uncovers a widespread coupling between transcription initiation and mRNA processing
Authors: Seyed Yahya Anvar, Guy Allard, Elizabeth Tseng, Gloria M. Sheynkman, Eleonora de Klerk, Martijn Vermaat, Raymund H. Yin, Hans E. Johansson, Yavuz Ariyurek, Johan T. den Dunnen, Stephen W. Turner, Peter A. C. ‘t Hoen
Journal: Genome biology (2018)

The multifaceted control of gene expression requires tight coordination of regulatory mechanisms at transcriptional and post-transcriptional level. Here, we studied the interdependence of transcription initiation, splicing and polyadenylation events on single mRNA molecules by full-length mRNA sequencing. In MCF-7 breast cancer cells, we find 2700 genes with interdependent alternative transcription initiation, splicing and polyadenylation events, both in proximal and distant parts of mRNA molecules, including examples of coupling between transcription start sites and polyadenylation sites. The analysis of three human primary tissues (brain, heart and liver) reveals similar patterns of interdependency between transcription initiation and mRNA processing events. We predict thousands of novel open reading frames from full-length mRNA sequences and obtained evidence for their translation by shotgun proteomics. The mapping database rescues 358 previously unassigned peptides and improves the assignment of others. By recognizing sample-specific amino-acid changes and novel splicing patterns, full-length mRNA sequencing improves proteogenomics analysis of MCF-7 cells. Our findings demonstrate that our understanding of transcriptome complexity is far from complete and provides a basis to reveal largely unresolved mechanisms that coordinate transcription initiation and mRNA processing.
Microglia in prion diseases
Authors: Adriano Aguzzi, Caihong Zhu
Journal: Journal of Clinical Investigation (2017)

Prion diseases are a group of progressive and fatal neurodegenerative disorders characterized by deposition of scrapie prion protein (PrPSc) in the CNS. This deposition is accompanied by neuronal loss, spongiform change, astrogliosis, and conspicuous microglial activation. Here, we argue that microglia play an overall neuroprotective role in prion pathogenesis. Several microglia-related molecules, such as Toll-like receptors (TLRs), the complement system, cytokines, chemokines, inflammatory regulators, and phagocytosis mediators, are involved in prion pathogenesis. However, the molecular mechanisms underlying the microglial response to prion infection are largely unknown. Consequently, we lack a comprehensive understanding of the regulatory network of microglial activation. On the positive side, recent findings suggest that therapeutic strategies modulating microglial activation and function may have merit in prion disease. Moreover, studies on the role of microglia in prion disease could deepen our understanding of neuroinflammation in a broad range of neurodegenerative disorders.
Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65 -mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial
Authors: Stephen Russell, Jean Bennett, Jennifer A Wellman, Daniel C Chung, Zi-Fan Yu, Amy Tillman, Janet Wittes, Julie Pappas, Okan Elci, Sarah McCague, Dominique Cross, Kathleen A Marshall, Jean Walshire, Taylor L Kehoe, Hannah Reichert, Maria Davis, Leslie Raffini, Lindsey A George, F Parker Hudson, Laura Dingfield, Xiaosong Zhu, Julia A Haller, Elliott H Sohn, Vinit B Mahajan, Wanda Pfeifer, Michelle Weckmann, Chris Johnson, Dina Gewaily, Arlene Drack, Edwin Stone, Katie Wachtel, Francesca Simonelli, Bart P Leroy, J Fraser Wright, Katherine A High, Albert M Maguire
Journal: The Lancet (2017)
Abstract 391: Endogenous Drp1 Modulates Cardiac Respiration Through mPTP and Independent of Fission
Authors: Huiliang Zhang, Sara Bisetto, Shey-Shing Sheu, Wang Wang
Journal: Circulation Research (2015)

Background: The cardiac mitochondria exhibit a stable morphology with a rather low level of dynamic changes. However, fission and fusion proteins, such as dynamin-related protein 1 (DRP1) are abundant in the heart. Whether these proteins bear other functions in the heart than mitochondrial dynamics regulation are largely unknown. We hypothesize that endogenous DRP1 in the heart regulates mitochondrial respiration independent of fission. Methods: Mitochondrial respiration was determined by measuring the OCR with Seahorse assay or Clark type electrode in adult rat cardiomyocytes or mitochondria isolated from adult mouse heart. Confocal imaging was used to quantify mitochondrial morphology in adult cardiomyocytes and H9C2 myoblasts. To evaluate the role of mitochondrial permeability transition pore (mPTP), we monitored superoxide flashes (SOF) and laser-induced mPTP openings, and used cyclophilin D knockout mice (CypD KO). Mitochondrial ROS and Ca2+ were also monitored. Results: Inhibiting the DRP1 GTPase activity by Mdivi-1 or overexpression of the dominant-negative mutant (DRP1-K38A) induced mild mitochondrial morphological changes in adult cardiomyocytes, and inhibited mitochondrial respiration. Modulation of fission/fusion by overexpressing DRP1 or treating cells with S3, a compound facilitates fusion, exhibited significant morphological changes, but failed to influence respiration. Therefore, endogenous DRP1 activity may regulate respiration in the heart and this effect is dissociated with morphological changes. Further, inhibiting DRP1 activity attenuated the frequency of SOF, indicating decreased transient mPTP openings, delayed laser-induced permanent mPTP opening, and increased mitochondrial Ca2+. Inhibiting DRP1 activity decreased mitochondrial ROS levels. The role of DRP1 inhibition on respiration absents in CypD KO myocytes, suggesting the involvement of mPTP in the modulation of respiration by endogenous DRP1. Conclusion: These results suggest that endogenous DRP1 positively regulates respiration in the heart. This effect is likely independent of its role in mitochondrial fission. DRP1 regulation of respiration may involve transient opening of mPTP and contribute to mitochondrial Ca2+ and ROS signaling.
Reply to Paolo Capogrosso, Francesco Montorsi, and Andrea Salonia's Letter to the Editor re: Philipp Mandel, Felix Preisser, Markus Graefen, et al. High Chance of Late Recovery of Urinary and Erectile Function Beyond 12 Months After Radical Prostatectomy. Eur Urol 2017;71:848–50. Late Recovery of Erectile Function After Radical Prostatectomy: Should We Modify the Way of Assessment?
Authors: Philipp Mandel, Markus Graefen, Hartwig Huland, Derya Tilki
Journal: European Urology (2017)
Efficacy of Tramadol Extended-Release for Opioid Withdrawal
Authors: Kelly E. Dunn, D. Andrew Tompkins, George E. Bigelow, Eric C. Strain
Journal: JAMA Psychiatry (2017)

Opioid use disorder (OUD) is a significant public health problem. Supervised withdrawal (ie, detoxification) from opioids using clonidine or buprenorphine hydrochloride is a widely used treatment.
Subclinical Atherosclerosis Burden by 3D Ultrasound in Mid-Life
Authors: Beatriz López-Melgar, Leticia Fernández-Friera, Belén Oliva, José Manuel García-Ruiz, José Luis Peñalvo, Sandra Gómez-Talavera, Javier Sánchez-González, José María Mendiguren, Borja Ibáñez, Antonio Fernández-Ortiz, Javier Sanz, Valentín Fuster
Journal: Journal of the American College of Cardiology (2017)
Reference values for skin microanatomy: A systematic review and meta-analysis of ex vivo studies
Authors: Haoming Xu, Maira Fonseca, Zachary Wolner, Esther Chung, Xinyuan Wu, Shamir Geller, Stephen W. Dusza, Antonio P. DeRosa, Ashfaq A. Marghoob, Klaus J. Busam, Allan C. Halpern, Michael A. Marchetti
Journal: Journal of the American Academy of Dermatology (2017)
The Linear Nail Streak
Authors: Neil S. Prose
Journal: JAMA Dermatology (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 Dermatology 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 Dermatology journal
Abstract 52: PPAR-γ Targeted by MicroRNA-130a Regulates Angiotensin II-Induced Cardiac Fibrosis
Authors: Sudhiranjan Gupta, Li Li
Journal: Circulation Research (2015)

Aims: Cardiac fibrosis which occurs due to disruption of extracellular matrix network resulted in the accumulation of excess collagens and other matrix components leading to myocardial dysfunction. Angiotensin II (Ang II), a critical effector of this system has been implicated in the development of hypertension-induced cardiac fibrosis. In recent years, miRNAs have identified as an attractive targets for therapeutic intervention in various disease pathologies including cardiac fibrosis. However, the exact effect and underlying mechanism of miRNAs in cardiac fibrosis remains unclear. Here, we sought to investigate and test our hypothesis that miR-130a plays a critical role in the development of myocardial fibrosis by restoring PPARγ level. Methods and Results: We have identified a panel of novel miRNAs via miRNA array in Ang II infused mice heart. Among them, we found that miR-130a was upregulated both in pressure overload and Ang II infused models targeting PPARγ. Overexpressing miR-130a in cardiac fibroblast promoted the pro-fibrotic gene expression (collagen I/III, fibronectin and CTGF) and myofibroblasts differentiation. Inhibition miR-130a reversed the process and weakened these activities. Using luciferase-linked constitutive and dominant negative constructs of PPARγ, we determined the underlying mechanism of cardiac fibrosis occurred via targeting PPARγ. The in vivo inhibition of miR-130a by subcutaneous injections of LNA-based anti-miR-130a in mice subjected to Ang II infusion significantly reduced the severity of cardiac fibrosis, hypertrophy. The protective mechanism is associated with restoration of PPARγ level, reduction of pro-fibrotic genes and apoptosis; reversion of myofibroblasts differentiation and improved cardiac function. Conclusions: Our findings provide evidence that miR-130a plays a critical role in the progression of cardiac fibrosis by directly targeting PPARγ, and that inhibition of miR-130a reversed the cardiac fibrosis. We conclude that miR-130a may be a new marker for cardiac fibrosis and inhibition of miR-130a would be a promising strategy in the treatment of cardiac fibrosis.
Inhibiting 4EBP1 in Glioblastoma
Authors: Qi Wen Fan, Theodore P. Nicolaides, William A. Weiss
Journal: Clinical Cancer Research (2017)

Glioblastoma is the most common and aggressive adult brain cancer. Tumors show frequent dysregulation of the PI3K-mTOR pathway. Although a number of small molecules target the PI3K-AKT-mTOR axis, their preclinical and clinical efficacy has been limited. Reasons for treatment failure include poor penetration of agents into the brain and observations that blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Clinical trials using allosteric mTOR inhibitors (rapamycin and rapalogs) to treat patients with glioblastoma have also been unsuccessful or uncertain, in part, because rapamycin inefficiently blocks the mTORC1 target 4EBP1 and feeds back to activate PI3K-AKT signaling. Inhibitors of the mTOR kinase (TORKi) such as TAK-228/MLN0128 interact orthosterically with the ATP- and substrate-binding pocket of mTOR kinase, efficiently block 4EBP1 in vitro, and are currently being investigated in the clinical trials. Preclinical studies suggest that TORKi have poor residence times of mTOR kinase, and our data suggest that this poor pharmacology translates into disappointing efficacy in glioblastoma xenografts. RapaLink-1, a TORKi linked to rapamycin, represents a drug with improved pharmacology against 4EBP1. In this review, we clarify the importance of 4EBP1 as a biomarker for the efficacy of PI3K-AKT-mTOR inhibitors in glioblastoma. We also review mechanistic data by which RapaLink-1 blocks p-4EBP1 and discuss future clinical strategies for 4EBP1 inhibition in glioblastoma. Clin Cancer Res; 24(1); 14-21. ©2017 AACR.
Isolate Loss of Y Chromosome Decreases the Risk of Leukemic Transformation in the Myelodysplastic Syndromes. a Study By the Spanish Group of Myelodysplastic Syndromes
Authors: Meritxell Nomdedeu, Arturo Pereira, Xavier Calvo, Joan Colomer, Amparo Arias, Candida Gomez, Elisa Luño, Jose Cervera, Montserrat Arnan, Helena Pomares, Fernando Ramos, Itziar Oiartzabal, Blanca Espinet, Carme Pedro, Beatriz Arrizabalaga, Salut Brunet, Mar Tormo, Jesus Maria Hernandez-Rivas, María Díez-Campelo, Margarita Ortega, David Valcárcel, Maria-Teresa Cedena, Rosa Collado, Javier Grau, Isabel Granada, Guillermo Sanz, Elias Campo, Jordi Esteve, Dolors Costa
Journal: Blood (2016)
AB0458 B cells depletion for the treatment of systemic autoimmune diseases
Authors: ML Velloso Feijoo, S Rodriguez Montero, N Plaza Aulestia, JL Marenco de la Fuente
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Systemic autoimmune diseases (SAD) have traditionally been treated with steroids and immunosuppressants, but not all patients respond to these measures. Rituximab (RTX) has been used in several SAD with favorable results, but there are only a few reports of isolated clinical experiences, with a very small number of patients. Data about use of this drug under conditions of daily clinical practice may be relevant. <h3>Objectives</h3> To describe the characteristics of patients with SAD who are candidates for treatment with RTX. To evaluate the response to this drug in the different SAD. <h3>Methods</h3> Demographic data and disease, treatment and response variables were included. We use the EULAR definitions of partial response (improvement of at least 50% of the main manifestations of the disease) and complete response (disappearance of the manifestations of the disease), because of the heterogeneity of the SAD and their multiple manifestations. <h3>Results</h3> We included 53 patients, 90.6% were women. The mean age at diagnosis was 31.42±14.33 years; and the median duration of disease at the onset of RTX 1.99 (0–7.5) years. Patients received a median of 2 cycles (1–3 min -1, max 12); and the median interval between cycles was 14.81 months (6–15.75, min 6, max 120). The EAS included SLE with 23 (43.4%) cases, systemic sclerosis with 7 (13.2%) cases, Sjögren9s syndrome with 6 (11.3%) cases, vasculitis with 5 (9.4%) cases, Still disease with 3 (5.7%) cases, autoinmune cytopenias with 3 (5.7%) cases, dermatomyositis with 2 (3.8%) cases, Behçet9s disease with 2 (3.8%) cases, IgG4 disease with 1 (1.9%) case and sarcoidosis with 1 case (1.9%). A partial response was observed in 27 patients (50.9%) and complete in 20 patients (37.7%). There was no response in 6 of the 53 patients (11.3%). The response by disease groups is detailed in Table 1. <h3>Conclusions</h3> In our study, patients treated with RTX achieved response in 88.7%; similar than some experiences of RTX off-label use. Remision of the disease occurs in 50% of the patients. The best results are observed in SLE, especially in lupus nephritis, and Sjögren disease. The results in SS are promising due to the limited therapeutic resources for this disease. <h3>References</h3> Ramos-Casals M, García-Hernández FJ, de Ramόn E, Callejas JL, Martínez-Berriotxoa A, Pallarés L, et al. Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune diseases. Clinical and experimental rheumatology 2010; 28 (4): 468–76. <h3>Disclosure of Interest</h3> None declared