tbuckley/cabot-search huggingface dataset:
Normalization of NAD <sup>+</sup> Redox Balance as a Therapy for Heart Failure
Authors: Chi Fung Lee, Juan D. Chavez, Lorena Garcia-Menendez, Yongseon Choi, Nathan D. Roe, Ying Ann Chiao, John S. Edgar, Young Ah Goo, David R. Goodlett, James E. Bruce, Rong Tian
Journal: Circulation (2016)

Background: Impairments of mitochondrial function in the heart are linked intricately to the development of heart failure, but there is no therapy for mitochondrial dysfunction. Methods: We assessed the reduced/oxidized ratio of nicotinamide adenine dinucleotide (NADH/NAD + ratio) and protein acetylation in the failing heart. Proteome and acetylome analyses were followed by docking calculation, mutagenesis, and mitochondrial calcium uptake assays to determine the functional role of specific acetylation sites. The therapeutic effects of normalizing mitochondrial protein acetylation by expanding the NAD + pool also were tested. Results: Increased NADH/NAD + and protein hyperacetylation, previously observed in genetic models of defective mitochondrial function, also are present in human failing hearts as well as in mouse hearts with pathologic hypertrophy. Elevation of NAD + levels by stimulating the NAD + salvage pathway suppressed mitochondrial protein hyperacetylation and cardiac hypertrophy, and improved cardiac function in responses to stresses. Acetylome analysis identified a subpopulation of mitochondrial proteins that was sensitive to changes in the NADH/NAD + ratio. Hyperacetylation of mitochondrial malate-aspartate shuttle proteins impaired the transport and oxidation of cytosolic NADH in the mitochondria, resulting in altered cytosolic redox state and energy deficiency. Furthermore, acetylation of oligomycin-sensitive conferring protein at lysine-70 in adenosine triphosphate synthase complex promoted its interaction with cyclophilin D, and sensitized the opening of mitochondrial permeability transition pore. Both could be alleviated by normalizing the NAD + redox balance either genetically or pharmacologically. Conclusions: We show that mitochondrial protein hyperacetylation due to NAD + redox imbalance contributes to the pathologic remodeling of the heart via 2 distinct mechanisms. Our preclinical data demonstrate a clear benefit of normalizing NADH/NAD + imbalance in the failing hearts. These findings have a high translational potential as the pharmacologic strategy of increasing NAD + precursors are feasible in humans.
Unique changes in prescription patterns of drugs for hematological malignancies in Japan.
Authors: Shoyo Shibata, Ai Tsuyuki, Yusuke Wayama, Maiko Matsushita, Koji Chiba, Eri Matsuki, Shinichiro Okamoto, Takeshi Suzuki
Journal: Journal of Clinical Oncology (2016)

e18016 Background: The number of patients with ML, MM, AML or MDS has been continually increasing following the aging of the Japanese society. However, little research has been done to clarify the prescription trend of the drugs used for the treatment of these diseases in Japan. The primary objective of this study is to reveal the recent prescription pattern (2010 – 2014) of blood cancer drugs in Japan. This is the first study to provide scientific evidences that recognize the uniqueness of the Japanese patient population that would lead to effective development of truly necessary drugs in Japan. Methods: We selected 44 drugs listed in Japanese Society of Hematology Clinical Practice Guideline for the management of hematologic malignancies as the drugs of interest. Data on prescription were collected through listing of oncology drug prescriptions obtained from the publicly available IMS database (N = 363). Univariate regression analysis was performed to detect the prescription trend and logistic regression was conducted to identify factors affecting the prescription patterns. Results: We identified that certain drug groups including monoclonal antibodies and protein kinase inhibitors to be associated with a long-term prescription pattern in Japan (OR: 4.4, 95%CI: 0.80 – 24.6, p = 0.08), indicating that molecularly targeted therapy is of high demand. Drugs launched with conditional approval was identified as a significant positive factor associated with long-term prescription (OR: 5.8, 95%CI: 1.1 – 29.8, p < 0.05). Indeed, among 11 drugs specifically used for targeted therapy of MM, CML and MDS, seven showed increasing trend of prescription and all-case surveillance condition was granted to six drugs. A significant correlation was confirmed between conditional approval and prescriptions (χ2 = 32.1, p < 0.01). Conclusions: This study indicates that novel agents especially molecularly targeted therapy for hematologic malignancies are of high demand in Japan. Due to the estimated increase in the elderly population, and since these are predominantly a disease of the elderly, we assume that this demand will continue to rise putting a pressure on the Japanese UHC system.
Development of Liposome containing sodium deoxycholate to enhance oral bioavailability of itraconazole
Authors: Zhenbao Li, Meiyu Zhang, Chang Liu, Shiwei Zhou, Wenjuan Zhang, Tianyang Wang, Mei Zhou, Xiaohong Liu, Yongjun Wang, Yinghua Sun, Jin Sun
Journal: Asian Journal of Pharmaceutical Sciences (2016)

The aim of this study was to enhance oral bioavailability of itraconazole (ITZ) by developing Liposome containing sodium deoxycholate (ITZ-Lip-NaDC). The liposome, consisting of egg yolk lecithin and sodium deoxycholate, was prepared by thin-film dispersion method. Differential Scanning Calorimetry (DSC) results indicated an amorphous state in the liposome. The physicochemical characteristics including particle size, morphology, entrapment efficiency, dissolution properties were also investigated. The performance of single-pass intestinal infusion exhibited that the transport order of intestinal segment was jejunum, duodenum, colon and ileum, and that all the segments participated in the absorption of ITZ in intestinal tract. The bioavailability study in rats showed that the AUC0-72 of the liposome was nearly 1.67-fold higher than that of commercial capsules (SPORANOX) in terms of oral administration, and the RSD of AUC0-72 of ITZ-Lip-NaDC was also decreased. Our results indicated that ITZ-Lip-NaDC liposome was facilitated to improve dissolution efficiency, augment transmembrane absorption, and then enhance the oral bioavailability of ITZ, successfully.
Further Limitations of the HOSPITAL Score in US Hospitals
Authors: Oanh Kieu Nguyen, Ethan A. Halm, Anil N. Makam
Journal: JAMA Internal Medicine (2016)

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 Internal Medicine 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 Internal Medicine journal
P0255 : Disruption of the GP130 signaling pathway in hepatocytes attenuates hepatocarcinogenesis
Authors: F.J. Cubero, M. Hatting, M. Spannbauer, J. Peng, M. Al Masaoudi, G. Sellge, Y.A. Nevzorova, N. Gassler, C. Liedtke, C. Trautwein
Journal: Journal of Hepatology (2015)
Abstract 490: High-throughput mutational analysis in cell-free DNA by targeted next-generation sequencing
Authors: Nga wan Rachel Tam, David Shames, Walter Darbonne
Journal: Cancer Research (2016)

Abstract Circulating cell-free DNA (cfDNA) in plasma offers a non-invasive approach to monitor tumor molecular profiling in real-time at multiple time-points, detection of emerging genomic alterations associated with drug resistance and clarifying cancer prognosis and diagnosis of cancer recurrence or progression. We developed a robust, multiplexed and PCR-based targeted next-generation sequencing approach to detect actionable mutations in cfDNA with low DNA input (1-5 ng). We employed the latest Ion TorrentTM S5/XL bench-top sequencer with Ion ChefTM Automation System and successfully automated the entire 2-day workflow from libraries preparation to semi-conducting chip sequencing. The hands-on time has been reduced to only 30 min. We will present data showing validation of this NGS platform using commercially available DNA control, archival FFPE tissue and cfDNA matched samples and demonstrate robust sensitivity and specificity by using the off-the-shelf Ion AmpliSeq Cancer Hotspot Panel v2 that covers 50 oncogenes. We also compared this approach to other orthogonal technologies, including quantitative PCR (qPCR) and droplet digital PCR (ddPCR) and achieved 100% concordance across these platforms. NGS can detect mutations down to 1% allelic frequency with 100% sensitivity and specificity. This robust and automated NGS platform is being routinely used in our lab to analyze cell-free DNA samples from multiple clinical trials. These efforts enable the development of a non-invasive method to overcome existing challenges to provide molecular understanding of patient's tumor evolution in real time, and aid in the development of personalized therapies for cancer patients. Citation Format: Nga wan Rachel Tam, David Shames, Walter Darbonne. High-throughput mutational analysis in cell-free DNA by targeted next-generation sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 490.
Infusions of Fresh Frozen Plasma to the Patients with a High-Risk Group for Hepatic VOD Associated with Stem Cell Transplantation Reduce Its Occurrence.
Authors: Masanori Matsumoto, Keisei Kawa, Hieo Yagi, Yong-Dong Park, Yasuhiro Takeshima, Yoshiyuki Kosaka, Hiroshi Hara, Shunro Kai, Masuji Yamamoto, Akihisa Kanemaru, Shirou Fukuhara, Masayuki Hino, Masahiko Sako, Akira Hiraoka, Hiroyasu Ogawa, Junichi Hara, Yoshihiro Fujimura
Journal: Blood (2006)
Case 5-1972
Authors: Richard C. Cabot, Benjamin Castleman, Betty U. McNeely, Jerold F. Lucey, James J. Galdabini
Journal: New England Journal of Medicine (1972)

Presentation of CaseA 13-month-old boy was admitted to the hospital because of jaundice.The child was the product of a pregnancy marked by spotting during the first four months, with a normal delivery at full term and a birth weight of 3 kg. During the first six weeks of life he had eczema, which was ascribed to allergy to cow's milk; a formula containing hydrolyzed casein was substituted. The child was otherwise well until five days before admission, when vomiting and diarrhea developed. Two days before entry vomiting ceased; diarrhea persisted, with the passage of two or three voluminous, . . .
Inositol 1,4,5-trisphosphate-mediated sarcoplasmic reticulum–mitochondrial crosstalk influences adenosine triphosphate production via mitochondrial Ca<sup>2+</sup>uptake through the mitochondrial ryanodine receptor in cardiac myocytes
Authors: Lea K. Seidlmayer, Johannes Kuhn, Annette Berbner, Paula-Anahi Arias-Loza, Tatjana Williams, Mathias Kaspar, Martin Czolbe, Jennifer Q. Kwong, Jeffery D. Molkentin, Katrin Gertrud Heinze, Elena N. Dedkova, Oliver Ritter
Journal: Cardiovascular Research (2016)

Elevated levels of inositol 1,4,5-trisphosphate (IP 3 ) in adult cardiac myocytes are typically associated with the development of cardiac hypertrophy, arrhythmias, and heart failure. IP 3 enhances intracellular Ca 2+ release via IP 3 receptors (IP 3 Rs) located at the sarcoplasmic reticulum (SR). We aimed to determine whether IP 3 -induced Ca 2+ release affects mitochondrial function and determine the underlying mechanisms. We compared the effects of IP 3 Rs- and ryanodine receptors (RyRs)-mediated cytosolic Ca 2+ elevation achieved by endothelin-1 (ET-1) and isoproterenol (ISO) stimulation, respectively, on mitochondrial Ca 2+ uptake and adenosine triphosphate (ATP) generation. Both ET-1 and isoproterenol induced an increase in mitochondrial Ca 2+ (Ca 2 +m ) but only ET-1 led to an increase in ATP concentration. ET-1-induced effects were prevented by cell treatment with the IP 3 antagonist 2-aminoethoxydiphenyl borate and absent in myocytes from transgenic mice expressing an IP 3 chelating protein (IP 3 sponge). Furthermore, ET-1-induced mitochondrial Ca 2+ uptake was insensitive to the mitochondrial Ca 2+ uniporter inhibitor Ru360, however was attenuated by RyRs type 1 inhibitor dantrolene. Using real-time polymerase chain reaction, we detected the presence of all three isoforms of IP 3 Rs and RyRs in murine ventricular myocytes with a dominant presence of type 2 isoform for both receptors. Stimulation of IP 3 Rs with ET-1 induces Ca 2+ release from the SR which is tunnelled to mitochondria via mitochondrial RyR leading to stimulation of mitochondrial ATP production.
Abstract 5086: Legumain-contained exosomes mediate remodeling of tumor extracellular matrix and protumor effects of TAMs
Authors: Long Shen, Yuzhi Shi, Jing Xun, Chuanai Chen, Lingfang Du, Xiaoyue Tan, Rong Xiang
Journal: Cancer Research (2016)

Abstract It has been recognized that tumor associated macrophages (TAMs) in tumor microenvironment play a variety of pro-tumor effects during the tumor progression, while the role of extracellular matrix in mediating these effects is still unclear. In this study, we focus on elucidating the way as well as the underlying mechanism about the involvement of an asparaginyl endopeptidase, legumain in the crosstalk between TAMs and ECM. Our data showed that co-culture of breast cancer cells 4T1 with macrophages Raw 264.7 promoted asparaginyl endopeptidase, legumain, expression with the introduction of markers of M2 - polarized macrophage. Legumain was detected in the condition medium (CM) collected from RAW 264.7 co-cultured with 4T1 cells by western blotting, with the existence of asparagine endopeptide enzyme activity assessed by enzyme activity assay. Result of western blotting showed that adding the CM of RAW 264.7 co-cultured with 4T1 cells depleted extracellular matrix (ECM) contents, fibronectin and collagen I. Transwell assay showed increased infiltration of 4T1 cells through the ECM contents after treatment with the CM of RAW 264.7 co-cultured with 4T1 cells. Furthermore, treatment with CM of RAW 264.7 co-cultured with 4T1 suppressed the adhesion of endothelial cells with ECM, promoting tube formation of endothelial cells compared with control. All the above results could be abolished by synthesized legumain inhibitor, RR-11a. Interestingly, legumain was also detected in the exosomes isolated from CM of RAW 264.7 co-cultured with 4T1. Applying legumain contained exosomes could replicate the effect of CM of RAW 264.7 co-cultured with 4T1 on the depletion of ECM contents, promotion of 4T1 infiltration and suppression of endothelial cell adhesion with ECM. Altogether, our results suggest that legumain is overexpressed and secreted out by TAMs; TAMs exosomes contain legumain and help delivering legumain to the ECM thus exert its effect on the depletion of ECM, pro-infiltration and angiogenesis. Citation Format: Long Shen, Yuzhi Shi, Jing Xun, Chuanai Chen, Lingfang Du, Xiaoyue Tan, Rong Xiang. Legumain-contained exosomes mediate remodeling of tumor extracellular matrix and protumor effects of TAMs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5086.
Benefit of Rituximab Addition to High-Dose Programs with Autograft for B-Cell Lymphoma: A Multicenter GITIL Survey on 957 Patients.
Authors: Corrado Tarella, Manuela Zanni, Michele Magni, Fabio Benedetti, Tiziano Barbui, Mario Boccadoro, Katia Patti, Fabio Ciceri, Andrea Gallamini, Sergio Cortelazzo, Valerio Zoli, Salvatore Mirto, Roberto Passera, Paolo Corradini, Giovanni Pizzolo, Alessandro M. Gianni, Alessandro Rambaldi
Journal: Blood (2006)
Abstract 74: Targeting nuclear export for triple-negative breast cancer therapy
Authors: Fabio Petrocca
Journal: Cancer Research (2016)

Abstract Triple-negative breast cancers (TNBC) comprise the most aggressive subtype of breast cancer. They rapidly acquire resistance to chemotherapy and are also refractory to endocrine therapy and HER2 inhibitors. In fact, no targeted therapies are currently available against these tumors. Genome sequencing studies have shown that TNBCs are exceedingly heterogeneous in genetic mutations as well as copy number variations. Yet, TNBC almost invariably harbor inactivating mutations in TP53, which seems to be a crucial event in the pathogenesis of these tumors. We recently performed a series of siRNA lethality screens in vitro (N = 11 cell lines) to identify, in an unbiased way, recurrent vulnerabilities that could be harnessed as novel targets for TNBC therapy. Hits were genes whose silencing triggered massive cell death in ≥ 30% of TNBC lines tested. The screens re-discovered mitosis as a frequent Achilles’ heel of these tumors (antimitotic drugs are currently a mainstay of TNBC therapy), supporting the validity of the approach. The nuclear transport gene RAN also scored among the most frequent TNBC selective dependencies. Moreover, TNBC cell lines were exquisitely sensitive to selinexor (KPT-330), a first-in-class inhibitor of exportin 1 (XPO-1) currently in phase 2 trials, both in vitro and in vivo. TNBC cells treated with selinexor died of apoptosis. In contrast, normal human primary breast epithelial progenitors (BPE) underwent cell cycle arrest (but not death) upon selinexor treatment, and were able to resume proliferation upon drug removal. The efficacy of selinexor across different TNBC models varied, suggesting that additional factors, beside the TNBC status, are at play. Preliminary data based on a genome-wide CRISPR screen for genes and networks conferring sensitivity to selinexor using a p53-mutant TNBC cell line (MDA-MB-231) implicated a number of TP53-related genes as key mediators of response. Together, these data support the notion that p53-mutant TNBC coopt nuclear export function to silence TP53-associated networks and that XPO-1 inhibitors could be a viable strategy to tackle TNBC in the clinic. Citation Format: Fabio Petrocca. Targeting nuclear export for triple-negative breast cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 74.
Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes
Authors: Pete J. Cox, Tom Kirk, Tom Ashmore, Kristof Willerton, Rhys Evans, Alan Smith, Andrew J. Murray, Brianna Stubbs, James West, Stewart W. McLure, M. Todd King, Michael S. Dodd, Cameron Holloway, Stefan Neubauer, Scott Drawer, Richard L. Veech, Julian L. Griffin, Kieran Clarke
Journal: Cell Metabolism (2016)
Investigation of Linarinic acid and one of its derivatives against cerebral ischemia in mice
Authors: Yihan Wang, Chao Zhao, Qiujv Wang, Huimin Wen, Yaru Gu, Linlin Fan, Chao Ma, Maosheng Cheng, Yuyang Zhang
Journal: Asian Journal of Pharmaceutical Sciences (2016)

The study aims to investigate the effects of (-)-Linarinic acid (LA) and one of its derivatives (LAd) on brain injury induced by ischemia. Malonaldehyde (MDA) is determined as an index for lipid peroxidation both in vitro and vivo. Mice were pre-treated with LA and LAd for 3 d. Thereafter, they were induced to have incomplete cerebral ischemia with both bilateral carotid artery occlusion and hypotension (BCAOH). In the first part of the in vivo experiment, mice were divided into four groups: sham (control), ischemia, ischemia + LA (200 mg/kg, i.g.) and ischemia + LAd (200 mg/kg, i.g.). In the second part, the dose-response of LAd was investigated at 100, 200 and 400 mg/kg i.g., respectively. A modified neurological severity score was developed for evaluating behavioral deficits of the mice with ischemia. Brains of the mice were excised in order to determinate MDA after ischemia for 6 h. Survival time, survival rate, neurological injury score and MDA level in brains were observed. Results were: 1) The data in vitro showed that both LA and LAd could inhibit the generation of MDA. IC50 values obtained by Probit analysis were 2.9 mM for LAd and 4.88 mM for LA; 2) BCAOH could significantly shorten the survival span, reduce the survival rate and cause neurological deficits, which were associated with high level of lipid hydroperoxide production in cerebral tissues; 3) LAd decreased lipid peroxidation and improved the neurological outcome more than LA. It is concluded that LAd offers a better neuroprotection than LA against brain damage caused by cerebral ischemia.
Abstract 3623: Comparison of dPCR versus hybridization capture methods for next generation sequencing of ctDNA for a SNV, copy number amplification, and fusion liquid biopsy assay
Authors: Jonathan Choi
Journal: Cancer Research (2016)

Abstract Circulating tumor DNA can be found in the plasma of cancer patients, and can be utilized for non-invasive cancer detection and genotyping through Next Generation Sequencing. However, unique characteristics of ctDNA pose technical challenges that limit technical sensitivities and robustness. ctDNA are fragmented, short, rare in abundance, and found in high background of normal DNA from leukocytes. Cancer variants range as low as 0.1-1% minor allele fractions, within the noise of NGS methods. Furthermore, clinical interest includes large number of genes and mutation types including single nucleotide variants, copy number amplification, and fusions. We compared two popular target enrichment categories, digital PCR and a hybridization-based capture panel for target enrichment. We assessed the assay performance and detection limitations, using a diverse sample set to test the range of input material that reflects ctDNA found in plasma. We titrated important cancer mutations (BRAF, EGFR, KRAS, PI3KCA, etc.) testing minor allele fractions ranging from 33% down to 0.1%, MET amplification ranges of 14x to 5x, and CCDC6-RET fusions of 50% to 2%. We also assessed input DNA ranges of 1ng and 10ng, well below manufacturer recommend input of library prep methods. Testing the performance of a 29kb amplicon panel and a 114kb hybridization-probes panel, we found superior on-target rates with digital PCR compared to the hybridization capture method across all samples. However, despite higher depths of coverage with droplet PCR, hybridization based methods had superior read mapping, uniformity (1.4x better), error rate (0.16% vs 0.02%), and greater linearity of SNV variants. Hybridization methods had greater accuracy of variant detection and were able to accurately identify the RET fusion. We demonstrated the feasibility of utilizing target enrichment methods for next generation sequencing for ctDNA variant detection. Citation Format: Jonathan Choi. Comparison of dPCR versus hybridization capture methods for next generation sequencing of ctDNA for a SNV, copy number amplification, and fusion liquid biopsy assay. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3623.