tbuckley/cabot-search huggingface dataset:
Abstract 354: Acetylation Regulates miR-133a Expression In Cardiac Hypertrophy
Authors: Ludivine Renaud, Santhosh Mani, Catalin Baicu, An Van Laer, Robert Stroud, Jeffrey Jones, Michael Zile, Donald Menick
Journal: Circulation Research (2013)

Background: The expression level of several microRNAs (miRNAs) is affected by pressure overload hypertrophy and has an impact on cardiac function. Histone deacetylases (HDACs) regulate the transcription of many genes whose expression is altered in hypertrophy. Therefore, we hypothesize that acetylation regulates the expression of some miRs during cardiac hypertrophy . Methods: Transverse aortic constriction (TAC) was performed to initiate cardiac hypertrophy induced by pressure overload. Mice were treated with the Class I and IIb HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) in the drinking water post-TAC for 2 and 4 weeks. miRNAs expression normalized to RNU6B was determined by qRT-PCR. Echocardiography was performed at baseline and post-TAC endpoints to assess physiological parameters. Chromatin immunoprecipitation (ChIP) was used to identify HDACs and transcription factors associated with miR-133a promoter. Results: Based on previous studies, we selected 8 miRNAs that play major roles in hypertrophy and assessed the effect of SAHA treatment on their expression level. The expression of one of the miRNAs, miR-133a was significantly (P &lt; 0.05) downregulated at both 2 weeks (1887 ±105, n=8) and 4 weeks post-TAC (1651 ±103, n=9) compared to control group (2972 ±334, n=11). SAHA treatment significantly de-repressed miR-133a expression 2 weeks post-TAC (3317 ±560, n=12) and to a lesser extent after 4 weeks post-TAC (2391 ±455, n=10). As expected, left atrium (LA) diameter, a marker of diastolic pressure, increased 2 weeks post-TAC, while SAHA treatment significantly reduced LA diameter. miR-133a targets connective tissue growth factor (CTGF) and collagen 1a1. Consistent with SAHA-mediated miR-133a de-repression, CTGF expression and collagen volume fraction were decreased compared to TAC alone. Importantly, ChIP analysis revealed that HDAC2 was present on the miR-133a promoter. Conclusion: We show that HDAC2, a Class I HDAC, plays a role in the regulation of miR-133a expression in cardiac hypertrophy. HDACs and miRNAs are key regulators of the events mediating cardiac pathology. Our work demonstrates that HDAC inhibition may be an attractive therapeutic strategy for the regulation of some miRNAs in heart disease.
Acute Autoimmune Hepatitis has Been Emerging in Japan
Authors: K. Tanaka, J.-H. Kang, T. Matsui, Y. Kimura, K. Tsuji, Y. Yosino, Y. Kodama, Y. Sakurai, A. Takiyama, T. Shinohara, H. Maguchi
Journal: Journal of Hepatology (2016)
A Phase II Study of Dasatinib and Dexamethasone As Primary Therapy Followed By Hematopoietic Cell Transplantation for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: CALGB Study 10701 (Alliance)
Authors: Matthew J. Wieduwilt, Jun Yin, Meir Wetzler, Geoffrey L. Uy, Bayard L Powell, Jonathan E. Kolitz, Michaela Liedtke, Wendy Stock, Jan H. Beumer, Ryan J. Mattison, Alese Halvorson, Steven M. Devine, Scott Smith, Richard M. Stone, Richard A. Larson
Journal: Blood (2016)
Depression is not a risk factor for dementia, large cohort study concludes
Authors: Jacqui Wise
Journal: BMJ (2017)

Depression does not seem to increase the risk for dementia, but depressive symptoms in later life could be a feature of dementia’s preclinical phase, a 28 year follow-up study in the UK has found.1

The research, published in JAMA Psychiatry , found that people with chronic or recurrent depressive symptoms early in the study did not have an increased risk of dementia, but people with depressive symptoms later in the study showed an …
Cetuximab modified collagen scaffold directs neurogenesis of injury-activated endogenous neural stem cells for acute spinal cord injury repair
Authors: Xing Li, Yannan Zhao, Shixiang Cheng, Sufang Han, Muya Shu, Bing Chen, Xuyi Chen, Fengwu Tang, Nuo Wang, Yue Tu, Bin Wang, Zhifeng Xiao, Sai Zhang, Jianwu Dai
Journal: Biomaterials (2017)
Safety and efficacy of eribulin in patients with advanced breast cancer treated outside of a clinical trial: A single institution experience.
Authors: Luisa Kessler, Jonas Bergh, Theodoros Foukakis
Journal: Journal of Clinical Oncology (2012)

e11510 Background: Eribulin is a non-taxane, microtubule dynamics inhibitor that was approved for the treatment of patients with metastatic breast cancer (MBC) in Europe in March 2011. Experience with routine use of eribulin is limited. Methods: All patients receiving eribulin at the Oncology Department, Karolinska University Hospital outside of a clinical trial are treated according to the approved indication and dosology. For the purpose of an internal quality control, treated patients are registered in a database. All patients registered at the time point of the analysis were evaluated for safety and efficacy. Treatment toxicity including fatigue, neurotoxicity and infection was graded according to CTCAE v4.0. Efficacy was investigated using the routinely performed radiological assessments. Results: To date, twenty patients have received a total of 104 cycles of eribulin. All patients were heavily pretreated with a median of 3 (range 1-6) previous chemotherapy lines for MBC. The median age of the patients was 54 years (range 35-74). Fourteen patients are alive and 12 are still undergoing treatment with eribulin. No hypersensitivity reactions and no toxic deaths were seen. Fatigue was observed in 45% of the patients (grade 3 20%), while 20% experienced neurotoxicity and 35% were treated for an infection (grade 3 20%). None of the patients experienced grade 3 neurotoxicity. Interestingly, 3 cases of Herpes zoster reactivation were observed. Fifteen of the patients have been radiologically assessed at the time point of the analysis. Six of those patients had partial response (PR), one patient had complete response (CR) and one patient had stable disease (SD). Seven patients had progressive disease (PD). Conclusions: Eribulin administered outside of a clinical trial in patients with advanced breast cancer was safe and well tolerated. Although the majority of the patients were heavily pretreated, objective response was seen in nearly half of the cases.
Abstract #3217: 3D in vitro model of breast cancer colonization of bone
Authors: Venkatesh Krishnan, Erwin Vogler, Andrea Mastro
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Breast cancer frequently metastasizes to bone where it causes osteolytic lesions. Although, the bone osteoclasts, not the cancer cells themselves, appear to be responsible for the bone resorbtion, we have evidence from 3D in vitro cell culture studies (bioreactor) that in the presence of breast cancer cells or their medium, the osteoblasts no longer make the proteins required for bone repair. Furthermore, they produce inflammatory cytokines, which in turn can stimulate osteoclasts. We hypothesize that a 3D mineralizing tissue incorporating both osteoblasts and osteoclasts (\#8216;biosynthetic bone\#8217;) would be a relevant in vitro bone surrogate for studying stages of breast-cancer metastasis. Toward realization of such a model, we have developed a bioreactor system that permits continuous growth of bone-accreting osteoblasts (MC3T3-E1) for > 10 months without subculture or perfusion. A mineralizing, multiple-cell-layer tissue results, that exhibits a normal phenotype with histology that strongly resembles normal bone tissue. We have also shown that, by challenging this osteoblast tissue with human metastatic breast cancer cells (MDA-MB-231GFP), important hallmarks of cancer metastasis including cancer-cell penetration of tissue and tumor formation can be observed. An up-regulation of the inflammatory cytokine, IL-6 and a reduction in osteocalcin levels, in the cultures challenged with breast cancer cells were observed. Also, soluble collagen (indicative of collagen formation) was decreased. Similar results were observed with primary murine calvarial osteoblasts after challenge with breast cancer cells. In standard tissue culture, we have also been able to differentiate osteoclasts from hematopoietic progenitor cells isolated from murine bone marrow. The osteoclasts formed by exposure to RANKL and M-CSF were multi-nucleated, TRAP positive cells. These cells will be introduced into the osteoblast 3D culture. Once the bone remodeling aspect of the system is established, breast cancer cells will be added. This 3D in-vitro cell culture system containing both osteoblast and osteoclast will help to further understand the cellular and molecular events that lead to successful breast cancer colonization of bone. Positive outcomes of the work will not only help clarify the etiology of metastasis but also create a much-needed in vitro tool for discovery of cancer therapeutics. Grants from the US Army Medical and Material Command Breast Cancer Program (W81XWH-06-1-0432), Susan G. Komen Breast Cancer Foundation (BCTR 0601044), and National Foundation for Cancer Research.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3217.
Abstract 13863: PGC-1α Mediates Differentiation Arrest of Murine Bone Marrow-derived Endothelial Progenitor Cells in Diabetes
Authors: Naoki Sawada, Dewi Sukmawati, Rie Ito-Hirano, Satoshi Fujimura, Seigo Itoh, Hiroshi Mizuno, Hiroyuki Daida, Rica Tanaka
Journal: Circulation (2016)

Introduction: Endothelial progenitor cells (EPCs) in murine bone marrow lineage-negative c-kit+Sca-1+ (BM-KSL) fraction are mobilized in circulation upon tissue injury to mediate a neovascularization process called vasculogenesis, which requires proper differentiative capacity of EPCs. Diabetics suffer defective vasculogenesis, a substantial mechanism for diabetic angiopathy in ischemic limb and heart. How it occurs, however, remains largely unknown. We recently demonstrated that type 1 (T1) and T2 diabetes (DM) induces a transcriptional coactivator PGC-1α in endothelial cells (ECs), and that EC PGC-1α mediates impaired cell migration and angiogenesis in DM. PGC-1α was also found to increase in EPCs cultivated from T2DM patients PB-MNCs. Building on these, we hypothesized roles for PGC-1α in EPC dysfunction. Methods and Results: We used Tie2-Cre-driven PGC-1α conditional null mice (KO), with or without T1DM induction by streptozocine. DM increased PGC-1α mRNA in WT BM-KSL cells whereas this induction was blocked in KO cells. DM decreased the differentiation capacity of WT BM-KSL cells and PB-MNCs, as determined by the formation of primitive (pEPC) and definitive (dEPC) colonies. PGC-1α ablation in KO rescued the defective EPCs differentiation in DM, most notably PB-MNCs formation of dEPC colonies, the known vasculogenic population. Consistent with this, endothelial marker gene expression (KDR, CD31, vWF), EPCs abundance, and EPCs vasculogenic functions of PB-MNCs was blunted by DM but rescued by PGC-1α ablation in KO. Importantly, T2DM induction by high-fat diet feeding also caused reduction in the EPCs abundance and EC gene expression of PB-MNCs, which was rescued by PGC-1α ablation in KO. Conclusions: Our data demonstrate critical new roles for PGC-1α in vasculogenesis. PGC-1α mediates the vasculogenic differentiation defect of circulating EPCs in T1 and T2 DM, in sharp contrast to the anti-migratory effect of EC PGC-1α in mediating diabetic angiostasis. Our data broadens the relevance of PGC-1α in the etiology of diabetic angiopathy, now with a potential to therapeutically restore EPCs vasculogenicity, and may provide an opportunity to improve the efficacy of autologous adoptive EPC therapy for limb and myocardial ischemia in DM.
STUDIES ON THE BLOOD CYTOLOGY OF THE RABBIT
Authors: Albert E. Casey, Paul D. Rosahn
Journal: The Journal of Experimental Medicine (1932)

1. Repeated platelet counts, 991 in number, were made on 148 adult male rabbits of various breeds and types which were specifically selected on the basis of physical fitness and continued freedom from disease. The observations extended over a 2(1/2) year period (1929-32). 2. A unimodal, peaked, moderately asymmetrical distribution curve was obtained and an analysis of the results gave the following values: the mean, 532,645 platelets per c.mm.; the median, 520,604 per c.mm.; the mode, 503,962 platelets per c.mm. respectively. 3. The extent of the variation among the counts is shown by the standard deviation of 124,960. High platelet counts were found to occur more frequently than low counts, a result that is reflected in a significant skew to the right in the frequency curve. 4. It was calculated that in healthy male rabbits a platelet count of less than 220,000 or more than 845,000 per c.mm. should be considered abnormal.
Simultaneous occurrence of lupus anticoagulant and factor VIII inhibitors in hemophilia
Authors: Alicia N. Blanco, Maria A. Lazzari
Journal: American Journal of Hematology (1998)

The letter published in the November 1997 issue, regarding simultaneous occurrence of lupus anticoagulant (LA) and factor VIII inhibitors [1,2], is very interesting.We agree with Dr. D.A. Triplett that it is of critical importance to differentiate an LA from a factor VIII inhibitor.Strict observance of the criteria recommended by the SSC Subcommittee on Lupus Anticoagulant/Phospholipid-Dependent Antibodies [3] is essential for this purpose.More than one test, with different assay principles, is necessary to screen for an LA, mainly in patients with other simultaneous coagulation defects, such as a neutralizing inhibitor or a factor deficiency.In a recently published study of 170 consecutive hemophilia A patients, we found 36 hemophiliacs who fulfilled the criteria for the diagnosis of LA, 18 of them with a time-dependent effect.It is possible that subjects with a strong time-dependent effect may have both a factor VIII inhibitor and an LA (n ‫ס‬ 12) [4].LAs were diagnosed based mainly on diluted Russell viper venom time (dRVVT).The activated partial thromboplastin time (APTT) is affected by factor VIII inhibitors; however, the platelet neutralization procedure of the APTT showed similar results to those obtained for dRVVT, except in three patients with positive dRVVT, for whom the shortening of the PNP was not sufficient to be considered positive.In our study, the StaclotLA results agreed with those from dRVVT; 8/8 were positive on LAs and 3/3 were negative on factor VIII inhibitors.We believe that factor VIII inhibitors could be masked by LA and the misdiagnosis could delay the prescription of the appropriate therapy [5].The above evidence stresses the need to develop a specific test to identify factor VIII inhibitors without interference of LA, and vice versa.
norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis
Authors: Peter Fickert, Gideon M. Hirschfield, Gerald Denk, Hanns-Ulrich Marschall, Istvan Altorjay, Martti Färkkilä, Christoph Schramm, Ulrich Spengler, Roger Chapman, Annika Bergquist, Erik Schrumpf, Frederik Nevens, Palak Trivedi, Florian P. Reiter, Istvan Tornai, Emina Halilbasic, Roland Greinwald, Markus Pröls, Michael P. Manns, Michael Trauner
Journal: Journal of Hepatology (2017)

Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease, currently lacking effective medical therapy. 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C23 homologue of UDCA and has shown potent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model. A randomized controlled trial, including 38 centers from 12 European countries, evaluated the safety and efficacy of three doses of oral norUDCA (500mg/d, 1,000mg/d or 1,500mg/d) compared with placebo in patients with PSC.One hundred sixty-one PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for a 12-week treatment followed by a 4-week follow-up. The primary efficacy endpoint was the mean relative change in ALP levels between baseline and end of treatment visit.norUDCA reduced ALP levels by -12.3%, -17.3%, and -26.0% in the 500, 1,000, and 1,500mg/d groups (p=0.029, p=0.003, and p<0.0001 when compared to placebo), respectively, while a +1.2% increase was observed in the placebo group. Similar dose-dependent results were found for secondary endpoints, such as ALT, AST, γ-GT, or the rate of patients achieving ALP levels <1.5× ULN. Serious adverse events occurred in seven patients in the 500mg/d, five patients in the 1,000mg/d, two patients in the 1500mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups.norUDCA significantly reduced ALP values dose-dependently in all treatment arms. The safety profile of norUDCA was excellent and comparable to placebo. Consequently, these results justify a phase III trial of norUDCA in PSC patients. Lay summary: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed. In this phase II clinical study in PSC patients, a side chain-shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA), significantly reduced serum alkaline phosphatase levels in a dose-dependent manner during a 12-week treatment. Importantly, norUDCA showed a favorable safety profile, which was similar to placebo. The use of norUDCA in PSC patients is promising and will be further evaluated in a phase III clinical study. ClinicalTrials.gov number: NCT01755507.
What’s in a Number? Platelet Count Dynamics as a Novel Mediator of Acute Respiratory Distress Syndrome Survival
Authors: Tiffanie K. Jones, Nuala J. Meyer
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

overextend the conclusions and implications of their work, it could be tempting to assume that the limited impact of the pedometerbased intervention extends to other settings.Before arriving at that premature conclusion, it should be clear that, as the authors explain, the addition of pedometers still confers benefits when used outside of rehabilitation programs.Equally important, improving outcomes of pulmonary rehabilitation in the direction of increasing physical activity could still be achieved with the use of pedometers, but only if they are just a component of a more comprehensive behavioral intervention.Although simple and elegant interventions, such as the one presented by Nolan and colleagues (10), using the available, easy-to-implement, elegant, and everyday smaller wearable technology, are very appealing, improving physical activity in COPD will require either more complex approaches or continuing to try simple innovative interventions, like the one tested by the authorsat least until we learn more about the physical and behavioral determinants of inactivity ( 18), something that will remain elusive if our professional organizations, research granting agencies, and journals do not make rehabilitation research, education, and implementation a priority.
Perioperative morbidity and mortality after radical lymphadenectomy for operable esophageal cancer
Authors: C. S. Pramesh, R. C. Mistry
Journal: Journal of Clinical Oncology (2009)

e15554 Background: The role of radical lymphadenectomy in localized resectable esophageal cancer is controversial. Radical lymphadenectomy confers more accurate staging, and improves locoregional control rates. However, there is no convincing evidence yet for a definite improvement in overall survival. Higher morbidity and mortality rates with radical lymphadenectomy are often quoted as reasons to avoid these procedures during esophageal resection. Methods: We retrieved data from October 2003 to December 2008 from a prospective surgical database maintained at a single tertiary cancer centre. Demographic data, operative details and postoperative morbidity and mortality were analysed. Postoperative complications analysed included need for prolonged ventilation, pulmonary complications, recurrent laryngeal nerve (RLN) paresis, cardiac ischemia and arrhythmias, and anastomotic leaks. Results: Six hundred and forty five patients (453 men, 192 women, mean age 53.6 years, range 19–76 years) were operated by transthoracic total esophagectomy for esophageal cancer between October 2003 and December 2007. Three hundred and ninety eight patients underwent two-field lymphadenectomy and 247 underwent three field radical lymphadenectomy. There was a higher incidence of prolonged ventilation (13.4% vs 6.6%, p=0.003), RLN paresis (61.4% vs 32.5%, p=0.000), and pulmonary complications (38.5% vs 24.4%, p=0.000) with radical three field lymphadenectomy compared to two field lymphadenectomy. The incidence of cardiac events (1.6% vs 2.6%, p=0.230), cardiac arrhythmias (5.8% vs 7.1%, p=0.640), anastomotic leaks (6.7% vs 8.2%, p=0.258) and postoperative mortality (5% vs 5.3%, p=0.80) were similar in the two groups. Conclusions: Radical three field lymphadenectomy increases pulmonary complication rates but has no impact on cardiac complications, anastomotic leaks, or operative mortality. No significant financial relationships to disclose.
High hepatitis C viral load and genotype 2 are strong predictors of chronic kidney disease
Authors: Tai-Shuan Lai, Mei-Hsuan Lee, Hwai-I. Yang, San-Lin You, Sheng-Nan Lu, Li-Yu Wang, Yong Yuan, Gilbert L’Italien, Kuo-Liong Chien, Chien-Jen Chen
Journal: Kidney International (2017)
Total and High–Molecular Weight Adiponectin in Relation to Metabolic Variables at Baseline and in Response to an Exercise Treatment Program: Comparative Evaluation of Three Assays
Authors: Maximilian von Eynatten, Philipp M. Lepper, Per M. Humpert
Journal: Diabetes Care (2007)

Recently, increasing attention has been paid to the relationship between multimeric forms of adiponectin and metabolic variables to assess the metabolic significance of high–molecular weight (HMW) adiponectin. Bluher et al. (1) investigated associations between total adiponectin and HMW with insulin resistance and the metabolic syndrome. The study did not demonstrate the superiority of HMW over total adiponectin in assessing insulin sensitivity that was previously reported in larger groups (2,3).

We studied 328 Caucasian men and women (114 non–insulin-resistant, 101 insulin-resistant, and …
Nicotinic Acid Phosphoribosyltransferase Regulates Cancer Cell Metabolism, Susceptibility to NAMPT Inhibitors, and DNA Repair
Authors: Francesco Piacente, Irene Caffa, Silvia Ravera, Giovanna Sociali, Mario Passalacqua, Valerio G. Vellone, Pamela Becherini, Daniele Reverberi, Fiammetta Monacelli, Alberto Ballestrero, Patrizio Odetti, Antonia Cagnetta, Michele Cea, Aimable Nahimana, Michel Duchosal, Santina Bruzzone, Alessio Nencioni
Journal: Cancer Research (2017)

Abstract In the last decade, substantial efforts have been made to identify NAD+ biosynthesis inhibitors, specifically against nicotinamide phosphoribosyltransferase (NAMPT), as preclinical studies indicate their potential efficacy as cancer drugs. However, the clinical activity of NAMPT inhibitors has proven limited, suggesting that alternative NAD+ production routes exploited by tumors confer resistance. Here, we show the gene encoding nicotinic acid phosphoribosyltransferase (NAPRT), a second NAD+-producing enzyme, is amplified and overexpressed in a subset of common types of cancer, including ovarian cancer, where NAPRT expression correlates with a BRCAness gene expression signature. Both NAPRT and NAMPT increased intracellular NAD+ levels. NAPRT silencing reduced energy status, protein synthesis, and cell size in ovarian and pancreatic cancer cells. NAPRT silencing sensitized cells to NAMPT inhibitors both in vitro and in vivo; similar results were obtained with the NAPRT inhibitor 2-hydroxynicotinic acid. Reducing NAPRT levels in a BRCA2-deficient cancer cell line exacerbated DNA damage in response to chemotherapeutics. In conclusion, NAPRT-dependent NAD+ biosynthesis contributes to cell metabolism and to the DNA repair process in a subset of tumors. This knowledge could be used to increase the efficacy of NAMPT inhibitors and chemotherapy. Cancer Res; 77(14); 3857–69. ©2017 AACR.