tbuckley/cabot-search huggingface dataset:
Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger–Huët anomaly)
Authors: Katrin Hoffmann, Christine K. Dreger, Ada L. Olins, Donald E. Olins, Leonard D. Shultz, Barbara Lucke, Hartmut Karl, Reinhard Kaps, Dietmar Müller, Amparo Vayá, Justo Aznar, Russell E. Ware, Norberto Sotelo Cruz, Tom H. Lindner, Harald Herrmann, André Reis, Karl Sperling
Journal: Nature Genetics (2002)
Abstract 3377: Glutamine mediated aggressiveness and drug sensitivity in ovarian cancer cells
Authors: Lifeng Yang, Tyler J. Moss, Juan C. Marini, Selanere Mangala, Stephen Wahlig, Julia Win, Dan Su, Anil K. Sood, Prahlad T. Ram, Deepak Nagrath
Journal: Cancer Research (2014)

Abstract Platinum-based drugs such as cisplatin, carboplatin and xoaliplatin hav been introduced into clinical trials and their outcomes has progressed the treatment on several tumors, including ovarian cancer. However, cancer cells acquire chemo-resistance in the long term incubation of drugs, which turns out to be the major limitation for cancer therapy. Recent studies have shown that cisplatin can accumulate in mitochondria and induce cytochrome C release, thereby resulting in apoptosis. We found that glutamine plays a vital role in maintaining mitochondrial integrity and function by regulating NAD+ and NADH. Using bioenergetics and isotopomer analysis we show that chemodrugs in presence of glutamine affect oxidative phosphorylation in drug sensitive parental ovarian cancer cells. Addition of NAD+ substrates increased NAD/NADH ratio abrogating cisplatin's effect on cell death and mitochondrial dysfunction. Furthermore, drug resistant cancer cells had relatively higher glutamine dependence when compared with parental cells. Importantly, we found that when glutamine's entry into TCA cycle was inhibited ovarian cancer cells became more sensitive to chemotherapy. Our findings are based on the quantification of metabolites, related to glycolysis, the pentose phosphate pathway, the TCA and urea cycles, and amino acids and nucleotide metabolism, and comparison of these pathways fluxes in drug sensitive and drug resistant ovarian cancer. The insights obtained present a unique opportunity for overcoming the drug resistance limitation in clinical trials in ovarian cancers. Citation Format: Lifeng Yang, Tyler J. Moss, Juan C. Marini, Selanere Mangala, Stephen Wahlig, Julia Win, Dan Su, Anil K. Sood, Prahlad T. Ram, Deepak Nagrath. Glutamine mediated aggressiveness and drug sensitivity in ovarian cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3377. doi:10.1158/1538-7445.AM2014-3377
TLR2 Limits Development of Hepatocellular Carcinoma by Reducing IL18-Mediated Immunosuppression
Authors: Shinan Li, Rui Sun, Yongyan Chen, Haiming Wei, Zhigang Tian
Journal: Cancer Research (2015)

Abstract Immune mechanisms underlying hepatocellular carcinoma (HCC) are not well understood. Here, we show that the Toll-like receptor TLR2 inhibits production of the proinflammatory cytokine IL18 and protects mice from DEN-induced liver carcinogenesis. On this protocol, Tlr2−/− mice exhibited more aggressive HCC development associated with impaired CD8+ T-cell function. Furthermore, Ly6ChighIL18Rα+ myeloid-derived suppressor cells (MDSC) were increased in number in the livers of Tlr2−/− mice before tumor onset. MDSC in this setting exhibited higher iNOS levels that could inhibit IFNγ production and CD8+ T-cell proliferation in vitro. Notably, Tlr2−/− hepatocytes produced more mature IL18 after DEN treatment that was sufficient to drive MDSC accumulation there. IL18 adminstration was sufficient to induce accumulation of MDSC, whereas hepatocyte-specific silencing of IL18 in Tlr2−/− mice decreased the proportion of MDSC, increased the proportion of functional CD8+ T cells, and alleviated HCC progression. IL18 production was mediated by caspase-8 insofar as the decrease in its silencing was sufficient to attenuate levels of mature IL18 in Tlr2−/− mice. Furthermore, the TLR2 agonist Pam3CSK4 inhibited both caspase-8 and IL18 expression, decreasing MDSC, increasing CD8+ T-cell function, and promoting HCC regression. Overall, our findings show how TLR2 deficiency accelerates IL18-mediated immunosuppression during liver carcinogenesis, providing new insights into immune control that may assist the design of effective immunotherapies to treat HCC. Cancer Res; 75(6); 986–95. ©2015 AACR.
Chronic Exposure of Smooth Muscle Cells to Minimally Oxidized LDL Results in Depressed Inositol 1,4,5-Trisphosphate Receptor Density and Ca <sup>2+</sup> Transients
Authors: Hamid Massaeli, J. Alejandro Austria, Grant N. Pierce
Journal: Circulation Research (1999)

Abstract —Oxidized LDL (oxLDL) (0.1 mg/mL) increased [Ca 2+ ] i in vascular smooth muscle cells (VSMCs) within 5 to 10 seconds of incubation. This increase was mediated via an inositol 1,4,5-trisphosphate (IP 3 )-dependent release of Ca 2+ from the sarcoplasmic reticulum. However, atherosclerosis is a gradual process in which VSMCs are more likely exposed to low concentrations of oxLDL over extended periods rather than acute exposures. It is very possible, therefore, that lower [oxLDL] and longer exposure times may induce a very different response with regard to regulation of [Ca 2+ ] i . VSMCs were incubated with 4- to 100-fold lower [oxLDL] for up to 6 days. The conditions were not cytotoxic. Basal [Ca 2+ ] i was not altered. Surprisingly, however, after chronic exposure to oxLDL, a brief addition of oxLDL (0.1 mg/mL) or norepinephrine failed to elicit the expected rise in Ca 2+ i . Because the acute effects of oxLDL on control cells were mediated through an IP 3 -dependent pathway, we investigated the integrity of the VSMC IP 3 receptors. Immunocytochemical analysis and Western blots revealed a depression in the density of IP 3 receptors after chronic exposure of VSMCs to oxLDL. These changes in IP 3 receptors have significance under atherosclerotic conditions as well. Immunocytochemical analysis revealed a decrease in IP 3 receptor density in the medial layer under atherosclerotic plaques in situ. Our data, therefore, demonstrate a striking difference between the acute and chronic effects of oxLDL on VSMC calcium. Whereas acute exposure to oxLDL stimulates [Ca 2+ ] i , chronic exposure results in depressed Ca 2+ transients, apparently through a decrease in IP 3 receptor density. These changes have functional implications for the atherosclerotic vessel in vivo, and our data implicates oxLDL in this process.
DNA Methylation of the <i>SLC16A3</i> Promoter Regulates Expression of the Human Lactate Transporter MCT4 in Renal Cancer with Consequences for Clinical Outcome
Authors: Pascale Fisel, Stephan Kruck, Stefan Winter, Jens Bedke, Jörg Hennenlotter, Anne T. Nies, Marcus Scharpf, Falko Fend, Arnulf Stenzl, Matthias Schwab, Elke Schaeffeler
Journal: Clinical Cancer Research (2013)

The monocarboxylate transporter 4 (MCT4) is a metabolic target in tumor biology because it mediates lactate transport across membranes resulting in antiapoptotic effects. Cell experiments support the importance of MCT4 in clear cell renal cell carcinoma (ccRCC). In this study, we assessed the prognostic potential of MCT4 expression in ccRCC and its epigenetic regulation by DNA methylation as novel predictive marker for patient outcome using independent ccRCC cohorts.MCT4 protein expression was quantified in 207 ccRCC and corresponding nontumor tissues. Data of an independent ccRCC cohort from The Cancer Genome Atlas (TCGA) were analyzed on MCT4 mRNA (n = 482) and DNA methylation (n = 283) level. The findings on MCT4 expression and DNA methylation in the SLC16A3 promoter were validated in a third cohort (n = 64). Promoter activity assays were conducted in four RCC cell lines.MCT4 protein expression was upregulated (P < 0.0001) in ccRCC and showed significant association with cancer-related death. Upregulation of MCT4 mRNA expression (P < 0.00001) was confirmed in the TCGA cohort. Single CpG sites correlated inversely with mRNA expression and were associated with overall survival in Kaplan-Meier analyses [HR = 0.39; 95% confidence interval (CI), 0.24-0.64; P[log-rank] = 1.23e(-04)]. Promoter activity studies confirmed MCT4 regulation by DNA methylation. The significant correlation between MCT4 protein and gene expression or DNA methylation at single CpG sites was validated in a third cohort. Again, higher methylation at individual CpG sites was associated with prolonged survival [HR = 0.05; 95% CI, 0.01-0.40; P[log-rank] = 6.91e(-05)].We identified SLC16A3 promoter DNA methylation as a novel epigenetic mechanism for MCT4 regulation in ccRCC with first evidence of a biological rationale for prognosis and clinical outcome.
Effectiveness of pilates on functionality, respiratory muscle strength and exercise capacity in hospitalized chronic renal patients: Randomized controlled trial
Authors: Luciana Chiavegato, Juliana Pinto, Lais Sarmento, Ana Paula Silva, Nathália Pacheco, Cristina Cabral
Journal: European Respiratory Journal (2014)

Background: Studies have shown that exercise programs have modified the morbidity and survival rates of CKD patients, thereby promoting their metabolic, physiological and psychological benefits.   Objective :Compare Pilates and conventional physiotherapy on functionality, respiratory muscle strength, exercise capacity (Step Test) and length of stay of patients with CKD during the hospitalization period.   Methods : 56 patients were randomized in two groups: Pilates and Control (conventional physiotherapy), each receiving their daily treatment for 30 minutes. Functionality was evaluated using Barthel Index, respiratory muscle strength (MIP and MEP) and Step Test were assessed at pre intervention period, after 5th and 10th treatment sessions and at the time of hospital discharge. The data was submitted to a normality test and Student9s t test, two-way ANOVA and/or their equivalents in non-normal distribution were used. The analysis was performed on intent to treat basis.   Results:  No statistically significant difference was found at discharge between groups when compared functionality (Barthel Index) 99.61 ± 1,63  vs  95,1 ± 1,66, MEP 85,80  vs  84,33 % pred, andlength of stay, 24±21  vs  28±22 days forPilates and Control group respectively.Step Test 95,9±17,39  vs  59,08±12,30 steps (pl0,03) and MIP 89,82  vs  72,95 % pred (pl0,05) were statistically significant when compared Pilates  vs  Control.   Conclusion : Pilates and Conventional Physiotherapy were able to maintain functionality and Pilates can improve inspiratory muscle strength and exercise capacity of CKD patients with during hospitalization avoiding losses caused by immobility.
Proximal Tubule Proliferation Is Insufficient to Induce Rapid Cyst Formation after Cilia Disruption
Authors: Neeraj Sharma, Erik B. Malarkey, Nicolas F. Berbari, Amber K. O’Connor, Gregory B. Vanden Heuvel, Michal Mrug, Bradley K. Yoder
Journal: Journal of the American Society of Nephrology (2013)

Disrupting the function of cilia in mouse kidneys results in rapid or slow progression of cystic disease depending on whether the animals are juveniles or adults, respectively. Renal injury can also markedly accelerate the renal cyst formation that occurs after disruption of cilia in adult mice. Rates of cell proliferation are markedly higher in juvenile than adult kidneys and increase after renal injury, suggesting that cell proliferation may enhance the development of cysts. Here, we induced cilia loss in the kidneys of adult mice in the presence or absence of a Cux-1 transgene, which maintains cell proliferation. By using this model, we were able to avoid additional factors such as inflammation and dedifferentiation, which associate with renal injury and may also influence the rate of cystogenesis. After induction of cilia loss, cystic disease was not more pronounced in adult mice with the Cux-1 transgene compared with those without the transgene. In conclusion, these data suggest that proliferation is unlikely to be the sole mechanism underlying the rapid cystogenesis observed after injury in mice that lose cilia function in adulthood.
Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes
Authors: G. Remuzzi
Journal: Journal of Clinical Investigation (2006)

The incidence of chronic kidney diseases is increasing worldwide, and these conditions are emerging as a major public health problem. While genetic factors contribute to susceptibility and progression of renal disease, proteinuria has been claimed as an independent predictor of outcome. Reduction of urinary protein levels by various medications and a low-protein diet limits renal function decline in individuals with nondiabetic and diabetic nephropathies to the point that remission of the disease and regression of renal lesions have been observed in experimental animals and even in humans. In animal models, regression of glomerular structural changes is associated with remodeling of the glomerular architecture. Instrumental to this discovery were 3D reconstruction studies of the glomerular capillary tuft, which allowed the quantification of sclerosis volume reduction and capillary regeneration upon treatment. Regeneration of capillary segments might result from the contribution of resident cells, but progenitor cells of renal or extrarenal origin may also have a role. This review describes recent advances in our understanding of the mechanisms and mediators underlying renal tissue repair ultimately responsible for regression of renal injury.
Elucidation of the enigmatic IgD class-switch recombination via germline deletion of the IgH 3′ regulatory region
Authors: Pauline Rouaud, Alexis Saintamand, Faten Saad, Claire Carrion, Sandrine Lecardeur, Michel Cogné, Yves Denizot
Journal: The Journal of Experimental Medicine (2014)

Classical class-switch recombination (cCSR) substitutes the Cμ gene with Cγ, Cε, or Cα, thereby generating IgG, IgE, or IgA classes, respectively. This activation-induced deaminase (AID)–driven process is controlled by the IgH 3′ regulatory region (3′RR). Regulation of rare IgD CSR events has been enigmatic. We show that μδCSR occurs in mouse mesenteric lymph node (MLN) B cells and is AID-dependent. AID attacks differ from those in cCSR because they are not accompanied by extensive somatic hypermutation (SHM) of targeted regions and because repaired junctions exhibit features of the alternative end-joining (A-EJ) pathway. In contrast to cCSR and SHM, μδCSR is 3′RR-independent, as its absence affects neither breakpoint locations in Sμ- and Sδ-like (σδ) nor mutation patterns at Sμ-σδ junctions. Although mutations occur in the immediate proximity of the μδ junctions, SHM is absent distal to the junctions within both Sμ and rearranged VDJ regions. In conclusion, μδCSR is active in MLNs, occurs independently of 3′RR-driven assembly, and is even dramatically increased in 3′RR-deficient mice, further showing that its regulation differs from cCSR.
Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial
Authors: Martin Dennis, Dott Building
Journal: The Lancet (2013)

Venous thromboembolism is a common, potentially avoidable cause of death and morbidity in patients in hospital, including those with stroke. In surgical patients, intermittent pneumatic compression (IPC) reduces the risk of deep vein thrombosis (DVT), but no reliable evidence exists about its effectiveness in patients who have had a stroke. We assessed the effectiveness of IPC to reduce the risk of DVT in patients who have had a stroke.The CLOTS 3 trial is a multicentre parallel group randomised trial assessing IPC in immobile patients (ie, who cannot walk to the toilet without the help of another person) with acute stroke. We enrolled patients from day 0 to day 3 of admission and allocated them via a central randomisation system (ratio 1:1) to receive either IPC or no IPC. A technician who was masked to treatment allocation did a compression duplex ultrasound (CDU) of both legs at 7-10 days and, wherever practical, at 25-30 days after enrolment. Caregivers and patients were not masked to treatment assignment. Patients were followed up for 6 months to determine survival and later symptomatic venous thromboembolism. The primary outcome was a DVT in the proximal veins detected on a screening CDU or any symptomatic DVT in the proximal veins, confirmed on imaging, within 30 days of randomisation. Patients were analysed according to their treatment allocation.ISRCTN93529999.Between Dec 8, 2008, and Sept 6, 2012, 2876 patients were enrolled in 94 centres in the UK. The included patients were broadly representative of immobile stroke patients admitted to hospital and had a median age of 76 years (IQR 67-84). The primary outcome occurred in 122 (8·5%) of 1438 patients allocated IPC and 174 (12·1%) of 1438 patients allocated no IPC; an absolute reduction in risk of 3·6% (95% CI 1·4-5·8). Excluding the 323 patients who died before any primary outcome and 41 without any screening CDU, the adjusted OR for the comparison of 122 of 1267 patients vs 174 of 1245 patients was 0·65 (95% CI 0·51-0·84; p=0·001). Deaths in the treatment period occurred in 156 (11%) patients allocated IPC and 189 (13%) patients allocated no IPC died within the 30 days of treatment period (p=0·057); skin breaks on the legs were reported in 44 (3%) patients allocated IPC and in 20 (1%) patients allocated no IPC (p=0·002); falls with injury were reported in 33 (2%) patients in the IPC group and in 24 (2%) patients in the no-IPC group (p=0·221).IPC is an effective method of reducing the risk of DVT and possibly improving survival in a wide variety of patients who are immobile after stroke.National Institute of Health Research (NIHR) Health Technology Assessment (HTA) programme, UK; Chief Scientist Office of Scottish Government; Covidien (MA, USA).
Analysis of Gercor Index in Kras Exon2 Wt Patients with Mcrc Treated with Salvage-Line Cmab-Based Regimen: Hgcsg0901
Authors: Soh Saitoh, Satoshi Yuki, Takahide Sasaki, Kazuteru Hatanaka, Hiroyuki Okuda, Yasushi Tsuji, Ayumu Hosokawa, Yasushi Sato, Yuh Sakata, Yoshito Komatsu
Journal: Annals of Oncology (2014)
Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib
Authors: Anja Lachenmayer, Clara Alsinet, Radoslav Savic, Laia Cabellos, Sara Toffanin, Yujin Hoshida, Augusto Villanueva, Beatriz Minguez, Philippa Newell, Hung-Wen Tsai, Jordi Barretina, Swan Thung, Stephen C. Ward, Jordi Bruix, Vincenzo Mazzaferro, Myron Schwartz, Scott L. Friedman, Josep M. Llovet
Journal: Clinical Cancer Research (2012)

Hepatocellular carcinoma (HCC) is a heterogeneous cancer with active Wnt signaling. Underlying biologic mechanisms remain unclear and no drug targeting this pathway has been approved to date. We aimed to characterize Wnt-pathway aberrations in HCC patients, and to investigate sorafenib as a potential Wnt modulator in experimental models of liver cancer.The Wnt-pathway was assessed using mRNA (642 HCCs and 21 liver cancer cell lines) and miRNA expression data (89 HCCs), immunohistochemistry (108 HCCs), and CTNNB1-mutation data (91 HCCs). Effects of sorafenib on Wnt signaling were evaluated in four liver cancer cell lines with active Wnt signaling and a tumor xenograft model.Evidence for Wnt activation was observed for 315 (49.1%) cases, and was further classified as CTNNB1 class (138 cases [21.5%]) or Wnt-TGFβ class (177 cases [27.6%]). CTNNB1 class was characterized by upregulation of liver-specific Wnt-targets, nuclear β-catenin and glutamine-synthetase immunostaining, and enrichment of CTNNB1-mutation-signature, whereas Wnt-TGFβ class was characterized by dysregulation of classical Wnt-targets and the absence of nuclear β-catenin. Sorafenib decreased Wnt signaling and β-catenin protein in HepG2 (CTNNB1 class), SNU387 (Wnt-TGFβ class), SNU398 (CTNNB1-mutation), and Huh7 (lithium-chloride-pathway activation) cell lines. In addition, sorafenib attenuated expression of liver-related Wnt-targets GLUL, LGR5, and TBX3. The suppressive effect on CTNNB1 class-specific Wnt-pathway activation was validated in vivo using HepG2 xenografts in nude mice, accompanied by decreased tumor volume and increased survival of treated animals.Distinct dysregulation of Wnt-pathway constituents characterize two different Wnt-related molecular classes (CTNNB1 and Wnt-TGFβ), accounting for half of all HCC patients. Sorafenib modulates β-catenin/Wnt signaling in experimental models that harbor the CTNNB1 class signature.
Skeletal Muscle Protein and Amino Acid Metabolism in Experimental Chronic Uremia in the Rat
Authors: Alan J. Garber
Journal: Journal of Clinical Investigation (1978)

The kinetics and factors regulating alanine and glutamine formation and release were investigated in skeletal muscle preparations from control and experimentally uremic rats. These preparations maintained phosphocreatine and ATP levels in vitro which closely approximated levels found in vivo. Alanine and glutamine release from uremic muscle were increased 45.8 and 36.0%, respectively, but tissue levels were unaltered. The increased release of alanine by uremic muscle was not accounted for by decreased rates of medium alanine reutilization via oxidation to CO2 or incorporation into muscle protein. The maximal capacity of added amino acids such as aspartate, cysteine, leucine, and valine to stimulate net alanine and glutamine formation was the same in uremic and control muscle. Epitrochlearis preparations were partially labeled in vivo with [guanido-14C]-arginine. On incubation, preparations from uremic animals showed a 54.6% increase in the rate of loss of 14C-label in acid precipitable protein. Correspondingly, these same uremic preparations showed a 62.7% increase in 14C-label appearance in the acid-soluble fraction of muscle and in the incubation media. Insulin decreased alanine and glutamine release to an extent threefold greater in uremic than in control preparations, and increased muscle glucose uptake approximately threefold in all preparations. Although basal rates of [4,5-3H]leucine incorporation into protein were decreased 25% in uremic muscles as compared with control muscles, insulin stimulated [3H]leucine incorporation nearly equally in both preparations.
Chronic benign familial pemphigus.
Authors: BARBARA LEPPARD, T. J. DELANEY, K. V. SANDERSON
Journal: British Journal of Dermatology (1973)

Journal Article Chronic benign familial pemphigus: INDUCTION OF LESIONS BY HERPESVIRUS HOMINIS Get access BARBARA LEPPARD, BARBARA LEPPARD Department of Dermatology, St George's Hospital, London, S.W.I Search for other works by this author on: Oxford Academic Google Scholar T. J. DELANEY, T. J. DELANEY Department of Dermatology, St George's Hospital, London, S.W.I Search for other works by this author on: Oxford Academic Google Scholar K. V. SANDERSON K. V. SANDERSON Department of Dermatology, St George's Hospital, London, S.W.I Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 88, Issue 6, 1 June 1973, Pages 609–613, https://doi.org/10.1111/j.1365-2133.1973.tb08027.x Published: 01 June 1973 Article history Accepted: 06 December 1972 Published: 01 June 1973