tbuckley/cabot-search huggingface dataset:
Phase II study of capecitabine and oxaliplatin as first-line treatment in advanced colorectal cancer
Authors: M. Zeuli, C. Nardoni, M.S. Pino, T. Gamucci, A. Gabriele, V. Ferraresi, D. Giannarelli, F. Cognetti
Journal: Annals of Oncology (2003)

BackgroundCapecitabine and oxaliplatin are both active anticancer agents in the treatment of patients with advanced colorectal cancer. The aim of this phase II study is to determine the efficacy and tolerability of combining oxaliplatin with capecitabine in the treatment of advanced non-pretreated colorectal cancer.Patients and methodsForty-three chemotherapy-naïve patients were enrolled. Capecitabine 2500 mg/m2/day was administered orally twice a day continuously for 14 days and oxaliplatin 120 mg/m2 was administered as a 2-h infusion on day 1, repeated every 3 weeks.ResultsForty-three patients were assessable for toxicity and 39 for clinical activity: the main toxicity was grade 3 or 4 diarrhea, which occurred in 28% of the patients. The response rates were 44% [95% confidence interval (CI), 29.3% to 59.0%] and 48.7% (95% CI 33.0% to 64.4%) (intention-to-treat and per protocol analysis, respectively). The median overall survival was 20 months (95% CI 12–28).ConclusionsCombining capecitabine and oxaliplatin yields promising activity in advanced colorectal cancer; therefore, the capecitabine dose we utilized is probably too high. The main toxicity is diarrhea, which is manageable with appropriate dose reductions.This combination may be preferable compared to a standard combination with infusional fluorouracil/leucovorin as it is more convenient and practical with similar efficacy. Thus, phase III trials are needed to clarify its role in the treatment of chemotherapy-naïve advanced colorectal cancer patients.
Central inhibitory dysfunctions in neuropathic pain: What is the relationship between basic science and clinical practice?
Authors: Philip J. Siddall
Journal: Behavioral and Brain Sciences (1997)

The possible dysfunction of γ aminobutyric acid (GABA) and opioid inhibitory mechanisms following central and peripheral nervous system injury is an important and potentially useful finding. However, effective clinical application must take into account the specific characteristics of the models used in the studies and the relationship of these models to specific clinical conditions. [dickenson; wiesenfeld-hallin et al.]
RhoA GTPase controls cytokinesis and programmed necrosis of hematopoietic progenitors
Authors: Xuan Zhou, Maria Carolina Florian, Paritha Arumugam, Xiaoyi Chen, Jose A. Cancelas, Richard Lang, Punam Malik, Hartmut Geiger, Yi Zheng
Journal: The Journal of Experimental Medicine (2013)

Hematopoietic progenitor cells (HPCs) are central to hematopoiesis as they provide large numbers of lineage-defined blood cells necessary to sustain blood homeostasis. They are one of the most actively cycling somatic cells, and their precise control is critical for hematopoietic homeostasis. The small GTPase RhoA is an intracellular molecular switch that integrates cytokine, chemokine, and adhesion signals to coordinate multiple context-dependent cellular processes. By using a RhoA conditional knockout mouse model, we show that RhoA deficiency causes a multilineage hematopoietic failure that is associated with defective multipotent HPCs. Interestingly, RhoA(-/-) hematopoietic stem cells retained long-term engraftment potential but failed to produce multipotent HPCs and lineage-defined blood cells. This multilineage hematopoietic failure was rescued by reconstituting wild-type RhoA into the RhoA(-/-) Lin(-)Sca-1(+)c-Kit(+) compartment. Mechanistically, RhoA regulates actomyosin signaling, cytokinesis, and programmed necrosis of the HPCs, and loss of RhoA results in a cytokinesis failure of HPCs manifested by an accumulation of multinucleated cells caused by failed abscission of the cleavage furrow after telophase. Concomitantly, the HPCs show a drastically increased death associated with increased TNF-RIP-mediated necrosis. These results show that RhoA is a critical and specific regulator of multipotent HPCs during cytokinesis and thus essential for multilineage hematopoiesis.
Role of Nrf2 in Oxidative Stress and Toxicity
Authors: Qiang Ma
Journal: The Annual Review of Pharmacology and Toxicology (2013)

Organismal life encounters reactive oxidants from internal metabolism and environmental toxicant exposure. Reactive oxygen and nitrogen species cause oxidative stress and are traditionally viewed as being harmful. On the other hand, controlled production of oxidants in normal cells serves useful purposes to regulate signaling pathways. Reactive oxidants are counterbalanced by complex antioxidant defense systems regulated by a web of pathways to ensure that the response to oxidants is adequate for the body's needs. A recurrent theme in oxidant signaling and antioxidant defense is reactive cysteine thiol–based redox signaling. The nuclear factor erythroid 2–related factor 2 (Nrf2) is an emerging regulator of cellular resistance to oxidants. Nrf2 controls the basal and induced expression of an array of antioxidant response element–dependent genes to regulate the physiological and pathophysiological outcomes of oxidant exposure. This review discusses the impact of Nrf2 on oxidative stress and toxicity and how Nrf2 senses oxidants and regulates antioxidant defense.
DOUBLE-BLIND CONTROLLED TRIAL OF IMMUNOSUPPRESSION IN THE TREATMENT OF MULTIPLE SCLEROSIS: FINAL REPORT
Authors: J. Mertin, M. Kremer, S.C. Knight, J.R. Batchelor, A.M. Halliday, P. Rudge, M.J.R. Healey, A. Compston, E.J. Thompson, M. Denman, P.B. Medawar
Journal: The Lancet (1982)
Targeted Deletion of Angiotensin II Type 1A Receptor Does not Protect Mice from Progressive Nephropathy of Overload Proteinuria
Authors: Ariela Benigni, Daniela Corna, Carla Zoja, Lorena Longaretti, Elena Gagliardini, Norberto Perico, Thomas M. Coffman, Giuseppe Remuzzi
Journal: Journal of the American Society of Nephrology (2004)

In experimental and human renal diseases, progression is limited by angiotensin-converting enzyme inhibitors. Whether renoprotection was due to their capacity of reducing proinflammatory and profibrotic effects of angiotensin II (Ang II) or limiting proteinuria and its long term toxicity is debated. For dissecting the relative contribution of Ang II and proteinuria to chronic renal damage, the protein-overload proteinuria model was used in genetically modified mice lacking the major isoform of murine AT1 receptor (AT1A). Uninephrectomized AT1A+/+ and −/− mice received a daily injection of BSA or saline for 4 or 11 wk. AT1A−/−BSA mice acquired a renal phenotype of proteinuria and renal glomerular and tubulointerstitial lesions, albeit attenuated with respect to AT1A+/+BSA. Administration of the calcium channel blocker lacidipine to reduce BP of AT1A+/+BSA mice to levels of AT1A−/−BSA translated into comparable values of protein excretion rate and glomerular and tubulointerstitial injury in both strains. These results confirm that the toxic effect of protein trafficking on renal disease progression is not necessarily dependent on Ang II to the extent that targeted deletion of AT1A does not prevent disease progression. A role of Ang II via AT1B or AT2 receptors is still a possibility that cannot be ruled out by the present experimental approach. These findings provide a clear rationale for specifically targeting proteinuria in pharmacologic interventions of chronic nephropathies.
PI3Kγ is required for NMDA receptor–dependent long-term depression and behavioral flexibility
Authors: Jae-Ick Kim, Hye-Ryeon Lee, Su-eon Sim, Jinhee Baek, Nam-Kyung Yu, Jun-Hyeok Choi, Hyoung-Gon Ko, Yong-Seok Lee, Soo-Won Park, Chuljung Kwak, Sung-Ji Ahn, So Yoen Choi, Hyun Kim, Kyoung-Han Kim, Peter H Backx, Clarrisa A Bradley, Eunjoon Kim, Deok-Jin Jang, Kyungmin Lee, Sang Jeong Kim, Min Zhuo, Graham L Collingridge, Bong-Kiun Kaang
Journal: Nature Neuroscience (2011)
Multicomponent indices to predict survival in COPD
Authors: J. M. Marin
Journal: European Respiratory Journal (2014)

From the author: 

As stated in our manuscript [1], we aimed to determine the prognostic value of a number of chronic obstructive pulmonary disease (COPD) multicomponent indices to predict death in the short term and very long term, not to create or modify other indices. For decades, we physicians who treat patients with COPD have expressed the deterioration of their lung function in relation to how it should be in individuals with unaffected physiological function, i.e. as per cent predicted. We must do this because lung …
Hemodynamic Patterns and Spectral Analysis of Heart Rate Variability during Dialysis Hypotension
Authors: MICHEL G. W. BARNAS, WALTHER H. BOER, HEIN A. KOOMANS
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Intradialytic hypotension, a major source of morbidity during hemodialysis and ultrafiltration, is often accompanied by paradoxical bradycardia. Relatively little is known about the sequential changes in autonomic nervous system activity up to and during the hypotensive episode. Continuous, beat-to-beat measurements of BP and heart rate were made during hemodialysis in patients prone ( n = 8) and not prone ( n = 11) to develop intradialytic hypotension. Off-line spectral analysis of heart rate variability (HRV) was performed to assess changes in autonomic nervous system activity during dialysis sessions both with and without hypotension. The low frequency (LF) component of HRV is thought to correlate with sympathetic nervous system activity, the high frequency (HF) component with that of the parasympathetic nervous system. In the sessions not complicated by symptomatic hypotension ( n = 26), mean arterial BP (MAP) hardly fell, whereas heart rate increased from 77 ± 2 to 89 ± 5 bpm ( P &lt; 0.05). The LF component of HRV increased from 45.2 ± 5.0 normalized units (nu) to 59.9 ± 4.9 nu ( P &lt; 0.05), whereas the HF component fell from 54.8 ± 5.0 to 40.2 ± 4.4 nu ( P &lt; 0.05). These changes agree with compensatory baroreflex-mediated activation of the sympathetic nervous system (and suppressed parasympathetic activity) during ultrafiltration-induced intravascular volume depletion. In the sessions complicated by severe symptomatic hypotension ( n = 22), the changes in heart rate and the results of spectral analysis of HRV were similar to those reported above up to the moment of sudden symptomatic (nausea, vomiting, dizziness, cramps) hypotension, whereas MAP had already fallen gradually from 94 ± 3 to 85 ± 3 mmHg ( P &lt; 0.05). The sudden further reduction in MAP (to 55 ± 2 mmHg, P &lt; 0.02) was invariably accompanied by bradycardia (heart rate directly before hypotension 90 ± 2 bpm, during hypotension 69 ± 3 bpm, P &lt; 0.002). The LF component of HRV fell from 62.8 ± 4.6 nu directly before to 40.0 ± 3.7 nu ( P &lt; 0.05) during hypotension, whereas the HF component increased from 37.9 ± 4.7 to 60.3 ± 3.7 nu ( P &lt; 0.05). These findings agree with activation of the cardiodepressor reflex, involving decreased sympathetic and increased parasympathetic nervous system activity, respectively. These findings indicate that activation of the sympatho-inhibitory cardiodepressor reflex (Bezold-Jarisch reflex), which is a physiologic response to a critical reduction in intravascular volume and cardiac filling, is the cause of sudden intradialytic hypotension.
Equivalence of human and mouse CD4 in enhancing antigen responses by a mouse class II-restricted T cell hybridoma.
Authors: P von Hoegen, M C Miceli, B Tourvieille, M Schilham, J R Parnes
Journal: The Journal of Experimental Medicine (1989)

We have examined the ability of hCD4 to interact functionally with mouse class II MHC molecules using the mouse T cell hybridoma BI-141, specific for beef insulin. We have previously shown that expression of mouse CD4 results in a marked enhancement of IL-2 release by BI-141 cells in response to beef insulin or, in a cross-reactive response, to pork insulin, on the appropriate mouse APCs. We now demonstrate that expression of hCD4 results in an equivalent stimulation of antigen responses by this mouse T cell hybridoma. The specificity of this effect was demonstrated by mAb and gp120 blocking studies. These data provide the first direct evidence for function of hCD4 and in an exclusively mouse system.
Impairment in Cardiac Autonomic Regulation Preceding Arterial Hypertension in Humans
Authors: Daniela Lucini, Giuseppe Sandro Mela, Alberto Malliani, Massimo Pagani
Journal: Circulation (2002)

Subjects in the upper-normal range of arterial pressure have an excess cardiovascular risk, which suggests that other factors, such as impaired autonomic regulation, might be implicated. This study was designed to assess whether noninvasive markers of cardiac and vascular autonomic regulation might already be altered in subjects with high-normal arterial pressure levels.We performed an observational study on a population comprising 300 subjects of both sexes with arterial pressure ranging from 90/60 to 210/120 mm Hg, who were divided into 3 groups (each n=100) with average systolic pressures of 103, 133, and 163 mm Hg. Autonomic regulation was inferred from spectral analysis of RR interval and systolic arterial pressure variability, considering rest and stand-induced changes, to account for sympathetic excitatory components. Significant alterations in markers of sinoatrial regulation (increased low-frequency normalized units, reduced high-frequency normalized units, and alpha-index) were already apparent in subjects in the second tertile, ie, those with arterial pressure within normal limits. Markers of vascular regulation instead showed significant alterations in the third (hypertensive) tertile. In response to standing, changes in markers of sinoatrial modulations were gradually reduced, whereas those of vascular regulation were increased. A tight link between progression of arterial pressure and the continuum of changes in autonomic markers as shown by simple correlation analysis appeared strongly affected by age and was spread across many spectral analysis-derived variables. Hypertensive autonomic dysregulation was particularly apparent in the youngest group.RR-variability parameters might prove useful to assess, with longitudinal studies, the mechanistic role of autonomic impairment in the increased risk of prehypertensive conditions.
miR-31 is consistently inactivated in EBV-associated nasopharyngeal carcinoma and contributes to its tumorigenesis
Authors: Chartia Ching-Mei Cheung, Grace Tin-Yun Chung, Samantha Wei-Man Lun, Ka-Fai To, Kwong-Wai Choy, Kin-Mang Lau, Sharie Pui-Kei Siu, Xin-Yuan Guan, Roger Kai-Cheong Ngan, Timothy Tak-Chun Yip, Pierre Busson, Sai-Wah Tsao, Kwok-Wai Lo
Journal: Molecular Cancer (2014)

As a distinctive type of head and neck cancers, nasopharyngeal carcinoma (NPC) is genesis from the clonal Epstein-Barr virus (EBV)-infected nasopharyngeal epithelial cells accumulated with multiple genetic lesions. Among the recurrent genetic alterations defined, loss of 9p21.3 is the most frequent early event in the tumorigenesis of EBV-associated NPC. In addition to the reported CDKN2A/p16, herein, we elucidated the role of a miRNA, miR-31 within this 9p21.3 region as NPC-associated tumor suppressor. The expression and promoter methylation of miR-31 were assessed in a panel of NPC tumor lines and primary tumors. Its in vitro and in vivo tumor suppression function was investigated through the ectopic expression of miR-31 in NPC cells. We also determined the miR-31 targeted genes and its involvement in the growth in NPC. Downregulation of miR-31 expression was detected in almost all NPC cell line, patient-derived xenografts (PDXs) and primary tumors. Both homozygous deletion and promoter hypermethylation were shown to be major mechanisms for miR-31 silencing in this cancer. Strikingly, loss of miR-31 was also obviously observed in the dysplastic lesions of nasopharynx. Restoration of miR-31 in C666-1 cells inhibited the cell proliferation, colony-forming and migratory capacities. Dramatic reduction of in v itro anchorage-independent growth and in vivo tumorigenic potential were demonstrated in the stable clones expressing miR-31. Furthermore, we proved that miR-31 suppressed the NPC cell growth via targeting FIH1 and MCM2. The findings provide strong evidence to support miR-31 as a new NPC-associated tumor suppressor on 9p21.3 region. The inactivation of miR-31 may contribute to the early development of NPC.
Tools for simulating evolution of aligned genomic regions with integrated parameter estimation
Authors: Avinash Varadarajan, Robert K Bradley, Ian H Holmes
Journal: Genome biology (2008)

Abstract Controlled simulations of genome evolution are useful for benchmarking tools. However, many simulators lack extensibility and cannot measure parameters directly from data. These issues are addressed by three new open-source programs: GSIMULATOR (for neutrally evolving DNA), SIMGRAM (for generic structured features) and SIMGENOME (for syntenic genome blocks). Each offers algorithms for parameter measurement and reconstruction of ancestral sequence. All three tools out-perform the leading neutral DNA simulator (DAWG) in benchmarks. The programs are available at http://biowiki.org/SimulationTools .
Increased soluble and platelet-associated CD40 ligand in essential thrombocythemia and reactive thrombocytosis
Authors: Jean-François Viallard, Anne Solanilla, Bruno Gauthier, Cécile Contin, Julie Déchanet, Christophe Grosset, Jean-François Moreau, Vincent Praloran, Paquita Nurden, Jean-Luc Pellegrin, Alan T. Nurden, Jean Ripoche
Journal: Blood (2002)
Preferential Cytotoxicity of 5-Thio-d-glucose Against Hypoxic Tumor Cells2
Authors: Chang W. Song, Jacob J. Clement, Seymour H. Levitt
Journal: JNCI Journal of the National Cancer Institute (1976)

Journal Article Preferential Cytotoxicity of 5-Thio-d-glucose Against Hypoxic Tumor Cells Get access Chang W. Song, Chang W. Song Search for other works by this author on: Oxford Academic PubMed Google Scholar Jacob J. Clement, Jacob J. Clement Search for other works by this author on: Oxford Academic PubMed Google Scholar Seymour H. Levitt Seymour H. Levitt Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 57, Issue 3, September 1976, Pages 603–605, https://doi.org/10.1093/jnci/57.3.603 Published: 01 September 1976 Article history Received: 02 January 1976 Accepted: 12 March 1976 Published: 01 September 1976
Nontransfusional approach to increased platelet count in patients with cirrhosis and thrombocytopenia
Authors: Armando Tripodi, Massimo Primignani
Journal: Hepatology (2013)

Background: Eltrombopag is an oral thrombopoietin-receptor agonist. This study evaluated the efficacy of eltrombopag for increasing platelet counts and reducing the need for platelet transfusions in patients with thrombocytopenia and chronic liver disease who are undergoing an elective invasive procedure.
Integrated Ca <sup>2+</sup> Signaling Between Smooth Muscle and Endothelium of Resistance Vessels
Authors: Yasuaki Yashiro, Brian R. Duling
Journal: Circulation Research (2000)

Cell-cell communication in the arteriolar wall was examined using the Ca(2+)-sensitive indicator fura-2 and the Ca(2+) buffer BAPTA as means of measuring and buffering cellular Ca(2+). The experiments focused on the role of endothelial cell [Ca(2+)](i) in modulating phenylephrine (PE)-induced contractions in in vitro arterioles of the hamster cremaster. Fura-2-AM and BAPTA-AM were applied intraluminally to accomplish endothelium-specific loading. PE was applied to short segments of arterioles using pressure-pulse ejection from a micropipette. Under control conditions at the site of stimulation, PE elicited a strong vasoconstriction preceded by an increase in endothelial cell [Ca(2+)](i). A very small biphasic conducted response was observed at sites upstream from the stimulation site. BAPTA sharply reduced the measured Ca(2+) response in the endothelium. This was associated with an enhanced local contractile response. In addition, the biphasic conducted response was converted into a strong conducted vasoconstriction. PE caused an initial rise in smooth muscle [Ca(2+)](i) at the stimulated site, which was followed by a rapid decrease below baseline. Endothelial cell loading of BAPTA had minimal effect on the initial [Ca(2+)](i) peak but eliminated the secondary decrease in smooth muscle [Ca(2+)](i). Intraluminal application of charybdotoxin plus apamin mimicked the change in vasomotor state induced by BAPTA. These data lead us to hypothesize that, after smooth muscle stimulation, intercellular Ca(2+) signaling between smooth muscle and endothelium causes a secondary rise in endothelial cell Ca(2+), which triggers a hyperpolarizing event and initiates a conducted vasodilation. We conclude that smooth muscle and endothelium operate as a functional unit in these vessels.
Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus.
Authors: C Mohan, S Adams, V Stanik, S K Datta
Journal: The Journal of Experimental Medicine (1993)

Only a fraction (12%) of 268 "autoreactive" T cell clones derived from lupus-prone mice can selectively induce the production of pathogenic anti-DNA autoantibodies in vitro and accelerate the development of lupus nephritis when transferred in vivo. The CDR3 loops of T cell receptor beta chains expressed by these pathogenic T helper (Th) clones contain a recurrent motif of anionic residues suggesting that they are selected by autoantigens with cationic residues. Herein, we found that approximately 50% of these pathogenic Th clones were specific for nucleosomal antigens, but none of them responded to cationic idiopeptides shared by variable regions of pathogenic anti-DNA autoantibodies. Nucleosomes did not stimulate the T cells as a nonspecific mitogen or superantigen. Only the pathogenic Th cells of lupus responded to nucleosomal antigens that were processed and presented via the major histocompatibility class II pathway. Although the presentation of purified mononucleosomes to the Th clones could be blocked by inhibitors of endosomal proteases, neither of the two components of the nucleosomes--free DNA or histones by themselves--could stimulate the Th clones. Thus critical peptide epitopes for the Th cells were probably protected during uptake and processing of the nucleosome particle as a whole. The nucleosome-specific Th clones preferentially augmented the production of IgG autoantibodies to histone-DNA complex in vitro. In vivo, nucleosome-specific, CD4+ T cells were not detectable in normal mice, but they were found in the spleens of lupus-prone mice as early as 1 mo of age, long before other autoimmune manifestations. Immunization of young, preautoimmune lupus mice with nucleosomes augmented the production of autoantibodies and markedly accelerated the development of severe glomerulonephritis. Previously, crude preparations containing nucleosomes were shown by others to have polyclonal mitogenic activity for B cells from normal as well as lupus mice. Identification here of pure mononucleosome as a lupus-specific immunogen for the Th cells that selectively help the pathogenic anti-DNA autoantibody producing B cells of lupus could lead to the design of specific therapy against this pathogenic autoimmune response.