tbuckley/cabot-search huggingface dataset:
Nucleotide Excision Repair Gene Expression after Cisplatin Treatment in Melanoma
Authors: Nikola A. Bowden, Katie A. Ashton, Kelly A. Avery-Kiejda, Xu Dong Zhang, Peter Hersey, Rodney J. Scott
Journal: Cancer Research (2010)

Abstract Two of the hallmark features of melanoma are its development as a result of chronic UV radiation exposure and the limited efficacy of cisplatin in the disease treatment. Both of these DNA-damaging agents result in large helix-distorting DNA damage that is recognized and repaired by nucleotide excision repair (NER). The aim of this study was to examine the expression of NER gene transcripts, p53, and p21 in melanoma cell lines treated with cisplatin compared with melanocytes. Basal expression of all genes was greater in the melanoma cell lines compared with melanocytes. Global genome repair (GGR) transcripts showed significantly decreased relative expression (RE) in melanoma cell lines 24 hours after cisplatin treatment. The basal RE of p53 was significantly higher in the melanoma cell lines compared with the melanocytes. However, induction of p53 was only significant in the melanocytes at 6 and 24 hours after cisplatin treatment. Inhibition of p53 expression significantly decreased the expression of all the GGR transcripts in melanocytes at 6 and 24 hours after cisplatin treatment. Although the RE levels were lower with p53 inhibition, the induction of the GGR genes was very similar to that in the control melanocytes and increased significantly across the time points. The findings from this study revealed reduced GGR transcript levels in melanoma cells 24 hours after cisplatin treatment. Our findings suggest a possible mechanistic explanation for the limited efficacy of cisplatin treatment and the possible role of UV light in melanoma. Cancer Res; 70(20); 7918–26. ©2010 AACR.
Financing End-of-Life Care in the USA
Authors: Carol Raphael, Joann Ahrens, Nicole Fowler
Journal: Journal of the Royal Society of Medicine (2001)

This paper offers an overview of how end-of-life care is currently financed in the USA. It discusses the limitations of the current system, as well as certain population and disease trends that lead us to recommend how financing should be restructured so that optimal end-of-life care is available for the entire population.
Chemotherapy-Induced Genotoxic Stress Promotes Sensitivity to Natural Killer Cell Cytotoxicity by Enabling Missing-Self Recognition
Authors: Jason H. Fine, Peter Chen, Aruz Mesci, David S.J. Allan, Stephan Gasser, David H. Raulet, James R. Carlyle
Journal: Cancer Research (2010)

Natural killer (NK) cells can recognize and kill tumor cells lacking "self" markers, such as class I MHC, but the basis for this recognition is not completely understood. NKR-P1 receptors are members of the C-type lectin-related NK receptor superfamily that are conserved from rodents to humans. Identification of Clr ligands for the NKR-P1 receptors has facilitated functional analysis of MHC-independent target cell recognition by NK cells. One receptor-ligand pair, NKR-P1B:Clr-b, can mediate "missing-self" recognition of tumor and infected cells, but the role of this axis in sensing stressed cells remains unknown. Here, we show that Clr-b is rapidly downregulated in cells undergoing genotoxic and cellular stress at the level of both RNA and surface protein. Stress-mediated loss of Clr-b on leukemia cells enhanced cytotoxicity mediated by NKR-P1B(+) NK cells. Notably, Clr-b downregulation was coordinated functionally with stress-mediated upregulation of NKG2D ligands (but not class I MHC). Our findings highlight a unique role for the MHC-independent NKR-P1B:Clr-b missing-self axis in recognition of stressed cells, and provide evidence of two independent levels of Clr-b regulation in stressed cells.
Spatiotemporal Relationship Between Intracellular Ca <sup>2+</sup> Dynamics and Wave Fragmentation During Ventricular Fibrillation in Isolated Blood-Perfused Pig Hearts
Authors: Mark Warren, José F. Huizar, Alexander G. Shvedko, Alexey V. Zaitsev
Journal: Circulation Research (2007)

Normal "master-slave" relationship between the action potential (AP) and intracellular Ca2+ transient (Ca(i)T) is sometimes altered during ventricular fibrillation (VF). The nature of AP/Ca(i)T dissociation during VF and its role in inducing wavebreaks (WBs) remain unclear. We simultaneously mapped AP (RH237) and Ca(i)T (Rhod-2) during VF in blood-perfused pig hearts. We computed AP and Ca(i)T dominant frequency (DF) and Ca(i)T delay in each AP cycle. We identified WBs as singularity points in AP phase movies and sites of conduction block (CB) as sites where an AP wavefront failed to propagate. We analyzed spatiotemporal relationship between abnormal AP/Ca(i)T sequences and CB sites. We used a calcium chelator (BAPTA-AM) to abolish Ca(i)T and test its involvement in WB formation. During VF, the DF difference between AP and Ca(i)T was <10% of the respective values in 95% of pixels, and 80% of all Ca(i)T upstrokes occurred during the initial 25% of the excitation cycle. Aberrant sequences of AP and Ca(i)T occurred almost exclusively near CB sites but could be traced to normal wavefront sequences away from CB sites. Thus, apparent AP/Ca(i)T dissociation was largely attributable to spatial uncertainty of the absolute position of block of each wave. BAPTA-AM reduced Ca(i)T amplitude to 30.5+/-12.9% of control and the DF of AP from 12.2+/-1.6 to 10.4+/-1.3 Hz (P<0.01), but did not significantly alter WB incidence (0.76+/-0.19 versus 0.72+/-0.19 SP/mm2). These results do not support presence of spontaneous, non-voltage-gated Ca(i)Ts during VF and suggest that AP/Ca(i)T dissociation is a consequence rather than a cause of wave fragmentation.
Effect of choline chloride in allergen-induced mouse model of airway inflammation
Authors: A. K. Mehta, S. N. Gaur, N. Arora, B. P. Singh
Journal: European Respiratory Journal (2007)

The incidence of asthma has increased the world over, and current therapies for the disease suffer from potential side-effects. This has created an opportunity to develop novel therapeutic approaches. Here, the anti-inflammatory activity of choline was investigated in a mouse model of allergic airway inflammation. Choline (1 mg·kg −1 ) was administered via oral gavage or intranasally before and after ovalbumin (OVA) challenge in sensitised mice. Airway hyperresponsiveness (AHR) to methacholine was measured in the mice by whole-body plethysmography. Type-2 T-helper cell cytokine and leukotriene levels were estimated in bronchoalveolar lavage fluid (BALF) and spleen culture supernatant by ELISA. Eosinophil peroxidase activity was also determined in the BALF supernatant. Choline treatment in sensitised mice before OVA challenge via oral/intranasal routes significantly inhibited eosinophilic airway inflammation and eosinophil peroxidase activity. It also reduced immunoglobulin E and G1 production and inhibited the release of type-2 T-helper cell cytokines and leukotrienes. However, the development of AHR was prevented effectively by intranasal choline treatment. Most importantly, choline treatment after OVA challenge by both routes could reverse established asthmatic conditions in mice by inhibiting AHR, eosinophilic airway inflammation and other inflammatory parameters. This study provides a new therapeutic approach for controlling as well as preventing asthma exacerbations.
An uncommon ankle sprain
Authors: Wart J F van Zoest, Rob P A Janssen, Carroll M E S Tseng
Journal: British Journal of Sports Medicine (2007)

Ankle sprain is the most frequently occurring acute injury in tennis, accounting for 20-25% of all injuries. In the current paper, we assess the cause of ankle sprain and suggest possibilities to be considered during diagnosis.We assessed a professional tennis player with a partial tear of the long peroneal tendon after an ankle sprain by physical exam, X-ray and MRI.Conservative treatment by means of soft cast and propriocepsis training led to full recovery.Peroneal tendon disorders must be part of the differential diagnosis after ankle sprain in the professional athlete.
Cytokinesis-Blocked Micronucleus Assay as a Novel Biomarker for Lung Cancer Risk
Authors: Randa A. El-Zein, Matthew B. Schabath, Carol J. Etzel, Mirtha S. Lopez, Jamey D. Franklin, Margaret R. Spitz
Journal: Cancer Research (2006)

In this case-control study, we modified the cytokinesis-block micronucleus (CBMN) assay, an established biomarker for genomic instability, to evaluate susceptibility to the nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by measuring the frequency of NNK-induced chromosomal damage endpoints (micronuclei, nucleoplasmic bridges, and nuclear buds) per 1,000 binucleated lymphocytes. Spontaneous and NNK-induced chromosomal damage were significantly higher in lung cancer patients compared with controls. Forty-seven percent of cases (versus 12% of controls) had >or=4 spontaneous micronuclei, 66% of cases (and no controls) had >or=4 spontaneous nucleoplasmic bridges, and 25% of cases (versus 5% of controls) had >or=1 spontaneous nuclear bud (P < 0.001). Similarly, 40% of cases (versus 6% of the controls) had >or=5 NNK-induced micronuclei, 89% of cases (and no controls) had >or=6 induced nucleoplasmic bridges, and 23% of cases (versus 2% of controls) had >or=2 induced nuclear buds (P < 0.001). When analyzed on a continuous scale, spontaneous micronuclei, nucleoplasmic bridges, and nuclear buds were associated with 2-, 29-, and 6-fold increases in cancer risk, respectively. Similarly, NNK-induced risks were 2.3-, 45.5-, and 10-fold, respectively. We evaluated the use of CBMN assay to predict cancer risk based on the numbers of micronuclei, nucleoplasmic bridges, and nuclear buds defined by percentile cut points in controls. Probabilities of being a cancer patient were 96%, 98%, and 100% when using the 95th percentiles of spontaneous and NNK-induced micronuclei, nucleoplasmic bridges, and nuclear buds, respectively. Our study indicates that the CBMN assay is extremely sensitive to NNK-induced genetic damage and may serve as a strong predictor of lung cancer risk.
Cdc42 and Rab8a are critical for intestinal stem cell division, survival, and differentiation in mice
Authors: Ryotaro Sakamori, Soumyashree Das, Shiyan Yu, Shanshan Feng, Ewa Stypulkowski, Yinzheng Guan, Veronique Douard, Waixing Tang, Ronaldo P. Ferraris, Akihiro Harada, Cord Brakebusch, Wei Guo, Nan Gao
Journal: Journal of Clinical Investigation (2012)

The constant self renewal and differentiation of adult intestinal stem cells maintains a functional intestinal mucosa for a lifetime. However, the molecular mechanisms that regulate intestinal stem cell division and epithelial homeostasis are largely undefined. We report here that the small GTPases Cdc42 and Rab8a are critical regulators of these processes in mice. Conditional ablation of Cdc42 in the mouse intestinal epithelium resulted in the formation of large intracellular vacuolar structures containing microvilli (microvillus inclusion bodies) in epithelial enterocytes, a phenotype reminiscent of human microvillus inclusion disease (MVID), a devastating congenital intestinal disorder that results in severe nutrient deprivation. Further analysis revealed that Cdc42-deficient stem cells had cell division defects, reduced capacity for clonal expansion and differentiation into Paneth cells, and increased apoptosis. Cdc42 deficiency impaired Rab8a activation and its association with multiple effectors, and prevented trafficking of Rab8a vesicles to the midbody. This impeded cytokinesis, triggering crypt apoptosis and disrupting epithelial morphogenesis. Rab8a was also required for Cdc42-GTP activity in the intestinal epithelium, where continued cell division takes place. Furthermore, mice haploinsufficient for both Cdc42 and Rab8a in the intestine demonstrated abnormal crypt morphogenesis and epithelial transporter physiology, further supporting their functional interaction. These data suggest that defects of the stem cell niche can cause MVID. This hypothesis represents a conceptual departure from the conventional view of this disease, which has focused on the affected enterocytes, and suggests stem cell-based approaches could be beneficial to infants with this often lethal condition.
GLP-1 Action and Glucose Tolerance in Subjects With Remission of Type 2 Diabetes After Gastric Bypass Surgery
Authors: Amanda Jiménez, Roser Casamitjana, Judith Viaplana-Masclans, Antonio Lacy, Josep Vidal
Journal: Diabetes Care (2013)

OBJECTIVE Glucagon like peptide-1 (GLP-1) has been suggested as a major factor for the improved glucose tolerance ensuing after Roux-en-Y gastric bypass (RYGBP) surgery. We examined the effect of blocking endogenous GLP-1 action on glucose tolerance in subjects with sustained remission of type 2 diabetes mellitus (T2DM) present before RYGBP. RESEARCH DESIGN AND METHODS Blood glucose, insulin, C-peptide, glucagon, GLP-1, and glucose-dependent insulinotropic peptide levels were measured after a meal challenge with either exendin-(9–39) (a GLP-1r antagonist) or saline infusion in eight subjects with sustained remission of T2DM after RYGBP and seven healthy controls. RESULTS Infusion of exendin-(9–39) resulted in marginal deterioration of the 2-h plasma glucose after meal intake in RYGBP subjects [saline 78.4 ± 15.1 mg/dL compared with exendin-(9–39) 116.5 ± 22.3 mg/dL; P &amp;lt; 0.001]. Furthermore, glucose response to meal intake was similarly enlarged in the two study groups [percent change in the area under the curve of glucose exendin-(9–39) infusion versus saline infusion: controls 10.84 ± 8.8% versus RYGBP 9.94 ± 8.4%; P = 0.884]. In the RYGBP group, the blockade of the enlarged GLP-1 response to meal intake resulted in reduced insulin (P = 0.001) and C-peptide (P &amp;lt; 0.001), but no change in glucagon (P = 0.258) responses. CONCLUSIONS The limited deterioration of glucose tolerance on blockade of GLP-1 action in our study suggests the resolution of T2DM after RYGBP may be explained by mechanisms beyond enhancement of GLP-1 action.
Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C
Authors: Yaron Rotman, Mazen Noureddin, Jordan J Feld, Jeremie Guedj, Michael Witthaus, Hwalih Han, Yoon J Park, Su-Hyung Park, Theo Heller, Marc G Ghany, Edward Doo, Christopher Koh, Adil Abdalla, Naveen Gara, Souvik Sarkar, Emmanuel Thomas, Golo Ahlenstiel, Birgit Edlich, Rachel Titerence, Leah Hogdal, Barbara Rehermann, Harel Dahari, Alan S Perelson, Jay H Hoofnagle, T Jake Liang
Journal: Gut (2013)

<h3>Objective</h3> Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. <h3>Design</h3> 70 treatment-naive patients were randomised to 4 weeks of ribavirin (1000–1200 mg/d) or none, followed by PEG-IFNα-2a and ribavirin at standard doses and durations. Patients were also randomised to a liver biopsy 24 h before or 6 h after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. <h3>Results</h3> After 4 weeks of ribavirin monotherapy, hepatitis C virus (HCV) levels decreased by 0.5±0.5 log<sub>10</sub> (p=0.009 vs controls) and ALT by 33% (p&lt;0.001). Ribavirin pretreatment, while modestly augmenting ISG induction by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological, response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs 22% non-responders, p=0.01; early virological response, 100% vs 68%, p=0.03; sustained virological response 83% vs 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC. <h3>Conclusions</h3> Ribavirin is a weak antiviral but its clinical effect seems to be mediated by a separate, indirect mechanism, which may act to reset IFN-responsiveness in HCV-infected liver.
Applications of Next-generation Sequencing in Systemic Autoimmune Diseases
Authors: Yiyangzi Ma, Na Shi, Mengtao Li, Fei Chen, Haitao Niu
Journal: Genomics Proteomics & Bioinformatics (2015)

Abstract Systemic autoimmune diseases are a group of heterogeneous disorders caused by both genetic and environmental factors. Although numerous causal genes have been identified by genome-wide association studies (GWAS), these susceptibility genes are correlated to a relatively low disease risk, indicating that environmental factors also play an important role in the pathogenesis of disease. The intestinal microbiome, as the main symbiotic ecosystem between the host and host-associated microorganisms, has been demonstrated to regulate the development of the body’s immune system and is likely related to genetic mutations in systemic autoimmune diseases. Next-generation sequencing (NGS) technology, with high-throughput capacity and accuracy, provides a powerful tool to discover genomic mutations, abnormal transcription and intestinal microbiome identification for autoimmune diseases. In this review, we briefly outlined the applications of NGS in systemic autoimmune diseases. This review may provide a reference for future studies in the pathogenesis of systemic autoimmune diseases.
Management of Drug and Alcohol Withdrawal
Authors: Thomas R. Kosten, Patrick G. O'Connor
Journal: New England Journal of Medicine (2003)

This review summarizes the current approaches to the management of withdrawal in patients addicted to sedatives such as alcohol or benzodiazepines, opioids, or stimulants such as amphetamines or cocaine. Included are details of detoxification regimens and guidelines for recognizing and managing the most common complications.
Primary allergic sensitization to environmental antigens: perinatal T cell priming as a determinant of responder phenotype in adulthood.
Authors: P G Holt
Journal: The Journal of Experimental Medicine (1996)

The prevalence and severity of allergic diseases, in particular those affecting the respiratory system, are increasing at an alarming rate in the developed countries, and the international research effort into the etiology and pathogenesis of these syndromes is rapidly expanding to meet this challenge. The immunoinflammatory reactions that mediate airway tissue damage in allergic (atopic) subjects stem from aberrant T cell responses to a range of airborne environmental antigens that seemingly are ignored by non-atopic individuals. At the T cell level, allergic reactivity manifests as production of a Th-2-1ike cytokine profile at each challenge (1, 2), and mounting evidence (reviewed briefly below) suggests that the development of this pattern of T cell sensitization is frequently associated with exposure to high levels of the relevant antigens during early infancy. This finding contrasts with the traditional experimental literature, in which parenteral antigenic challenge of neonatal animals leads preferentially to tolerance induction, a process most commonly ascribed to T cell anergy and/or deletion (3-5). However in this issue of the journal, Singh et al. (6) present the results of a comprehensive study from a murine model, which focuses on the pattern of underlying antigen-specific T cell cytokine responses during the induction and subsequent expression of classical neonatal tolerance. They demonstrate that neonatal antigen exposure triggers an initially heterogeneous T cell response containing both Th-1- and Th-2-like elements, which results not in eventual T cell deletion/anergy but instead in priming for subsequent immune deviation toward a pattern ofT cell immunity that is skewed toward Th-2. Their discussion of the relevance of this neonatal tolerance model is couched specifically in terms of autoimmune diseases. However, as argued below, the underlying T cell selection process is equally relevant to the etiology of human allergic diseases.
Fas-Mediated Apoptosis in Ewing's Sarcoma Cell Lines by Metalloproteinase Inhibitors
Authors: N. Mitsiades, V. Poulaki, A. Leone, M. Tsokos
Journal: JNCI Journal of the National Cancer Institute (1999)

Fas ligand (FasL) is a transmembrane protein that induces apoptosis (programmed cell death) in susceptible cells by interacting with its receptor, Fas. Transmembrane FasL is cleaved by a metalloproteinase enzyme into a soluble form that is released into the extracellular medium. Tumors of the Ewing's sarcoma family express functional transmembrane FasL and release soluble FasL. This cleavage is inhibited by a matrix metalloproteinase inhibitor (MMPI). We therefore hypothesized that MMPIs can lead to apoptosis of tumor cells by inducing accumulation of transmembrane FasL.Ewing's sarcoma and neuroblastoma cell lines were treated with two synthetic MMPIs (BB-3103 and A-151011) and examined for apoptosis and expression of FasL and Fas.Although MMPIs increase levels of FasL and Fas proteins on the surface of all tumor cells studied, they induced apoptosis in Fas-sensitive but not in Fas-resistant cell lines; the induction of apoptosis was inhibited by a Fas-neutralizing antibody. The increase in protein expression was not associated with enhanced transcription. Treatment with an MMPI sensitized the Ewing's sarcoma cells to Fas-activating antibody and to doxorubicin-induced apoptosis.MMPIs cause accumulation of transmembrane FasL by inhibiting its cleavage, accumulation of Fas (probably secondarily to FasL cleavage inhibition), and decreased levels of soluble FasL. These effects lead to apoptosis in Fas-sensitive cell lines. The observed cooperative action of MMPIs and doxorubicin suggests a possible role of MMPIs in combination treatments with standard apoptosis-inducing chemotherapeutic agents.
ORBITAL CORTEX SYNDROME FOLLOWING LEUCOTOMY
Authors: F. REITMAN
Journal: American Journal of Psychiatry (1946)

1. The orbital cortex was partly isolated on 22 schizophrenics, and good response was observed where there were symptoms of introversion, blockage, emotional dulling and depersonalisation present. 2. The isolation of the orbital lobe produced a triad of symptoms described as: extroversion, increased motor activity and euphoria. 3. It was emphasised that the new symptoms produced, balance well with the pre-existing psychotic symptoms.
Pim1 Reconstitutes Thymus Cellularity in Interleukin 7–And Common γ Chain–Mutant Mice and Permits Thymocyte Maturation in Rag- but Not Cd3γ-Deficient Mice
Authors: Heinz Jacobs, Paul Krimpenfort, Mariëlle Haks, John Allen, Bianca Blom, Corinne Démollière, Ada Kruisbeek, Hergen Spits, Anton Berns
Journal: The Journal of Experimental Medicine (1999)

The majority of lymphomas induced in Rag-deficient mice by Moloney murine leukemia virus (MoMuLV) infection express the CD4 and/or CD8 markers, indicating that proviral insertions cause activation of genes affecting the development from CD4−8− pro-T cells into CD4+8+ pre-T cells. Similar to MoMuLV wild-type tumors, 50% of CD4+8+ Rag-deficient tumors carry a provirus near the Pim1 protooncogene. To study the function of PIM proteins in T cell development in a more controlled setting, a Pim1 transgene was crossed into mice deficient in either cytokine or T cell receptor (TCR) signal transduction pathways. Pim1 reconstitutes thymic cellularity in interleukin (IL)-7– and common γ chain–deficient mice. In Pim1-transgenic Rag-deficient mice but notably not in CD3γ-deficient mice, we observed slow expansion of the CD4+8+ thymic compartment to almost normal size. Based on these results, we propose that PIM1 functions as an efficient effector of the IL-7 pathway, thereby enabling Rag-deficient pro-T cells to bypass the pre-TCR–controlled checkpoint in T cell development.