tbuckley/cabot-search huggingface dataset:
An Msh2 Point Mutation Uncouples DNA Mismatch Repair and Apoptosis
Authors: Diana P. Lin, Yuxun Wang, Stefan J. Scherer, Alan B. Clark, Kan Yang, Elena Avdievich, Bo Jin, Uwe Werling, Tchaiko Parris, Naoto Kurihara, Asad Umar, Raju Kucherlapati, Martin Lipkin, Thomas A. Kunkel, Winfried Edelmann
Journal: Cancer Research (2004)

Mutations in the human DNA mismatch repair gene MSH2 are associated with hereditary nonpolyposis colorectal cancer as well as a significant proportion of sporadic colorectal cancer. The inactivation of MSH2 results in the accumulation of somatic mutations in the genome of tumor cells and resistance to the genotoxic effects of a variety of chemotherapeutic agents. Here we show that the DNA repair and DNA damage-induced apoptosis functions of Msh2 can be uncoupled using mice that carry the G674A missense mutation in the conserved ATPase domain. As a consequence, although Msh2(G674A) homozygous mutant mice are highly tumor prone, the onset of tumorigenesis is delayed as compared with Msh2-null mice. In addition, tumors that carry the mutant allele remain responsive to treatment with a chemotherapeutic agent. Our results indicate that Msh2-mediated apoptosis is an important component of tumor suppression and that certain MSH2 missense mutations can cause mismatch repair deficiency while retaining the signaling functions that confer sensitivity to chemotherapeutic agents.
Diffuse Interstitial Pulmonary Disease: Pathophysiology and Steroid Therapy.
Authors: Jerome E. Cohn
Journal: Annals of Internal Medicine (1965)

s1 November 1965Diffuse Interstitial Pulmonary Disease: Pathophysiology and Steroid Therapy.Jerome E. Cohn, M.D., F.A.C.P.Jerome E. Cohn, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-63-5-919_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptClinical and physiological investigations were performed in 20 patients having diffuse nodular and linear densities in chest roentgenograms. Pathologic diagnoses were established by lung biopsy or autopsy: nonspecific fibrosis, Hamman-Rich disease, sarcoidosis, eosinophilic granuloma of lung, postirradiation fibrosis, and probable periarteritis.Pulmonary functions were measured before a biopsy or treatment. Seventeen subjects had normal ventilatory function and expiratory flow velocity, and two exhibited moderately severe obstructive airway disease. Inspiratory capacity was reduced in eight, each of whom had a small vital capacity. Lung compliance was very low in 11 and normal in 5. Intrapulmonary distribution of blood and gas was... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Lexington, Kentucky, and Salt Lake City, Utah PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 November 1965Volume 63, Issue 5Page: 919-919KeywordsBiopsyBloodGranulomasLungsPulmonary diseasesPulmonary fibrosisPulmonary functionSarcoidosisSteroid therapyThorax Issue Published: 1 November 1965 PDF DownloadLoading ...
Organometallic nucleosides induce non-classical leukemic cell death that is mitochondrial-ROS dependent and facilitated by TCL1-oncogene burden
Authors: Christian Prinz, Elena Vasyutina, Gregor Lohmann, Alexandra Schrader, Steffen Romanski, Christoph Hirschhäuser, Petra Mayer, Corazon Frias, Carmen D. Herling, Michael Hallek, Hans-Günther Schmalz, Aram Prokop, Dimitrios Mougiakakos, Marco Herling
Journal: Molecular Cancer (2015)

Redox stress is a hallmark of the rewired metabolic phenotype of cancer. The underlying dysregulation of reactive oxygen species (ROS) is interconnected with abnormal mitochondrial biogenesis and function. In chronic lymphocytic leukemia (CLL), elevated ROS are implicated in clonal outgrowth and drug resistance. The pro-survival oncogene T-cell leukemia 1 (TCL1) is causally linked to the high threshold towards classical apoptosis in CLL. We investigated how aberrant redox characteristics and bioenergetics of CLL are impacted by TCL1 and if this is therapeutically exploitable. Bio-organometallic chemistry provided compounds containing a cytosine nucleobase, a metal core (ferrocene, ruthenocene, Fe(CO)3), and a 5'-CH2O-TDS substituent. Four of these metal-containing nucleoside analogues (MCNA) were tested for their efficacy and mode of action in CLL patient samples, gene-targeted cell lines, and murine TCL1-transgenic splenocytes. The MCNA showed a marked and selective cytotoxicity towards CLL cells. MCNA activity was equally observed in high-risk disease groups, including those of del11q/del17p cytogenetics and of clinical fludarabine resistance. They overcame protective stromal cell interactions. MCNA-evoked PARP-mediated cell death was non-autophagic and non-necrotic as well as caspase- and P53-independent. This unconventional apoptosis involved early increases of ROS, which proved indispensible based on mitigation of MCNA-triggered death by various scavengers. MCNA exposure reduced mitochondrial respiration (oxygen consumption rate; OCR) and induced a rapid membrane depolarization (∆ΨM). These characteristics distinguished the MCNA from the alkylator bendamustine and from fludarabine. Higher cellular ROS and increased MCNA sensitivity were linked to TCL1 expression. The presence of TCL1 promoted a mitochondrial release of in part caspase-independent apoptotic factors (AIF, Smac, Cytochrome-c) in response to MCNA. Although basal mitochondrial respiration (OCR) and maximal respiratory capacity were not affected by TCL1 overexpression, it mediated a reduced aerobic glycolysis (lactate production) and a higher fraction of oxygen consumption coupled to ATP-synthesis. Redox-active substances such as organometallic nucleosides can confer specific cytotoxicity to ROS-stressed cancer cells. Their P53- and caspase-independent induction of non-classical apoptosis implicates that redox-based strategies can overcome resistance to conventional apoptotic triggers. The high TCL1-oncogenic burden of aggressive CLL cells instructs their particular dependence on mitochondrial energetic flux and renders them more susceptible towards agents interfering in mitochondrial homeostasis.
Host-Derived Tumor Endothelial Marker 8 Promotes the Growth of Melanoma
Authors: Mike Cullen, Steven Seaman, Amit Chaudhary, Mi Young Yang, Mary Beth Hilton, Daniel Logsdon, Diana C. Haines, Lino Tessarollo, Brad St. Croix
Journal: Cancer Research (2009)

Abstract Tumor endothelial marker 8 (TEM8) was initially identified as a gene overexpressed in the vasculature of human tumors and was subsequently identified as an anthrax toxin receptor. To assess the functional role of TEM8, we disrupted the TEM8 gene in mice by targeted homologous recombination. TEM8−/− mice were viable and reached adulthood without defects in physiologic angiogenesis. However, histopathologic analysis revealed an excess of extracellular matrix in several tissues, including the ovaries, uterus, skin, and periodontal ligament of the incisors, the latter resulting in dental dysplasia. When challenged with B16 melanoma, tumor growth was delayed in TEM8−/− mice, whereas the growth of other tumors, such as Lewis lung carcinoma, was unaltered. These studies show that host-derived TEM8 promotes the growth of certain tumors and suggest that TEM8 antagonists may have utility in the development of new anticancer therapies. [Cancer Res 2009;69(15):6021–6]
Randomized Trial of Postoperative Adjuvant Chemotherapy With or Without Radiotherapy for Carcinoma of the Rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02
Authors: N. Wolmark
Journal: JNCI Journal of the National Cancer Institute (2000)

BACKGROUND: The conviction that postoperative radiotherapy and chemotherapy represent an acceptable standard of care for patients with Dukes' B (stage II) and Dukes' C (stage III) carcinoma of the rectum evolved in the absence of data from clinical trials designed to determine whether the addition of radiotherapy results in improved disease-free survival and overall survival. This study was carried out to address this issue. An additional aim was to determine whether leucovorin (LV)-modulated 5-fluorouracil (5-FU) is superior to the combination of 5-FU, semustine, and vincristine (MOF) in men. PATIENTS AND METHODS: Eligible patients (n = 694) with Dukes' B or C carcinoma of the rectum were enrolled in National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol R-02 from September 1987 through December 1992 and were followed. They were randomly assigned to receive either postoperative adjuvant chemotherapy alone (n = 348) or chemotherapy with postoperative radiotherapy (n = 346). All female patients (n = 287) received 5-FU plus LV chemotherapy; male patients received either MOF (n = 207) or 5-FU plus LV (n = 200). Primary analyses were carried out by use of a stratified log-rank statistic; P values are two-sided. RESULTS: The average time on study for surviving patients is 93 months as of September 30, 1998. Postoperative radiotherapy resulted in no beneficial effect on disease-free survival (P = .90) or overall survival (P= .89), regardless of which chemotherapy was utilized, although it reduced the cumulative incidence of locoregional relapse from 13% to 8% at 5-year follow-up (P = .02). Male patients who received 5-FU plus LV demonstrated a statistically significant benefit in disease-free survival at 5 years compared with those who received MOF (55% versus 47%; P = .009) but not in 5-year overall survival (65% versus 62%; P = .17). CONCLUSIONS: The addition of postoperative radiation therapy to chemotherapy in Dukes' B and C rectal cancer did not alter the subsequent incidence of distant disease, although there was a reduction in locoregional relapse when compared with chemotherapy alone.
Matrix Metalloproteinase 9 Protects Mice from Anti–Glomerular Basement Membrane Nephritis through Its Fibrinolytic Activity
Authors: Brigitte Lelongt, Soraya Bengatta, Madeleine Delauche, Leif R. Lund, Zena Werb, Pierre M. Ronco
Journal: The Journal of Experimental Medicine (2001)

Matrix metalloproteinase (MMP)9/gelatinase B is increased in various nephropathies. To investigate its role, we used a genetic approach. Adult MMP9-deficient (MMP9(-/)-) mice showed normal renal histology and function at 3 mo. We investigated the susceptibility of 3-mo-old mice to the accelerated model of anti-glomerular basement membrane nephritis, in which fibrin is an important mediator of glomerular injury and renal impairment. Unexpectedly, nephritis was more severe in MMP9(-/)- than in control mice, as attested by levels of serum creatinine and albuminuria, and the extent of crescents and fibrin deposits. Circulating or deposited immunoglobulin G, interleukin (IL)-1beta, or IL-10 were the same in MMP9(-/-) and MMP9(+/+) mice. However, we found that fibrin is a critical substrate for MMP9, and in its absence fibrin accumulated in the glomeruli. These data indicate that MMP9 is required for a novel protective effect on the development of fibrin-induced glomerular lesions.
Analysis of the factorial validity and reliability of the Malay version of the revised Competitive State Anxiety Inventory-2
Authors: Hairul Anuar Hashim, Erie-Zuraidee Zulkifli
Journal: British Journal of Sports Medicine (2010)

Sport competition can be a major source of stress among youth sport athletes. Knowledge of competitive state anxiety may be beneficial for both sport performance and development of young athletes. The Competitive State Anxiety Inventory-2 (CSAI-2), and more recently the Revised Competitive State Anxiety Inventory-2 (CSAI-2R) are often used instruments to measure competitive state anxiety. Indeed, there is evidence suggesting excellent psychometric properties of these instruments in their original as well culturally adapted forms. Given the potential benefits of this instrument in understanding youth athletes’ affective states, CSAI-2R was translated into Malaysian language and has been a precursor to several studies. However, given no prior assessment of the psychometric properties of the translated version, the present study sought to examine the factorial validity and reliability of the Malaysian version of the CSAI-2R. The questionnaire was administered to 236 young Taekwondo athletes. Using Confirmatory Factor Analysis (CFA), three models were tested, a 1-factor model, a 2-factor model and a 3-factor model. The 3-factor model consisting of self-confidence, somatic anxiety and cognitive anxiety factors was expected to yield the best model fit. As expected, CFA results revealed close model fit of the 3-factor model when compared to two others tested models (χ 2 = 170.197, df = 116, p &lt;0.05; RMR = 0.06; GFI = 0.0.92; RMSEA = 0.05, ECVI = 1.04, AIC = 244.19). Furthermore, significant unstandardised regression weights (&lt;0.05) for all of the path loadings were obtained indicating good convergent validity of the subscales. The results also revealed an acceptable reliability for the subscales (α = 0.65 for somatic anxiety, 0.77 for cognitive anxiety and 0.76 for self-confidence subscales). Overall, the findings support the factorial validity and reliability of the Malaysian version of CSAI-2R. However, future studies with larger sample are needed to confirm if the findings are sample specific or more general.
Role of Interleukin-10 in the Intracellular Sequestration of Human Leukocyte Antigen-DR in Monocytes during Septic Shock
Authors: Thierry Fumeaux, Jérôme Pugin
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Monocytes from many critically ill patients show a low level of major histocompatibility complex type II (MHC II) expression. This phenomenon is believed to play a role in these patients' increased susceptibility to secondary infections. In the present study, we show that the level of monocyte human leukocyte antigen (HLA)-DR expression inversely correlates with the degree of severity of the sepsis syndrome. The defect of the monocyte HLA-DR expression resides in an intracellular sequestration of the MHC II molecules, a posttranslational effect. No significant decrease in the rate of transcription of HLA-DR, or its major transcriptional inducer, Class II transactivator, was noted. The levels of HLA-DR protein produced by monocytes from patients with septic shock were comparable to those from healthy volunteers. Plasma from patients with septic shock induced significant HLA-DR endocytosis resulting in decreased surface HLA-DR expression of normal donor monocytes. This effect was partially blocked by anti-interleukin (IL)-10 monoclonal antibody, but not by antagonists to transforming growth factor-beta1, prostaglandins, or beta-adrenergic agonists. Altogether, these data suggest that HLA-DR molecules are re-endocytosed and retained intracellularly in monocytes from patients with septic shock, and that this phenomenon is partially mediated by IL-10. IL-10 may represent a future target for immunomodulating patients with the sepsis syndrome or critically ill patients at risk of developing infections.
NATURAL CONSEQUENCE OF STENT MALAPOSITION ASSESSED BY OPTICAL COHERENCE TOMOGRAPHY
Authors: Hiroyuki Kawamori, Junya Shite, Toshiro Shinke, Hiromasa Otake, Daisuke Matumoto, Masayuki Nakagawa, Yoshiharu Nagoshi, Amane Kozuki, Hirotoshi Hariki, Takumi Inoue, Tsuyoshi Ohsue, Yu Taniguchi, Ryo Nishio, Noritoshi Hiranuma, Ken-ichi Hirata
Journal: Journal of the American College of Cardiology (2011)
Managing retinal vein occlusion
Authors: C. A. Kiire, N. V. Chong
Journal: BMJ (2012)

#### Summary points

Retinal vein occlusion—obstruction of the retinal venous system by thrombus formation, external compression, or disease of the vein wall1—is the second most common retinal vascular disease after diabetic retinopathy.2 Pooled data from population studies in the United States, Europe, Asia, and Australia suggest that about 16 million adults are affected by this condition.3 Not all cases need treatment. In the past, the visual prognosis for most patients was poor because treatment comprised lowering the pressure in the eye, if raised, and laser treatment to try to control associated complications. However, two new treatments have recently been licensed in the US and the European Union, one of which has been approved by the National Institute for Health and Clinical Excellence (NICE) for use in England and Wales. Consequently, the outlook for patients with retinal vein occlusion is likely to improve. We review the diagnosis and management of retinal vein occlusion and examine the evidence for the effectiveness of the newly licensed drugs.

#### Sources and selection criteria

We searched PubMed for articles on retinal vein occlusion that had been published in 2010 and 2011 and looked for published evidence that had been presented in major ophthalmology meetings up to 1 October 2011, focusing mainly on well designed randomised …
Generation of CD133+ cells from CD133− peripheral blood mononuclear cells and their properties
Authors: E SUURONEN, S WONG, V KAPILA, G WAGHRAY, S WHITMAN, T MESANA, M RUEL
Journal: Cardiovascular Research (2006)

CD133 may be the most specific marker of endothelial progenitor cells (EPCs), which are thought to be largely confined to the bone marrow milieu. This study reports on the phenotypic characterization and functional analysis of human CD133+ cells and their generation from cells in the peripheral circulation.Adult human CD133+ and CD133- cells were isolated from peripheral blood mononuclear cells, and the generation of CD133+ cells in culture was attempted using different culture combinations. The phenotypic, migratory, adhesive, and angiogenic properties of the native and generated populations were investigated.In adherent and in suspension culture systems, CD133+ cells also expressing CD34 and VEGFR-2 were successfully derived from a previously CD133- population. The migratory potential of CD133+ cells was enhanced by the presence of the CD133- cells. Also, the CD133+ cells derived from the CD133- cells demonstrated improved adhesion to extracellular matrix and endothelial monolayer substrates, and their contribution to in vitro angiogenesis was enhanced compared to freshly isolated CD133+ cells.These results demonstrate a source of blood CD133+ cells other than direct mobilization from the bone marrow. Cellular interaction was observed between fractions, with CD133+ cells showing better in vitro function in the presence of CD133- cells. These findings provide a novel source for CD133+ cells and a rationale for the investigation of angiogenic cell recruitment or delivery strategies involving more than one cell type at ischemic sites.
Antihemostatic, antiinflammatory, and immunosuppressive properties of the saliva of a tick, Ixodes dammini.
Authors: J M Ribeiro, G T Makoul, J Levine, D R Robinson, A Spielman
Journal: The Journal of Experimental Medicine (1985)

Pilocarpine-induced saliva of the tick, Ixodes dammini, inhibited platelet aggregation triggered by ADP and collagen, as well as platelet-aggregation factor. In addition, we found apyrase activity (which degrades ATP and ADP to AMP and orthophosphate) and an anticoagulant. We showed the presence of prostaglandin E2 (PGE2) by bioassay and radioimmunoassay. This saliva inhibited interleukin 2 production by T cell hybridomas, an activity consistent with that of PGE2. A kininase was demonstrated, and this may counteract the algesia- and edema-promoting properties of PGE2. Together, these salivary components produce antihemostatic, antiinflammatory, and immunosuppressive effects that may facilitate feeding, as well as transmission of tick-borne pathogens.
Urea and Renal Function in the 21st Century
Authors: Robert A. Fenton, Mark A. Knepper
Journal: Journal of the American Society of Nephrology (2007)

Since the turn of the 21st century, gene knockout mice have been created for all major urea transporters that are expressed in the kidney: the collecting duct urea transporters UT-A1 and UT-A3, the descending thin limb isoform UT-A2, and the descending vasa recta isoform UT-B. This article discusses the new insights that the results from studies in these mice have produced in the understanding of the role of urea in the urinary concentrating mechanism and kidney function. Following is a summary of the major findings: (1) Urea accumulation in the inner medullary interstitium depends on rapid transport of urea from the inner medullary collecting duct (IMCD) lumen via UT-A1 and/or UT-A3; (2) as proposed by Robert Berliner and colleagues in the 1950s, the role of IMCD urea transporters in water conservation is to prevent a urea-induced osmotic diuresis; (3) the absence of IMCD urea transport does not prevent the concentration of NaCl in the inner medulla, contrary to what would be predicted from the passive countercurrent multiplier mechanism in the form proposed by Kokko and Rector and Stephenson; (4) deletion of UT-B (vasa recta isoform) has a much greater effect on urinary concentration than deletion of UT-A2 (descending limb isoform), suggesting that the recycling of urea between the vasa recta and the renal tubules quantitatively is less important than classic countercurrent exchange; and (5) urea reabsorption from the IMCD and the process of urea recycling are not important elements of the mechanism of protein-induced increases in GFR. In addition, the clinical relevance of these studies is discussed, and it is suggested that inhibitors that specifically target collecting duct urea transporters have the potential for clinical use as potassium-sparing diuretics that function by creation of urea-dependent osmotic diuresis.
C-Reactive Protein as a Cardiovascular Risk Factor
Authors: Wim K. Lagrand, Cees A. Visser, Willem T. Hermens, Hans W. M. Niessen, Freek W. A. Verheugt, Gert-Jan Wolbink, C. Erik Hack
Journal: Circulation (1999)

Background —Circulating levels of C-reactive protein (CRP) may constitute an independent risk factor for cardiovascular disease. How CRP as a risk factor is involved in cardiovascular disease is still unclear. Methods and Results —By reviewing available studies, we discuss explanations for the associations between CRP and cardiovascular disease. CRP levels within the upper quartile/quintile of the normal range constitute an increased risk for cardiovascular events, both in apparently healthy persons and in persons with preexisting angina pectoris. High CRP responses after acute myocardial infarction indicate an unfavorable outcome, even after correction for other risk factors. This link between CRP and cardiovascular disease has been considered to reflect the response of the body to the inflammatory reactions in the atherosclerotic (coronary) vessels and adjacent myocardium. However, because CRP localizes in infarcted myocardium (with colocalization of activated complement), we hypothesize that CRP may directly interact with atherosclerotic vessels or ischemic myocardium by activation of the complement system, thereby promoting inflammation and thrombosis. Conclusions —CRP constitutes an independent cardiovascular risk factor. Unraveling the molecular background of this association may provide new directions for prevention of cardiovascular events.