tbuckley/cabot-search huggingface dataset:
Overexpression of Hypoxia-Inducible Factor 1α and p53 Is a Marker for an Unfavorable Prognosis in Gastric Cancer
Authors: Yasushi Sumiyoshi, Yoshihiro Kakeji, Akinori Egashira, Ken Mizokami, Hiroyuki Orita, Yoshihiko Maehara
Journal: Clinical Cancer Research (2006)

To investigate the effects of the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) and p53 on the prognosis of human gastric cancer, the clinicopathologic characteristics of the tumors and the clinical outcome were analyzed.The expressions of HIF-1alpha and p53 proteins were studied by immunohistochemistry in 216 specimens of primary gastric cancer.HIF-1alpha(+)/p53(+) tumors more frequently showed an undifferentiated type, an infiltrative growth appearance, and an invasive lymphatic involvement compared with HIF-1alpha(-)/p53(-) tumors. HIF-1alpha(+)/p53(+) tumors also had more lymph node metastasis compared with HIF-1alpha(-)/p53(-) tumors. When stratified for HIF-1alpha and p53 positivity, the patients who were p53-negative and HIF-1alpha-negative had the most favorable prognosis, whereas patients who were p53-positive and HIF-1alpha-positive had the worst prognosis (P=0.0018). Using a multivariate Cox regression analysis, the depth of invasion, lymph node metastasis, and HIF-1alpha positivity were all found to be independent prognostic factors in patients with gastric cancer.Thus, HIF-1alpha is considered to be a useful independent prognostic factor in gastric cancer, and the combination of a HIF-1alpha protein overexpression with nonfunctional p53 tends to indicate a dismal prognosis.
Contrasting roles of SPARC-related granuloma in bacterial containment and in the induction of anti–<i>Salmonella typhimurium</i> immunity
Authors: Gianluca Rotta, Gianluca Matteoli, Elisa Mazzini, Paolo Nuciforo, Mario P. Colombo, Maria Rescigno
Journal: The Journal of Experimental Medicine (2008)

The role of matricellular proteins in bacterial containment and in the induction of pathogen-specific adaptive immune responses is unknown. We studied the function of the matricellular protein secreted protein, acidic and rich in cysteine (SPARC/osteonectin) in the dissemination of locally injected Salmonella typhimurium and in the subsequent immune response. We show that SPARC was required for the development of organized acute inflammatory reactions with granuloma-like (GL) features and for the control of bacterial spreading to draining lymph nodes (DLNs). However, SPARC-related GL also inhibited dendritic cell (DC) migration to the DLNs and limited the development of adaptive immune response, thus conferring increased susceptibility to the pathogen. In SPARC-deficient mice, both DC migration and antigen-specific responses were restored against bacteria, leading to protective anti–S. typhimurium immunity. This highlights a new function of matricellular proteins in bacterial infection and suggests that initial containment of bacteria can have drawbacks.
Modeling the cumulative genetic risk for multiple sclerosis from genome-wide association data
Authors: Joanne H Wang, Derek Pappas, Philip L De Jager, Daniel Pelletier, Paul Iw de Bakker, Ludwig Kappos, Chris H Polman, Lori B Chibnik, David A Hafler, Paul M Matthews, Stephen L Hauser, Sergio E Baranzini, Jorge R Oksenberg
Journal: Genome Medicine (2011)

Multiple sclerosis (MS) is the most common cause of chronic neurologic disability beginning in early to middle adult life. Results from recent genome-wide association studies (GWAS) have substantially lengthened the list of disease loci and provide convincing evidence supporting a multifactorial and polygenic model of inheritance. Nevertheless, the knowledge of MS genetics remains incomplete, with many risk alleles still to be revealed.We used a discovery GWAS dataset (8,844 samples, 2,124 cases and 6,720 controls) and a multi-step logistic regression protocol to identify novel genetic associations. The emerging genetic profile included 350 independent markers and was used to calculate and estimate the cumulative genetic risk in an independent validation dataset (3,606 samples). Analysis of covariance (ANCOVA) was implemented to compare clinical characteristics of individuals with various degrees of genetic risk. Gene ontology and pathway enrichment analysis was done using the DAVID functional annotation tool, the GO Tree Machine, and the Pathway-Express profiling tool.In the discovery dataset, the median cumulative genetic risk (P-Hat) was 0.903 and 0.007 in the case and control groups, respectively, together with 79.9% classification sensitivity and 95.8% specificity. The identified profile shows a significant enrichment of genes involved in the immune response, cell adhesion, cell communication/signaling, nervous system development, and neuronal signaling, including ionotropic glutamate receptors, which have been implicated in the pathological mechanism driving neurodegeneration. In the validation dataset, the median cumulative genetic risk was 0.59 and 0.32 in the case and control groups, respectively, with classification sensitivity 62.3% and specificity 75.9%. No differences in disease progression or T2-lesion volumes were observed among four levels of predicted genetic risk groups (high, medium, low, misclassified). On the other hand, a significant difference (F = 2.75, P = 0.04) was detected for age of disease onset between the affected misclassified as controls (mean = 36 years) and the other three groups (high, 33.5 years; medium, 33.4 years; low, 33.1 years).The results are consistent with the polygenic model of inheritance. The cumulative genetic risk established using currently available genome-wide association data provides important insights into disease heterogeneity and completeness of current knowledge in MS genetics.
Pharmacogenomic and Pharmacoproteomic Studies of Cetuximab in Metastatic Colorectal Cancer: Biomarker Analysis of a Phase I Dose-Escalation Study
Authors: Josep Tabernero, Andres Cervantes, Fernando Rivera, Erika Martinelli, Federico Rojo, Anja von Heydebreck, Teresa Macarulla, Edith Rodriguez-Braun, Maria Eugenia Vega-Villegas, Stefanie Senger, Francisco Javier Ramos, Susana Roselló, Ilhan Celik, Christopher Stroh, José Baselga, Fortunato Ciardiello
Journal: Journal of Clinical Oncology (2010)

Purpose This study assessed biomarkers for cetuximab efficacy in tissue samples collected during a phase I dose-escalation study exploring every second week administration of cetuximab as first-line therapy in patients with metastatic colorectal cancer (mCRC). Patients and Methods Sixty-two patients received cetuximab monotherapy for 6 weeks, followed by cetuximab plus infusional fluorouracil, leucovorin, and irinotecan until disease progression. Patients in the control arm received cetuximab as a 400 mg/m 2 initial dose then 250 mg/m 2 per week; patients in the dose-escalation arms received 400 to 700 mg/m 2 every second week. Tumor and skin biopsies were taken for immunohistochemical and microarray expression analyses (tumor only) at baseline and week 4. Plasma was collected for proteomic analysis at baseline and week 4. KRAS tumor mutation status was assessed. Results In subsets of paired skin samples from 35 patients, cetuximab treatment was associated with substantial downregulation of phospho(p)-EGFR, p-MAPK and proliferation and substantial upregulation of p27 Kip1 and p-STAT3 levels. No marked difference in these effects was noted for different schedules of administration and dose levels. In the cetuximab monotherapy phase, responses were seen only in patients whose tumors were wild-type for KRAS (eight of 29 v zero of 19 for KRAS mutant tumors; P = .015). Progression-free survival was longer for patients with KRAS wild-type compared with KRAS mutant tumors (log-rank P = .048). Genomics/proteomics analyses (42 and 45 patients, respectively) identified candidate biomarkers associated with response. Conclusion Biomarker analysis supported the functional equivalence of weekly and every second week administration of cetuximab and provided further confirmation that patients with KRAS wild-type mCRC were those most likely to benefit from cetuximab treatment.
The Importance of Waist Circumference in the Definition of Metabolic Syndrome
Authors: Peter T. Katzmarzyk, Ian Janssen, Robert Ross, Timothy S. Church, Steven N. Blair
Journal: Diabetes Care (2006)

OBJECTIVE—The purpose of this study was to compare the predictive ability of the National Cholesterol Education Panel (NCEP), revised NCEP (NCEP-R), and International Diabetes Federation (IDF) metabolic syndrome criteria for mortality risk, and to examine the effects of waist circumference on mortality within the context of these criteria. RESEARCH DESIGN AND METHODS—The sample included 20,789 white, non-Hispanic men 20–83 years of age from the Aerobics Center Longitudinal Study. The main outcome measures were all-cause and cardiovascular disease (CVD) mortality over 11.4 years of follow-up. RESULTS—The proportions of men with the metabolic syndrome were 19.7, 27, and 30% at baseline, respectively, according to NCEP, NCEP-R, and IDF criteria. A total of 632 deaths (213 CVD) occurred. The relative risks (RRs) and 95% CIs of all-cause mortality were 1.36 (1.14–1.62), 1.31 (1.11–1.54), and 1.26 (1.07–1.49) for the NCEP, NCEP-R, and IDF definitions, respectively. The corresponding RRs for CVD mortality were 1.79 (1.35–2.37), 1.67 (1.27–2.19), and 1.67 (1.27–2.20). Additionally, there was a significant trend for a higher risk of CVD mortality across waist circumference categories (&amp;lt;94, 94–102, and &amp;gt;102 cm) among men with at least two additional metabolic syndrome risk factors (P = 0.01). CONCLUSIONS—The prediction of mortality with IDF and NCEP metabolic syndrome criteria was comparable in men. Waist circumference is a valuable component of metabolic syndrome; however, the IDF requirement of an elevated waist circumference warrants caution given that a large proportion of men with normal waist circumference have multiple risk factors and an increased risk of mortality.
Bowel muscle in diverticular disease.
Authors: W W Slack
Journal: Gut (1966)

EDITORIAL COMMENT The thickened muscle found in diverticular disease of the colon could be due to a local increase in the number or size of the muscle cells or to sustained contraction.This study, by an ingenious chemical technique, does not resolve the controversy but provides strong evidence that the increase in muscle bulk is not due to an increase in the size of the muscle cells.
Prophylactic and Therapeutic Efficacy of Human Monoclonal Antibodies against H5N1 Influenza
Authors: Cameron P Simmons, Nadia L Bernasconi, Amorsolo L Suguitan, Kimberly Mills, Jerrold M Ward, Nguyen Van Vinh Chau, Tran Tinh Hien, Federica Sallusto, Do Quang Ha, Jeremy Farrar, Menno D de Jong, Antonio Lanzavecchia, Kanta Subbarao
Journal: PLoS Medicine (2007)

Background New prophylactic and therapeutic strategies to combat human infections with highly pathogenic avian influenza (HPAI) H5N1 viruses are needed. We generated neutralizing anti-H5N1 human monoclonal antibodies (mAbs) and tested their efficacy for prophylaxis and therapy in a murine model of infection. Methods and Findings Using Epstein-Barr virus we immortalized memory B cells from Vietnamese adults who had recovered from infections with HPAI H5N1 viruses. Supernatants from B cell lines were screened in a virus neutralization assay. B cell lines secreting neutralizing antibodies were cloned and the mAbs purified. The cross-reactivity of these antibodies for different strains of H5N1 was tested in vitro by neutralization assays, and their prophylactic and therapeutic efficacy in vivo was tested in mice. In vitro, mAbs FLA3.14 and FLD20.19 neutralized both Clade I and Clade II H5N1 viruses, whilst FLA5.10 and FLD21.140 neutralized Clade I viruses only. In vivo, FLA3.14 and FLA5.10 conferred protection from lethality in mice challenged with A/Vietnam/1203/04 (H5N1) in a dose-dependent manner. mAb prophylaxis provided a statistically significant reduction in pulmonary virus titer, reduced associated inflammation in the lungs, and restricted extrapulmonary dissemination of the virus. Therapeutic doses of FLA3.14, FLA5.10, FLD20.19, and FLD21.140 provided robust protection from lethality at least up to 72 h postinfection with A/Vietnam/1203/04 (H5N1). mAbs FLA3.14, FLD21.140 and FLD20.19, but not FLA5.10, were also therapeutically active in vivo against the Clade II virus A/Indonesia/5/2005 (H5N1). Conclusions These studies provide proof of concept that fully human mAbs with neutralizing activity can be rapidly generated from the peripheral blood of convalescent patients and that these mAbs are effective for the prevention and treatment of H5N1 infection in a mouse model. A panel of neutralizing, cross-reactive mAbs might be useful for prophylaxis or adjunctive treatment of human cases of H5N1 influenza.
Selective Activation of Ceruloplasmin Promoter in Ovarian Tumors
Authors: Christine M. Lee, Hui-Wen Lo, Ru-Ping Shao, Shao-Chun Wang, Weiya Xia, David M. Gershenson, Mien-Chie Hung
Journal: Cancer Research (2004)

Abstract Gene therapy provides a novel treatment approach to cancer patients. Ideally, expression of therapeutic genes driven by cancer-specific promoters would only target tumors resulting in minimal toxicity to normal tissues. While there is a need of more effective and tolerable treatments for ovarian cancer patients, we aimed to identify gene promoters with high activity in ovarian tumors that can be potentially used in gene therapy to drive the expression of a therapeutic gene in tumors. To identify such promoters, a literature search was performed to reveal genes that are preferentially expressed in ovarian cancer compared with normal ovarian tissue. We found that the ceruloplasmin promoter drove up to 30-fold higher luciferase expression in ovarian cancer cells compared with immortalized normal cells. Furthermore, deletion studies revealed an activator protein-1 (AP-1) site in the ceruloplasmin promoter to be critical for optimal ceruloplasmin promoter activity. Ceruloplasmin promoter activity was significantly activated by 1-O-tetradecanoyl phorbol-13-acetate, a c-jun activator, and conversely suppressed by SP600125, a c-jun inhibitor. Consistently, the ceruloplasmin AP-1 site was specifically recognized by c-jun both in vitro and in vivo. Immunohistochemical analyses of human ovarian cancer specimens showed a direct correlation (r = 0.7, P = 0.007) between expression levels of c-jun and ceruloplasmin. In nude mice carrying SKOV3.ip1 xenografts, the ceruloplasmin promoter demonstrated significantly higher activities in tumors compared with normal organs. Together, these results suggest that the ceruloplasmin promoter activity is significantly enhanced in ovarian cancer and therefore may be exploited as a promising cancer-specific promoter in developing new gene therapy strategies for ovarian cancer.
Diagnostic accuracy of saline infusion sonography in the evaluation of uterine cavity abnormalities prior to assisted reproductive techniques: a systematic review and meta-analyses
Authors: S. Seshadri, T. El-Toukhy, A. Douiri, K. Jayaprakasan, Y. Khalaf
Journal: Human Reproduction Update (2014)

The diagnostic accuracy of a 2-D transvaginal scan, which is commonly employed to evaluate the regularity and shape of the uterine cavity in subfertile women, is relatively poor compared with other diagnostic modalities like saline infusion sonography (SIS) or hysteroscopy. SIS is a minimally invasive, cost-effective and acceptable diagnostic modality. Therefore the aim of this systematic review was to assess the diagnostic accuracy of SIS in the evaluation of the uterine cavity in subfertile women.A systematic review was conducted of diagnostic studies that compared SIS with hysteroscopy. Twenty relevant studies (including 1645 procedures) were identified and a subsequent meta-analysis was performed. Electronic databases were searched for relevant studies and references of relevant studies were cross checked. Validity was assessed and data were extracted independently by two authors. Heterogeneity was examined, studies were plotted in an ROC area and data were pooled. The main outcome measure was the diagnostic accuracy of saline infusion sonography. The pooled sensitivity, specificity, likelihood ratios and the post-test probabilities of saline infusion sonography on the prediction of uterine cavity abnormalities were calculated.The pooled sensitivity of SIS in the detection of all intrauterine abnormalities was 0.88 (95% confidence interval (CI): 0.85-0.90). The pooled specificity was 0.94 (95% CI 0.93-0.96). The positive and negative likelihood ratios were 20.93 (95% CI: 9.06-48.34) and 0.15 (95% CI: 0.10-0.22), respectively. SIS had good accuracy in the detection of all intrauterine abnormalities (area under the summary receiver operating curve (sROC) = 0.97 ± 0.01). SIS also had a high pooled sensitivity and specificity in the detection of congenital uterine anomalies, 0.85 (95% CI: 0.79-0.90) and 1.00 (95% CI 0.99-1.00), respectively. However the limitations of the review include the heterogeneity amongst the included studies.SIS is a highly sensitive investigative modality and comparable to the gold standard tool, hysteroscopy in the detection of intrauterine abnormalities in subfertile women. SIS is a highly sensitive and specific test in the diagnosis of uterine polyps, submucous myomas, uterine anomalies and intrauterine adhesions and can be used as a screening tool for subfertile patients prior to IVF treatment.
Users' Guides to the Medical Literature
Authors: Mark C. Wilson
Journal: JAMA (1995)

<h3>CLINICAL SCENARIO</h3> At the conclusion of our first article on practice guidelines<sup>1</sup>in this series, we left you examining the full text of a practice guideline<sup>2</sup>that could help you marshal a convincing response to a colleague who disagrees with your approach to hormone replacement therapy (HRT) in postmenopausal women. Later that day, chatting with another colleague, you mention the disagreement. He shrugs, and avows, "It's entirely a matter of personal preference, the evidence doesn't support either of you." You return to the guideline, looking for how particular recommendations may be justified and adapted to your patient's circumstances. <h3>WHAT ARE THE RECOMMENDATIONS?</h3> Are Practical, Clinically Important, Recommendations Made? To be useful, recommendations should give practical, unambiguous advice about a specific health problem. For guidelines about managing health conditions, you should determine if the intent is to prevent, screen for, diagnose, treat, or palliate the disorder. For guidelines about
Autopathogenic T Helper Cell Type 1 (Th1) and Protective Th2 Clones Differ in Their Recognition of the Autoantigenic Peptide of Myelin Proteolipid Protein
Authors: Mercy Prabhu Das, Lindsay B. Nicholson, Judith M. Greer, Vijay K. Kuchroo
Journal: The Journal of Experimental Medicine (1997)

We previously generated a panel of T helper cell 1 (Th1) clones specific for an encephalitogenic peptide of myelin proteolipid protein (PLP) peptide 139–151 (HSLGKWLGHPDKF) that induces experimental autoimmune encephalomyelitis (EAE) upon adoptive transfer. In spite of the differences in their T cell receptor (TCR) gene usage, all these Th1 clones required W144 as the primary and most critical TCR contact residue for the activation. In this study, we determined the TCR contact residues of a panel of Th2/Th0 clones specific for the PLP peptide 139–151 generated either by immunization with the PLP 139–151 peptide with anti– B7-1 antibody or by immunization with an altered peptide Q144. Using alanine-substituted peptide analogues of the native PLP peptide, we show that the Th2 clones have shifted their primary contact residue to the NH2-terminal end of the peptide. These Th2 cells do not show any dependence on the W144, but show a critical requirement for L141/G142 as their major TCR contact residue. Thus, in contrast with the Th1 clones that did not proliferate to A144-substituted peptide, the Th2 clones tolerated a substitution at position 144 and proliferated to A144 peptide. This alternative A144 reactive repertoire appears to have a critical role in the regulation of autoimmune response to PLP 139–151 because preimmunization with A144 to expand the L141/G142-reactive repertoire protects mice from developing EAE induced with the native PLP 139–151 peptide. These data suggest that a balance between two different T cell repertoires specific for same autoantigenic epitope can determine disease phenotype, i.e., resistance or susceptibility to an autoimmune disease.
INULIN AND ENDOGENOUS AMINO ACID RENAL CLEARANCES IN CYSTINURIA: EVIDENCE FOR TUBULAR SECRETION*
Authors: George W. Frimpter, Melvin Horwith, Eugene Furth, Robert E. Fellows, David D. Thompson
Journal: Journal of Clinical Investigation (1962)

Cystinuria is manifested by cystine calculi and high urinary excretion of cystine (2), lysine, ar- ginine (3), and ornithine (4).Abnormally low plasma levels have been established for cystine (5, 6), lysine (7), arginine, and ornithine (5, 8).Several investigators have previously demonstrated increased renal clearances for cystine, lysine, argi- nine, and ornithine (7-11).These four amino acids each have two amino groups separated by 4 to 6 carbon atoms.This led Dent and Rose to suggest that a common en- zymatic mechanism for their renal tubular reab- sorption is missing in cystinuria (11).Further support for this hypothesis was provided by the demonstration that intravenous infusion of lysine produced increased excretion of cystine and argi- nine in nomal individuals but not in those with cystinuria (7, 10).In addition to the four amino acids previously mentioned, studies in this laboratory have re- cently demonstrated that significant amounts of the asymmetrical disulfide of L-cysteine and L-ho- mocysteine were excreted by all of 10 patients with classical cystinuria (12).This substance was recorded by Stein as a peak in the isoleucine area of the ion-exchange chromatogram (4).He determined the relative molar excretion of cystine, arginine, lysine, and ornithine in the urine of five patients with cystinuria, without reference, however, to plasma concentrations or renal func-