tbuckley/cabot-search huggingface dataset:
Genomic Grade Index Is Associated With Response to Chemotherapy in Patients With Breast Cancer
Authors: Cornelia Liedtke, Christos Hatzis, William Fraser Symmans, Christine Desmedt, Benjamin Haibe-Kains, Vicente Valero, Henry Kuerer, Gabriel N. Hortobagyi, Martine Piccart-Gebhart, Christos Sotiriou, Lajos Pusztai
Journal: Journal of Clinical Oncology (2009)

PURPOSE The genomic grade index (GGI) is a 97-gene measure of histological tumor grade. High GGI is associated with decreased relapse-free survival in patients receiving either endocrine or no systemic adjuvant therapy. Herein we examined whether GGI predicts pathologic response to neoadjuvant chemotherapy in patients with HER-2-normal breast cancer. METHODS Gene expression data (gene chips) was generated from fine-needle aspiration biopsies (n = 229) prospectively collected before neoadjuvant paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. Pathologic response was quantified using the residual cancer burden (RCB) method. The association between the GGI and pathologic response was assessed in univariate and multivariate analyses. The performance of a response predictor combining clinical variables and GGI was evaluated under cross-validation. Results Eighty-five percent of grade 1 tumors had low GGI, 89% of grade 3 tumors had high GGI, and 63% of grade 2 tumors had low GGI. Among both estrogen receptor (ER)-positive and -negative cancers, high GGI score was associated with pathologic complete response (RCB-0) or minimal residual disease (RCB-1). A multivariate model combining GGI and clinical parameters had an overall accuracy of 71%, compared with 58% for the GGI alone, for prediction of pathologic response. However, high GGI score was also associated with significantly worse distant relapse-free survival in patients with ER-positive cancer (P = .005), and was not associated with survival in patients with ER-negative cancer. CONCLUSION High GGI is associated with increased sensitivity to neoadjuvant paclitaxel plus fluorouracil, adriamycin, and cyclophosphamide chemotherapy in both ER-negative and ER-positive patients, but it remains a predictor of worse survival in ER-positive patients.
Synovial fluid neutrophil function in RA: the effect of pregnancy associated proteins
Authors: C Belcher
Journal: Annals of the Rheumatic Diseases (2002)

Although high serum total cholesterol and LDL cholesterol levels are predictive of cardiovascular diseases in the general population, this association is more complex in the dialysis patients. Two recent randomized trials failed to show significant beneficial effects of statins on the primary cardiovascular outcomes in these patients. The reasons for this lack of benefits are unclear. The postulates include the possibilities that LDL cholesterol is not important in atherogenesis and that atherosclerosis is not a major contributor to cardiovascular diseases in the dialysis population. It is important to note that high serum LDL cholesterol level is not a prominent feature of uremic dyslipidemia. Instead, the hallmark dyslipidemias in the dialysis population are hypertriglyceridemia as a result of the accumulation of lipoprotein remnant particles, low serum HDL cholesterol levels, high serum levels of lipoprotein(a) [Lp(a)], and the modification of LDL cholesterol by oxidation and carbamylation. <i>In vitro</i> and epidemiologic studies have further suggested that these abnormal lipoproteins or aberrant serum lipoprotein levels are atherogenic. More research efforts should be directed toward these dyslipidemic states and the multitude of other putative cardiovascular risk factors in dialysis patients.
Eating disorder predisposition is associated with ESRRA and HDAC4 mutations
Authors: Huxing Cui, Jarrette Moore, Sunbola S. Ashimi, Brittany L. Mason, Jordan N. Drawbridge, Shizhong Han, Benjamin Hing, Abigail Matthews, Carrie J. McAdams, Benjamin W. Darbro, Andrew A. Pieper, David A. Waller, Chao Xing, Michael Lutter
Journal: Journal of Clinical Investigation (2013)

Anorexia nervosa and bulimia nervosa are common and severe eating disorders (EDs) of unknown etiology. Although genetic factors have been implicated in the psychopathology of EDs, a clear biological pathway has not been delineated. DNA from two large families affected by EDs was collected, and mutations segregating with illness were identified by whole-genome sequencing following linkage mapping or by whole-exome sequencing. In the first family, analysis of twenty members across three generations identified a rare missense mutation in the estrogen-related receptor α (ESRRA) gene that segregated with illness. In the second family, analysis of eight members across four generations identified a missense mutation in the histone deacetylase 4 (HDAC4) gene that segregated with illness. ESRRA and HDAC4 were determined to interact both in vitro in HeLa cells and in vivo in mouse cortex. Transcriptional analysis revealed that HDAC4 potently represses the expression of known ESRRA-induced target genes. Biochemical analysis of candidate mutations revealed that the identified ESRRA mutation decreased its transcriptional activity, while the HDAC4 mutation increased transcriptional repression of ESRRA. Our findings suggest that mutations that result in decreased ESRRA activity increase the risk of developing EDs.
THE DISSEMINATION OF INTRA-ABDOMINAL MALIGNANT DISEASE BY MEANS OF THE LYMPHATICS AND THORACIC DUCT
Authors: W. M. Stevens
Journal: BMJ (1907)

plastic and not suppurative; and that in cases of diffused septic peritonitis in which great distension and frequent vomiting set in a day or two after operation, but which eventually recover, there is possibly an increase of the peritonitis for a time.But it would be a great mistake to suppose that such symptoms coming on soon after an abdominal operation indicate a fatal termination.I have already referred to the fact that some surgeons have recorded post-mortem observations on some of these cases of flatulent distension and have found no peritonitis, but have regarded the condition as one of primary paralytic distension.In operations on the gall bladder and bile ducts, usually the only parts manipulated, or even seen, are the pylorus, duodenum, and hepatic flexure of the colon, and yet I have seen several times most marked distension of coils in the whole abdomen after these operations.It is true such distension has not been associated with vomiting, or other bad symptoms, but yet it was very marked, and could not have been due to peri- tonitis, from manipulation of the affected coils or from contamination of the general cavity by septic fluids, nor .eould it have been due to thrombosis of the mesenteric vessels, as the distension was soon removed by enemata.Et is an interesting question as to the nature of this dis- tension when no peritonitis is present.The fact that it may result from traumatism in only one corner of the abdomen, would suggest that it may be a reflex nervous
Genetic Modifier Loci Affecting Survival and Cardiac Function in Murine Dilated Cardiomyopathy
Authors: Miwako Suzuki, Kerri M. Carlson, Douglas A. Marchuk, Howard A. Rockman
Journal: Circulation (2002)

Understanding the role for genetic factors in human heart failure is difficult because environmental factors cannot be standardized and genetic variation is great. One approach to identify genes that modify disease outcome is to use mouse models that show strong genetic variation of the disease phenotype.In this study, we used transgenic mice that develop severe dilated cardiomyopathy due to the cardiac-specific overexpression of calsequestrin. Transgenic mice showed marked strain-specific variation of cardiac function and survival, independent of transgene expression. A reciprocal backcross strategy was employed using two inbred strains showing distinct differences in survival and cardiac function. To map the genes that modified the heart failure phenotype, progeny from the 2 reciprocal backcrosses were used in a genome-wide scan for linkage. We identified two loci significantly linked to survival with a maximum likelihood ratio statistic of 36.2 (LOD score approximately 7.8) on chromosome 2 and of 26.5 (LOD score approximately 5.7) on chromosome 3. The chromosome 3 locus was also significantly linked to cardiac function with a maximum likelihood ratio statistic of 42.9 (LOD score approximately 9.3). Because only a single strong modifier locus was found in each backcross, we applied a haplotype analysis to map crossovers and successfully narrowed the critical intervals for each locus.Using a sensitized mouse model, we identified major modifier loci that affect the genetically complex disease of heart failure. This approach should allow the rapid identification of candidate genes involved in disease susceptibility in human populations and new insights into the pathogenesis of heart failure.
National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: Analytical Issues for Biomarkers of Heart Failure
Authors: Fred S. Apple, Alan H.B. Wu, Allan S. Jaffe, Mauro Panteghini, Robert H. Christenson, Robert H. Christenson, Fred S. Apple, Christopher P. Cannon, Gary Francis, Robert L. Jesse, David A. Morrow, L. Kristen Newby, Alan B. Storrow, W.H. Wilson Tang, Alan H.B. Wu, Fred S. Apple, Robert H. Christenson, Allan S. Jaffe, Franca Pagani, Jillian Tate, Jordi Ordonez-Llanos, Johannes Mair
Journal: Circulation (2007)
Involvement of annexin I and annexin II in hepatocyte proliferation: Can annexins I and II be markers for proliferative hepatocytes?
Authors: Tsutomu Masaki, Masaaki Tokuda, Takashi Fujimura, Makoto Ohnishi, Yuji Tai, Kazuhiro Miyamoto, Toshifumi Itano, Hideki Matsui, Seishiro Watanabe, Ken-Ichi Sogawa, Takahisa Yamada, Ryoji Konishi, Mikio Nishioka, Osamu Hatase
Journal: Hepatology (1994)

Annexin is the name of a new family of Ca2+-dependent membrane-binding proteins. Eleven types of its related proteins have been reported to date. Among those, annexin I and annexin II have been reported to possess many biological functions in vitro. Its actual role in vivo, however, is yet unknown. The involvement of annexin I and annexin II in the proliferation processes of hepatocytes was examined in the following aspects: (a) hepatocyte proliferation after carbon tetrachloride—induced liver damage, (b) hepatocyte regeneration after partial hepatectomy and (c) postnatal development of hepatocytes. These results showed collectively that annexin I and annexin II were increased in proliferative (or regenerative) hepatocytes, suggesting that both proteins play a certain role in the proliferation event. Furthermore, annexin I—and annexin II—positive hepatocytes always show a wider distribution than that of proliferating cell nuclear antigen or cytokeratin 7—positive hepatocytes, indicating that annexin I and annexin II may be useful markers for detecting not only actively proliferating hepatocytes but also hepatocytes in preproliferative and postproliferative stages. (Hepatology 1994;20:425–435.)
Run-In Phase III Trial Design With Pharmacodynamics Predictive Biomarkers
Authors: Fangxin Hong, Richard Simon
Journal: JNCI Journal of the National Cancer Institute (2013)

Developments in biotechnology have stimulated the use of predictive biomarkers to identify patients who are likely to benefit from a targeted therapy. Several randomized phase III designs have been introduced for development of a targeted therapy using a diagnostic test. Most such designs require biomarkers measured before treatment. In many cases, it has been very difficult to identify such biomarkers. Promising candidate biomarkers can sometimes be effectively measured after a short run-in period on the new treatment.We introduce a new design for phase III trials with a candidate predictive pharmacodynamic biomarker measured after a short run-in period. Depending on the therapy and the biomarker performance, the trial would either randomize all patients but perform a separate analysis on the biomarker-positive patients or only randomize marker-positive patients after the run-in period. We evaluate the proposed design compared with the conventional phase III design and discuss how to design a run-in trial based on phase II studies.The proposed design achieves a major sample size reduction compared with the conventional randomized phase III design in many cases when the biomarker has good sensitivity (≥0.7) and specificity (≥0.7). This requires that the biomarker be measured accurately and be indicative of drug activity. However, the proposed design loses some of its advantage when the proportion of potential responders is large (>50%) or the effect on survival from run-in period is substantial.Incorporating a pharmacodynamic biomarker requires careful consideration but can expand the capacity of clinical trials to personalize treatment decisions and enhance therapeutics development.
Reply to Ma et al.: Osteomyelitis caused by Aspergillus species
Authors: E. Gabrielli, A.W. Fothergill, L. Brescini, D.A. Sutton, E. Marchionni, E. Orsetti, S. Staffolani, P. Castelli, R. Gesuita, F. Barchiesi
Journal: Clinical Microbiology and Infection (2014)
Effects of intra-articular corticosteroids and anti-TNF therapy on neutrophil activation in rheumatoid arthritis
Authors: H. Wittkowski, D. Foell, E. a. Klint, L. D. Rycke, F. D. Keyser, M. Frosch, A.-K. Ulfgren, J. Roth
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> To determine the safety and tolerability of mexiletine in a phase II double-blind randomized controlled trial of sporadic amyotrophic lateral sclerosis (SALS). <h3>Methods:</h3> Sixty participants with SALS from 10 centers were randomized 1:1:1 to placebo, mexiletine 300 mg/d, or mexiletine 900 mg/d and followed for 12 weeks. The primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetic study from plasma and CSF, ALS Functional Rating Scale–Revised (ALSFRS-R) score, slow vital capacity (SVC), and muscle cramp frequency and severity. <h3>Results:</h3> The only serious adverse event among active arm participants was one episode of imbalance. Thirty-two percent of participants receiving 900 mg of mexiletine discontinued study drug vs 5% on placebo (<i>p</i> = 0.026). Pharmacokinetic study demonstrated a peak plasma concentration 2 hours postdose and strong correlation between plasma and CSF (<i>p</i> &lt; 0.001). Rates of decline of ALSFRS-R and SVC did not differ from placebo. Analysis of all randomized patients demonstrated significant reductions of muscle cramp frequency (300 mg: rate = 31% of placebo, <i>p</i> = 0.047; 900 mg: 16% of placebo, <i>p</i> = 0.002) and cramp intensity (300 mg: mean = 45% of placebo, <i>p</i> = 0.08; 900 mg: 25% of placebo, <i>p</i> = 0.005). <h3>Conclusions:</h3> Mexiletine was safe at both doses and well-tolerated at 300 mg/d but adverse effects at 900 mg/d led to a high rate of discontinuation. Mexiletine treatment resulted in large dose-dependent reductions in muscle cramp frequency and severity. No effect on rate of progression was detected, but clinically important differences could not be excluded in this small and short-duration study. <h3>Classification of evidence:</h3> This study provides Class I evidence that mexiletine is safe when given daily to patients with amyotrophic lateral sclerosis at 300 and 900 mg and well-tolerated at the lower dose.
Testosterone Levels and Quality of Life in Diverse Male Patients With Cancers Unrelated to Androgens
Authors: Stewart B. Fleishman, Hina Khan, Peter Homel, Mohammad F. Suhail, Rotraud Strebel-Amrhein, Farhan Mohammad, Divya Mahajan, Victoria Rosenwald, Michael J. Guarino, Tahir Mirzoyev, Timothy F. Wozniak, Kathiresan Suppiah
Journal: Journal of Clinical Oncology (2010)

Symptoms secondary to hormonal changes significantly impact quality of life (QoL) in patients with cancer. This cross-sectional study examines prevalence of hypogonadism and its correlation with QoL and sexual dysfunction.We collected blood and medical histories from 428 male patients with non-testosterone-related cancer at three cancer centers. Serum was analyzed for total testosterone (TT), free testosterone (FT), bioavailable testosterone (BAT), and sex hormone binding globulin (SHBG). The Functional Assessment of Cancer Therapy-Prostate (FACT-P) QoL questionnaire measured physical, social, emotional, and functional domains as well as sexual function. Exclusion criteria were prostate, testicular, or male breast cancer; known hypogonadism; and HIV.Mean and median TTs were 337.46 and 310 ng/dL, respectively. The mean age of patients was 62.05 years. The crude prevalence of hypogonadism (ie, TT < 300 ng/dL) was 48%, and mean TT in hypogonadal patients was 176 ng/dL. The prevalences that were based on FT (ie, hypogonadal < 52 pg/dL) and BAT (ie, hypogonadal < 95 ng/dL) were 78% and 66%, respectively. The mean FT and BAT values in hypogonadal patients were 25 pg/dL and 45 ng/dL, respectively. Hypogonadal patients had decreased total QoL scores on FACT-P (P = .01) and decreased three-item sexual function subset (P = .003).The prevalence of hypogonadism was unexpectedly high. Measurement of FT or BAT detected a higher prevalence than TT alone, which confirmed previous studies. Correlation of T with FACT-P showed significant reduction of both overall QoL and sexual function for hypogonadal men. BAT and FT levels showed a stronger correlation than TT with overall FACT-P and subscales. The prevalence of symptomatic hypogonadism in male patients with cancer exceeds that found in comparable studies in noncancer populations.
PICOT Attenuates Cardiac Hypertrophy by Disrupting Calcineurin–NFAT Signaling
Authors: Dongtak Jeong, Ji Myoung Kim, Hyeseon Cha, Jae Gyun Oh, Jaeho Park, Soo-Hyeon Yun, Eun-Seon Ju, Eun-Seok Jeon, Roger J. Hajjar, Woo Jin Park
Journal: Circulation Research (2008)

PICOT (protein kinase C-interacting cousin of thioredoxin) was previously shown to inhibit pressure overload-induced cardiac hypertrophy, concomitant with an increase in ventricular function and cardiomyocyte contractility. The combined analyses of glutathione S-transferase pull-down experiments and mass spectrometry enabled us to determine that PICOT directly interacts with muscle LIM protein (MLP) via its carboxyl-terminal half (PICOT-C). It was also shown that PICOT colocalizes with MLP in the Z-disc. MLP is known to play a role in anchoring calcineurin to the Z-disc in the sarcomere, which is critical for calcineurin-NFAT (nuclear factor of activated T cells) signaling. We, therefore, suggested that PICOT may affect calcineurin-NFAT signaling through its interaction with MLP. Consistent with this hypothesis, PICOT, or more specifically PICOT-C, abrogated phenylephrine-induced increases in calcineurin phosphatase activity, NFAT dephosphorylation/nuclear translocation, and NFAT-dependent transcriptional activation in neonatal cardiomyocytes. In addition, pressure overload-induced upregulation of NFAT target genes was significantly diminished in the hearts of PICOT-overexpressing transgenic mice. PICOT interfered with MLP-calcineurin interactions in a dose-dependent manner. Moreover, calcineurin was displaced from the Z-disc, concomitant with an abrogated interaction between calcineurin and MLP, in the hearts of PICOT transgenic mice. Replenishment of MLP restored the hypertrophic responses and the increase in calcineurin phosphatase activity that was inhibited by PICOT in phenylephrine-treated cardiomyocytes. Finally, PICOT-C inhibited cardiac hypertrophy to an extent that was comparable to that of full-length PICOT. Taken together, these data suggest that PICOT inhibits cardiac hypertrophy largely by negatively regulating calcineurin-NFAT signaling via disruption of the MLP-calcineurin interaction.
Differentiation in the short- and long-term effects of smoking on plasma total ghrelin concentrations between male nonsmokers and habitual smokers
Authors: Alexander Kokkinos, Nicholas Tentolouris, Evgenia Kyriakaki, Georgia Argyrakopoulou, John Doupis, Michael Psallas, Despoina Kyriaki, Nicholas Katsilambros
Journal: Metabolism (2007)
Plasma tumour necrosis factor alpha in cystic fibrosis.
Authors: D Norman, J S Elborn, S M Cordon, R J Rayner, M S Wiseman, E J Hiller, D J Shale
Journal: Thorax (1991)

Plasma tumour necrosis factor alpha (alpha) concentration is increased in acute Gram negative sepsis, but the effect of chronic infection on plasma concentrations is unknown. A study was carried out in patients with cystic fibrosis to determine the effect of chronic lung infection with Pseudomonas aeruginosa on the plasma concentration of tumour necrosis factor and two other indicators of the inflammatory response, circulating C reactive protein and neutrophil elastase-alpha 1 antiproteinase complex (elastase complex). The concentration of immunoreactive tumour necrosis factor in plasma was greater than the upper 95% confidence interval for healthy subjects (2.6 U/ml) on 129 out of 189 occasions in 14 patients observed for about a year. The increase in tumour necrosis factor was associated with increased circulating C reactive protein and elastase complex. Twelve patients with an exacerbation of respiratory symptoms were studied before and after two weeks9 treatment with anti-pseudomonal antibiotics. All three indicators of the inflammatory response fell after treatment, though median tumour necrosis factor (4.8 U/ml) and elastase complex (0.41 microgram/ml) concentrations remained above the upper limits for healthy subjects. During a period of clinical stability plasma tumour necrosis factor was increased in 10 of the 12 patients, elastase complex was increased in 10 of the 12, and C reactive protein was increased in seven. Increased plasma immunoreactive tumour necrosis factor was a feature of the near continuous inflammatory response to chronic P aeruginosa infection in cystic fibrosis and may be a factor contributing to the progressive lung destruction seen in this disease.
BLOOD SUGAR STUDIES
Authors: Isolde T. Zeckwer, Helen Goodell
Journal: The Journal of Experimental Medicine (1925)

1. During bacterial anaphylaxis there is a gradual rise in the blood sugar level, which attains an extremely high value at the time of death. 2. The curve of blood sugar is quite similar whether anaphylaxis is induced by organisms which affect the blood sugar in the unsensitized animal or by organisms which have no such effect. 3. No instances occurred in which there was not a marked hyperglycemia in anaphylaxis.