tbuckley/cabot-search huggingface dataset:
Enzastaurin, an Oral Serine/Threonine Kinase Inhibitor, As Second- or Third-Line Therapy of Non–Small-Cell Lung Cancer
Authors: Yun Oh, Roy S. Herbst, Howard Burris, Ann Cleverly, Luna Musib, Michael Lahn, Gerold Bepler
Journal: Journal of Clinical Oncology (2008)

Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses protein kinase C (PKC) and protein kinase B/AK transforming (AKT) signaling, induces tumor cell apoptosis, and inhibits proliferation and angiogenesis. Increased PKC and AKT activity is associated with poor prognosis in non-small-cell lung cancer (NSCLC). This phase II trial of enzastaurin was conducted to determine the 6-month progression-free survival (PFS) rate in advanced, metastatic NSCLC.Patients with metastatic (stage IV and wet IIIB) NSCLC, Eastern Cooperative Oncology Group performance status <or= 2, and <or= two prior systemic regimens (including one or more platinum-based chemotherapy regimens) received 500 mg of enzastaurin administered once daily.Fifty-five patients were enrolled (55% male patients, 45% female patients; median age, 63 years; range, 44 to 82 years; 78% of patients having stage IV disease). Adenocarcinoma was the most common diagnosis (65%). Prior therapies included radiotherapy (73%) and epidermal growth factor inhibitors (29%). Median PFS was 1.8 months (95% CI, 1.7 to 1.9). Six-month PFS rate was 13% (95% CI, 3.9% to 21.5%). Median overall survival (OS) was 8.4 months (95% CI, 6.0 to 13.6 months). The 12-month OS rate was 44% (95% CI, 30.5% to 57.3%). Nineteen patients (35%) had stable disease. No objective responses were observed. Seven patients (13%) had PFS >or= 6 months, three of whom continued for more than 10 months. The most common toxicity was fatigue (grade <or= 3; n = 17). Grade 3 or worse toxicities were fatigue (n = 2), thromboembolism (n = 1), ataxia (n = 1), and anemia (n = 1). Two patients discontinued treatment because of drug-related fatigue and dizziness. Five patients died while enrolled in the study (non drug-related).Although the primary end point of a 20% PFS rate was not achieved, 13% of the patients had PFS for >or= 6 months. Given the tolerability and survival data, evaluation of enzastaurin in combination with cytotoxic drugs is warranted in NSCLC.
Release Kinetics of Inflammatory Biomarkers in a Clinical Model of Acute Myocardial Infarction
Authors: Christoph Liebetrau, Jedrzej Hoffmann, Oliver Dörr, Luise Gaede, Johannes Blumenstein, Hannes Biermann, Lukas Pyttel, Peter Thiele, Christian Troidl, Alexander Berkowitsch, Andreas Rolf, Sandra Voss, Christian W. Hamm, Holger Nef, Helge Möllmann
Journal: Circulation Research (2014)

Rationale: Inflammation in the setting of acute myocardial infarction (MI) has been linked to risk stratification; however, the release kinetics of inflammatory biomarkers in patients with acute MI has been difficult to establish. Objective: The aim of this study was to determine the kinetics of changes in the levels of several biomarkers specifically linked to inflammation after transcoronary ablation of septal hypertrophy, a procedure that mimics acute MI. Methods and Results: We analyzed release kinetics of C-reactive protein, high-sensitivity C-reactive protein, interleukin-6, soluble CD40 ligand, and peripheral blood leukocyte subsets in patients (n=21) undergoing transcoronary ablation of septal hypertrophy. Blood samples were collected before transcoronary ablation of septal hypertrophy and at various times after transcoronary ablation of septal hypertrophy. Serum levels of C-reactive protein were increased at 24 hours (1.0 mg/dL [interquartile range [IQR], 0.7–1.75] versus 0.2 mg/dL [IQR, 0.1–1.05] at baseline [BL]; P &lt;0.001), whereas high-sensitivity C-reactive protein increased as early as 8 hours (2.68 mg/L [IQR, 1.23–11.80] versus 2.17 mg/L [IQR, 1.15–5.06] at BL; P =0.002). Interleukin-6 was significantly increased at 45 minutes (2.59 pg/mL [IQR, 1.69–5.0] versus 1.5 pg/mL [IQR, 1.5–2.21] at BL; P =0.002), and soluble CD40 ligand was significantly decreased at 60 minutes (801.6 pg/mL [IQR, 675.0–1653.5] versus 1750.0 pg/mL [IQR, 1151.0–2783.0] at BL; P =0.016). Elevated counts of polymorphonuclear neutrophils were detectable at 15 minutes, with a significant increase at 2 hours (6415 cells/μL [IQR, 5288–7827] versus 4697 cells/μL [IQR, 2892–5620] at BL; P =0.004). Significant monocytosis was observed at 24 hours (729 cells/μL [IQR, 584–1344] versus 523 cells/μL [IQR, 369–701] at BL; P =0.015). Conclusions: Interleukin-6 and neutrophil granulocytes showed a continuous rise at all prespecified time points after induction of MI. Our results provide valuable additional evidence of the diagnostic value of inflammatory biomarkers in the setting of early acute MI.
Strangulated Hernia of the Left Ovary in the Femoral Region
Authors: A. E. Maylard
Journal: BMJ (1892)

TM ftrf 761tion varied from one hour in Case i-in which we have to rely altogether on the mother's statement-to forty-eight itours in the fourth case, death appearing, as a rule, to result from exhaustion consequent on the violence of the move- maents.
Index-based dietary patterns and risk of incident hepatocellular carcinoma and mortality from chronic liver disease in a prospective study
Authors: Wen-Qing Li, Yikyung Park, Katherine A. McGlynn, Albert R. Hollenbeck, Philip R. Taylor, Alisa M. Goldstein, Neal D. Freedman
Journal: Hepatology (2014)

The role of diet in hepatocellular carcinoma (HCC) and its typical precursor, chronic liver disease (CLD), is poorly understood. Following dietary recommendations has been shown to reduce risk of many cancers, but whether such diets are associated with HCC and CLD is unknown. We prospectively evaluated the association of two dietary indices, the Healthy Eating Index-2010 (HEI-2010) and the alternate Mediterranean Diet Score (aMED), with HCC incidence and CLD mortality in a large U.S. prospective cohort. We calculated the HEI-2010 and aMED scores for 494,942 participants in the National Institutes of Health-AARP Diet and Health study, based on typical diet assessed using a food frequency questionnaire FFQ between 1995 and 1996. Hazard ratios (HRs) and 95% confidence intervals (CIs) for quintiles of each index were estimated using Cox's proportional hazards regression, after adjusting for alcohol intake, smoking, body mass index, diabetes, and other covariates. A total of 509 HCC cases (1995-2006) and 1,053 CLD deaths (1995-2011) were documented during follow-up. Higher HEI-2010 scores, reflecting favorable adherence to dietary guidelines, were associated with lower risk of HCC (HR, 0.72, 95% CI: 0.53-0.97 for the highest quintile, compared to lowest; P trend = 0.03) and lower mortality resulting from CLD (HR, 0.57; 95% CI: 0.46-0.71; P trend &lt; 0.0001). High aMED scores were also associated with lower risk of HCC (HR, 0.62; 95% CI: 0.47-0.84; P trend = 0.0002) and lower risk of CLD mortality (HR, 0.52; 95% CI: 0.42-0.65; P trend &lt; 0.0001). Conclusions: Adhering to dietary recommendations may reduce the risk of developing HCC and dying of CLD. (Hepatology 2014;60:588–597)
Surgical management of large rotator cuff tears combined with instability in elite rugby football players
Authors: J A Goldberg, K Y Chan, J P Best, W J M Bruce, W Walsh, W Parry
Journal: British Journal of Sports Medicine (2003)

Large rotator cuff tears are extremely uncommon in young people and when they occur they may be associated with shoulder instability. This paper reports on a series of six elite rugby union and rugby league footballers who presented with shoulder instability and large rotator cuff tears. They were treated with a two stage procedure: an open rotator cuff repair followed by an open shoulder stabilisation some 10 weeks later. All had successful outcomes. The paper also highlights the risk of tearing the rotator cuff when a patient continues to play contact sport with an untreated unstable shoulder.
From Breaking Bad to Worse: Exploiting Homologous DNA Repair Deficiency in Cancer
Authors: Michael T. Hemann
Journal: Cancer Discovery (2014)

DNA repair deficiencies are common among cancer cells and represent a potential vulnerability that might be exploited by targeting compensatory repair pathways. However, the identification of synthetically lethal combinations of DNA repair defects, although of significant clinical relevance, has been somewhat anecdotal. Although numerous models have been proposed to explain synthetic lethality among DNA repair mutations, we have only a limited understanding of why a given mutation should render cells sensitive to another. In this issue of Cancer Discovery, Dietlein and colleagues define a general connection between mutations in genes involved in homologous recombination and sensitivity to inhibitors of non-homologous end joining. In doing so, they provide a mechanism to demarcate a set of seemingly diverse tumors that may be highly responsive to established DNA repair-targeted therapeutics.
Comparison of the [13C]Glucose Breath Test to the Hyperinsulinemic-Euglycemic Clamp When Determining Insulin Resistance
Authors: Richard Z. Lewanczuk, Breay W. Paty, Ellen L. Toth
Journal: Diabetes Care (2004)

OBJECTIVE—With increasing emphasis on the recognition of the metabolic syndrome and early type 2 diabetes, a clinically useful measure of insulin resistance is desirable. The purpose of this study was to evaluate whether an index of glucose metabolism, as measured by 13CO2 generation from ingested [13C]glucose, would correlate with indexes from the hyperinsulinemic-euglycemic clamp. RESEARCH DESIGN AND METHODS—A total of 26 subjects with varying degrees of insulin sensitivity underwent both the [13C]glucose breath test and the hyperinsulinemic-euglycemic clamp. Results from the [13C]glucose breath test were compared with measures of insulin sensitivity from the glucose clamp as well as with other commonly used indexes of insulin sensitivity. RESULTS—There was a strong correlation between the [13C]glucose breath test result and the glucose disposal rate (r = 0.69, P &amp;lt; 0.0001) and insulin sensitivity index (r = 0.69, P &amp;lt; 0.0001) from the insulin clamp. The magnitude of these correlations compared favorably with QUICKI and were superior to the homeostasis model assessment. CONCLUSIONS—The [13C]glucose breath test may provide a useful noninvasive assessment of insulin sensitivity.
NEAT: a domain duplicated in genes near the components of a putative Fe3+siderophore transporter from Gram-positive pathogenic bacteria
Authors: Miguel A Andrade, Francesca D Ciccarelli, Carolina Perez-Iratxeta, Peer Bork
Journal: Genome biology (2002)

Iron uptake from the host is essential for bacteria that infect animals. To find potential targets for drugs active against pathogenic bacteria, we have searched all completely sequenced genomes of pathogenic bacteria for genes relevant for iron transport.We identified a protein domain that appears in variable copy number in bacterial genes that are usually in the vicinity of a putative Fe3+ siderophore transporter. Accordingly, we have denoted this domain NEAT for 'near transporter'. Most of the bacterial species containing this domain are pathogenic. Sequence features indicate that the domain is anchored to the extracellular side of the membrane. The domain seems to be under high selective pressure for rapid independent duplications that are typical of sequences involved in signaling and binding.The NEAT domain might be functionally related to iron transport. The taxonomic specificity of this domain and its predicted extracellular position could make it an interesting target for designing new drugs against some highly pathogenic bacteria.
In brief
Authors: Zosia Kmietowicz
Journal: BMJ (2002)

Scientists in the United Kingdom believe that an innovative “map” of how money is spent on cancer research could help to streamline research on cancer, target areas of underfunding, and advance new discoveries in the field.

The National Cancer Research Institute has produced what is thought to be the world's first detailed breakdown of cancer research in any country. It estimates that funding of more than £250m ($390m; €400m) from 15 leading …
Expression Profile of Cancer-Testis Genes in 121 Human Colorectal Cancer Tissue and Adjacent Normal Tissue
Authors: Ming Li, Yan-Hua Yuan, Yan Han, Yue-Xiang Liu, Li Yan, Yu Wang, Jin Gu
Journal: Clinical Cancer Research (2005)

Among tumor antigens identified to date, cancer-testis (CT) antigens, which are coded by CT genes, are identified as a group of highly attractive targets for cancer vaccines. This study is the first to analyze the mRNA expression and possible correlation with pathologic characteristics of multiple CT genes in a large cohort of colorectal cancer (CRC) patients.The expression of 10 individual CT genes in 121 CRC and adjacent tissues were analyzed by RT-PCR method. The presence of autologous antibodies against NY-ESO-1 was examined in serum samples by ELISA. To confirm the protein expression, immunohistochemistry was done for detecting the NY-ESO-1 antigen in mRNA-positive CRC tissues.The CT genes were detected with various frequencies in CRC tissue, SCP-1, 1.7%; SSX-2, 2.5%; SSX-4, 2.5%; SSX-1, 5.0%; CT10, 6.6%; NY-ESO-1, 9.9%; MAGE-1, 11.6%; LAGE-1, 15.7%; MAGE-4, 22.3%; and MAGE-3, 27.3%. In 56.2% of tumor tissues examined in this study, at least one CT gene was detected. In contrast, no CT gene expression was found in cancer adjacent tissues. Among 10 CT genes investigated, NY-ESO-1 and LAGE-1 are of particular interest because their mRNA expression in CRC was rarely reported before. In our study, NY-ESO-1 mRNA was found to express in 9.9% of the samples, and also correlated significantly with stages (P = 0.041) and local lymph node metastasis (P = 0.002). In addition, we also identified one NY-ESO-1 antibody-positive serum sample. MAGE-4 mRNA was expressed at a high frequency in tumor tissues with vessel emboli samples (P = 0.025).These results suggested that CT genes, especially NY-ESO-1 and LAGE-1, do express in CRC. More than 50% of the CRC patients in this study express at least one CT gene, making them eligible for CT vaccination. NY-ESO-1 gene may serve as a marker for local metastasis and advanced disease. MAGE-4 gene is significantly associated with the vessel emboli.
Injurious Mechanical Ventilation and End-Organ Epithelial Cell Apoptosis and Organ Dysfunction in an Experimental Model of Acute Respiratory Distress Syndrome
Authors: Yumiko Imai
Journal: JAMA (2003)

Recent clinical trials have demonstrated a decrease in multiple organ dysfunction syndrome (MODS) and mortality in patients with acute respiratory distress syndrome (ARDS) treated with a protective ventilatory strategy.To examine the hypothesis that an injurious ventilatory strategy may lead to end-organ epithelial cell apoptosis and organ dysfunction.In vivo animals: 24 rabbits with acid-aspiration lung injury were ventilated with injurious or noninjurious ventilatory strategies. In vitro: rabbit epithelial cells were exposed to plasma from in vivo rabbit studies. In vivo human: plasma samples from patients included in a previous randomized controlled trial examining a lung protective strategy were analyzed (lung protection group, n = 9 and controls, n = 11).In vivo animals: biochemical markers of liver and renal dysfunction; apoptosis in end organs. In vitro: induction of apoptosis in LLC-RK1 renal tubular epithelial cells. In vivo human: correlation of plasma creatinine and soluble Fas ligand.The injurious ventilatory strategy led to increased rates of epithelial cell apoptosis in the kidney (mean [SE]: injurious, 10.9% [0.88%]; noninjurious, 1.86% [0.17%]; P<.001) and small intestine villi (injurious, 6.7% [0.66%]; noninjurious, 0.97% [0.14%]; P<.001), and led to the elevation of biochemical markers indicating renal dysfunction in vivo. Induction of apoptosis was increased in LLC-RK1 cells incubated with plasma from rabbits ventilated with injurious ventilatory strategy at 4 hours (P =.03) and 8 hours (P =.002). The Fas:Ig, a fusion protein that blocks soluble Fas ligand, attenuated induction of apoptosis in vitro. There was a significant correlation between changes in soluble Fas ligand and changes in creatinine in patients with ARDS (R = 0.64, P =.002).Mechanical ventilation can lead to epithelial cell apoptosis in the kidney and small intestine, accompanied by biochemical evidence of organ dysfunction. This may partially explain the high rate of MODS observed in patients with ARDS and the decrease in morbidity and mortality in patients treated with a lung protective strategy.
<i>PIK3R1</i> (p85α) Is Somatically Mutated at High Frequency in Primary Endometrial Cancer
Authors: Mary E. Urick, Meghan L. Rudd, Andrew K. Godwin, Dennis Sgroi, Maria Merino, Daphne W. Bell
Journal: Cancer Research (2011)

Phosphoinositide 3-kinase (PI3K) is an important therapeutic target. Mutations in PIK3CA, which encodes p110α, the catalytic subunit of PI3K, occur in endometrioid endometrial cancers (EEC) and nonendometrioid endometrial cancers (NEEC). The goal of this study was to determine whether PIK3R1, which encodes p85α, the inhibitory subunit of PI3K, is mutated in endometrial carcinoma. We carried out exonic sequencing of PIK3R1 from 42 EECs and 66 NEECs. The pattern of PIK3R1 mutations was compared with the patterns of PIK3CA, PTEN, and KRAS mutations. The biochemical effect of seven PIK3R1 mutations was examined by stable expression in U2OS cells, followed by coimmunoprecipitation analysis of p110α, and Western blotting of phospho-AKT(Ser473) (p-AKT(Ser473)). We found that PIK3R1 was somatically mutated in 43% of EECs and 12% of NEECs. The majority of mutations (93.3%) were localized to the p85α-nSH2 and -iSH2 domains. Several mutations were recurrent. PIK3R1 mutations were significantly (P = 0.0015) more frequent in PIK3CA-wild type EECs (70%) than in PIK3CA mutant EECs (18%). Introduction of wild-type p85α into U2OS cells reduced the level of p-AKT(Ser473) compared with the vector control. Five p85α mutants, p85αdelH450-E451, p85αdelK459, p85αdelY463-L466, p85αdelR574-T576, and the p85αN564D positive control, were shown to bind p110α and led to increased levels of p-AKT(Ser473). The p85αR348X and p85αK511VfsX2 mutants did not bind p110α and showed no appreciable change in p-AKT(Ser473) levels. In conclusion, our study has revealed a new mode of PI3K alteration in primary endometrial tumors and warrants future studies to determine whether PIK3R1 mutations correlate with clinical outcome to targeted therapies directed against the PI3K pathway in EEC and NEEC.
Activation of Extracellular Signal–Regulated Kinases (ERK1/2) by Angiotensin II Is Dependent on c-Src in Vascular Smooth Muscle Cells
Authors: Mari Ishida, Takafumi Ishida, Sheila M. Thomas, Bradford C. Berk
Journal: Circulation Research (1998)

Abstract —Among the angiotensin II (Ang II)–mediated signal events likely to be important in vascular smooth muscle cells (VSMCs) is activation of extracellular signal–regulated kinases 1 and 2 (ERK1/2). The upstream mediators by which Ang II activates ERK1/2 remain poorly defined. Recently, we showed that Ang II activated c-Src, a nonreceptor kinase, which is a candidate to mediate Ang II signal events. To determine whether c-Src is required for ERK1/2 activation by Ang II, we studied the effects of Src family–selective tyrosine kinase inhibitors on ERK1/2 activation and also studied Ang II–mediated signal events in Src-deficient and Src-overexpressing VSMCs. The tyrosine kinase inhibitors, genistein and CP-188,556, blocked Ang II–mediated ERK1/2 activation in rat VSMCs (rVSMCs). We derived Src-deficient VSMCs from the aortas of c-Src knockout mice (Src −/− mVSMCs). Basal ERK1/2 activity was lower, and activation of ERK1/2 by Ang II was significantly decreased in Src −/− mVSMCs compared with wild-type mVSMCs, whereas ERK1/2 protein expression and ERK1/2 activation by phorbol 12-myristate 13-acetate were similar. To examine the role of c-Src further, we overexpressed wild-type or dominant-negative c-Src in rVSMCs using retroviral vectors. ERK1/2 activation by Ang II was significantly increased in rVSMCs that overexpressed c-Src, whereas ERK1/2 activation by Ang II was significantly inhibited in rVSMCs that overexpressed dominant-negative c-Src compared with control rVSMCs. These findings demonstrate that c-Src activation is required for Ang II stimulation of ERK1/2 in VSMCs and suggest an important role for c-Src in Ang II–mediated signal transduction.
Adjuvant Therapy in Patients With Adrenocortical Carcinoma: A Position of an International Panel
Authors: Alfredo Berruti, Martin Fassnacht, Eric Baudin, Gary Hammer, Harm Haak, Sophie Leboulleux, Britt Skogseid, Bruno Allolio, Massimo Terzolo
Journal: Journal of Clinical Oncology (2010)

Adjuvant therapy in patients with adrenocortical carcinoma : a position of an international panel
Control of Massive Bleeding From Hemorrhoidal Veins
Authors: C. Jack Bark
Journal: JAMA (1981)

<h3>To the Editor.—</h3> The CLINICAL NOTE of Johansen et al (1980;244:2084) on the transanal ligation of hemorrhoidal veins in a bleeding patient with portal hypertension reminded me of a middle-aged alcoholic patient I cared for as an intern 19 years ago at the San Diego County General Hospital. She also had cirrhosis and ascites. Late one night she suddenly passed several units of red blood from the rectum. Transfusions were not keeping up with the loss. Transposing a therapeutic modality for esophageal varices to the opposite end of the gastrointestinal tract, I inserted a large Foley catheter in her rectum, over inflated the retaining cuff, and applied gentle traction by tying a small weight at the end of the catheter and letting it hang over the bed. The bleeding stopped, and the catheter was removed the next day. A few days later a similar episode necessitated repeated tamponade for 48
A measure of quality of life for clinical trials in chronic lung disease.
Authors: G H Guyatt, L B Berman, M Townsend, S O Pugsley, L W Chambers
Journal: Thorax (1987)

Since the relationships between pulmonary function, exercise capacity, and functional state or quality of life are generally weak, a self report questionnaire has been developed to determine the effect of treatment on quality of life in clinical trials. One hundred patients with chronic airflow limitation were asked how their quality of life was affected by their illness, and how important their symptoms and limitations were. The most frequent and important items were used to construct a questionnaire evaluating four dimensions: dyspnoea, fatigue, emotional function, and the patient9s feeling of control over the disease (mastery). Reproducibility, tested by repeated administration to patients in a stable condition, was excellent: the coefficient of variation was less than 12% for all four dimensions. Responsiveness (sensitivity to change) was tested by administering the questionnaire to 13 patients before and after optimisation of their drug treatment and to another 28 before and after participation in a respiratory rehabilitation programme. In both cases large, statistically significant improvements in all four dimensions were noted. Changes in questionnaire score were correlated with changes in spirometric values, exercise capacity, and patients9 and physicians9 global ratings. Thus it has been shown that the questionnaire is precise, valid, and responsive. It can therefore serve as a useful disease specific measure of quality of life for clinical trials.