tbuckley/cabot-search huggingface dataset:
Determinants of the decline in mortality from acute myocardial infarction in England between 2002 and 2010: linked national database study
Authors: K. Smolina, F. L. Wright, M. Rayner, M. J. Goldacre
Journal: BMJ (2012)

<b>Objective</b> To report trends in event and case fatality rates for acute myocardial infarction and examine the relative contributions of changes in these rates to changes in total mortality from acute myocardial infarction by sex, age, and geographical region between 2002 and 2010. <b>Design</b> Population based study using person linked routine hospital and mortality data. <b>Setting</b> England. <b>Participants</b> 840 175 people of all ages who were admitted to hospital for acute myocardial infarction or died suddenly from acute myocardial infarction. <b>Main outcome measures</b> Acute myocardial infarction event, 30 day case fatality, and total mortality rates. <b>Results</b> From 2002 to 2010 in England, the age standardised total mortality rate fell by about half, whereas the age standardised event and case fatality rates both declined by about one third. In men, the acute myocardial infarction event, case fatality, and total mortality rates declined at an average annual rate of, respectively, 4.8% (95% confidence interval 3.0% to 6.5%), 3.6% (3.4% to 3.7%), and 8.6% (5.4% to 11.6%). In women, the corresponding figures were 4.5% (1.7% to 7.1%), 4.2% (4.0% to 4.3%), and 9.1% (4.5% to 13.6%). Overall, the relative contributions of the reductions in event and case fatality rates to the decline in acute myocardial infarction mortality rate were, respectively, 57% and 43% in men and 52% and 48% in women; however, the relative contributions differed by age, sex, and geographical region. <b>Conclusions</b> Just over half of the decline in deaths from acute myocardial infarction during the 2000s in England can be attributed to a decline in event rate and just less than half to improved survival at 30 days. Both prevention of acute myocardial infarction and acute medical treatment have contributed to the decline in deaths from acute myocardial infarction over the past decade.
The role of histidine in human epidermis
Authors: J. BAYNES, M. LEVINE
Journal: British Journal of Dermatology (1977)

Incorporation of radioactively-labelled histidine into half-thickness skin and into the major protein fraction extracted from epidermis by urea (protein Fraction A) has been measured and compared with the amount of labelled urocanic acid appearing in the same specimen. After a short lag period, incorporation into half-thickness skin and into protein Fraction A was found to be linear up to 23 h of the study. Histidine appeared to be initially preferentially deaminated to urocanic acid. The somewhat erratic presence of urocanic acid at later periods is attributed to its high instability and solubility.
Selective Role for Mek1 but not Mek2 in the Induction of Epidermal Neoplasia
Authors: Florence A. Scholl, Phillip A. Dumesic, Deborah I. Barragan, Kazutoshi Harada, Jean Charron, Paul A. Khavari
Journal: Cancer Research (2009)

Abstract The Ras/Raf/Mek/Erk mitogen-activated protein kinase pathway regulates fundamental processes in normal and malignant cells, including proliferation, differentiation, and cell survival. Mutations in this pathway have been associated with carcinogenesis and developmental disorders, making Mek1 and Mek2 prime therapeutic targets. In this study, we examined the requirement for Mek1 and Mek2 in skin neoplasia using the two-step 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) skin carcinogenesis model. Mice lacking epidermal Mek1 protein develop fewer papillomas than both wild-type and Mek2-null mice following DMBA/TPA treatment. Mek1 knockout mice had smaller papillomas, delayed tumor onset, and half the tumor burden of wild-type mice. Loss of one Mek1 allele, however, did not affect tumor development, indicating that one Mek1 allele is sufficient for normal papilloma formation. No difference in TPA-induced hyperproliferation, inflammation, or Erk activation was observed between wild-type, conditional Mek1 knockout, and Mek2-null mice, indicating that Mek1 findings were not due to a general failure of these processes. These data show that Mek1 is important for skin tumor development and that Mek2 cannot compensate for the loss of Mek1 function in this setting. [Cancer Res 2009;69(9):3772–8]
The Radiolabeled Frog Red Blood Cell
Authors: RICHARD W. BAEHLER, ANDREW J. CATANZARO, JAY H. STEIN, WILLIAM HUNTER
Journal: Circulation Research (1973)

The red cell of the bullfrog Bufo vulgaris was used to measure the intrarenal distribution of blood flow in the kidney of the dog. These cells were fixed in 1% glutaraldehyde and labeled with sodium pertechnetate ( 99M Tc); they were 18 x 10µ in size and had a specific gravity of 1.076--a value close to that of the dog red blood cell. These cells had no discernible effect on systemic or renal hemodynamics after injection, did not agglutinate, were well mixed and evenly distributed throughout different areas of the renal cortex, and were completely extracted in one circulation through the kidney. When the renal cortex was divided into four equal zones, the fractional distribution of the frog red blood cells was 39, 33, 20, and 8% going from the outer to the inner cortex. These values were not significantly different from those obtained in the same dogs with radioactive microspheres--particles much denser than the frog red cells. In two other models involving intrarenal acetylcholine administration and hemorrhagic hypotension, there was no difference between the regional blood flow distribution measured with the frog red cell method and that measured with the microsphere method. However, with both acetylcholine infusion and hemorrhage, there was a redistribution of renal cortical blood flow to the inner cortex compared with the distribution determined by either method during hydropenia. Thus, a similar intrarenal distribution of blood flow was found with two indicators of different size, shape, and density. We suggest that the primary rheologic factor affecting a particle such as a frog red blood cell or a microsphere markedly diluted among circulating red cells is its interaction with these normal cells.
Genome-wide expression patterns of invasion front, inner tumor mass and surrounding normal epithelium of colorectal tumors
Authors: Eike Staub, Joern Groene, Maya Heinze, Detlev Mennerich, Stefan Roepcke, Irina Klaman, Bernd Hinzmann, Esmeralda Castanos-Velez, Christian Pilarsky, Benno Mann, Thomas Brümmendorf, Birgit Weber, Heinz-Johannes Buhr, André Rosenthal
Journal: Molecular Cancer (2007)

Colorectal tumors have characteristic genome-wide expression patterns that allow their distinction from normal colon epithelia and facilitate clinical prognosis. The expression heterogeneity within a primary colorectal tumor has not been studied on a genome scale yet. Here we investigated three compartments of colorectal tumors, the invasion front, the inner tumor mass, and surrounding normal epithelial tissue by microdissection and microarray-based expression profiling. In both tumor compartments many genes were differentially expressed when compared to normal epithelium. The sets of significantly deregulated genes in both compartments overlapped to a large extent and revealed various interesting known and novel pathways that could have contributed to tumorigenesis. Cells from the invasion front and inner tumor mass, however, did not show significant differences in their expression profile, neither on the single gene level nor on the pathway level. Instead, gene expression differences between individuals are more pronounced as all patient-matched tumor samples clustered in close proximity to each other. With respect to invasion front and inner tumor mass we conclude that the specific tumor cell micro-environment does not have a strong influence on expression patterns: largely similar genome-wide expression programs operate in the invasion front and interior compartment of a colorectal tumor.
Patterns and Correlates of Emergency Department Use by Individuals With Diabetes
Authors: Leonard E. Egede
Journal: Diabetes Care (2004)

In the U.S., there has been a rapid increase in emergency department visits, and studies indicate that up to 50% of emergency department visits are for nonurgent problems (1,2). Several studies have suggested that individuals with diabetes are significantly more likely to use the emergency department than their nondiabetic counterparts (3–5). However, most of these studies did not adequately control for key factors that influence health utilization, and many did not explore potential predictors of emergency department use in individuals with diabetes.

The objectives of this study were to use nationally representative data to 1 ) compare patterns of emergency department use in people with and without diabetes, 2 ) compare the odds of emergency department use in both groups while controlling for potential confounders, and 3 ) determine correlates of single and multiple emergency department use in people with diabetes. It was hypothesized that while controlling for known confounders, the odds of emergency department use would not differ significantly between people with and without diabetes.

Data from the sample adult core of 1999 National Health Interview Survey (NHIS) (6) were analyzed. The NHIS is a nationally representative household survey of U.S. adults aged ≥18 years. The sample is selected by a complex sampling design involving stratification, clustering, and multistage sampling with a nonzero probability of …
Serum proteomic profiling of obese patients: correlation with liver pathology and evolution after bariatric surgery
Authors: V Trak-Smayra, D Dargere, R Noun, M Albuquerque, C Yaghi, M-H Gannage-Yared, P Bedossa, V Paradis
Journal: Gut (2008)

<h3>Objective:</h3> Chronic liver diseases, including cirrhosis, may develop in obese patients. Steatosis and non-alcoholic steatohepatitis (NASH) are risk factors for progression to fibrosis. To date, diagnosis of steatosis and NASH relies on liver biopsy. The aim of the study was to identify serum markers of steatosis and NASH in obese patients using SELDI–TOF ProteinChip. <h3>Patients:</h3> Eighty obese non-alcoholic patient candidates for bariatric surgery and devoid of hepatitis B and C infection were selected. Serum samples were collected before surgery and at 6 months after surgery for 33 of these patients. Wedge liver biopsy was performed at the time of bariatric surgery. Twenty-four serum samples from healthy blood donors served as controls. The protein profiles of each serum were assessed using SELDI–TOF ProteinChip technology and were compared according to liver histological lesions. <h3>Results:</h3> Twenty-four obese patients (30%) had non-significant liver lesions, 32 (40%) had significant steatosis and 24 (30%) had NASH. Comparison of serum protein profiles according to liver lesions identified three peaks (CM10-7558.4, CM10-7924.2 and Q10-7926.9) the intensity of which significantly increased according to the severity of the liver lesions (steatosis and NASH) and returned to normal after bariatric surgery. None was correlated with either liver function tests or metabolic parameters. Identification using immunoSELDI assay characterised these peaks as the double charged ions of α- and β-haemoglobin subunits. <h3>Conclusion:</h3> The differential proteomic method demonstrated changes in serum protein profiles in obese patients according to severity of liver lesions. Free haemoglobin subunits may serve as a serum biomarker of the severity of liver damages.
Photodynamic therapy of acne vulgaris using methyl aminolaevulinate: a blinded, randomized, controlled trial
Authors: S.R. Wiegell, H.C. Wulf
Journal: British Journal of Dermatology (2006)

Background Inflammatory acne vulgaris is a very common condition, particularly in adolescents and young adults, and new effective and well-tolerated treatments are needed. Objectives To evaluate the efficacy and tolerability of methyl aminolaevulinate-based photodynamic therapy (MAL-PDT) in patients with moderate to severe facial acne vulgaris in a randomized, controlled and investigator-blinded trial. Methods Twenty-one patients were assigned to the treatment group and 15 patients to the control group. The treatment group received two MAL-PDT treatments, 2 weeks apart. Both groups were evaluated 4, 8 and 12 weeks after treatment. Efficacy evaluation included changes from baseline in numbers of noninflammatory and inflammatory lesions, changes from baseline in global acne severity grade and clinical assessments of clinical improvement by patient and evaluating dermatologist. Pain scores during treatment and local adverse effects were also evaluated. Results Twelve weeks after treatment the treatment group showed a 68% reduction from baseline in inflammatory lesions vs. no change in the control group (P = 0·0023). We found no reduction in number of noninflammatory lesions after treatment. All patients experienced moderate to severe pain during treatment and developed severe erythema, pustular eruptions and epithelial exfoliation. Seven patients did not receive the second treatment due to adverse effects. Conclusions MAL-PDT proved to be an efficient treatment for inflammatory acne. The treatment was associated with severe pain during treatment and severe adverse effects after treatments. Efforts must be made to optimize the treatment regimen and to avoid adverse effects.
Induction of Vasculogenic Mimicry Overrides VEGF-A Silencing and Enriches Stem-like Cancer Cells in Melanoma
Authors: Caroline I. Schnegg, Moon Hee Yang, Subrata K. Ghosh, Mei-Yu Hsu
Journal: Cancer Research (2015)

The basis for resistance to VEGF inhibition is not fully understood despite its clinical importance. In this study, we examined the adaptive response to VEGF-A inhibition by a loss-of-function analysis using plasmid-based shRNA. Tumor xenografts that initially responded to VEGF-A inhibition underwent an adaptation in vivo, leading to acquired resistance. VEGF-A blockade in tumors was associated with HIF1α expression and an increase in CD144(+) vasculogenic mimicry (VM), leading to formation of channels displaying Tie-1 and MMP-2 upregulation. CD133(+) and CD271(+) melanoma stem-like cells (MSLC) accumulated in the perivascular niche. Tumor xenografts of melanoma cell populations that were intrinsically resistant to VEGF-A blockade did not exhibit any of these features, compared with nontarget control counterparts. Thus, melanomas that are initially sensitive to VEGF-A blockade acquire adaptive resistance by adopting VM as an alternate angiogenic strategy, thereby enriching for deposition of MSLC in the perivascular niche through an HIF1α-dependent process. Conversely, melanomas that are intrinsically resistant to VEGF-A blockade do not show any evidence of compensatory survival mechanisms that promote MSLC accumulation. Our work highlights the potential risk of anti-VEGF treatments owing to a selective pressure for an adaptive resistance mechanism that empowers the development of stem-like cancer cells, with implications for how to design combination therapies that can improve outcomes in patients.
Obesity and Therapy-Related Toxicity in Patients Treated for Small-Cell Lung Cancer
Authors: M. S. Georgiadis, S. M. Steinberg, L. A. Hankins, D. C. Ihde, B. E. Johnson
Journal: JNCI Journal of the National Cancer Institute (1995)

Obese individuals have altered pharmacokinetics for many medications when compared with the non-obese. For the oncologist treating an obese cancer patient, these changes in drug disposition may potentially cause increased therapy-related toxicity. As a consequence, oncologists frequently treat obese patients with dose reductions in an effort to decrease chemotherapy toxicity. However, little clinical data exist to either support or refute this policy. The clinical course of a cohort of patients treated for small-cell lung cancer (SCLC) was evaluated to determine if the obese patients had an increase in therapy-related toxicity. The study sample included 262 patients with histologically confirmed SCLC treated in clinical trials from 1977 through 1993. Before 1986, patients with limited stage SCLC were treated with a cyclophosphamide-based regimen with (n = 47) or without (n = 46) chest radiotherapy. Subsequent patients with limited stage disease (n = 54) received etoposide and cisplatin plus twice-daily chest radiotherapy. Patients with extensive stage SCLC were randomly treated with standard-dose (n = 46) or high-dose etoposide plus cisplatin (n = 44); poorrisk patients with extensive stage disease (n = 25) were assigned to standard dose etoposide plus cisplatin. For all patients, actual body weight was used when determining initial doses of chemotherapy. The measure of relative weight was the body mass index (BMI), which was calculated from the pretreatment height and weight data. The BMI was evaluated both on a continuum and with patients grouped into BMI levels (normal, obese, and severely obese). Toxicity parameters were collected during induction chemotherapy and were compared with the BMI. In addition, the overall survival of the entire cohort was evaluated, with patients divided into different groups based on their BMI level. We performed 170 comparisons between the BMI as a continuum or the BMI level and the 15 toxicity parameters. There were no consistent associations of significance found between increasing BMI or BMI levels and increasing toxicity from therapy. When survival was evaluated, no statistically significant differences were found between the survival of patients within the different BMI levels. In this group of 262 patients with SCLC, obesity at the start of treatment was not associated with increased toxicity from treatment or a shortened survival. No support for empiric chemotherapy dose reductions based on ideal body weight was evident from this study. [J Natl Cancer Inst 87:361-366,1995]
Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas
Authors: Mark L. McCleland, Adam S. Adler, Laura Deming, Ely Cosino, Leslie Lee, Elizabeth M. Blackwood, Margaret Solon, Janet Tao, Li Li, David Shames, Erica Jackson, William F. Forrest, Ron Firestein
Journal: Clinical Cancer Research (2012)

This study is aimed to identify genes within the KRAS genomic amplicon that are both coupregulated and essential for cell proliferation when KRAS is amplified in lung cancer.We used an integrated genomic approach to identify genes that are coamplified with KRAS in lung adenocarcinomas and subsequently preformed an RNA interference (RNAi) screen to uncover functionally relevant genes. The role of lactate dehydrogenase B (LDHB) was subsequently investigated both in vitro and in vivo by siRNA and short hairpin RNA (shRNA)-mediated knockdown in a panel of lung adenocarcinoma cells lines. LDHB expression was also investigated in patient tumors using microarray and immunohistochemistry analyses.RNAi-mediated depletion of LDHB abrogated cell proliferation both in vitro and in xenografted tumors in vivo. We find that LDHB expression correlates to both KRAS genomic copy number gain and KRAS mutation in lung cancer cell lines and adenocarcinomas. This correlation between LDHB expression and KRAS status is specific for lung cancers and not other tumor types that harbor KRAS mutations. Consistent with a role for LDHB in glycolysis and tumor metabolism, KRAS-mutant lung tumors exhibit elevated expression of a glycolysis gene signature and are more dependent on glycolysis for proliferation compared with KRAS wild-type lung tumors. Finally, high LDHB expression was a significant predictor of shorter survival in patients with lung adenocarcinomas.This study identifies LDHB as a regulator of cell proliferation in a subset of lung adenocarcinoma and may provide a novel therapeutic approach for treating lung cancer.
Transcriptional Codes and the Control of Neuronal Identity
Authors: Ryuichi Shirasaki, Samuel L. Pfaff
Journal: Annual Review of Neuroscience (2002)

▪ Abstract The topographic assembly of neural circuits is dependent upon the generation of specific neuronal subtypes, each subtype displaying unique properties that direct the formation of selective connections with appropriate target cells. Studies of motor neuron development in the spinal cord have begun to elucidate the molecular mechanisms involved in controlling motor projections. In this review, we first describe the actions of transcription factors within motor neuron progenitors, which initiate a cascade of transcriptional interactions that lead to motor neuron specification. We next highlight the contribution of the LIM homeodomain (LIM-HD) transcription factors in establishing motor neuron subtype identity. Importantly, it has recently been shown that the combinatorial expression of LIM-HD transcription factors, the LIM code, confers motor neuron subtypes with the ability to select specific axon pathways to reach their distinct muscle targets. Finally, the downstream targets of the LIM code are discussed, especially in the context of subtype-specific motor axon pathfinding.
Faecal calprotectin and faecal occult blood tests in the diagnosis of colorectal carcinoma and adenoma
Authors: J Tibble
Journal: Gut (2001)

<h3>BACKGROUND AND AIMS</h3> Testing for faecal occult blood has become an accepted technique of non-invasive screening for colorectal neoplasia but lack of sensitivity remains a problem. The aim of this study was to compare the sensitivity and specificity of faecal calprotectin and faecal occult blood in patients with colorectal cancer and colonic polyps. <h3>METHODS</h3> Faecal calprotectin and occult blood were assessed in 62 patients with colorectal carcinoma and 233 patients referred for colonoscopy. The range of normality for faecal calprotectin (0.5–10.5 mg/l) was determined from 96 healthy subjects. <h3>RESULTS</h3> Median faecal calprotectin concentration in the 62 patients with colorectal carcinoma (101 mg/l, 95% confidence interval (CI) 57–133) differed significantly from normal (2.3 mg/l, 95% CI 1.6–5.0) with 90% of patients having elevated levels (normal &lt;10 mg/l) whereas only 36/62 (58%) had positive faecal occult bloods. There was no significant difference in faecal calprotectin levels when considering location or Dukes9 staging of tumour. Percentage positivity of faecal occult bloods was significantly higher for Dukes9 stage C and D cancers compared with Dukes9 A and B. In the colonoscopy group, 29 patients with adenomatous polyps were detected in whom the median faecal calprotectin was 12 mg/l (95% CI 2.9–32). Sensitivity for detection of adenomatous polyps was 55% using the calprotectin method and 10% using faecal occult blood testing. The overall sensitivity and specificity of calprotectin for colorectal cancer and adenomatous polyps as a combined group was 79% and 72%, respectively, compared with a sensitivity and specificity of faecal occult blood of 43% and 92%. <h3>CONCLUSIONS</h3> Faecal calprotectin is a simple and sensitive non-invasive marker of colorectal cancer and adenomatous polyps. It is more sensitive than faecal occult blood tests for detection of colorectal neoplasia at the cost of a somewhat lower specificity.