tbuckley/cabot-search huggingface dataset:
Selection of Patients for Anti–Epidermal Growth Factor Receptor Treatment in Colorectal Cancer: The Potential Pitfalls of Retrospective Analyses of <i>RAS</i> Mutations
Authors: Sylwia Debska-Szmich, Magdalena Krakowska, Piotr Potemski
Journal: Journal of Clinical Oncology (2015)

reassessed the outcome of the phase III CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) study in subgroups defined by extended RAS mutation testing, and the accompanying comment by Atreya et al 2 discussed the results.Van Cutsem et al 1 reanalyzed evaluable tumor DNA samples from 430 (64.6%) of 666 patients with KRAS exon 2 wild-type mutations for other mutations in four additional KRAS codons (exons 3 and 4) and in six NRAS codons (exons 2, 3, and 4) by using a 5% mutant allele cutoff to call mutations.Other RAS mutations were detected in 63 (14.7%) of 430 patients.In those with RAS wild-type tumors, a significant benefit across all efficacy end points was associated with the addition of cetuximab to fluorouracil, leucovorin, and irinotecan.There was an increase in the difference between overall survival (OS) time from a median of 3.5 months in patients with KRAS exon 2 wild-type group (hazard ratio [HR], 0.80) to a median of 8.2 months in the RAS wild-type group (HR, 0.69).In addition, there was a difference between the progression-free survival (PFS; median 1.5 months; HR, 0.70 in KRAS wild-type group; median 3.0 months; HR, 0.56 in RAS wild-type group) because of the more accurate patient selection for treatment with cetuximab and fluorouracil, leucovorin, and irinotecan.In patients with other RAS mutations, cetuximab was not effective.Atreya et al 2 discuss these results extensively, and they note that broadening the definition of RAS mutations entails a decrease in the number of patients eligible for the targeted treatment.First, they remind us that different RAS mutations may not be equivalent, because a modest benefit from anti-epidermal growth factor receptor (EGFR) treatment is possible in patients who harbor some of the RAS mutations.Second, the authors also pay attention to the methods used to detect the mutations and the various thresholds for calling mutations.We would like to congratulate the authors on these important articles.However, in addition to the comment by Atreya et al, 2 we would like toexpresssomeotherdoubts,whichhaveemergedafterreadingthearticle by Van Cutsem et al. 1 The authors report that samples from 236 patients with KRAS exon 2 wild-type tumors from the CRYSTAL study were not evaluable, either because of insufficient residual DNA or because of the failure of one or more mutation assay.Exclusion of this group of patients, whichweassumewastherandomgroup,seemstocauseaclearincreasein effectiveness of cetuximab.In a group of 430 patients in whom other RAS mutations were tested, the difference between the OS time was a median of 5.9 months (HR, 0.75), and between the PFS time was a median of 3.6 months (HR, 0.58).In comparison, in the KRAS exon 2 wild-type group, the differences in the median OS and PFS times were 3.5 months (HR,
Good interactions are hard to find
Authors: Akira Miyake, Michael J. Emerson, Naomi P. Friedman
Journal: Behavioral and Brain Sciences (1999)

Caplan &amp; Waters's arguments for separate working memory subsystems for “interpretive” and “post-interpretive” comprehension processes do not have a solid empirical basis. The likely involvement of a separate phonological loop makes their memory-load data irrelevant to theory evaluation, and the lack of statistical power from nonoptimal experimental designs and analyses unfairly reduces the chances of detecting the relevant interactions.
Is "sugar" the same as diabetes? A community-based study among rural African-Americans.
Authors: J B Schorling, J T Saunders
Journal: Diabetes Care (2000)

To determine if differing beliefs about high blood glucose exist and are associated with blood glucose control among rural African-Americans.A community-based sample of rural African-Americans completed a survey, and a subsample underwent a subsequent screening that included glucose and GHb measurement. Participants were asked if they thought they had diabetes or sugar-diabetes on the survey; "sugar" was added to the screening along with specific questions about this condition.A total of 1,031 people completed the survey, and 403 the screening exam. The total prevalence of diabetes was 13.6% for men and 15.5% for women. Among those who reported having one of the three conditions, 64% said they had diabetes, 7% sugar-diabetes, and 29% sugar. There was a discrepancy between the survey and screening in that 31% of subjects who answered "yes" to whether they had sugar at the screening had answered "no" to the survey question about diabetes. Subjects who believed they had sugar felt their condition was less serious and had higher glucose levels than those who said they had diabetes.Diabetes was very common in this population. Over one-fourth of those with diabetes believed they had the condition "sugar." Efforts are needed to improve control of diabetes in this population and should consider these disparate health beliefs.
Hybrid selection for sequencing pathogen genomes from clinical samples
Authors: Alexandre Melnikov, Kevin Galinsky, Peter Rogov, Timothy Fennell, Daria Van Tyne, Carsten Russ, Rachel Daniels, Kayla G Barnes, James Bochicchio, Daouda Ndiaye, Papa D Sene, Dyann F Wirth, Chad Nusbaum, Sarah K Volkman, Bruce W Birren, Andreas Gnirke, Daniel E Neafsey
Journal: Genome biology (2011)

We have adapted a solution hybrid selection protocol to enrich pathogen DNA in clinical samples dominated by human genetic material. Using mock mixtures of human and Plasmodium falciparum malaria parasite DNA as well as clinical samples from infected patients, we demonstrate an average of approximately 40-fold enrichment of parasite DNA after hybrid selection. This approach will enable efficient genome sequencing of pathogens from clinical samples, as well as sequencing of endosymbiotic organisms such as Wolbachia that live inside diverse metazoan phyla.
Admissions processes for five year medical courses at English schools: review
Authors: Jayne Parry, Jonathan Mathers, Andrew Stevens, Amanda Parsons, Richard Lilford, Peter Spurgeon, Hywel Thomas
Journal: BMJ (2006)

To describe the current methods used by English medical schools to identify prospective medical students for admission to the five year degree course.Review study including documentary analysis and interviews with admissions tutors.All schools (n = 22) participating in the national expansion of medical schools programme in England.Though there is some commonality across schools with regard to the criteria used to select future students (academic ability coupled with a "well rounded" personality demonstrated by motivation for medicine, extracurricular interests, and experience of team working and leadership skills) the processes used vary substantially. Some schools do not interview; some shortlist for interview only on predicted academic performance while those that shortlist on a wider range of non-academic criteria use various techniques and tools to do so. Some schools use information presented in the candidate's personal statement and referee's report while others ignore this because of concerns over bias. A few schools seek additional information from supplementary questionnaires filled in by the candidates. Once students are shortlisted, interviews vary in terms of length, panel composition, structure, content, and scoring methods.The stated criteria for admission to medical school show commonality. Universities differ greatly, however, in how they apply these criteria and in the methods used to select students. Different approaches to admissions should be developed and tested.
PGC-1β Deficiency Accelerates the Transition to Heart Failure in Pressure Overload Hypertrophy
Authors: Christian Riehle, Adam R. Wende, Vlad G. Zaha, Karla Maria Pires, Benjamin Wayment, Curtis Olsen, Heiko Bugger, Jonathan Buchanan, Xiaohui Wang, Annie Bello Moreira, Torsten Doenst, Gema Medina-Gomez, Sheldon E. Litwin, Christopher J. Lelliott, Antonio Vidal-Puig, E. Dale Abel
Journal: Circulation Research (2011)

Rationale: Pressure overload cardiac hypertrophy, a risk factor for heart failure, is associated with reduced mitochondrial fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) proteins that correlate in rodents with reduced PGC-1α expression. Objective: To determine the role of PGC-1β in maintaining mitochondrial energy metabolism and contractile function in pressure overload hypertrophy. Methods and Results: PGC-1β deficient (KO) mice and wildtype (WT) controls were subjected to transverse aortic constriction (TAC). Although LV function was modestly reduced in young KO hearts, there was no further decline with age so that LV function was similar between KO and WT when TAC was performed. WT-TAC mice developed relatively compensated LVH, despite reduced mitochondrial function and repression of OXPHOS and FAO genes. In nonstressed KO hearts, OXPHOS gene expression and palmitoyl-carnitine-supported mitochondrial function were reduced to the same extent as banded WT, but FAO gene expression was normal. Following TAC, KO mice progressed more rapidly to heart failure and developed more severe mitochondrial dysfunction, despite a similar overall pattern of repression of OXPHOS and FAO genes as WT-TAC. However, in relation to WT-TAC, PGC-1β deficient mice exhibited greater degrees of oxidative stress, decreased cardiac efficiency, lower rates of glucose metabolism, and repression of hexokinase II protein. Conclusions: PGC-1β plays an important role in maintaining baseline mitochondrial function and cardiac contractile function following pressure overload hypertrophy by preserving glucose metabolism and preventing oxidative stress.
Glioblastoma blood flow measured with stable xenon CT indicates tumor necrosis, vascularity, and brain invasion
Authors: M. Crocker, S. Saadoun, A. Jury, C. Jones, S. Zacharoulis, S. Thomas, R. Zwiggelaar, L. R. Bridges, B. A. Bell, M. C. Papadopoulos
Journal: Neuro-Oncology (2012)

Tumor vasculature is a promising therapeutic target in glioblastoma. Imaging tumor blood flow may help assess the efficacy of anti-angiogenic treatments. We determined the clinical usefulness of stable xenon CT performed preoperatively in patients with glioblastoma. This is a prospective cohort study. We determined absolute tumor blood flow before surgery in 38 patients with glioblastoma using stable xenon CT. We also histologically examined tumor specimens obtained from surgery and quantified their vascularity (by CD31 and CD105 immunostain), necrosis (by hematoxylin and eosin stain), and the presence of neuronal processes (by neurofilament immunostain). According to the xenon CT blood flow map, there are 3 types of glioblastoma. Type I glioblastomas have unimodal high blood flow histograms; histologically there is little necrosis and vascular proliferation. Type II glioblastomas have unimodal low blood flow histograms; histologically there is prominent necrosis and vascular proliferation. We propose that in type II glioblastoma, the abnormal vessels induced by hypoxia are inefficient at promoting blood flow. Type III glioblastomas have multimodal blood flow histograms. Histologically there is significant neuronal tissue within the tumor. Patients with type III glioblastomas were more likely to develop a post-surgical deficit, consistent with the inclusion of normal tissue within the tumor. Preoperative measurement of absolute blood flow with stable xenon CT in patients with glioblastoma predicts key biological features of the tumor and may aid surgical planning.
Estrogen Suppresses MLK3-Mediated Apoptosis Sensitivity in ER+ Breast Cancer Cells
Authors: Velusamy Rangasamy, Rajakishore Mishra, Suneet Mehrotra, Gautam Sondarva, Rajarshi S. Ray, Arundhati Rao, Malay Chatterjee, Basabi Rana, Ajay Rana
Journal: Cancer Research (2010)

Little knowledge exists about the mechanisms by which estrogen can impede chemotherapy-induced cell death of breast cancer cells. 17beta-Estradiol (E(2)) hinders cytotoxic drug-induced cell death in estrogen receptor-positive (ER(+)) breast cancer cells. We noted that the activity of the proapoptotic mixed lineage kinase 3 (MLK3) kinase was relatively higher in estrogen receptor-negative (ER(-)) breast tumors, suggesting that E(2) might inhibit MLK3 activity. The kinase activities of MLK3 and its downstream target, c-Jun NH(2)-terminal kinase, were rapidly inhibited by E(2) in ER(+) but not in ER(-) cells. Specific knockdown of AKT1/2 prevented MLK3 inhibition by E(2), indicating that AKT mediated this event. Furthermore, MLK3 inhibition by E(2) involved phosphorylation of MLK3 Ser(674) by AKT, attenuating the proapoptotic function of MLK3. We found that a pan-MLK inhibitor (CEP-11004) limited Taxol-induced cell death and that E(2) accentuated this limitation. Taken together, our findings indicate that E(2) inhibits the proapoptotic function of MLK3 as a mechanism to limit cytotoxic drug-induced death of ER(+) breast cancer cells.
Thyroid function tests in chronic liver disease: evidence for multiple abnormalities despite clinical euthyroidism.
Authors: M Borzio, R Caldara, F Borzio, V Piepoli, P Rampini, C Ferrari
Journal: Gut (1983)

To further evaluate thyroid function in patients with liver disease, we have measured total and free T3 and T4, thyroxine binding globulin, basal and thyrotropin releasing hormone-stimulated thyrotropin and thyroglobulin antibodies in 33 patients with liver cirrhosis, in 22 with chronic hepatitis and in 30 healthy controls. All the patients but one were clinically euthyroid. T3, FT3, T3/thyroxine binding globulin and T4/thyroxine binding globulin ratios and thyrotropin after thyrotropin releasing hormone were significantly reduced, while FT4, thyroxine binding globulin and thyrotropin were significantly increased in liver cirrhosis. In chronic hepatitis group, FT3 and T3/thyroxine binding globulin ratio were significantly lower and thyroxine binding globulin and FT4 were higher than in healthy controls. The between patients comparison revealed a significantly lower T3, FT3, T3/thyroxine binding globulin and T4/thyroxine binding globulin ratios and delta thyrotropin in cirrhotics. Thyroglobulin antibodies were present at high titre only in two patients one of whom having evidence of Hashimoto's thyroiditis with subclinical hypothyroidism. The correlation coefficient between T4/thyroxine binding globulin ratio and FT4 were lower in patients than in controls. Furthermore an abnormal thyrotropin response to thyrotropin releasing hormone was shown in 10 cirrhotics and in four patients with chronic hepatitis. Serum T3 significantly correlated with serum bilirubin, albumin, and prothrombin time in both groups of patients. The present data confirm the existence of several abnormalities of thyroid function tests in patients with chronic liver disease, although showing that euthyroidism is almost always maintained, probably as a result of low-normal FT3 and high-normal FT4. Furthermore, T3 serum levels appear to parallel the severity of liver dysfunction.
Interfering with disease: opportunities and roadblocks to harnessing RNA interference
Authors: Judy Lieberman, Erwei Song, Sang-Kyung Lee, Premlata Shankar
Journal: Trends in Molecular Medicine (2003)

RNA interference (RNAi) is an evolutionarily conserved mechanism for silencing gene expression by targeted degradation of mRNA. Short double-stranded RNAs, known as small interfering RNAs (siRNA), are incorporated into an RNA-induced silencing complex that directs degradation of RNA containing a homologous sequence. RNAi has been shown to work in mammalian cells, and can inhibit viral infection and control tumor cell growth in vitro. Recently, it has been shown that intravenous injection of siRNA or of plasmids expressing sequences processed to siRNA can protect mice from autoimmune and viral hepatitis. RNAi could provide an exciting new therapeutic modality for treating infection, cancer, neurodegenerative disease and other illnesses.
Robert Arthur Bruce, MD
Authors: J. Ward Kennedy, Leonard A. Cobb, Werner E. Samson
Journal: Circulation (2005)

He became Professor Emeritus in 1987 but continued to be actively interested in the division for the remainder of his life.As a young cardiologist at the University of Rochester, Dr Bruce recognized that exercise stress testing could play an important role in the evaluation of cardiac patients.The cumbersome Master's Two-Step test, in common use at that time, was clearly inadequate to assess respiratory and circulatory function during varying degrees of sustained exertion.He and his early coworker, Dr Paul Yu, who had recently arrived from China, collaborated to develop a treadmill exercise test.His first publication on exercise testing was in 1949, in which he reported observations relating to the basis of dyspnea in beryllium workers with cor pulmonale.After his initial experience with treadmill exercise testing, he came to the conclusion that "a technique of standardized exercise is considered satisfactory for the investigation of dyspnea in clinical patients" (Bruce et al.
Acupuncture inhibits vagal gastric acid secretion stimulated by sham feeding in healthy subjects.
Authors: G Lux, J Hagel, P Backer, G Backer, R Vogl, H Ruppin, S Domschke, W Domschke
Journal: Gut (1994)

In a prospective randomised study, the effect of acupuncture on sham feeding stimulated gastric acid secretion was investigated. In eight healthy volunteers (five men, three women, mean (SEM) age 26.3 (4.7) years) various methods of acupuncture were performed. Apart from the sham procedure, the acupuncture was performed at the classic acupuncture points. Electroacupuncture reduced gastric acid secretion expressed as median (range) significantly during the first 30 minute period to 1.6 (0-5.2) mmol compared with 3.8 (2.3-14.5) mmol (p &lt; 0.05) during control period (sham feeding without acupuncture). Inhibition of gastric acid secretion by electroacupuncture was also significant during the second 30 minute period (0.2 (0-5.6) v 3.6 (0.3-9.1) mmol; p &lt; 0.05) and for peak acid output (0.8 (0.2-5.1) v 7.6 (3.4-12.1) mmol; p &lt; 0.05). Transcutaneous electrical nerve stimulation also resulted in significant reduction of gastric acid secretion during the first 30 minute period (1.0 (0-3.6) mmol v 3.8 (2.3-14.5) mmol; p &lt; 0.05), and peak acid output (3.6 (1.2-12.0) v 7.6 (3.4-12.1) mmol; p &lt; 0.05). The classic needle acupuncture, laser acupuncture, and sham acupuncture had no significant effect on gastric acid secretion. This study shows firstly that in healthy volunteers, only the versions of acupuncture using more pronounced stimulation (electroacupuncture, transcutaneous electrical nerve stimulation), but not those with only mild stimulation of the nerves (classic needle acupuncture, laser acupuncture), and secondly only acupuncture performed at defined points lead to significant reduction in gastric acid secretion.
Effect of chronic experimental renal insufficiency on urate metabolism.
Authors: N D Vaziri, R W Freel, M Hatch
Journal: Journal of the American Society of Nephrology (1995)

The rise in plasma uric acid (UA) in chronic renal failure (CRF) is quite limited. This may be due to either increased extrarenal excretion, diminished biosynthesis, and/or enhanced degradation of uric acid. The intestinal flux studies revealed a striking modification of urate transport from no net flux to a net secretory flux in the jejunum and from a basal net absorptive to a net secretory flux in the colon of CRF animals. In addition, CRF animals showed a marked reduction in hepatic, renal, and enteric tissue xanthine oxidase activity and no significant change in tissue uricase activity. The correction of anemia with erythropoietin did not significantly alter the plasma concentration or urinary excretion of urate. Thus, enhanced enteric excretion and depressed production of uric acid (reduced xanthine oxidase activity) may account for the lack of significant hyperuricemia in CRF.
Teratomas Obtained Through Extrauterine Growth of Seven-Day Mouse Embryos
Authors: I. Damjanov, D. Solter, M. Belicza, N. Škreb
Journal: JNCI Journal of the National Cancer Institute (1971)

Segments of 7-day mouse egg cylinders were transplanted under the kidney capsules of adult mice. Two-thirds of the transplants developed into teratomas consisting of well-differentiated adult tissues. One-third also displayed large undifferentiated areas, which were considered malignant when examined under the light micrsocope. A few large teratomas were successfully retransplanted for 5 generations. Microscopically, tumors obtained by retransplantation had the same appearance as the teratomas from which they stemmed. The tumors were examined ultrastructurally, The cytoplasm of undifferentiated cells had a simple architecture typical of embryonal carcinoma. It was replete with ribosomes but devoid of other organelles except a well-developed Golgi apparatus, a few mitochondria, and occasional tubules of rough endoplasmic reticulum. Many of these tumor cells contained somewhat more cytoplasmic organelles or displayed some signs of cytoplasmic specialization, such as myofibrils or secretory granules. Some of these more differentiated cells contained many autophagic vacuoles. It is concluded that most of the undifferentiated cells look like embryonal cells in the early stages of development. The retention of the embryonal character is considered the basis for continuous and progressive growth of embryo-derived malignant teratomas.
Effects of an external resistance on maximum flow in chronic obstructive lung disease: implications for recognition of coincident upper airway obstruction.
Authors: D R Robertson, C R Swinburn, T N Stone, G J Gibson
Journal: Thorax (1989)

To determine how the presence of generalised airflow limitation due to chronic obstructive lung disease affects the recognition of simulated upper airway obstruction, a study was carried out in 12 patients (mean (SD) age 57 (7) years) with chronic obstructive lung disease (FEV1% predicted 53 (22), range 21-70) and 12 matched control subjects. Patients and control subjects performed maximal inspiratory and expiratory flow-volume curves in a variable volume plethysmograph with and without upper airway obstruction simulated at the mouth with a series of polythene washers of internal diameter 4, 6, 8, 10, and 12 mm. In patients, as in normal subjects, peak expiratory flow (PEF) and maximum inspiratory flow at 50% of vital capacity (Vmax50) were more sensitive to upper airway obstruction than were FEV1 or maximum expiratory flow at 50% VC (VEmax50); but the reductions in all indices caused by simulated upper airway obstruction were smaller in the patients than in the controls. The fall in PEF (whether expressed in absolute units or as a percentages) consequent on severe (4 mm) upper airway obstruction became smaller with increasing severity of chronic obstructive lung disease. The subjects also produced flow-volume curves with and without 6 mm upper airway obstruction while breathing helium and oxygen (heliox). In both groups the effects of heliox on PEF and Vmax50 were increased when upper airway obstruction was simulated. It was confirmed that the functional recognition of upper airway obstruction is more difficult in patients with chronic obstructive lung disease than in normal subjects and this difficulty increases with severity of disease; an unusually large increase in PEF or Vmax50 while the patient is breathing heliox should raise the suspicion of coexisting upper airway obstruction, but such a pattern is not specific.