tbuckley/cabot-search huggingface dataset:
Vitamin D<sub>3</sub>upregulated protein 1 deficiency promotes<i>N</i>-methyl-<i>N</i>-nitrosourea and<i>Helicobacter pylori</i>-induced gastric carcinogenesis in mice
Authors: Hyo-Jung Kwon, Young-Suk Won, Ki-Taek Nam, Yeo-Dae Yoon, Hyang Jee, Won-Kee Yoon, Ki-Hoan Nam, Jong-Soon Kang, Sang-Uk Han, In-Pyo Choi, Dae-Yong Kim, Hyoung-Chin Kim
Journal: Gut (2011)

<h3>Objective</h3> Vitamin D<sub>3</sub> upregulated protein 1 (VDUP1) is a potent tumour suppressor whose expression is dramatically reduced in various types of human cancers, including gastric cancer. However, the precise mechanisms underlying tumour development remain unclear. In the present study, the authors examined the effect of VDUP1 on <i>Helicobacter pylori</i>-induced gastric carcinogenesis in mice. <h3>Design</h3> Gastric cancer was generated in VDUP1 knockout (KO) and wild-type mice using a combination of <i>N</i>-methyl-<i>N</i>-nitrosourea treatment and <i>H pylori</i> infection. Fifty weeks after treatment, gastric tissues from both types of mice were examined by histopathology, immunohistochemistry and immunoblotting. In vitro tests on the human gastric cancer cell line, AGS, were also performed to identify the underlying mechanisms of cancer development. <h3>Results</h3> The overall incidence of gastric cancer was significantly higher in VDUP1 KO mice than in wild-type mice. Similarly, VDUP1 KO mice showed more severe chronic gastritis, glandular atrophy, foveolar hyperplasia, metaplasia and dysplasia. Although no differences in the apoptotic index were apparent, lack of VDUP1 increased the rate of gastric epithelial cell proliferation in non-cancerous stomachs, with corresponding increases in tumour necrosis factor alpha (TNFα) level, nuclear transcription factor kappa B (NF-κB) activation and cyclooxygenase-2 (COX-2) expression. An in vitro study showed that <i>H pylori</i>-associated cell proliferation and induction of TNFα, NF-κB and COX-2 were inhibited in cells transfected with VDUP1. In addition, overexpression of VDUP1 in AGS cells suppressed TNFα-induced NF-κB activation and COX-2 expression. <h3>Conclusion</h3> Our data show that VDUP1 negatively regulates <i>H pylori</i>-associated gastric carcinogenesis, in part by disrupting cell growth and inhibiting the induction of TNFα, NF-κB and COX-2. These findings provide important insights into the role of VDUP1 in <i>H pylori</i>-associated tumourigenesis.
CK2 Modulation of NF-κB, TP53, and the Malignant Phenotype in Head and Neck Cancer by Anti-CK2 Oligonucleotides<i>In vitro</i>or<i>In vivo</i>via Sub–50-nm Nanocapsules
Authors: Matthew S. Brown, Oumou T. Diallo, Michael Hu, Reza Ehsanian, Xinping Yang, Pattatheyil Arun, Hai Lu, Vicci Korman, Gretchen Unger, Khalil Ahmed, Carter Van Waes, Zhong Chen
Journal: Clinical Cancer Research (2010)

The aim of this study is to investigate the expression of CK2 subunits and CK2 effects on NF-kappaB-mediated and TP53-mediated signal activation and gene expression, the malignant phenotype, and chemosensitivity in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo.Protein expression of CK2 subunits was investigated by Western blot and immunohistochemistry. CK2 subunits were knocked down by small interfering RNA, and NF-kappaB activation was examined using DNA binding, Western blot, and luciferase reporter assays. Gene expression was measured by quantitative reverse transcription-PCR. Cell growth, survival, motility, and sensitivity to cisplatin were measured by MTT, flow cytometry, and migration assays. In vivo targeting of CK2alpha/alpha' in HNSCC xenograft models was achieved using anti-CK2alpha/alpha' oligodeoxynucleotide encapsulated in sub-50-nm tenfibgen nanocapsules.CK2 subunit proteins were overexpressed in HNSCC lines and tissues. Knockdown of CK2 subunits differentially inhibited IkappaBalpha degradation, NF-kappaB nuclear localization, phosphorylation, DNA binding, and reporter activity. CK2 subunits modulated gene expression and the malignant phenotype involved in cell cycle and migration, whereas CK2alpha is critical to promote proliferation, antiapoptosis, and cisplatin resistance in vitro. Furthermore, in vivo delivery of anti-CK2alpha/alpha' oligodeoxynucleotide nanocapsules significantly suppressed tumor growth in HNSCC xenograft models, in association with modulation of CK2 and NF-kappaB regulated molecules, TP53 family proteins, and induction of apoptosis.Our study reveals a novel role of CK2 in coregulating NF-kappaB activation, TP53/p63 expression, and downstream gene expression. Downregulation of CK2 in HNSCC models in vitro and in vivo shows antitumor effects as well as sensitization to cisplatin.
Infectivity of tuberculosis.
Authors: B H Davies
Journal: Thorax (1980)

<b>Objective:</b> To assess the determinants of poor mid-term health related quality of life (HRQoL) at one year after primary isolated coronary artery bypass grafting (CABG). <b>Methods:</b> 463 patients who underwent primary isolated CABG for multivessel disease and came for their annual follow up at the outpatient clinic during one year at Harefield Hospital, Middlesex, were approached to participate in the present study. Prospective clinical data were collected as part of the clinical care of the patients and were retrospectively analysed when the patients consented to participate in the study at their outpatient visit. After their consent they were given three HRQoL assessment questionnaires. Scores, together with clinical data, were analysed by both univariate and multivariate analyses with regard to poor HRQoL outcome. <b>Results:</b> 437 (94.4%) patients consented to participate in the study and filled in the HRQoL questionnaires. Ten variables were identified in the univariate analysis as potential predictors of poor scores of the physical element of HRQoL; however, only three variables—gastrointestinal problems, congestive heart failure, and type D personality trait—predicted poor physical scores independently. Eleven variables were identified in the univariate analysis as potential predictors of poor scores of the mental element of HRQoL; however, only three variables—peripheral vascular disease, infective complications, and type D personality trait—predicted poor physical scores independently. <b>Conclusion:</b> Preoperative gastrointestinal problems, preoperative congestive heart failure, and type D personality trait were independent predictors of the poor physical component of HRQoL. Peripheral vascular disease, infective complications, and type D personality trait were independent predictors of the poor mental component of HRQoL. Interestingly, patients with type D personality were more than twice as likely to have poor physical HRQoL and more than five times as likely to have poor mental HRQoL.
Unexpected Hypoglycemia in a Critically Ill Patient
Authors: David W. Bates
Journal: Annals of Internal Medicine (2002)

Administration of the wrong medication is a serious and understudied problem. Because physicians are not directly involved in the drug administration process, they tend to overlook the possibility of adverse drug events and medication errors in their differential diagnoses of patient illnesses or acute deterioration. This article analyzes the case of a patient with iatrogenic hypoglycemia due to administration of the wrong medication: Insulin instead of heparin was used to flush the patient's arterial line. In addition to assessing the results of the institution's "root-cause analysis" of the factors contributing to this particular adverse event and the institution's response, this article reviews the literature on preventing medication errors. Key strategies that might have been helpful in this case include using checklists for common emergency conditions (such as altered level of consciousness) and automated paging for "panic laboratory values," as well as instituting protocols for medication administration. Changing the system of administering medications by bar coding drugs, with checks of the medication, patient, and provider, could have prevented this accident. Finally, organizations need to strive for a "culture of safety" by providing opportunities to discuss errors and adverse events in constructive, supportive environments and by resisting pressure to find a scapegoat.
Pharmacokinetic–Pharmacodynamic Analysis of Vismodegib in Preclinical Models of Mutational and Ligand-Dependent Hedgehog Pathway Activation
Authors: Harvey Wong, Bruno Alicke, Kristina A. West, Patricia Pacheco, Hank La, Tom Januario, Robert L. Yauch, Frederic J. de Sauvage, Stephen E. Gould
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Vismodegib (GDC-0449) is a potent and selective inhibitor of the Hedgehog (Hh) pathway that shows antitumor activity in preclinical models driven by mutational or ligand-dependent activation of the Hh pathway. We wished to characterize the pharmacokinetic–pharmacodynamic (PK/PD) relationship of vismodegib in both model systems to guide optimal dose and schedule for vismodegib in the clinic. Experimental Design: Preclinical efficacy and PK/PD studies were carried out with vismodegib in a Ptch+/− allograft model of medulloblastoma exhibiting mutational activation of the Hh pathway and patient-derived colorectal cancer (CRC) xenograft models exhibiting ligand-dependent pathway activation. Inhibition of the hedgehog pathway was related to vismodegib levels in plasma and to antitumor efficacy using an integrated population-based PK/PD model. Results: Oral dosing of vismodegib caused tumor regressions in the Ptch+/− allograft model of medulloblastoma at doses ≥25 mg/kg and tumor growth inhibition at doses up to 92 mg/kg dosed twice daily in two ligand-dependent CRC models, D5123, and 1040830. Analysis of Hh pathway activity and PK/PD modeling reveals that vismodegib inhibits Gli1 with a similar IC50 in both the medulloblastoma and D5123 models (0.165 μmol/L ±11.5% and 0.267 μmol/L ±4.83%, respectively). Pathway modulation was linked to efficacy using an integrated PK/PD model revealing a steep relationship where &amp;gt; 50% of the activity of vismodegib is associated with &amp;gt;80% repression of the Hh pathway. Conclusions: These results suggest that even small reductions in vismodegib exposure can lead to large changes in antitumor activity and will help guide proper dose selection for vismodegib in the clinic. Clin Cancer Res; 17(14); 4682–92. ©2011 AACR.
Multinuclear Magnetic Resonance Spectroscopy Studies of Brain Purines in Major Depression
Authors: P F Renshaw, A M Parow, F Hirashima, Y Ke, C M Moore, B de B Frederick, M Fava, J Hennen, B M Cohen
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: Studies of depressed adults have shown abnormalities in cerebral energy metabolism, as noted by low brain levels of nucleoside triphosphate (NTP), which primarily represents adenosine triphosphate (ATP). This study was undertaken to determine whether proton magnetic resonance spectroscopy (1H MRS) measures of the low-field purine resonance, which arises primarily from adenosine phosphates, can be used to assess abnormalities in cerebral purine metabolism in depressed adults. METHOD: Data from 1H MRS and phosphorus-31 (31P) MRS were acquired for depressed and nondepressed comparison subjects. Intensities of the purine resonance, by 1H MRS (7.5–8.5 ppm), and of NTP, by 31P MRS, were determined. RESULTS: Purine resonance intensities did not differ on average between depressed patients and comparison subjects. However, purine levels were approximately 30% lower in female depressed subjects who subsequently responded to fluoxetine treatment than in those who did not respond. Beta-NTP was lower by 21% in responders than in nonresponders and was correlated with purine levels for the depressed subjects. CONCLUSIONS: Brain purine levels are low in female depressed patients who respond to treatment with fluoxetine, suggesting that response to treatment might be predicted by using 1H MRS. These observations also suggest that agents that increase brain adenosine levels may have antidepressant efficacy.
Effect of Alendronate on Risk of Fracture in Women With Low Bone Density but Without Vertebral Fractures&lt;SUBTITLE&gt;Results From the Fracture Intervention Trial&lt;/SUBTITLE&gt;
Authors: S R Cummings, D M Black, D E Thompson, W B Applegate, E Barrett-Connor, T A Musliner, L Palermo, R Prineas, S M Rubin, J C Scott, T Vogt, R Wallace, A J Yates, A Z LaCroix
Journal: JAMA (1998)

Context.—Alendronate sodium reduces fracture risk in postmenopausal women who have vertebral fractures, but its effects on fracture risk have not been studied for women without vertebral fractures.Objective.—To test the hypothesis that 4 years of alendronate would decrease the risk of clinical and vertebral fractures in women who have low bone mineral density (BMD) but no vertebral fractures.Design.—Randomized, blinded, placebo-controlled trial.Setting.—Eleven community-based clinical research centers.Subjects.—Women aged 54 to 81 years with a femoral neck BMD of 0.68 g/cm2 or less (Hologic Inc, Waltham, Mass) but no vertebral fracture; 4432 were randomized to alendronate or placebo and 4272 (96%) completed outcome measurements at the final visit (an average of 4.2 years later).Intervention.—All participants reporting calcium intakes of 1000 mg/d or less received a supplement containing 500 mg of calcium and 250 IU of cholecalciferol. Subjects were randomly assigned to either placebo or 5 mg/d of alendronate sodium for 2 years followed by 10 mg/d for the remainder of the trial.Main Outcome Measures.—Clinical fractures confirmed by x-ray reports, new vertebral deformities detected by morphometric measurements on radiographs, and BMD measured by dual x-ray absorptiometry.Results.—Alendronate increased BMD at all sites studied (P&lt;.001) and reduced clinical fractures from 312 in the placebo group to 272 in the intervention group, but not significantly so (14% reduction; relative hazard [RH], 0.86; 95% confidence interval [CI], 0.73-1.01). Alendronate reduced clinical fractures by 36% in women with baseline osteoporosis at the femoral neck (&gt;2.5 SDs below the normal young adult mean; RH, 0.64; 95% CI, 0.50-0.82; treatment-control difference, 6.5%; number needed to treat [NNT], 15), but there was no significant reduction among those with higher BMD (RH, 1.08; 95% CI, 0.87-1.35). Alendronate decreased the risk of radiographic vertebral fractures by 44% overall (relative risk, 0.56; 95% CI, 0.39-0.80; treatment-control difference, 1.7%; NNT, 60). Alendronate did not increase the risk of gastrointestinal or other adverse effects.Conclusions.—In women with low BMD but without vertebral fractures, 4 years of alendronate safely increased BMD and decreased the risk of first vertebral deformity. Alendronate significantly reduced the risk of clinical fractures among women with osteoporosis but not among women with higher BMD.
Improvement in Breast Cancer Outcomes Over Time: Are Older Women Missing Out?
Authors: Benjamin D. Smith, Jing Jiang, Sandra S. McLaughlin, Arti Hurria, Grace L. Smith, Sharon H. Giordano, Thomas A. Buchholz
Journal: Journal of Clinical Oncology (2011)

Women aged ≥ 75 years account for 40,000 breast cancers/yr and are the most rapidly growing demographic. Recent data demonstrated that breast cancer death rates in the US population are declining, but it is not known whether death rates have declined similarly for older and younger women. We examined the following two outcomes: the rate of breast cancer death in the general population and the risk of breast cancer death in newly diagnosed patients, and we compared change over time in these outcomes for older versus younger women.By using data from National Vital Statistics Reports that spanned from 1990 to 2007, the yearly change in the age-specific rate of breast cancer death was characterized with linear regression. With the use of the Surveillance, Epidemiology, and End Results nine-registry cohort that spanned from 1980 to 1997, the yearly change in age-specific risk of breast cancer death was characterized by using competing-risks regression adjusted for race and stage.Relative to 1990, the rate of breast cancer death in the general population decreased by 2.5%/yr for women age 20 to 49 years, 2.1%/yr for women age 50 to 64 years, 2.0%/yr for women age 65 to 74 years, and 1.1%/yr for women age ≥ 75 years. From 1980 to 1997, the adjusted risk of breast cancer death in newly diagnosed patients decreased by 3.6%/yr for women age less than 75 years versus 1.3%/yr for women age ≥ 75 years (P < .001). Over this time interval, the 10-year absolute risk of breast cancer death decreased by 15.3% for women age 50 to 64 years (from 31.9% to 16.6%) but by only 7.5% (from 24.8% to 17.4%) for women age ≥ 75 years.Breast cancer outcomes have preferentially improved in women age less than 75 years. Focused research is needed to improve outcomes in older women.
The president speaks: prevention is best: lessons from protecting the ozone layer
Authors: Ashley Woodcock
Journal: Thorax (2012)

The Montreal Protocol was signed 25 years ago. As a result, the irreversible destruction of the ozone layer was prevented. However, stratospheric ozone will not recover completely until 2060 and the consequent epidemic in skin cancer cases will persist until 2100. Many millions of patients with asthma and chronic obstructive pulmonary disease have safely switched from chlorofluorocarbon (CFC)-powered metered-dose inhalers (MDIs) to either hydrofluorocarbon (HFC) or DPIs. China will be the last country to phase out CFCs by 2016. HFCs are global warming gases which will be controlled in the near future. HFCs in MDIs may be phased out over the next 10–20 years.
Decreased Effective Blood Volume in Edematous Disorders
Authors: Robert W. Schrier
Journal: Journal of the American Society of Nephrology (2007)

Edematous patients with renal sodium and water retention, particularly cardiac failure and cirrhosis, have been suggested to have a decreased "effective blood volume." This enigmatic and undefined term was coined because edematous patients were found to have increased, rather than the earlier proposed decreased, blood volumes. This article discusses the advances that have occurred in understanding the pathophysiology of edema as occurs in conditions such as cardiac failure, cirrhosis, and pregnancy. The regulatory mechanisms that lead to increased sodium and water retention by the normal kidney are related to arterial underfilling, as a result of a decrease in cardiac output, arterial vasodilation, or both.
Validation of a skinfold based index for tracking proportional changes in lean mass
Authors: G J Slater, G M Duthie, D B Pyne, W G Hopkins
Journal: British Journal of Sports Medicine (2006)

The lean mass index (LMI) is a new empirical measure that tracks within-subject proportional changes in body mass adjusted for changes in skinfold thickness.To compare the ability of the LMI and other skinfold derived measures of lean mass to monitor changes in lean mass.20 elite rugby union players undertook full anthropometric profiles on two occasions 10 weeks apart to calculate the LMI and five skinfold based measures of lean mass. Hydrodensitometry, deuterium dilution, and dual energy x ray absorptiometry provided a criterion choice, four compartment (4C) measure of lean mass for validation purposes. Regression based measures of validity, derived for within-subject proportional changes through log transformation, included correlation coefficients and standard errors of the estimate.The correlation between change scores for the LMI and 4C lean mass was moderate (0.37, 90% confidence interval -0.01 to 0.66) and similar to the correlations for the other practical measures of lean mass (range 0.26 to 0.42). Standard errors of the estimate for the practical measures were in the range of 2.8-2.9%. The LMI correctly identified the direction of change in 4C lean mass for 14 of the 20 athletes, compared with 11 to 13 for the other practical measures of lean mass.The LMI is probably as good as other skinfold based measures for tracking lean mass and is theoretically more appropriate. Given the impracticality of the 4C criterion measure for routine field use, the LMI may offer a convenient alternative for monitoring physique changes, provided its utility is established under various conditions.
Biomarker-enhanced triage in respiratory infections: a proof-of-concept feasibility trial
Authors: Werner C. Albrich, Kristina Rüegger, Frank Dusemund, Philipp Schuetz, Birsen Arici, Alexander Litke, Claudine A. Blum, Rita Bossart, Katharina Regez, Ursula Schild, Merih Guglielmetti, Antoinette Conca, Petra Schäfer, Maria Schubert, Sabina de Geest, Barbara Reutlinger, Sarosh Irani, Ulrich Bürgi, Andreas Huber, Beat Müller
Journal: European Respiratory Journal (2013)

Concerns about inadequate performance and complexity limit routine use of clinical risk scores in lower respiratory tract infections. Our aim was to study feasibility and effects of adding the biomarker proadrenomedullin (proADM) to the confusion, urea &gt;7 mmol·L −1 , respiratory rate ≥30 breaths·min −1 , blood pressure &lt;90 mmHg (systolic) or ≤60 mmHg (diastolic), age ≥65 years (CURB-65) score on triage decisions and length of stay. In a randomised controlled proof-of-concept intervention trial, triage and discharge decisions were made for adults with lower respiratory tract infection according to interprofessional assessment using medical and nursing risk scores either without (control group) or with (proADM group) knowledge of proADM values, measured on admission, and on days 3 and 6. An adjusted generalised linear model was calculated to investigate the effect of our intervention. On initial presentation the algorithms were overruled in 123 (39.3%) of the cases. Mean length of stay tended to be shorter in the proADM (n=154, 6.3 days) compared with the control group (n=159, 6.8 days; adjusted regression coefficient -0.19, 95% CI -0.41–0.04; p=0.1). This trend was robust in subgroup analyses and for overall length of stay within 90 days (7.2 versus 7.9 days; adjusted regression coefficient -0.18, 95% CI -0.40–0.05; p=0.13). There were no differences in adverse outcomes or readmission. Logistic obstacles and overruling are major challenges to implement biomarker-enhanced algorithms in clinical settings and need to be addressed to shorten length of stay.
Small Tumor Size and Node-Negative <i>HER2</i>-Positive Breast Cancer: A Step Forward for a Better Treatment?
Authors: Diana Crivellari, Annamaria Molino
Journal: Journal of Clinical Oncology (2010)

Small tumors are an emerging problem that isincreasing from the epidemiological point of view mainly due toscreening programs, but also to the particular concern about theimportance of earlier breast cancer diagnosis by new generations ofwomen. There is an urgent need to try to understand whether thesetumors are biologically similar to those clinically detected becausenowadays treatments may not be equally indicated in these tumors.One example may be derived by the article recently published byCurigliano et al.