tbuckley/cabot-search huggingface dataset:
Abstract 19822: Arterial Calcification Can Be Inhibited via Stress Protein Induction Through a PPAR-dependent Pathway
Authors: Kenneth Lim, Jen Xu, E-Jay Kao, Tianqing Kong, Tzongshi Lu
Journal: Circulation (2014)

Introduction: Cardiovascular disease occurs prematurely in chronic inflammatory conditions such as Chronic Kidney Disease (CKD) and unfortunately, remains the leading cause of death in these patients. Vascular calcification (VC) is a significant contributor to cardiovascular mortality in CKD patients with the sequela of arterial hardening, congestive heart failure and sudden cardiac death. We recently reported that heat shock protein 72 (HSP72) when inducted, can inhibit the development of VC. Hypothesis: We hypothesize that HSP72 exerts its vasculo-protective effects by functioning as a molecular chaperon for peroxisome proliferator-activated receptor γ (PPARγ). Methods: We developed an in vitro long-term calcification model using HA-SMCs treated with calcification medium (CM) containing 5mM CaCl2 and 5mM β-glycerophosphate for 21 days. Cells were subjected to heat shock treatment at 43°C for 30 minutes daily to induce HSP72. Calcification was assessed qualitatively by alizarin red staining and quantitatively by the arsenazo III method. Results: Our results show that inducible HSP72 is significantly expressed following heat shock treatment in HA-SMCs. Induction of HSP72 inhibited the development of VC in our long-term calcification model and these effects were abolished by HSP72 siRNA, in vitro. We next showed that HSP72 formed a protein-protein complex with PPARγ by co-immunoprecipitation. Expression of both these proteins was down-regulated in calcific HA-SMCs and their gene expression was down regulated in atherosclerotic human arteries. Furthermore, we found that the PPARγ inhibitor, FABP4 (fatty acid binding protein-4) which function as an atherosclerosis promoter was up-regulated in calcified human arteries. Lastly, induction of HSP72 restored expression of the HSP72-PPARγ complex and inhibited upregulation of FABP4 with reduction in calcification in our in vitro calcification model. These vasculo-protective effects were abolished by HSP72 siRNA. Conclusion: HSP72 is a powerful inhibitor of VC and exerts its vasculo-protective effects by functioning as a molecular chaperon to stabilize PPARγ and regulate the PPARγ-FABP4 pathway. We suggest treatment strategies involving induction of HSP72 as a new approach to inhibit VC.
G03 : Rifaximin and propranolol combination therapy is more effective than propranolol monotherapy in the hepatic venous pressure gradient response and propranolol dose reduction – A pilot study
Authors: S.K. Baik, Y.L. Lim, Y.Z. Cho, M.Y. Kim, Y.O. Jang, K.T. Suk, G.J. Cheon, Y.D. Kim, D.H. Choi
Journal: Journal of Hepatology (2015)
Impaired mitochondrial network excitability in failing guinea-pig cardiomyocytes
Authors: Kah Yong Goh, Jing Qu, Huixian Hong, Ting Liu, Louis J. Dell'Italia, Yong Wu, Brian O'Rourke, Lufang Zhou
Journal: Cardiovascular Research (2015)

Studies in guinea-pig cardiomyocytes show that reactive oxygen species (ROS) produced by a few mitochondria can propagate to their neighbours, triggering synchronized, cell-wide network oscillations via an ROS-induced ROS release (RIRR) mechanism. How mitochondria in cardiomyocytes from failing hearts (HF) respond to local oxidative stress perturbations has not been investigated. Since mitochondrial ultrastructure is reportedly disrupted in HF, and propagation of ROS signals depends on mitochondrial network integrity, we hypothesized that the laser flash-induced RIRR is altered in HF. To test the hypothesis, pressure-overload HF was induced in guinea pigs by ascending aortic constriction leading to left ventricular dilatation and decreased ejection fraction after 8 weeks. Isolated cardiomyocytes were studied with two-photon/confocal microscopy to determine their basal oxidative stress and propensity to undergo mitochondrial depolarization/oscillations in response to local laser flash stimulations. The expression of mitofusin proteins and mitochondrial network structure were also analysed. Results showed that HF cardiomyocytes had higher baseline ROS levels and less reduced glutathione, and were more prone to laser flash-induced mitochondrial depolarization. In contrast, the delay between the laser flash and synchronized cell-wide network oscillations was prolonged in HF myocytes compared with shams, and the spatial extent of coupling was diminished, suggesting dampened RIRR and ROS signal propagation. In addition, the expressions of mitofusin proteins in HF myocardium were down-regulated compared with these from sham-operated animals, and the mitochondrial network structure altered. The disrupted inter-mitochondrial tethering and loss of structural organization may underlie decreased ROS-dependent mitochondrial coupling in HF.
How many biopsy fragments will be necessary to assess HER2 status for gastric cancer?
Authors: Eiji Shinozaki, Noriko Yamamoto, Keisho Chin, Mariko Ogura, Mitsukuni Suenaga, Satoshi Matsusaka, Nobuyuki Mizunuma, Toshiharu Yamaguchi, Kiyohiko Hatake
Journal: Journal of Clinical Oncology (2012)

40 Background: Trastuzumab (T) has been shown to confer overall survival benefit adding to capecitabine or 5-FU and CDDP in HER2-positive advanced gastric cancer in ToGA study. Data from the study, overexpression of HER2 according to immunohistochemistry (IHC) has been confirmed as potential responders. HER2 scoring is essential to decide the strategy of the personalized therapy with T. There are some differences in details to assess HER2 score between surgically resected materials and the biopsy fragments. Moreover it is not unclear how many biopsy fragments will be necessary to assess HER2 status. In this study we attemped to prove the optimal biopsy for HER2 scoring of gastric cancer. Methods: HER2 status was evaluated in 30 cases who were scored HER2 as 3+ and 44 cases who were selected for reference as HER2 score of 2+, 1+, 0 in previous tests of surgical specimens. In total 74 cases of 232 biopsies we investigated HER2 protein expression by IHC using HercepTest (DAKO) and assessed according to Gastric Cancer Scoring System. We analyzed the concordance of HER2 score between surgically specimens and the biopsy fragments. Results: Average numbers of biopsy fragments were 3.13(1-6)/case. The concordances between surgical specimens and biopsy specimens were 80.0% in HER2 3+ group of surgical specimens, 47.8% and 47.6% in HER2 2+ and 1+ or 0. The concordances per each biopsy were 73.5%, 34.7% and 69.1%, respectively. Both concordances in HER2 positive group were significant higher than those in HER 2 negative or equivocal groups. There were not statistic differences of the concordances between 3 or less fragments of biopsy and 4 or more. Conclusions: Our data suggested in HER2 score 3+ according to surgical materials, the concordance of HER2 scoring between surgically resected materials and the prior biopsy specimens was high and at least 3 fragments were seemed enough to assess whether IHC HER2 is positive in biopsy. Other hands in HER 2 negative or equivocal groups, the concordances were low.
The epidemiology of herpes zoster in patients with invasive cancer
Authors: L. A. Habel, G. T. Ray, M. Horberg, B. Yawn, A. Castillo, Y. Li, M. Silverberg, C. Quesenberry, T. Tran
Journal: Journal of Clinical Oncology (2009)

9562 Background: Given the limited available data, the aim of this study was to estimate the incidence of Herpes Zoster (HZ) in cancer patients. Methods: In this retrospective cohort study, we used the Kaiser Permanente Northern California cancer registry to identify adult health plan members diagnosed with an invasive hematologic malignancy (HM) or solid tumor malignancy (STM) during 2001–2005. Potential episodes of HZ were ascertained from time of cancer diagnosis through 2006 from electronic databases using inpatient and outpatient diagnoses, laboratory tests, and prescriptions for antivirals. HZ diagnoses were confirmed by abstraction and clinical review of information from patients' inpatient and outpatient medical records. Incidence rates were calculated as the number of new occurrences of HZ per person-time of follow-up. Age-standardized incidence ratios (SIRs) were computed to compare HZ rates in cancer patients to reported rates in the general population (Yawn et al, 2007). Results: Among the 4,728 STM patients (mean age 66 years, range 18–102), the rate of HZ was 12/1000 person years (py) of follow-up (total 9170 py). Among the 1504 HM patients (mean age 67 years, range 18–97), the rate of HZ was 33/1000 py (total 2355 py). The SIRs and 95% confidence intervals for STM and HM were 1.7 (1.4–2.1) and 4.5 (3.5–5.6), respectively. Among patients with HM, incidence rates were highest in the first year after cancer diagnosis (40/1000 py); rates did not appear to vary markedly over time among patients with STM. For either cancer type, HZ rates were similar for males and females and did not increase consistently with increasing age. Conclusions: Compared to the general population, the incidence of HZ was nearly 2 times higher in patients with STM and over 4 times higher in patients with HM. HZ rates did not differ markedly by age or gender. [Table: see text]
Hematocrit Level and Associated Mortality in Hemodialysis Patients
Authors: JENNIE Z. MA, JIM EBBEN, HONG XIA, ALLAN J. COLLINS
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Although a number of clinical studies have shown that increased hematocrits are associated with improved outcomes in terms of cognitive function, reduced left ventricular hypertrophy, increased exercise tolerance, and improved quality of life, the optimal hematocrit level associated with survival has yet to be determined. The association between hematocrit levels and patient mortality was retrospectively studied in a prevalent Medicare hemodialysis cohort on a national scale. All patients survived a 6-mo entry period during which their hematocrit levels were assessed, from July 1 through December 31, 1993, with follow-up from January 1 through December 31, 1994. Patient comorbid conditions relative to clinical events and severity of disease were determined from Medicare claims data and correlated with the entry period hematocrit level. After adjusting for medical diseases, our results showed that patients with hematocrit levels less than 30% had significantly higher risk of all-cause (12 to 33%) and cause-specific death, compared to patients with hematocrits in the 30% to less than 33% range. Without severity of disease adjustment, patients with hematocrit levels of 33% to less than 36% appear to have the lowest risk for all-cause and cardiac mortality. After adjusting for severity of disease, the impact of hematocrit levels of 33% to less than 36% is vulnerable to the patient sample size but also demonstrates a further 4% reduced risk of death. Overall, these findings suggest that sustained increases in hematocrit levels are associated with improved patient survival.
A new naturalistic asthma model in the environmental exposure chamber to study mild asthmatics safely and consistently
Authors: Anne Marie Salapatek, Erin Beattie, Piyush Patel
Journal: European Respiratory Journal (2014)

Background : A low dose naturalistic allergen challenge model to study mild asthmatics would aid in the development of effective drug therapies. We investigated both model specificity and SPT or IgE classification as a predictor of change in lung function and lower airway symptoms in asthmatics.

Methods : A meta-analysis was conducted on 323 subjects (53 mild asthmatics) with a history of cat allergy and positive SPT to cat allergen. Subjects were exposed to airborne cat allergen in a naturalistic Environmental Exposure Chamber (EEC) model for 3 hrs over 4 consecutive days. FEV1 was assessed before and after EEC and asthma symptom scores were recorded every 30 mins in the EEC.

Results : Low dose airborne naturalistic challenge resulted in: 1) A consistent drop in FEV1 over 4 days allergen challenge. Asthmatics have a greater reduction in FEV1 (L) over all days (p≤0.001). 2) Increase in SPT moderately predicts a larger decline in lung function. 3) Increase in IgE class (C) predicts a larger drop in lung function (ΔFEV1 (L)) with allergen exposure: IgE ≥ C1 = 0.56 ± 0.06L vs. 0.31 ± 0.02L (p≤0.001); IgE ≥ C2= 0.59 ± 0.06L vs 0.34 ± 0.02L (p≤0.001); and IgE ≥ C3=0.66 ± 0.08L vs 0.44 ± 0.03L (p=0.01) in asthmatics compared to non-asthmatics, respectively. 4) Asthma symptom scores were higher in asthmatics than non-asthmatics (Mean Score 3.23 ± 0.30 vs. 2.60 ± 0.12 (p=0.05)). 5) Neither SPT or IgE class is predictive of asthma symptoms with allergen exposure.

Conclusions : The EEC Asthma Model represents a more naturalistic model for the study of asthma. IgE and SPT are useful to characterize asthmatic patients and safely predict their response in the EEC.
Trends in National Institutes of Health Funding for Clinical Trials Registered in ClinicalTrials.gov
Authors: Stephan Ehrhardt, Lawrence J. Appel, Curtis L. Meinert
Journal: JAMA (2015)

This study characterizes trends in the total number of clinical trials and in the proportion of trials funded by the National Institutes of Health and registered at ClinicalTrials.gov between 2006 and 2014.
JANUS 2: A phase III study of survival, tumor response, and symptom response with ruxolitinib plus capecitabine or placebo plus capecitabine in patients with advanced or metastatic pancreatic cancer (mPC) who failed or were intolerant to first-line chemotherapy.
Authors: Eileen Mary O'Reilly, Christopher Walker, Jason Clark, Kimberli J. Brill, Fitzroy W. Dawkins, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2015)

TPS4146 Background: The systemic inflammatory response characteristic of PC is mediated in part by JAK-STAT signaling and may contribute to local tumor growth and disease-related weight loss, decreased muscle mass, and poor performance status. In the phase II, randomized, double-blind RECAP study, the combination of the JAK1/JAK2 inhibitor ruxolitinib with capecitabine improved overall survival (OS) versus placebo + capecitabine in patients with mPC and elevated C-reactive protein (CRP) levels or a modified Glasgow Prognostic Score (mGPS) of 1 or 2 (Hurwitz et al. J Clin Oncol. 32:5s, 2014 [suppl; abstr 4000]). Methods: JANUS 2 is a phase III, randomized, double-blind, multicenter study. Eligible patients are ≥ 18 years of age and have histologically or cytologically confirmed pancreatic ductal adenocarcinoma, advanced and inoperable or metastatic disease; ECOG performance status of 0–2; only 1 prior chemotherapy regimen for advanced or metastatic disease (not including neoadjuvant and/or adjuvant therapy); no concurrent anticancer therapy; and an mGPS of 1 (CRP > 10 mg/L and albumin ≥ 35 g/L) or 2 (CRP > 10 mg/L and albumin < 35 g/L). Exclusion criteria are prior severe reaction to fluoropyrimidines, dihydropyrimidine dehydrogenase deficiency, or other sensitivity to 5-fluorouracil. Patients are randomized 1:1 to receive 21-day cycles of capecitabine 2000 mg/m2/d (days 1−14) + ruxolitinib 15 mg twice-daily or capecitabine 2000 mg/m2/d + placebo twice-daily. The primary endpoint is OS; secondary endpoints include progression-free survival, tumor response per RECIST 1.1, and duration of response. An exploratory endpoint is the assessment of change from baseline in PC symptoms using the Pancreatic Cancer Symptom Assessment Form electronic diary. Treatment will continue as long as it is tolerated and discontinuation criteria are not met. Patients who discontinue treatment will be followed for subsequent anticancer treatments and survival. Enrollment began in April 2014 and is ongoing. The planned enrollment is 270 patients. Clinical trial information: NCT02119663.
Abstract 12115: Phthalate Substitute Plasticizers Activate PXR and Induce Dyslipidemia in Mice
Authors: Yipeng Sui, Robert N Helsley, Se-Hyung Park, Zun Liu, Changcheng Zhou
Journal: Circulation (2014)

The pregnane X receptor (PXR) is a nuclear receptor activated by numerous drugs, xenobiotic and dietary chemicals. Many endocrine disrupting chemicals (EDCs) activate PXR, including organochlorine and organophosphate pesticides, alkylphenols, phthalates, polychlorinated biphenyls, bisphenol A and phthalate plasticizers. However, the role of PXR in mediating the pathophysiological effects of EDCs in humans and animals remains elusive. Mounting evidence implicates EDC exposure in the development of chronic human diseases, but the contribution of these EDCs to the etiology of cardiovascular disease (CVD) is poorly understood. In the present study, we identified several widely used phthalate substitute plasticizers used in food packaging materials, medical devices, cosmetics, and pharmaceutical drugs as agonists of PXR. Tributyl citrate (TBC), one of a large group of FDA-approved pharmaceutical plasticizers, is a potent and selective PXR agonist but does not activate other nuclear receptors. TBC can efficiently activate PXR and induce its target gene expression in vitro and in vivo. Short-term TBC exposure increased plasma total cholesterol and atherogenic LDL cholesterol levels in wild-type mice, but not in PXR-deficient mice. Interestingly, TBC is an intestine-specific PXR ligand but does not affect hepatic PXR activity. TBC-mediated PXR activation stimulated the expression of intestinal cholesterol transporter, Niemann Pick-C1 Like 1 (NPC1L1). Chromatin Immunoprecipitation experiments revealed that PXR can bind to the NPC1L1 promoter. Further, TBC treatment also significantly increased NPC1L1 expression and cholesterol uptake in human intestinal cells and murine primary enterocytes. These findings provide critical mechanistic insight for understanding the impact of EDC-mediated PXR activation on lipid homeostasis and demonstrate a potential role of PXR in mediating adverse effects of EDCs on CVD risk in humans.
Seasonal rhythm of platelet [3H]imipramine binding in adolescents who attempted suicide
Authors: D S Pine, P D Trautman, D Shaffer, L Cohen, M Davies, M Stanley, B Parsons
Journal: American Journal of Psychiatry (1995)

This study was designed to determine the seasonality of serotonin functions among adolescents who attempt suicide.Platelet [3H]imipramine binding was assessed over a period of 18 months in 98 adolescents who attempted suicide and a comparison group of 23 never-suicidal youths with conduct disorder.[3H]Imipramine (Bmax) was uncorrelated with age, but showed considerable seasonal variability over time in those who had attempted suicide.[3H]Imipramine binding density in adolescents who attempted suicide exhibited significant seasonality, reaching a nadir in late winter/early spring.
The impact of miscoding of community -acquired pneumonia in a UK district general hospital
Authors: Nadia Gildeh, Tom Errington, Iona Maxwell, Simon Merritt, David Maxwell, Osei Kankam
Journal: European Respiratory Journal (2014)

Background:   The incidence of Community-Acquired Pneumonia (CAP) in the United Kingdom is 5-11/1000. 1  Misdiagnosis is common. 2  Coding information, following episodes of inpatient care, is derived from diagnoses recorded in clinical notes. There is little published data on financial implications of incorrect coding in CAP.   Method:   We conducted a retrospective review of records incorrectly coded as CAP between March 2012 and March 2013, and assessed whether this had an impact on length of stay and income. Patients with clear radiographic evidence (CXR or CT) of pneumonia were excluded along with those who actually had HAP or were immunocompromised.We sought to determine if miscoding of CAP (ICD-10) would negatively impact on income streams and length of stay.  We analyzed length of stay and Healthcare Resource Group (HRG) codes for each miscoded episode of care.   Results:   602 patients were coded as pneumonia. 233 (38.7%) were accurately coded .195 (32.3%) were miscoded as CAP (non-CAP). Of the latter 32 were excluded due to lack of data, leaving 163 patients whose records were then examined.  Alternative diagnoses included; Infective exacerbation of COPD (9%), non-infective exacerbation COPD (9%), lower respiratory tract infection (45%), heart failure (10%), HAP (12%) and other (17%).  Median age for CAP was 78 yrs (range: 31-102) and non-CAP was 83 yrs (36-99). Mean length of stay was 10 days for CAP and 12 days for non-CAP (P=0.14). Mean income for each episode of care was € 1124 for CAP and € 1288 for non-CAP (P l0.0001).   Conclusions:   Our data show that a misdiagnosis and subsequent miscoding of CAP may lead to an apparent increase in length of stay and can lead to a real loss of income .
Euthanasia is an option which alleviates patients' fear
Authors: I. Loudon
Journal: BMJ (1995)

perpetuated the myths of the distress of dying, in particular of dying from motor neurone disease.The Motor Neurone Disease Association has been encouraging discussion about the fears of dying and providing information about the care of patients as death approaches.Their Breathing Space Programme has provided leaflets for patients and professionals to facilitate discussion of these fears and the positive ways to alleviate these concerns.This discussion may lead to the provision of medication for use in an emergency, and the Breathing Space Kit can be provided to store this medication and to give details of its use for everyone involved in the patient's care.3Euthanasia is an issue that needs to be discussed openly, but a film like "Death on Request" may confuse and frighten, epecially when further information is not immediately available at the time of the broadcast.A round table discussion at 1 1 15, when many of the viewers will have switched off, is insufficient.