tbuckley/cabot-search huggingface dataset:
In search for a disease-modifying treatment in irritable bowel syndrome
Authors: Hans Törnblom, Magnus Simrén
Journal: Gut (2015)

IBS continues to evade the efforts of medical science to translate knowledge of putative pathogenetic or pathophysiological mechanisms into successful pharmacological treatments. To some extent, laxatives and antidiarrhoeal medications are able to improve the erratic bowel habits associated with IBS, and recently linaclotides have been shown to relieve abdominal pain and constipation in IBS-C.1 Even so, in those experiencing treatment success this cannot be linked to a disease-modifying effect, since stopping the treatment leads to recurrence of symptoms.

From this point of view, a hot topic during the past decades has been the many reports of low-grade immune activation in subgroups of patients with IBS.2 The early observations of GI infections as a risk factor for developing IBS,3 but also other functional GI disorders such as functional dyspepsia,4 has sent signals of hope for anti-inflammatory treatment as a promising approach for a subset of patients. Epidemiological observations of a reduced risk for IBS in users of oral steroids pointed in the same direction.5 The lack of a positive effect of prednisolone treatment in postinfectious IBS, except for reducing the number of lamina propria lymphocytes,6 was disappointing but has not hampered the conceptual interest. Instead, it has rather focused efforts into medications with a better possibility for long-term treatment such as the mast cell stabiliser ketotifen7 and even more interesting, 5-aminosalicylic acid in the form of mesalazine8 that might affect …
Muscle volume loss after the induction of first-line chemotherapy as a novel prognostic factor in metastatic colorectal cancer patients.
Authors: Yusuke Yoshikawa, Koji Okabayashi, Hirotoshi Hasegawa, Masashi Tsuruta, Ryo Seishima, Hidena Takahashi, Toru Yamada, Shimpei Matsui, Takayuki Kondo, Takehiro Shimada, Mutsuhito Matsuda, Masashi Yahagi, Yusuke Asada, Kiyoaki Sugiura, Yoshiyuki Suzuki, Yuki Tajima, Junpei Nakadai, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2015)

558 Background: Muscle volume loss (MVL) is observed in end-stage cancer patients as cachexia. However, the impact of MVL on tumor response and survival still remains unclear during chemotherapy in metastatic colorectal cancer (mCRC) patients. The aim of this study is to evaluate correlation between MVL and oncologic outcomes in mCRC patients. Methods: A total of 91 mCRC patients who received first-line chemotherapy were identified in our prospective registry between February 2007 and April 2013. Skeletal muscle index at the level of L3 vertebra (SMI) was calculated by muscle volume normalized by stature at the time of the induction of first-line chemotherapy (bSMI) and first evaluation of tumor response (fSMI). Patients whose SMI decreased more than 10% were classified as MVL group. The impact of these variables on oncologic outcomes (overall survival [OS], progression free survival [PFS], and tumor response rate [RR]) were analyzed. Results: Mean bSMI and fSMI were 35.0 (SD: 7.11) cm 2 /m 2 , and 34.2 (SD: 6.85) cm 2 / m 2 , respectively. Eighteen patients were classified into the MVL group. The patients in MVL group significantly responded to the chemotherapy (RR of MVL: 11.1% vs. RR of non-MVL: 49.3%, p &lt; 0.01). There was no significant difference in terms of high grade adverse effect between MVL and non-MVL group. Patients in MVL group had a significant shorter median PFS (MVL: 5.5 [2.5 - 10.1] months vs. non-MVL: 12.8 (3.8-80.5) months, p &lt; 0.01) and median OS (MVL: 13.9 [6.2-61.2] months vs. non-MVL: 29.3 (8.2-94.0) months, p &lt; 0.01). Multivariate analysis demonstrated that patients with MVL had significantly worse prognostic factor (OS: HR 3.51 [1.99-6.21], p &lt; 0.01 and PFS: HR 8.27 [2.91-23.5], p &lt; 0.01. Conclusions: The findings of this study suggested that MVL after the induction of the first line chemotherapy could be a novel predictive factor for chemotherapy response and prognosis. Further investigation should be required to clarify the mechanistic background.
Validity of the pediatric electronic quality of life instrument for childhood asthma in the Netherlands
Authors: Lisette van den Bemt, Stephanie van Bragt, Bart Thoonen, Peter Merkus, Tjard Schermer
Journal: European Respiratory Journal (2011)

Introduction:  Assessment of health-related quality of life (HRQL) for children with asthma in daily care may facilitate shared decision-making and contribute to patient-centred care. Pediatric HRQL is unique to children and it is essential that an instrument used in daily care has an individualised part to prioritise issues that are especially important for the particular child. We have developed a pediatric HRQL instrument that is designed as a web based game and has an individualised part (Pelican instrument).   Aim:  The aim of this study was to determine the clinometric properties of the Pelican instrument.   Methods:  68 children with asthma aged 6 – 12 years were recruited. Children completed the Pelican instrument on 3 occasions within a 2-month period. Additional information was collected on various aspects, including asthma control (ACQ, C-ACT) and HRQL (Feeling Thermometer and PAQLQ).   Results:  The instrument had good test-retest reliability (ICC 0.83) and internal consistency (Cronbach9s α: 0.90). Moreover, the instrument was able to discriminate between children with controlled and uncontrolled asthma and we observed good correlations with the PAQLQ and Feeling Thermometer (r ≥ 0.6). Finally, the items selected by the children as “worst things about my asthma” (i.e., individualised part) were scored higher by the child than items they did not select (mean difference 0.97; scale 1-5).   Conclusions:  The results indicate that the Pelican instrument is a valid and reliable instrument. The responsiveness of the instrument needs to be established. Further studies are needed to assess whether implementation of the Pelican instrument can facilitate patient-centred care.
Occupational exposure to organic solvents: a risk factor for pulmonary veno-occlusive disease
Authors: David Montani, Edmund M. Lau, Alexis Descatha, Xavier Jaïs, Laurent Savale, Pascal Andujar, Lynda Bensefa-Colas, Barbara Girerd, Inès Zendah, Jerome Le Pavec, Andrei Seferian, Frédéric Perros, Peter Dorfmüller, Elie Fadel, Florent Soubrier, Oliver Sitbon, Gérald Simonneau, Marc Humbert
Journal: European Respiratory Journal (2015)

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension characterised by predominant remodelling of pulmonary venules. Bi-allelic mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene were recently described as the major cause of heritable PVOD, but risk factors associated with PVOD remain poorly understood. Occupational exposures have been proposed as a potential risk factor for PVOD, but epidemiological studies are lacking.A case-control study was conducted in consecutive PVOD (cases, n=33) and pulmonary arterial hypertension patients (controls, n=65). Occupational exposure was evaluated via questionnaire interview with blinded assessments using an expert consensus approach and a job exposure matrix (JEM).Using the expert consensus approach, PVOD was significantly associated with occupational exposure to organic solvents (adjusted OR 12.8, 95% CI 2.7-60.8), with trichloroethylene being the main agent implicated (adjusted OR 8.2, 95% CI 1.4-49.4). JEM analysis independently confirmed the association between PVOD and trichloroethylene exposure. Absence of significant trichloroethylene exposure was associated with a younger age of disease (54.8±21.4 years, p=0.037) and a high prevalence of harbouring bi-allelic EIF2AK4 mutations (41.7% versus 0%, p=0.015).Occupational exposure to organic solvents may represent a novel risk factor for PVOD. Genetic background and environmental exposure appear to influence the phenotypic expression of the disease.
Cancer risk has no effect on mortality
Authors: W D Atkinson, M Marshall, B O Wade
Journal: BMJ (1994)

Prostatic cancer and radionuclidesEvidence implicates zinc-65EDrroR,-In their paper on prostatic cancer in employees of the United Kingdom Atomic Energy Authority, Cleone Rooney and colleagues raise the possibility of localisation of zinc-65 in the prostate being an aetiological factor but state that "there are no reliable data on 65Zn uptake by the human prostate."'Prout et al showed in 1959 that 65Zn localises avidly in the prostate in human males, and especially in benign adenomas.2In 1956 Daniel et al showed that the ratio of the 65Zn concentration in normal prostates to that in blood was over 2-5:1; one patient had a ratio of 27:1.3The consensus of both groups was that neoplastic prostates concentrated less zinc.The uptake of zinc by the human prostate is so high that it is technically possible to image the prostate with ""9Zn."(Unfortunately, there are no isotopes of zinc suitable for routine imaging, so this approach has not found a place in routine nuclear medicine.)This avid uptake of zinc by the prostate must increase the probability of 65Zn being a relevant factor in carcinogenesis in this population.
Abstract 32: Loss of Ideal Cardiovascular Health Factors from Early Young Adulthood to Middle Age
Authors: Holly C Gooding, Christina M Shay, Matthew W Gillman, Hongyan Ning, Stephanie E Chiuve, Norrina B Allen, Jared Reis, Darwin R Labarthe, Kiang J Liu, Donald M Lloyd-Jones
Journal: Circulation (2014)

Introduction: Adults who reach middle age with ideal blood pressure, cholesterol, and glucose levels have lower rates of CVD mortality compared to those with one or more adverse levels. AHA identified four healthy lifestyle factors (HLFs) - BMI, smoking, diet, and physical activity - important for preventing loss of this low CVD risk state. The purpose of this study was to quantify associations between combinations of HLFs measured in young adulthood and loss of ideal CVH factors into middle age. Methods: Analyses included 2,421 young adults (age 18-30 years at baseline in 1985-6) in the Coronary Artery Risk Development in Young Adults study who met criteria for ideal CVH factors at baseline: untreated blood pressure &lt;120/80 mmHg, total cholesterol &lt;200 mg/dL, fasting blood glucose &lt;100 mg/dL and absence of CVD. Cox proportional hazards regression models were used to estimate hazard ratios for loss of all ideal CVH factors status over 25 years of follow-up according to 16 combinations of HLFs measured in young adulthood: BMI &lt;25kg/m2, physical activity &gt;300 exercise units, never smoking/quitting ≥ 12 months prior, and scoring in the top tertile of the AHEI diet score. Models were adjusted for age, sex, race, education, and study center. Results: Most (86%, 69 of 80) young adults with 0 HLFs lost the all ideal CVH factor status by middle age. Relative to young adults with no ideal HLFs, those with all 4 ideal HLFs were least likely to lose the low risk CVD state (HR 0.53, 95% CI 0.40-0.70). In the absence of ideal BMI, no combination of other HLFs was significantly protective (Figure 1). When analysis was restricted to the 1,708 young adults with ideal BMI, participants with ideal smoking, diet, and physical activity had a lower likelihood of losing the ideal CVH factor state compared to those with ideal BMI only (HR 0.79, 95% CI: 0.63-0.99). Conclusions: Ideal BMI in early young adulthood was protective against loss of ideal CVH factors over time. Among those with ideal BMI, ideal smoking status, diet, and physical activity conferred additional benefit.
Expectations of benefit in survival in patients choosing treatment for localized prostate cancer
Authors: R. Mohan, L. Lee, Y. Zhao, J. Davis, R. Lance, P. Schellhammer
Journal: Journal of Clinical Oncology (2008)

6549 Background: Three-fourths of screen-detected localized prostate cancer (LPC) has a Gleason score of <7. Untreated, such cancer has been projected to result in only 1% mortality over 15 years. However, despite serious risk of treatment side-effects, 94% of patients in the U.S. choose treatment for LPC. We surveyed, to our knowledge for the first time, how much longer survival patients expect by choosing treatment. Methods: 160 patients were studied before treatment for LPC. Their health-adjusted life expectancy (HALE) exceeded 10 years except for 2 patients. They were asked about their perceived reduction in survival (PRS) due to the cancer, and perceived benefit in survival (PBS) due to treatment for the cancer. Baseline HALE was calculated based on age and co-morbidities. Results: Mean age of patients was 61 years. Mean Gleason score of cancer was 6.5. Patients were mostly healthy, educated, and had higher than average health literacy and family incomes. 66% patients had HALE of >20 years; of them, over half believed they would live less than 10 years without treatment (PRS). Similarly, 106 patients expected to live over 20 years with treatment, but 45% of them believed they would live less than 10 years without treatment (PBS). PRS and PBS were higher in patients with higher HALE, cancer grade, anxiety, and depression, but were unrelated to race or scores of co-morbidities, functional capacity, generic health-related quality of life, social support, education, health literacy, family income, and satisfaction with life, health, and education given by physicians in treatment choices. Conclusions: Choice of treatment for LPC was associated with unrealistic pessimism regarding survival without treatment, and unrealistic optimism regarding benefit in survival due to treatment. No significant financial relationships to disclose.
Systematic Effect of Testosterone on Rat Liver Tumor Induction by &lt;italic&gt;N&lt;/italic&gt;-2-Fluorenylacetamide&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Yee-Chu Toh
Journal: JNCI Journal of the National Cancer Institute (1972)

Inbred Wistar male and female rats were castrated within 24 hours after birth and received either subcutaneous or intrasplenic implantation of testosterone pellets on the 50th day of life. A week later, they were given 8 mg N-2-fluorenylacetamide by stomach tube, twice weekly for 25 weeks, and were killed at 48–50 weeks of age. Most of the lesions were in the livers of male and female rats that had received subcutaneous testosterone implantations. The weights of thyroid and pituitary glands were significantly less and the levels of growth hormone as assayed by the tibial test were notably higher than in any other groups. It is concluded that testosterone has no direct effect but acts indirectly via other endocrine glands to cause liver carcinogenesis. Its possible mechanism is discussed.
<i>TP53</i> and <i>CHEK2</i> *<i>1100delC</i> gene mutation in North American families suggestive Li-Fraumeni syndrome: Memorial Sloan-Kettering experience
Authors: R. Siddiqui, L. Robles Diaz, K. Nafa, N. Kauff, F. Facio, H. Huang, K. Onel, M. Robson, N. Ellis, K. Offit
Journal: Journal of Clinical Oncology (2004)

9537 Background: Li-Fraumeni syndrome (LFS) is a dominantly inherited cancer predisposition syndrome characterized by a wide spectrum of neoplasms including soft-tissue and bone sarcomas, brain tumors, adrenocortical tumors, breast cancers and leukemia occurring at young age. Germline mutations in the tumor suppressor gene TP53 have been identified in approximately 71% of LFS patients and 22% of Li-Fraumeni like (LFL) patients meeting Eeles's or Birch's criteria. Mutations within the checkpoint gene, CHEK2, encoding a kinase required for cell cycle regulation have also been reported in some patients with LFS/LFL not carrying TP53 mutation. Methods: We conducted a study to explore the possible association between a specific CHEK2*1100delC mutation and LFS/LFL. All patients who were evaluated for LFS/LFL at the Clinical Genetics Service at MSKCC from 1994–2003, who underwent testing for a TP53 mutation, and did not have a deleterious mutation identified were anonymously tested for CHEK2*1100delC. Testing for the CHEK2*1100delC mutation was done by DNA sequencing. Results: A total of 23 patients who underwent TP53 testing were identified. M:F ratio was 6:17. 13% of the patients met LFS criteria, 78% LFL and 9% patients did not meet these criteria. All patients tested had at least one primary malignancy (14 breast, 7 sarcoma, 5 hematological, 4 brain, 3 melanoma and 4 other). Median age at diagnosis of first tumor was 30. 57%, 30% and 9% of patients had a total of 2, 3 and 4 primary malignancies respectively. Overall, TP53 mutations were identified in 7 of 23 patients and variants of unknown clinical significance in 2 patients. TP53 germline mutations were identified in 2 of 3 LFS's and 4 of 18 LFL's patients. 15 of 16 patient who did not have a deleterious TP53 mutation were tested for CHEK2*1100delC. None of these TP53 negative patients were found to harbor CHEK2*1100delC. Conclusions: Our results do not support the causative role of the CHEK2*1100delC mutation in patients with LFS/LFL not carrying a TP53 mutation. No significant financial relationships to disclose.
Survival and secondary malignancy rates for adjuvant radiation therapy versus observation in stage I testicular seminoma: A Surveillance, Epidemiology, and End Results (SEER) analysis
Authors: N. Vudarla, I. Jawed, H. Kaya, J. D. Tward, O. K. Macdonald, D. Martincic, D. K. Gaffney, A. T. Shivnani, T. L. Odom- Maryon, C. M. Lee
Journal: Journal of Clinical Oncology (2007)

5020 Background: The standard adjuvant treatment for men with stage I testicular seminoma remains controversial within the literature. We analyzed survival and secondary malignancy rates in men with stage I seminoma who underwent adjuvant radiation therapy (RT) or observation (OB) following orchiectomy. Methods: Data was obtained from the Surveillance, Epidemiology, and End Results program (SEER) of the U.S. National Cancer Institute from 1973 - 2003. The primary end points were overall survival (OS) and cause-specific survival (CSS). Multivariate Cox regression models were utilized to study the significance of clinical variables: age at diagnosis, laterality of primary disease, race (white, black, American Indian, Asian/pacific islander) and radiation group. Standardized incidence ratios (observed-to-expected [O/E] ratio) and absolute excess risks of secondary malignancies were also assessed for each subgroup. Results: Out of 6,764 patients eligible for analysis, 5,265 were treated with RT and 1,499 with OB. After a median follow up of 7.6 years, the 5-, 10- and 20- year OS rates for the RT versus OB were 97.9 vs. 95.0; 92.2 vs. 92.2; and 83.6 vs. 84.1 (p= 0.005), respectively. The CSS rates for the same time periods were 99.6 vs. 98.7; 99.2 vs. 98.7; and 99.2 vs. 98.7 (p= 0.002), respectively. Adjuvant RT was associated with improved CSS on multivariate analysis with HR 0.37 (CI 0.19–0.70, p= 0.002). Overall, 312 patients developed secondary malignancies which was significantly higher than the endemic rate (O/E 1.43, p&lt;0.05). RT patients had an increased rate of secondary malignancies when compared with the OB population (O/E 1.93, p&lt;0.05). RT population were at excess risk for contralateral testicular, pancreatic, and hematologic malignancies (p&lt;0.05). Conclusions: Within this large United States population analysis, adjuvant RT was associated with improved CSS for men with stage I testicular seminoma. The incidence of secondary malignancies was also found to be significantly increased for the RT group. Further studies are needed to determine if modern RT techniques and field-size reductions may lead to improvements in the therapeutic ratio. No significant financial relationships to disclose.
Expression of Aquaporin-1 in Human Peritoneal Mesothelial Cells and Its Upregulation by Glucose In Vitro
Authors: KAR NENG LAI, FU KEUNG LI, HAO YUI LAN, SYDNEY TANG, ANITA W. L. TSANG, DANIEL T. M. CHAN, JOSEPH C. LEUNG
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Aquaporin (AQP) is a family of water channels that are highly selective for the passage of water and occasionally glycerol. In previous studies, only AQP1 was found in human peritoneal endothelial cells in both control subjects and patients on peritoneal dialysis. As human peritoneal mesothelial cells (HPMC) play an important role in dialysis adequacy and fluid balance in continuous ambulatory peritoneal dialysis patients, this study examined whether AQP1 is present in HPMC. It was found that AQP1 mRNA and protein are present in HPMC constitutively. The localization of AQP1 protein in peritoneal mesothelial cells was confirmed by double immunohistochemical staining of the mesothelial lining of human peritoneal membrane. More important, the expression of AQP1 in HPMC is not constitutive and the transcription and biosynthesis of AQP1 in HPMC is inducible by osmotic agents such as glucose and mannitol. There was significant enhancement of AQP1 biosynthesis upon exposure to glucose in a time- and dose-dependent manner ( P &lt; 0.0001). Similar findings were observed in the AQP1 biosynthesis by an endothelial cell line, EA.hy 926. Of particular interest, the upregulation in AQP1 mRNA or biosynthesis in mesothelial cells was always significantly higher than that of endothelial cells when the experiments were conducted under identical settings ( P &lt; 0.001). AQP1 expression in HPMC was demonstrated for the first time. Osmotic agents upregulate both mRNA and protein expression of this aquaporin. The role of AQP1 in HPMC in maintaining the ultrafiltration of the peritoneal membrane is potentially of clinical interest.
Abstract 176: Intravenous Infusion Of Glycated End Products Induces Cardiac Remodeling And Fibrosis Through RAGE Mediated Oxidative Stress
Authors: Umadevi Subramanian, Elangovan Vellaichamy
Journal: Circulation Research (2013)

Advanced glycation end products (AGEs) play a major role in the development of cardiovascular disorders in diabetic patients. Growing evidence has shown that the western diet is a plentiful source of exogenous AGEs. However, the direct impact of these AGEs on cardiac remodeling process is not well understood. Thus, the present study was intended to scrutinize the long term effects of circulating AGEs on cardiac extracellular matrix alterations both in vivo , Wistar rats, and in vitro , H9C2(2-1) cardiac myofibroblast cells. In vivo Rats (n=8/group) were administered with an intravenous infusion of in vitro prepared glycated-RSA (AGEs-RSA) (50 mg/kg /day for 30 days), while control animals received the non-glycated-RSA. In vitro , H9C2 (2-1) cardiac myofibroblast cells were exposed to AGEs (100µg/ml) for 24 hours. Upon AGEs infusion, a significant increase in fibrosis (3-fold, p&lt;0.01) with increased expression of matrix genes MMP-2 and -9 (P&lt;0.01, respectively), CTGF (p&lt;0.01) and TGF-β (P&lt;0.01) was found in the heart tissues compared to non-glycated-RSA infused rats. Furthermore, an increase in mRNA and protein expression of RAGE (receptor for AGE), and NADPH oxidase (NOX-p47 phox subunit), iNOS and NF-κB was observed in the heart tissue of AGEs infused rats. Furthermore, induction of lipid peroxides (p&lt;0.001) were also found in the heart tissue of AGEs-RSA infused rats. Similarly, H9C2 (2-1) cells exposed to AGEs-RSA demonstrated a significant increase in ROS release (DCF fluorescence, p&lt;0.001) with augmented expression of RAGE ( P &lt;0.01) and NOX-p47 phox ( p &lt;0.001) compared to untreated cells. Whereas, cells pre-treated with N-Acetyl cysteine and RAGE neutralizing antibody significantly impeded the NOX expression ( p &lt;0.01) and attenuated the up-regulation of RAGE and NF-κB in AGEs-RSA treated H9C2 cells. Thus, the results of the present study demonstrated the deleterious effect of AGEs that directly induces oxidative stress and matrix derangement in heart tissue even when ingested through exogenous sources.