tbuckley/cabot-search huggingface dataset:
Phase I Clinical and Pharmacokinetic Study of Pemetrexed and Carboplatin in Patients With Malignant Pleural Mesothelioma
Authors: Andy Hughes, Paula Calvert, Ashraf Azzabi, Ruth Plummer, Rob Johnson, Jim Rusthoven, Melanie Griffin, Kevin Fishwick, Alan V Boddy, Mark Verrill, Hilary Calvert
Journal: Journal of Clinical Oncology (2002)

To determine the maximum tolerated dose (MTD) of pemetrexed and carboplatin given in combination, to derive a recommended dose for phase II studies, and to explore its efficacy. We assessed toxicities and explored the activity of the drug combination exclusively in patients with malignant pleural mesothelioma (MPM). The pharmacokinetics of both agents was investigated.Twenty-seven patients (23 male, four female) with MPM were treated on five escalating dose levels. Doses ranged from pemetrexed 400 mg/m(2) (as a 10-minute intravenous infusion), followed by carboplatin area under the plasma concentration-time curve (AUC) 4 mg/mL.min (as a 30-minute intravenous infusion) to pemetrexed 500 mg/m(2), carboplatin AUC 6 mg/mL.min. All patients had a World Health Organization performance status of 1. A total of 163 courses of treatment were administered (median, six; range, one to 10).The main toxicity was hematologic, particularly neutropenia, although this was characteristically short-lived and caused few clinical problems. The MTD was pemetrexed 500 mg/m(2), carboplatin AUC 6, because three of the five patients treated at this dose level experienced a dose-limiting toxicity. Eight partial responses (in 25 assessable patients) were observed for a response rate of 32%. Seventy percent of patients noticed an improvement in symptoms, usually (84%) after only two courses. Median time to progression was 305 days, and median survival time was 451 days.The MTD was pemetrexed 500 mg/m(2) and carboplatin AUC 6 mg/mL.min. The recommended phase II dose of the combination is pemetrexed 500 mg/m(2) and carboplatin AUC 5 mg/mL.min. The combination is both active and well tolerated in MPM and deserves further exploration.
Suppression of Centrosome Amplification after DNA Damage Depends on p27 Accumulation
Authors: Eiji Sugihara, Masayuki Kanai, Soichiro Saito, Takayuki Nitta, Hideo Toyoshima, Keiko Nakayama, Keiichi I. Nakayama, Kenji Fukasawa, Manfred Schwab, Hideyuki Saya, Masanao Miwa
Journal: Cancer Research (2006)

The centrosome plays a fundamental role in cell division, cell polarity, and cell cycle progression. Centrosome duplication is mainly controlled by cyclin-dependent kinase 2 (CDK2)/cyclin E and cyclin A complexes, which are inhibited by the CDK inhibitors p21Cip1 and p27Kip1. It is thought that abnormal activation of CDK2 induces centrosome amplification that is frequently observed in a wide range of aggressive tumors. We previously reported that overexpression of the oncogene MYCN leads to centrosome amplification after DNA damage in neuroblastoma cells. We here show that centrosome amplification after gamma-irradiation was caused by suppression of p27 expression in MYCN-overexpressing cells. We further show that p27-/- and p27+/- mouse embryonic fibroblasts and p27-silenced human cells exhibited a significant increase in centrosome amplification after DNA damage. Moreover, abnormal mitotic cells with amplified centrosomes were frequently observed in p27-silenced cells. In response to DNA damage, the level of p27 gradually increased in normal cells independently of the ataxia telangiectasia mutated/p53 pathway, whereas Skp2, an F-box protein component of an SCF ubiquitin ligase complex that targets p27, was reduced. Additionally, p27 levels in MYCN-overexpressing cells were restored by treatment with Skp2 small interfering RNA, indicating that down-regulation of p27 by MYCN was due to high expression of Skp2. These results suggest that the accumulation of p27 after DNA damage is required for suppression of centrosome amplification, thereby preventing chromosomal instability.
OPG Is Regulated by β-Catenin and Mediates Resistance to TRAIL-Induced Apoptosis in Colon Cancer
Authors: Enrico N. De Toni, Susanne E. Thieme, Andreas Herbst, Andrea Behrens, Petra Stieber, Andreas Jung, Helmut Blum, Burkhard Göke, Frank T. Kolligs
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Resistance to apoptosis is a hallmark of cancer and correlates with aggressiveness of tumors and poor prognosis. The Wnt/β-catenin pathway plays a pivotal role in the genesis of colorectal cancer by mechanisms not fully elucidated yet. Previous studies have linked regulation of osteoprotegerin (OPG) in bone to Wnt/β-catenin signaling. As OPG also serves as a decoy receptor for tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), we hypothesized that OPG might play a role in mediating resistance to apoptosis in colorectal cancer cells. Experimental Design: Expression analysis and functional studies in human colorectal cancer cell lines and determination of expression in primary tumors and sera from patients with colorectal cancer. Results: We found production of OPG in colorectal cancer cells to be regulated by β-catenin/Tcf-4. Addition of exogenous OPG to colorectal cancer cells caused resistance to TRAIL. Similarly, accumulation of OPG in medium of cultivated cells caused resistance to TRAIL, and this could be reverted by removal of OPG. Furthermore, OPG levels were significantly increased in serum of patients with advanced disease. Conclusions: We conclude that the Wnt/β-catenin pathway contributes to carcinogenesis and cancer cell survival by driving expression of OPG. Expression of the survival factor OPG might provide colorectal cancer cells with an essential growth advantage and contribute to cell invasion and metastasis. Inhibition of OPG expression might offer a new therapeutic approach for the treatment of patients with colorectal tumors overexpressing OPG and make these tumors sensitive to TRAIL-induced apoptosis.
Book Review Gynecologic Oncology: Current diagnosis and treatment Edited by Hugh M. Shingleton, Wesley C. Fowler, Jr., Joseph A. Jordan, and W. Dwayne Lawrence. 604 pp., illustrated. Philadelphia, W.B. Saunders, 1996. $95. 0-7020-1839-2
Authors: James Tate Thigpen
Journal: New England Journal of Medicine (1996)
Tumor-Associated Transplantation Antigen Distinct From H-2k-like Antigens on a BALB/c (H-2d) Fibrosarcoma2
Authors: Giorgio Parmiani, Angela Meschini, Giovanni Invernizzi, Giusi Carbone
Journal: JNCI Journal of the National Cancer Institute (1978)

To ascertain whether the foreign H-2.1, H-2.5, H-2.11, H-2.23, and H-2.25 antigens on a 3-methylcholanthrene-induced BALB/cLacDp (C) (H-2d) fibrosarcoma C-1 may represent the fibrosarcoma's Individual tumor-associated transplantation antigen (TATA), in vivo Immunogenicity tests were performed in C mice (H-2d); In (BALB/cLacDp × C3Hf/HeDp)F1 (CC3F1), (BALB/cLacDp × AKR/RdDp)F1 (CAKF1), and (BALB/cLacDp × B10.BR/SgSn)F1 (CBRF1) mice (all H-2d × H-2k); In (BALB/cLacDp ×A/HeN)F1 (CAF1) mice (H-2d × H-2Q); In (BALB/cLacDp ×DBA/2ChR)F1 (CD2F1) mice (H-2d ×H-2d); in (BALB/cLacDp × C57BL/6JDp)F1 (CB6F1) mice (H-2d ×H-2"); and In (BALB/cLacDp × N:NIH/Dp)F1 (CNIHF1) mice (H-2d × H-2q). The C-1 tumor lost its Immunogenlclty only In CC3F1 mice and partially in CAF1 mice. Multiple immunizations with C-1 cells in C and hybrid mice showed that C mice developed both In vivo resistance to tumor challenges of 105 C-1 cells (anti-TATA immunity) and production of antibodies to H-2k antigens as revealed by a complement-dependent cytotoxicity assay on normal C3Hf/HeDp (C3) lymphocytes. No effector lymphocytes to H-2k antigens were, however, found In the mice that had detectable levels of anti-H-2k antibodies. CC3F1 animals were unable to mount both antl-TATA and antl-H-2k Immune responses, whereas CAKF1, CBRF1 and, to a lesser extent, CAF1 mice displayed antlTATA Immunity In the absence of anti-H-2k antibody production. CD2F1 mice behaved like C mice, whereas CB6F1 and CNIHF1 crosses were resistant to tumor challenge but had lower titers of anti-H-2k antibodies than did C mice. A time-course study of ant-H-2k antibody production in C mice revealed a peak In the production of antibody after the sixth Immunization, with a very low or undetectable level of such antibodies being evident after one or two immunizations, when a clear antitumor Immunity was present. In the last experiment, immunization of C mice with irradiated C-1 cells “coated” with C anti-C3 sera or C anti-C-1 sera inhibited antl-H-2k antibody production without affecting the anti-TATA Immunity. We conclude that H-2k antigens and TATA are probably independent antigenic entities on C-1 cells or at least that the largest part of TATA cannot be formed by H-2 allen determlnants.
Effect of Fructose on Glycemic Control in Diabetes
Authors: Adrian I. Cozma, John L. Sievenpiper, Russell J. de Souza, Laura Chiavaroli, Vanessa Ha, D. David Wang, Arash Mirrahimi, Matt E. Yu, Amanda J. Carleton, Marco Di Buono, Alexandra L. Jenkins, Lawrence A. Leiter, Thomas M.S. Wolever, Joseph Beyene, Cyril W.C. Kendall, David J.A. Jenkins
Journal: Diabetes Care (2012)

OBJECTIVE The effect of fructose on cardiometabolic risk in humans is controversial. We conducted a systematic review and meta-analysis of controlled feeding trials to clarify the effect of fructose on glycemic control in individuals with diabetes. RESEARCH DESIGN AND METHODS We searched MEDLINE, EMBASE, and the Cochrane Library (through 22 March 2012) for relevant trials lasting ≥7 days. Data were aggregated by the generic inverse variance method (random-effects models) and expressed as mean difference (MD) for fasting glucose and insulin and standardized MD (SMD) with 95% CI for glycated hemoglobin (HbA1c) and glycated albumin. Heterogeneity was assessed by the Cochran Q statistic and quantified by the I2 statistic. Trial quality was assessed by the Heyland methodological quality score (MQS). RESULTS Eighteen trials (n = 209) met the eligibility criteria. Isocaloric exchange of fructose for carbohydrate reduced glycated blood proteins (SMD −0.25 [95% CI −0.46 to −0.04]; P = 0.02) with significant intertrial heterogeneity (I2 = 63%; P = 0.001). This reduction is equivalent to a ∼0.53% reduction in HbA1c. Fructose consumption did not significantly affect fasting glucose or insulin. A priori subgroup analyses showed no evidence of effect modification on any end point. CONCLUSIONS Isocaloric exchange of fructose for other carbohydrate improves long-term glycemic control, as assessed by glycated blood proteins, without affecting insulin in people with diabetes. Generalizability may be limited because most of the trials were &amp;lt;12 weeks and had relatively low MQS (&amp;lt;8). To confirm these findings, larger and longer fructose feeding trials assessing both possible glycemic benefit and adverse metabolic effects are required.
Downregulation of microRNA-182-5p contributes to renal cell carcinoma proliferation via activating the AKT/FOXO3a signaling pathway
Authors: Xin Xu, Jian Wu, Shiqi Li, Zhenghui Hu, Xianglai Xu, Yi Zhu, Zhen Liang, Xiao Wang, Yiwei Lin, Yeqing Mao, Hong Chen, Jindan Luo, Ben Liu, Xiangyi Zheng, Liping Xie
Journal: Molecular Cancer (2014)

Emerging evidence has suggested that dysregulation of miR-182-5p may contribute to tumor development and progression in several types of human cancers. However, its role in renal cell carcinoma (RCC) is still unknown.Quantitative RT-PCR was used to quantify miR-182-5p expression in RCC clinical tissues. Bisulfite sequencing PCR was used for DNA methylation analysis. The CCK-8, colony formation, flow cytometry, and a xenograft model were performed. Immunohistochemistry was conducted using the peroxidase and DAB methods. A miR-182-5p target was determined by luciferase reporter assays, quantitative RT-PCR, and Western blotting.miR-182-5p is frequently down-regulated in human RCC tissues. Epigenetic modulation may be involved in the regulation of miR-182-5p expression. Enforced expression of miR-182-5p in RCC cells significantly inhibited the proliferation and tumorigenicity in vitro and in vivo. Additionally, overexpression of miR-182-5p induced G1-phase arrest via inhibition of AKT/FOXO3a signaling. Moreover, FLOT1 was confirmed as a target of miR-182-5p. Silencing FLOT1 by small interfering RNAs phenocopied the effects of miR-182-5p overexpression, whereas restoration of FLOT1 in miR-182-5p -overexpressed RCC cells partly reversed the suppressive effects of miR-182-5p.These findings highlight an important role for miR-182-5p in the pathogenesis of RCC, and restoration of miR-182-5p could be considered as a potential therapeutic strategy for RCC therapy.
Gastric pathology in patients with common variable immunodeficiency
Authors: A Zullo, A Romiti, V Rinaldi, A Vecchione, S Tomao, F Aiuti, L Frati, G Luzi
Journal: Gut (1999)

Common variable immunodeficiency (CVID) is an immunological disorder characterised by defective antibody production. Patients with CVID have a high risk of gastric cancer. It has been suggested that gastric cancer results from an interaction between environmental factors and a genetic predisposition. The role of Helicobacter pylori as an environmental factor in gastric carcinogenesis is of current interest. Moreover, p53 gene mutations have been reported in gastric cancer. This study focuses on the gastric pathology of patients with CVID and correlation with H pylori infection.Thirty four consecutive dyspeptic patients with CVID (mean age 49.6 years, range 14-72; 17 men) were included in the study. An upper gastrointestinal endoscopy was performed and biopsy specimens were taken from the antrum, incisura angularis, and gastric body. Biopsies were used for histological assessment, to identify the presence of H pylori, and to evaluate p53 overexpression.H pylori infection was detected in 14/34 (41%) patients. Chronic active gastritis involving both antrum and body was observed more frequently in H pylori positive (79%) than H pylori negative (20%) patients (p = 0.001). Similarly, a histological feature of multifocal atrophic gastritis was found more frequently in infected (50%) than uninfected patients (10%) (p = 0.012). In addition, one case of gastric adenocarcinoma and another of notable dysplasia were observed in the H pylori positive group. Overexpression of p53 was found in six (18%) patients, including one with normal gastric mucosa.It can be hypothesised that both H pylori and p53 alterations play a role in the gastric carcinogenesis of patients with CVID.
Altered Placebo and Drug Labeling Changes the Outcome of Episodic Migraine Attacks
Authors: Slavenka Kam-Hansen, Moshe Jakubowski, John M. Kelley, Irving Kirsch, David C. Hoaglin, Ted J. Kaptchuk, Rami Burstein
Journal: Science Translational Medicine (2014)

In 459 migraine attacks, information provided to patients (from negative to neutral to positive) modified placebo and medication outcomes in a progressive fashion.
Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors
Authors: C.J.A. van Moorsel, J.R. Kroep, H.M. Pinedo, G. Veerman, D.A. Voorn, P.E. Postmus, J.B. Vermorken, C.J. van Groeningen, W.J.F. van der Vijgh, G.J. Peters
Journal: Annals of Oncology (1999)
Microvascular Perfusion Abnormalities of the Thalamus in Painful but Not Painless Diabetic Polyneuropathy
Authors: Dinesh Selvarajah, Iain D. Wilkinson, Rajiv Gandhi, Paul D. Griffiths, Solomon Tesfaye
Journal: Diabetes Care (2011)

The pathogenesis of painful diabetic neuropathy (DN) remains undetermined, with both central and peripheral mechanisms implicated. This study investigates whether thalamic perfusion abnormalities occur in painful DN.Eighteen subjects with type 1 diabetes (no DN = 6, painful DN = 5, painless DN = 7) and six healthy volunteers (HV) were recruited. Microvascular perfusion characteristics (relative cerebral blood volume [rCBV], flow [rCBF], and transit time [tt(FM)]) of the thalamus and caudate nucleus were assessed using magnetic resonance perfusion imaging. The caudate nucleus was chosen to serve as an in vivo control region.Subjects with painful DN had significantly greater thalamic rCBV (means [SD]; painful DN, 228.7 [19.5]; no DN, 202.3 [25.8]; painless DN, 216.5 [65.5]; HV, 181.9 [51.7]; P = 0.04) and the longest tt(FM)(s) (painful DN, 38.4 [3.6]; no DN, 35.3 [13.2]; painless DN, 35.9 [13.7]; HV, 33.7 [14.9]; P = 0.07). There was no significant difference in markers of caudate nucleus perfusion.Painful DN is associated with increased thalamic vascularity. This may provide an important clue to the pathogenesis of pain in DN.
Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation
Authors: Guido von Figura, John P Morris, Christopher V E Wright, Matthias Hebrok
Journal: Gut (2013)

<h3>Objectives</h3> Emerging evidence from mouse models suggests that mutant Kras can drive the development of pancreatic ductal adenocarcinoma (PDA) precursors from acinar cells by enforcing ductal de-differentiation at the expense of acinar identity. Recently, human genome-wide association studies have identified <i>NR5A2</i>, a key regulator of acinar function, as a susceptibility locus for human PDA. We investigated the role of Nr5a2 in exocrine maintenance, regeneration and Kras driven neoplasia. <h3>Design</h3> To investigate the function of Nr5a2 in the pancreas, we generated mice with conditional pancreatic Nr5a2 deletion (<i>PdxCre<sup>late</sup>; Nr5a2<sup>c/c</sup></i>). Using this model, we evaluated acinar differentiation, regeneration after caerulein pancreatitis and Kras driven pancreatic neoplasia in the setting of Nr5a2 deletion. <h3>Results</h3> We show that Nr5a2 is not required for the development of the pancreatic acinar lineage but is important for maintenance of acinar identity. Nr5a2 deletion leads to destabilisation of the mature acinar differentiation state, acinar to ductal metaplasia and loss of regenerative capacity following acute caerulein pancreatitis. Loss of Nr5a2 also dramatically accelerates the development of oncogenic Kras driven acinar to ductal metaplasia and PDA precursor lesions. <h3>Conclusions</h3> Nr5a2 is a key regulator of acinar plasticity. It is required for maintenance of acinar identity and re-establishing acinar fate during regeneration. Nr5a2 also constrains pancreatic neoplasia driven by oncogenic Kras, providing functional evidence supporting a potential role as a susceptibility gene for human PDA.
Prevalence and Timing of Postpartum Glucose Testing and Sustained Glucose Dysregulation After Gestational Diabetes Mellitus
Authors: Jean M. Lawrence, Mary Helen Black, Jin-Wen Hsu, Wansu Chen, David A. Sacks
Journal: Diabetes Care (2009)

OBJECTIVE To estimate the prevalence of postpartum glucose testing within 6 months of pregnancies complicated by gestational diabetes mellitus (GDM), assess factors associated with testing and timing of testing after delivery, and report the test results among tested women. RESEARCH DESIGN AND METHODS This was a retrospective study of 11,825 women who were identified as having GDM using the 100-g oral glucose tolerance test (OGTT) from 1999 to 2006. Postpartum testing (75-g 2-h OGTT or fasting plasma glucose [FPG]) within 6 months of delivery and test results from laboratory databases are reported. Postpartum test results are categorized as normal, impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), and provisionally diabetic. RESULTS About half (n = 5,939) the women were tested with either a FPG or 75-g OGTT from 7 days to 6 months postpartum. Of these women, 46% were tested during the 6- to 12-week postpartum period. Odds of testing were independently associated with age, race/ethnicity, household income, education, foreign-born status, parity, mode of delivery, having a postpartum visit, having GDM coded at discharge, and pharmacotherapy for GDM. Of the 5,857 women with test results, 16.3% (n = 956) had IFG/IGT and 1.1% (n = 66) had provisional diabetes. After adjustment for demographic and clinical factors, abnormal postpartum test results was associated with having required insulin, glyburide, or metformin during pregnancy and with longer period from delivery to postpartum testing. CONCLUSIONS After a pregnancy complicated by GDM, automated orders for postpartum testing with notification to physicians and electronically generated telephone and e-mail reminder messages to patients may improve the rates of postpartum testing for persistence of glucose intolerance.
Phospholipase A2 gene expression and activity in histologically normal ileal mucosa and in Crohn's ileitis.
Authors: I Lilja, K Smedh, G Olaison, R Sjodahl, C Tagesson, C Gustafson-Svard
Journal: Gut (1995)

Increased activity of phospholipase A2 (PLA2) in the ileal mucosa may contribute to the inflammation in Crohn9s disease. The results of this study showed that (a) three months after ileocolonic resection for Crohn9s disease the neoterminal ileal mucosa showed endoscopically new inflammation and had higher PLA2 activity than at the time of the operation (n = 8); no such findings were seen in controls (n = 7), (b) histologically normal ileal mucosa (n = 3) contained mRNA for three isoforms of PLA2 (PLA2-I, PLA2-II, and cPLA2), but the amounts of PLA2-II mRNA clearly exceeded the amounts of mRNA for PLA2-I and cPLA2, (c) ileal mucosa from Crohn9s patients (n = 2) contained higher values of PLA2-II mRNA than ileal mucosa from two controls, (d) ileal mucosa from Crohn9s patients (n = 4) showed increased PLA2-II mRNA three months after ileocolonic resection. In conclusion, these results show that the predominating PLA2 mRNA in the human ileal mucosa is type II PLA2, and the increased synthesis of PLA2-II might be responsible for the increased PLA2 activity found in the ileal mucosa accompanying recurrent ileal inflammation in Crohn9s disease.
Sex-specific trends in lung cancer incidence and survival: a population study of 40 118 cases
Authors: C. M. T. Sagerup, M. Smastuen, T. B. Johannesen, A. Helland, O. T. Brustugun
Journal: Thorax (2011)

<h3>Background and aim</h3> Lung cancer is increasingly affecting women. The aim of this study was to identify sex-specific trends in lung cancer incidence and survival. <h3>Methods</h3> Complete national data on 40 118 cases from the Cancer Registry of Norway sampled from 1988 to 2007 are presented, with incidence rates, 1- and 5-year relative survival in 5 year intervals and multivariate HRs adjusted for covariates, each with 95% CIs. <h3>Results</h3> Lung cancer incidence increased by 64%, with an age-adjusted annual average increase of 4.9% in women and 1.4% in men in this period. Relative survival was lower in men than in women in all time periods, and men had an increased risk of dying within 5 years of diagnosis compared with women (HR 1.14, 95% CI 1.11 to 1.17), adjusted for covariates. Adenocarcinoma is now the most frequent histological group in men and women, yet the risk of dying was higher in men in all histological subtypes except squamous cell carcinoma. A higher proportion of women than men were diagnosed with localised disease, and the risk of dying was significantly higher in men among all stages, most apparent in localised disease (HR 1.25, 95% CI 1.18 to 1.33). <h3>Conclusion</h3> The findings highlight important characteristics of the lung cancer epidemic; despite a rising incidence of female lung cancer cases, women are diagnosed with less advanced disease than men; when adjusted for covariates, men have an increased risk of excess death at 5 years compared with women, irrespective of stage, age, period of diagnosis and selected histological subgroups.