tbuckley/cabot-search huggingface dataset:
Popular drugs in sport: descriptive analysis of the enquiries made via the Drug Information Database (DID)
Authors: A Petróczi, D P Naughton
Journal: British Journal of Sports Medicine (2008)

To analyse enquiries made in the Drug Information Database (DID) to develop a better understanding of athletes' interests and concerns regarding the prohibited status of available substances.Retrospective analyses of anonymous enquiries recorded in the DID in 2006 and 2007.Athletes and supporting personnel.The DID recorded 223 717 enquiries with 200 of the >6000 UK licensed pharmaceutical products receiving over 100 enquiries each. The majority (79.2%) of these enquiries were in the pharmaceutical product category, followed by recreational drugs (10.4%). A variety of common medications were subject to enquiry, with anti-inflammatory agents, decongestants and bronchodilators being most common; a trend in keeping with reported medication use by athletes. Of all enquiries, 42% were not found owing to misspelled words or enquiries about unregulated substances. The proportion of enquiries about substances not listed in the database is relatively high and has increased over the 24 month observation period.The DID is a well-used information resource with some 10 000 enquiries being made each month. Of the c. 60% of successful enquiries, the major focus was on pharmaceutical products. With some 73% of enquiries being made by the athletes themselves, further investigations are warranted to explore enquiry patterns in relation to specific sports. Of the unsuccessful enquiries, a large number were related to nutritional supplements, which warrants further investigation. The DID database appears to be a valid mirror of athletes' chemically assisted practices and may be successfully used to inform health professionals as well as antidoping prevention programmes.
<i>ERG</i> Rearrangement for Predicting Subsequent Cancer Diagnosis in High-Grade Prostatic Intraepithelial Neoplasia and Lymph Node Metastasis
Authors: Xin Gao, Liao-Yuan Li, Fang-Jian Zhou, Ke-Ji Xie, Chun-Kui Shao, Zu-Lan Su, Qi-Peng Sun, Ming-Kun Chen, Jun Pang, Xiang-Fu Zhou, Jian-Guang Qiu, Xing-Qiao Wen, Ming Yang, Xian-Zhong Bai, Hao Zhang, Li Ling, Zhong Chen
Journal: Clinical Cancer Research (2012)

We aimed to analyze whether ERG rearrangement in biopsies could be used to assess subsequent cancer diagnosis in high-grade prostatic intraepithelial neoplasia (HGPIN) and the risk of lymph node metastasis in early prostate cancer.Samples from 523 patients (361 with early prostate cancer and 162 with HGPIN) were collected prospectively. On the basis of the cutoff value established previously, the 162 patients with HGPIN were stratified to two groups: one with an ERG rearrangements rate ≥1.6% (n = 59) and the other with an ERG rearrangements rate <1.6% (n = 103). For the 361 prostate cancer cases undergoing radical prostatectomy, 143 had pelvic lymph node dissection (node-positive, n = 56 and node-negative, n = 87). All ERG rearrangement FISH data were validated with ERG immunohistochemistry.A total of 56 (of 59, 94.9%) HGPIN cases with an ERG rearrangements rate ≥1.6% and 5 (of 103, 4.9%) HGPIN cases with an ERG rearrangements rate <1.6% were diagnosed with prostate cancer during repeat biopsy follow-ups (P < 0.001). There were significant differences in ERG rearrangement rates between lymph node-positive and -negative prostate cancer (P < 0.001). The optimal cutoff value to predict lymph node metastasis by ERG rearrangement was established, being 2.6% with a sensitivity at 80.4% [95% confidence interval (CI), 67.6-89.8] and a specificity at 85.1% (95% CI, 75.8-91.8). ERG protein expression by immunohistochemistry was highly concordant with ERG rearrangement by FISH.The presence of ERG rearrangement in HGPIN lesions detected on initial biopsy warrants repeat biopsies and measuring ERG rearrangement could be used for assessing the risk of lymph node metastasis in early prostate cancer.
Molecular Pathways: Emerging Pathways Mediating Growth, Invasion, and Metastasis of Tumors Progressing in an Irradiated Microenvironment
Authors: François Kuonen, Chiara Secondini, Curzio Rüegg
Journal: Clinical Cancer Research (2012)

Abstract Radiotherapy is a well-established therapeutic modality in oncology. It provides survival benefits in several different cancer types. However, cancers relapsing after radiotherapy often develop into more aggressive conditions that are difficult to treat and are associated with poor prognosis. Cumulative experimental evidence indicates that the irradiated tumor bed contributes to such aggressive behavior. The involved mechanisms have for long remained elusive. Recent progress in the field revealed previously unrecognized cellular and molecular events promoting growth, invasion, and metastasis of tumors progressing in an irradiated microenvironment. Cellular mechanisms include inhibition of sprouting angiogenesis, formation of hypoxia, activation and differentiation of stromal cells, and recruitment of bone marrow–derived cells with vasculogenic and prometastatic activities. Identified pathways include TGF-β/ALK5, CXCL12/CXCR4, KITL/KIT, and CYR61/αVβ5 integrin. The availability of pharmacologic inhibitors impinging on these pathways opens novel opportunities for translational and clinical studies. These experimental results and ongoing work highlight the importance of the irradiated microenvironment in modulating the tumor response to radiotherapy and open new opportunities for the development of novel therapeutic strategies for patients with cancer who relapse after radiotherapy. Here, we review and discuss recent advances in the field and their translational and therapeutic implications to human cancer treatment. Clin Cancer Res; 18(19); 5196–202. ©2012 AACR.
αENaC-Mediated Lithium Absorption Promotes Nephrogenic Diabetes Insipidus
Authors: Birgitte Mønster Christensen, Annie Mercier Zuber, Johannes Loffing, Jean-Christophe Stehle, Peter M.T. Deen, Bernard C. Rossier, Edith Hummler
Journal: Journal of the American Society of Nephrology (2010)

Lithium-induced nephrogenic diabetes insipidus (NDI) is accompanied by polyuria, downregulation of aquaporin 2 (AQP2), and cellular remodeling of the collecting duct (CD). The amiloride-sensitive epithelial sodium channel (ENaC) is a likely candidate for lithium entry. Here, we subjected transgenic mice lacking αENaC specifically in the CD (knockout [KO] mice) and littermate controls to chronic lithium treatment. In contrast to control mice, KO mice did not markedly increase their water intake. Furthermore, KO mice did not demonstrate the polyuria and reduction in urine osmolality induced by lithium treatment in the control mice. Lithium treatment reduced AQP2 protein levels in the cortex/outer medulla and inner medulla (IM) of control mice but only partially reduced AQP2 levels in the IM of KO mice. Furthermore, lithium induced expression of H+-ATPase in the IM of control mice but not KO mice. In conclusion, the absence of functional ENaC in the CD protects mice from lithium-induced NDI. These data support the hypothesis that ENaC-mediated lithium entry into the CD principal cells contributes to the pathogenesis of lithium-induced NDI.
Isolated cranial nerve syndromes without proximal carotid involvement in aortoarteritis
Authors: G R Shroff
Journal: Annals of the Rheumatic Diseases (2004)

Takayasu’s arteritis or aortoarteritis affects the aorta and its proximal branches.1 Cranial nerve involvement in the form of ischaemic optic neuropathy secondary to proximal carotid involvement is common.2 Involvement of other cranial nerves has been reported only once before.3 We report two patients with aortoarteritis who developed isolated cranial nerve palsies. Notably, in both cases it occurred without proximal carotid involvement.

Patient 1, a 30 year old businessman, presented with malignant hypertension because of right renal artery stenosis due to aortoarteritis affecting the abdominal aorta. After successful balloon angioplasty, blood pressure was well controlled with antihypertensive drugs. Two years later he developed sudden headache and diplopia on looking towards the left. Examination showed a convergent squint in the left eye due to abducens nerve palsy. Contrast enhanced brain …
TNF mediates lung leak, but not neutrophil accumulation, in lungs of rats given IL-1 intratracheally.
Authors: B M Hybertson, E K Jepson, O J Cho, J H Clarke, Y M Lee, J E Repine
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Interleukin-1 (IL-1) is increased in lung lavages obtained from patients with acute respiratory distress syndrome, and administering IL-1 intratracheally to rats causes an acute, neutrophil-dependent, oxidative lung leak. We found that rats given IL-1 intratracheally had increased lung lavage fluid tumor necrosis factor (TNF) levels, and that rats treated with TNF binding protein (TNFbp) intravenously did not develop the increased lung leak that occurs after administration of IL-1 intratracheally. In contrast, rats given IL-1 intratracheally and TNFbp intravenously had the same elevations in lung lavage neutrophil accumulation and lung lavage cytokine-induced neutrophil chemoattractant levels as rats given IL-1 intratracheally. Our results show that TNFbp decreases neutrophil-mediated lung leak, but not lung neutrophil accumulation, after administration of IL-1 intratracheally in rats.
Visceral adiposity and risk of type 2 diabetes: a prospective study among Japanese Americans.
Authors: E J Boyko, W Y Fujimoto, D L Leonetti, L Newell-Morris
Journal: Diabetes Care (2000)

OBJECTIVE: We conducted a prospective study among Japanese Americans of diabetes incidence in relation to visceral and regional adiposity, fasting insulin and C-peptide, and a measure of insulin secretion, because little prospective data exist on these associations. RESEARCH DESIGN AND METHODS: Baseline variables included plasma glucose, C-peptide, and insulin measured after an overnight fast and 30 and 120 min after a 75-g oral glucose tolerance test; abdominal, thoracic, and thigh fat areas by computed tomography (CT); BMI (kg/m2); and insulin secretion (incremental insulin response [IIR]). RESULTS: Study subjects included 290 second-generation (nisei) and 230 third-generation (sansei) Japanese Americans without diabetes, of whom 65 and 13, respectively, developed diabetes. Among nisei, significant predictors of diabetes risk for a 1 SD increase in continuous variables included intra-abdominal fat area (IAFA) (odds ratio, 95% CI) (1.6, 1.1-2.3), fasting plasma C-peptide (1.4, 1.1-1.8), and the IIR (0.5, 0.3-0.9) after adjusting for age, sex, impaired glucose tolerance, family diabetes history, and CT-measured fat areas other than intra-abdominal. Intra-abdominal fat area remained a significant predictor of diabetes incidence even after adjustment for BMI, total body fat area, and subcutaneous fat area, although no measure of regional or total adiposity was related to development of diabetes. Among sansei, all adiposity measures were related to diabetes incidence, but, in adjusted models, only IAFA remained significantly associated with higher risk (2.7, 1.4-5.4, BMI-adjusted). CONCLUSIONS: Greater visceral adiposity precedes the development of type 2 diabetes in Japanese Americans and demonstrates an effect independent of fasting insulin, insulin secretion, glycemia, total and regional adiposity, and family history of diabetes.
Increased Fc RII expression and aberrant tumour necrosis factor production by mature dendritic cells from patients with active rheumatoid arthritis
Authors: T R D J Radstake
Journal: Annals of the Rheumatic Diseases (2004)

To investigate potential differences in phenotype and behaviour of immature (iDC) and mature dendritic cells (mDC) from patients with RA and healthy subjects.iDC and mDC were derived from blood monocytes of patients with RA and healthy controls following standardised protocols. FACS was used to analyse expression of FcgammaRI, II, and III and molecules to characterise DC. Discrimination between FcgammaRIIa and FcgammaRIIb was achieved by RT-PCR. Immunohistochemistry was performed on synovial biopsy specimens of three patients with RA and three healthy controls. TNFalpha production by iDC and mDC upon FcgammaR dependent stimulation was compared between patients with RA and controls by ELISA.iDC from patients with active RA but not from patients with inactive RA or healthy controls markedly up regulated FcgammaRII. mDC from patients with active RA also lacked the physiological down regulation of FcgammaRII that occurs upon maturation in both control groups. RT-PCR analysis confirmed the increased expression of FcgammaRII in RA-especially marked for FcgammaRIIb. FcgammaR dependent stimulation of DC using antigen-IgG immune complexes (IC) significantly increased TNFalpha production by DC from healthy subjects, but significantly decreased TNFalpha by DC from patients with RA. Overlapping expression patterns between FcgammaRII and DC-LAMP in the synovial tissue of patients with RA imply that in vivo, also, mature DC express increased levels of FcgammaRIIb.The presence and altered characteristics of DC during active RA suggest that DC help to modulate autoimmunity in RA. Further studies should elucidate the role of local factors in altering the function of DC in RA and in increasing expression of FcgammaRII.
Heterogeneous Distribution of <i>EGFR</i> Mutations Is Extremely Rare in Lung Adenocarcinoma
Authors: Yasushi Yatabe, Keitaro Matsuo, Tetsuya Mitsudomi
Journal: Journal of Clinical Oncology (2011)

Some studies have shown that epidermal growth factor receptor (EGFR) mutations can be heterogeneously distributed in individual tumors. In this study, we re-evaluated the distribution of EGFR mutations within tumors.We used multiple approaches, including an analysis of simultaneous dual hot spot mutations, a trans-sectional analysis of individual lung adenocarcinomas, and comparisons of the mutation patterns between primary and metastatic sites and between primary and recurrent tumors.None of the 862 tumors harboring an EGFR mutation showed simultaneous dual hot spot mutations, although identical EGFR mutations were found throughout individual tumors in a trans-sectional analysis involving 50 tumors divided into three parts and five lung adenocarcinomas divided into 100 parts. In addition, no discordant mutation patterns were detected among 77 paired primary and metastatic site samples or among 54 primary and recurrent tumor pairs.All of these results suggest that the heterogeneous distribution of EGFR mutations is extremely rare. However, it is possible that pseudoheterogeneity occurs because of a combination of mutant allele-specific imbalance and heterogeneously distributed EGFR amplification, especially when a less sensitive method is used for detection. Specifically, when EGFR amplification occurs, the mutant allele is amplified, and this amplification is involved in invasive growth. Accordingly, invasive growth area significantly over-represents the mutation signal. In contrast, weak EGFR mutation signals in the area without EGFR amplification may not reach the threshold of detection because of the mixture with normal cells. Such unbalanced mutation signals might lead to pseudoheterogeneity.
Effect of a protein and energy dense n-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial
Authors: K C H Fearon
Journal: Gut (2003)

N-3 fatty acids, especially eicosapentaenoic acid (EPA), may possess anticachectic properties. This trial compared a protein and energy dense supplement enriched with n-3 fatty acids and antioxidants (experimental: E) with an isocaloric isonitrogenous control supplement (C) for their effects on weight, lean body mass (LBM), dietary intake, and quality of life in cachectic patients with advanced pancreatic cancer.A total of 200 patients (95 E; 105 C) were randomised to consume two cans/day of the E or C supplement (480 ml, 620 kcal, 32 g protein +/- 2.2 g EPA) for eight weeks in a multicentre, randomised, double blind trial.At enrolment, patients' mean rate of weight loss was 3.3 kg/month. Intake of the supplements (E or C) was below the recommended dose (2 cans/day) and averaged 1.4 cans/day. Over eight weeks, patients in both groups stopped losing weight (delta weight E: -0.25 kg/month versus C: -0.37 kg/month; p = 0.74) and LBM (Delta LBM E: +0.27 kg/month versus C: +0.12 kg/month; p = 0.88) to an equal degree (change from baseline E and C, p<0.001). In view of evident non-compliance in both E and C groups, correlation analyses were undertaken to examine for potential dose-response relationships. E patients demonstrated significant correlations between their supplement intake and weight gain (r = 0.50, p<0.001) and increase in LBM (r = 0.33, p = 0.036). Such correlations were not statistically significant in C patients. The relationship of supplement intake with change in LBM was significantly different between E and C patients (p = 0.043). Increased plasma EPA levels in the E group were associated with weight and LBM gain (r = 0.50, p<0.001; r = 0.51, p = 0.001). Weight gain was associated with improved quality of life (p<0.01) only in the E group.Intention to treat group comparisons indicated that at the mean dose taken, enrichment with n-3 fatty acids did not provide a therapeutic advantage and that both supplements were equally effective in arresting weight loss. Post hoc dose-response analysis suggests that if taken in sufficient quantity, only the n-3 fatty acid enriched energy and protein dense supplement results in net gain of weight, lean tissue, and improved quality of life. Further trials are required to examine the potential role of n-3 enriched supplements in the treatment of cancer cachexia.
Hyperoxemic reperfusion with aqueous oxygen improves left ventricular function and microvascular flow in the postischemic canine myocardium
Authors: J.R. Spears, P. Prcevski, A.J. Jiang, X. Wu, A. Spanta, R.V. Heide, M. DiCarli, S. Lavine, R.J. Crilly
Journal: Journal of the American College of Cardiology (1998)
Hypoxic Activation of the PERK/eIF2α Arm of the Unfolded Protein Response Promotes Metastasis through Induction of LAMP3
Authors: Hilda Mujcic, Anika Nagelkerke, Kasper M.A. Rouschop, Stephen Chung, Naz Chaudary, Paul N. Span, Blaise Clarke, Michael Milosevic, Jenna Sykes, Richard P. Hill, Marianne Koritzinsky, Bradly G. Wouters
Journal: Clinical Cancer Research (2013)

Conditions of poor oxygenation (hypoxia) are present in many human tumors, including cervix cancer, and are associated with increased risk of metastasis and poor prognosis. Hypoxia is a potent activator of the PERK/eIF2α signaling pathway, a component of the unfolded protein response (UPR) and an important mediator of hypoxia tolerance and tumor growth. Here, the importance of this pathway in the metastasis of human cervix carcinoma was investigated.Amplification and expression of LAMP3, a UPR metastasis-associated gene, was examined using FISH and immunofluorescence in a cohort of human cervix tumors from patients who had received oxygen needle electrode tumor oxygenation measurements. To evaluate the importance of this pathway in metastasis in vivo, we constructed a series of inducible cell lines to interfere with PERK signaling during hypoxia and used these in an orthotopic cervix cancer model of hypoxia-driven metastasis.We show that LAMP3 expression in human cervix tumors is augmented both by gene copy number alterations and by hypoxia. Induced disruption of PERK signaling in established orthotopic xenografts resulted in complete inhibition of hypoxia-induced metastasis to the lymph nodes. This is due, in part, to a direct influence of the UPR pathway on hypoxia tolerance. However, we also find that LAMP3 is a key mediator of hypoxia-driven nodal metastasis, through its ability to promote metastatic properties including cell migration.These data suggest that the association between hypoxia, metastasis, and poor prognosis is due, in part, to hypoxic activation of the UPR and expression of LAMP3. Clin Cancer Res; 19(22); 6126-37. ©2013 AACR.
Incidence of <i>BRCA1</i> and <i>BRCA2</i> Mutations in Young Korean Breast Cancer Patients
Authors: Doo Ho Choi, Min Hyuk Lee, Allen E. Bale, Darryl Carter, Bruce G. Haffty
Journal: Journal of Clinical Oncology (2004)

Purpose The prevalence of BRCA-associated breast carcinoma in the Korean population has not been evaluated extensively. Methods Sixty Korean women who developed breast cancer by age 40 years were studied. Lymphocyte specimens from peripheral blood were processed for BRCA1 and BRCA2 by complete sequencing. Family history through three generations was obtained. Available paraffin-embedded tissue blocks were processed for immunohistochemical staining. Results In the cohort of 60 patients, nine patients with 11 deleterious mutations (six in BRCA1 and five in BRCA2) and seven missense mutations of unknown significance were found. Two patients had deleterious mutations in both BRCA1 and BRCA2 (double mutant). One half of the mutations were novel, and no founder mutations were observed in this cohort. Most of the BRCA-associated patients had no family history of breast and/or ovarian cancer. The expression of HER-2/neu, cyclin D1, and hormone receptors was less common, and p53 overexpression was more common in BRCA-associated tumors. Conclusion The prevalence of BRCA1 and BRCA2 mutations in Korean women with breast cancer at a young age was high. However, the penetrance, as evidenced by the low frequency of breast and ovarian cancers in family members, appears to be low. These data suggest that there may be different genetic and etiologic factors affecting transmission and penetrance of the BRCA genes in Korean patients with breast cancer diagnosed at a young age.