tbuckley/cabot-search huggingface dataset:
Dual Targeting of the Epidermal Growth Factor Receptor Using the Combination of Cetuximab and Erlotinib: Preclinical Evaluation and Results of the Phase II DUX Study in Chemotherapy-Refractory, Advanced Colorectal Cancer
Authors: Andrew J. Weickhardt, Tim J. Price, Geoff Chong, Val Gebski, Nick Pavlakis, Terrance G. Johns, Arun Azad, Effie Skrinos, Kate Fluck, Alexander Dobrovic, Renato Salemi, Andrew M. Scott, John M. Mariadason, Niall C. Tebbutt
Journal: Journal of Clinical Oncology (2012)

This preclinical and phase II study evaluated the efficacy and safety of the combination of cetuximab and erlotinib in metastatic colorectal cancer (mCRC).The activity and mechanism of action of the combination of cetuximab plus erlotinib were investigated in vitro in colorectal cancer cell lines. In the clinical study, patients with chemotherapy-refractory mCRC were treated with cetuximab 400 mg/m(2) as a loading dose and then weekly cetuximab 250 mg/m(2) with erlotinib 100 mg orally daily. The primary end point was response rate (RR), which was evaluated separately in KRAS wild-type (WT) versus KRAS mutant tumors. Secondary end points included toxicity, progression-free survival (PFS), and overall survival. Target accrual was 50 patients, with a one-stage design.Preclinical studies demonstrated synergistic activity of cetuximab and erlotinib cotreatment on growth inhibition of colon cancer cell lines both as a result of enhanced inhibition of the epidermal growth factor receptor pathway and differential effects on STAT3. In the clinical study, 50 patients were enrolled, with 48 patients evaluable for response. The overall RR was 31% (95% CI, 26% to 57%), with a median PFS of 4.6 months (95% CI, 2.8 to 5.6 months). RR was 41% (95% CI, 26% to 57%) in KRAS WT tumors, with a median PFS of 5.6 months (95% CI, 2.9 to 5.6 months). There was no response in 11 patients with KRAS mutations. Frequent grade 3 and 4 toxicities were rash (48%), hypomagnesaemia (18%), and fatigue (10%).The combination of cetuximab and erlotinib synergistically inhibits growth of colon cancer cell lines, achieves promising efficacy in patients with KRAS WT mCRC, and merits evaluation in further randomized studies.
Widespread CXCR4 Activation in Astrocytomas Revealed by Phospho-CXCR4-Specific Antibodies
Authors: B. Mark Woerner, Nicole M. Warrington, Andrew L. Kung, Arie Perry, Joshua B. Rubin
Journal: Cancer Research (2005)

Abstract The chemokine receptor CXCR4 is expressed in many cancers where it may regulate tumor cell growth and migration. The role of CXCR4 in cancer will depend on it being in an activated, signaling state. To better define the significance of CXCR4 expression in cancer, we developed an antibody that can distinguish CXCR4 phosphorylated on serine 339, a residue previously identified as a site for ligand-induced phosphorylation. With this antibody, we investigated the mechanisms of CXCR4 phosphorylation and evaluated the phosphorylation status of CXCR4 in human astrocytomas. In vitro, phosphorylation of serine 339 occurred in response to CXCL12 or epidermal growth factor (EGF) treatment and was increased by protein kinase C activation. In all grades of astrocytomas, CXCR4 was expressed in tumor cells and some endothelial cells, whereas CXCL12 was present in endothelial cells and infiltrating microglia. We found that CXCR4 phosphorylated on serine 339 was present in tumor cells and vascular endothelial cells in all grades of astrocytoma. These data indicate that CXCR4 is expressed and activated in astrocytomas and that phosphorylation of CXCR4 can occur through ligand activation or transactivation via the EGF receptor. These studies extend the potential roles of CXCR4 in cancer to include functions associated with benign (grade 1) tumors. The ability to distinguish phosphorylated CXCR4 will be invaluable for the continued analysis of the role of CXCR4 in cancer and the development of CXCR4 antagonist therapy for patients suffering with primary tumors of the brain and other sites. (Cancer Res 2005; 65(24): 11392-9)
Clinical Use of Bone Densitometry
Authors: Steven R. Cummings, David Bates, Dennis M. Black
Journal: JAMA (2002)

ContextOsteoporosis causes substantial morbidity and costs $13.8 billion annually in the United States. Measurement of bone mass by densitometry is a primary part of diagnosing osteoporosis and deciding a preventive treatment course. Bone mineral densitometry has become more widely available and commonly used in practice.ObjectiveTo review evidence about the value of various clinical applications of bone densitometry.Data SourcesA MEDLINE search was performed to update previous meta-analyses of the relationship between various measurements of bone density and risk of vertebral and hip fracture. We used data from the prospective Study of Osteoporotic Fractures to estimate risk of fracture from bone density and age in postmenopausal women.Study Selection and Data ExtractionWhen available, meta-analyses and systematic reviews are emphasized in the review.Data SynthesisBone mineral density (BMD) predicts fracture and can be used in combination with age to estimate absolute risk of fractures in postmenopausal white women. Hip BMD predicts hip fracture more strongly than other measurements of BMD. There are insufficient data to translate BMD results into risk of fracture for men and nonwhite women. The benefits of treatments to prevent fractures depend on BMD: women with osteoporosis have a greater risk of fractures and greater benefit from treatments than women without osteoporosis.ConclusionsGuidelines based on systematic reviews and a cost-effectiveness analysis have suggested that it is worthwhile to measure BMD in white women older than 65 years and perhaps to use risk factors to select younger postmenopausal women for densitometry. Other potential clinical applications of BMD that have not yet been adequately studied include screening men or nonwhite women, monitoring BMD in patients receiving treatment, and using BMD to identify patients who should be evaluated for secondary causes of osteoporosis.
Intrathymic differentiation of V gamma 3 T cells.
Authors: G Leclercq, J Plum, D Nandi, M De Smedt, J P Allison
Journal: The Journal of Experimental Medicine (1993)

Whereas there is considerable information on the phenotypic and functional maturation of T cell receptor (TCR) alpha/beta thymocytes, comparatively little is known of the maturational processes that affect development of TCR-gamma/delta thymocytes. One class of gamma/delta T cells, those bearing the V gamma 3 gene product, are generated only during the early fetal stages of thymic development, and then migrate to the skin. Here we examine the intrathymic differentiation of these V gamma 3+ cells. The earliest V gamma 3 cells to appear in the thymus expressed low levels of TCR (V gamma 3low) and high levels of heat stable antigen (HSA). Over the next few days, V gamma 3+ thymocytes appeared which expressed high levels of TCR (V gamma 3high) and very low levels of HSA. The antigens CD5, CD45RB, and MEL14 were also differentially expressed on V gamma 3low versus V gamma 3high thymocytes, but the shift in expression was the opposite as compared with immature and mature TCR-alpha/beta thymocytes. Transfer experiments of sorted V gamma 3low/HSAhigh thymocytes to SCID thymic lobes showed that these cells were indeed the precursors of V gamma 3high/HSAlow thymocytes. The phenotype of the V gamma 3high thymocytes was similar to that of the postthymic V gamma 3+ cells found in the skin of adult mice. The differentiation of V gamma 3low in V gamma 3high thymocytes was also observed in fetal thymic organ culture. Addition of cyclosporin A (CsA) to these cultures had little effect on the appearance of V gamma 3low/HSAhigh cells, but blocked the appearance of V gamma 3high/HSAlow cells. These results show that, like alpha/beta T cells, V gamma 3+ thymocytes differentiate from TCRlow precursors to cells with a mature phenotype and that CsA inhibits this transition.
The Role of Smoking and Diet in Explaining Educational Inequalities in Lung Cancer Incidence
Authors: G. Menvielle, H. Boshuizen, A. E. Kunst, S. O. Dalton, P. Vineis, M. M. Bergmann, S. Hermann, P. Ferrari, O. Raaschou-Nielsen, A. Tjonneland, R. Kaaks, J. Linseisen, M. Kosti, A. Trichopoulou, V. Dilis, D. Palli, V. Krogh, S. Panico, R. Tumino, F. L. Buchner, C. H. van Gils, P. H. M. Peeters, T. Braaten, I. T. Gram, E. Lund, L. Rodriguez, A. Agudo, M.-J. Sanchez, M.-J. Tormo, E. Ardanaz, J. Manjer, E. Wirfalt, G. Hallmans, T. Rasmuson, S. Bingham, K.-T. Khaw, N. Allen, T. Key, P. Boffetta, E. J. Duell, N. Slimani, V. Gallo, E. Riboli, H. B. Bueno-de-Mesquita
Journal: JNCI Journal of the National Cancer Institute (2009)

Studies in many countries have reported higher lung cancer incidence and mortality in individuals with lower socioeconomic status.To investigate the role of smoking in these inequalities, we used data from 391,251 participants in the European Prospective Investigation into Cancer and Nutrition study, a cohort of individuals in 10 European countries. We collected information on smoking (history and quantity), fruit and vegetable consumption, and education through questionnaires at study entry and gathered data on lung cancer incidence for a mean of 8.4 years. Socioeconomic status was defined as the highest attained level of education, and participants were grouped by sex and region of residence (Northern Europe, Germany, or Southern Europe). Relative indices of inequality (RIIs) of lung cancer risk unadjusted and adjusted for smoking were estimated using Cox regression models. Additional analyses were performed by histological type.During the study period, 939 men and 692 women developed lung cancer. Inequalities in lung cancer risk (RII(men) = 3.62, 95% confidence interval [CI] = 2.77 to 4.73, 117 vs 52 per 100,000 person-years for lowest vs highest education level; RII(women) = 2.39, 95% CI = 1.77 to 3.21, 46 vs 25 per 100,000 person-years) decreased after adjustment for smoking but remained statistically significant (RII(men) = 2.29, 95% CI = 1.75 to 3.01; RII(women) = 1.59, 95% CI = 1.18 to 2.13). Large RIIs were observed among men and women in Northern European countries and among men in Germany, but inequalities in lung cancer risk were reverse (RIIs < 1) among women in Southern European countries. Inequalities differed by histological type. Adjustment for smoking reduced inequalities similarly for all histological types and among men and women in all regions. In all analysis, further adjustment for fruit and vegetable consumption did not change the estimates.Self-reported smoking consistently explains approximately 50% of the inequalities in lung cancer risk due to differences in education.
Antioxidants attenuate myocyte apoptosis in the remote non-infarcted myocardium following large myocardial infarction
Authors: H Oskarsson
Journal: Cardiovascular Research (2000)

Objective: Increased oxidative stress and myocyte apoptosis co-exist in the remote non-infarcted myocardium (RM) following a large myocardial infarction. We proposed that these phenomena are causally related. Methods and results: On day 3 after induction of myocardial infarction, Sprague–Dawley rats were randomized to receive probucol and pyrrolidine dithiocarbamate (MI-T), or vehicle only (MI) for 7 weeks. Control rats (C) received vehicle. At 7 weeks, lipidperoxidation within the RM was assessed by measuring thiobarbituric acid reactive substances, which were significantly increased in MI vs. C, while MI-T was not different from C. There was a significant increase in cardiac myocytes positive for in situ TdT-UTP nick-end labeling within the RM in MI vs. C, which was inhibited in MI-T. Furthermore, internucleosomal DNA fragmentation was clearly demonstrated on agarose gels from RM in the MI group, while it was much less apparent on gels from RM in the C and MI-T groups. Western blot analysis showed a significant increase in p53, Bax and caspase-3 protein expression within the RM of MI vs. C, all of which were inhibited in the MI-T group. Furthermore, there was evidence for an increase in caspase-3 activity within the RM from MI vs. C, which was normalized in the MI-T group. Conclusions: Long-term treatment with the antioxidants probucol and pyrrolidine dithiocarbamate attenuates oxidative stress, myocyte apoptosis, caspase-3 like activity and the expression of p53, bax and caspase-3 within RM in rats after a large myocardial infarction.
Fibroblast Growth Factor Homologous Factors Modulate Cardiac Calcium Channels
Authors: Jessica A. Hennessey, Eric Q. Wei, Geoffrey S. Pitt
Journal: Circulation Research (2013)

Fibroblast growth factor (FGF) homologous factors (FHFs; FGF11-14) are intracellular modulators of voltage-gated Na+ channels, but their cellular distribution in cardiomyocytes indicated that they performed other functions.We aimed to uncover novel roles for FHFs in cardiomyocytes, starting with a proteomic approach to identify novel interacting proteins.Affinity purification of FGF13 from rodent ventricular lysates followed by mass spectroscopy revealed an interaction with junctophilin-2, a protein that organizes the close apposition of the L-type Ca2+ channel CaV1.2 and the ryanodine receptor 2 in the dyad. Immunocytochemical analysis revealed that overall T-tubule structure and localization of ryanodine receptor 2 were unaffected by FGF13 knockdown in adult ventricular cardiomyocytes but localization of CaV1.2 was affected. FGF13 knockdown decreased CaV1.2 current density and reduced the amount of CaV1.2 at the surface as a result of aberrant localization of the channels. CaV1.2 current density and channel localization were rescued by expression of an shRNA-insensitive FGF13, indicating a specific role for FGF13. Consistent with these newly discovered effects on CaV1.2, we demonstrated that FGF13 also regulated Ca(2+)-induced Ca2+ release, indicated by a smaller Ca2+ transient after FGF13 knockdown. Furthermore, FGF13 knockdown caused a profound decrease in the cardiac action potential half-width.This study demonstrates that FHFs not only are potent modulators of voltage-gated Na+ channels but also affect Ca2+ channels and their function. We predict that FHF loss-of-function mutations would adversely affect currents through both Na+ and Ca2+ channels, suggesting that FHFs may be arrhythmogenic loci, leading to arrhythmias through a novel, dual-ion channel mechanism.
Epidemiology of cutaneous melanoma and non-melanoma skin cancer in Schleswig-Holstein, Germany: incidence, clinical subtypes, tumour stages and localization (epidemiology of skin cancer)
Authors: A. Katalinic, U. Kunze, T. Schafer
Journal: British Journal of Dermatology (2003)

Background Population-based figures on skin cancer are essential for a realistic assessment of the personal disease burden, prevention modes and the need for caring. The Robert Koch Institute in Germany estimates the incidence of melanoma skin cancer as seven cases in 100 000 persons (age-standardized by the European standard rate). Population-based studies presumably show higher incidence rates of 10–16 cases in 100 000 persons. Few data exist for non-melanoma skin cancer (NMSC) as this is not systematically registered in Germany. Objectives To present the first population-based results from the Schleswig-Holstein (Germany) Cancer Registry on incidence, stage distribution, clinical types and localization of skin cancer and to compare the results with other studies. Methods The Cancer Registry of the Bundesland Schleswig-Holstein with 3500 registering institutions, 100 of which are dermatological institutions, investigates all notifiable incident cancer cases according to international standards. From the recorded data all melanoma and NMSC cases were identified and evaluated. Results Between 1998 and 2001, 1784 malignant melanoma (MM) and 12 956 NMSC cases underwent diagnostic and analytical evaluation. For MM, age-standardized incidence rates were 12·3 and 14·8 in 100 000 men and women, respectively, and the mean age of men was greater than that of women (56·6 vs. 54·9 years, P < 0·05). Superficial spreading melanoma was the most frequent clinical type (39·1%). The tumours were predominantly located on the trunk in men (46·8%) in contrast to leg and hip in women (39·5%). For NMSC, the age-standardized incidence rates were 100·2 and 72·6 in 100 000 men and women, respectively. More than 80% of all tumours were basal cell carcinoma. Conclusions The first population-based data from Schleswig-Holstein on the characteristics (age, sex, histological subtypes, localization and stage) of skin tumours agree well with the existing literature and may thus be regarded as representative. However, markedly higher incidences for MM and NMSC in the north of Germany compared with other parts of the country were observed. As the incidence rates from the north of Germany fit well into the European geographical pattern, we assume no regional increase. Therefore, the official German estimates on cutaneous tumours may largely depend on regional factors and may not be regarded as representative for all regions in Germany.
Thrombin-induced Vasodilatation and Hypotension in Dogs: Role of Fibrinogen, Plasma Kinins, and Blood Cells
Authors: P. Olsson, J. Swedenborg, A.-C. Teger-Nilsson
Journal: Cardiovascular Research (1969)

Some hypotheses on the mechanism of the vasodilating activity of thrombin have been investigated. It was shown that the presence of thrombin together with blood cells was necessary for the vasodilating activity. Products of the thrombin-fibrinogen reaction were not mediators of this effect of thrombin. No relation was found between thrombin-induced vasoactivity and plasma kinins. It was, furthermore, shown that larger amounts of thrombin infused into defibrinogenated animals gave rise to hypotension, probably due to generalized vasodilatation.
Paricalcitol for Secondary Hyperparathyroidism in Renal Transplantation
Authors: Matias Trillini, Monica Cortinovis, Piero Ruggenenti, Jorge Reyes Loaeza, Karen Courville, Claudia Ferrer-Siles, Silvia Prandini, Flavio Gaspari, Antonio Cannata, Alessandro Villa, Annalisa Perna, Eliana Gotti, Maria Rosa Caruso, Davide Martinetti, Giuseppe Remuzzi, Norberto Perico
Journal: Journal of the American Society of Nephrology (2014)

Secondary hyperparathyroidism contributes to post-transplant CKD mineral and bone disorder. Paricalcitol, a selective vitamin D receptor activator, decreased serum parathyroid hormone levels and proteinuria in patients with secondary hyperparathyroidism. This single-center, prospective, randomized, crossover, open-label study compared the effect of 6-month treatment with paricalcitol (1 μg/d for 3 months and then uptitrated to 2 µg/d if tolerated) or nonparicalcitol therapy on serum parathyroid hormone levels (primary outcome), mineral metabolism, and proteinuria in 43 consenting recipients of renal transplants with secondary hyperparathyroidism. Participants were randomized 1:1 according to a computer-generated sequence. Compared with baseline, median (interquartile range) serum parathyroid hormone levels significantly declined on paricalcitol from 115.6 (94.8–152.0) to 63.3 (52.0–79.7) pg/ml (P<0.001) but not on nonparicalcitol therapy. At 6 months, levels significantly differed between treatments (P<0.001 by analysis of covariance). Serum bone-specific alkaline phosphatase and osteocalcin decreased on paricalcitol therapy only and significantly differed between treatments at 6 months (P<0.001 for all comparisons). At 6 months, urinary deoxypyridinoline-to-creatinine ratio and 24-hour proteinuria level decreased only on paricalcitol (P<0.05). L3 and L4 vertebral mineral bone density, assessed by dual-energy x-ray absorption, significantly improved with paricalcitol at 6 months (P<0.05 for both densities). Paricalcitol was well tolerated. Overall, 6-month paricalcitol supplementation reduced parathyroid hormone levels and proteinuria, attenuated bone remodeling and mineral loss, and reduced eGFR in renal transplant recipients with secondary hyperparathyroidism. Long-term studies are needed to monitor directly measured GFR, ensure that the bone remodeling and mineral effects are sustained, and determine if the reduction in proteinuria improves renal and cardiovascular outcomes.
Guidelines for Premeal Insulin Dose Reduction for Postprandial Exercise of Different Intensities and Durations in Type 1 Diabetic Subjects Treated Intensively With a Basal-Bolus Insulin Regimen (Ultralente-Lispro)
Authors: Rémi Rabasa-Lhoret, Josée Bourque, Francine Ducros, Jean-Louis Chiasson
Journal: Diabetes Care (2001)

OBJECTIVE—To evaluate and validate appropriate premeal insulin dose reductions for postprandial exercises of different intensities and durations to minimize the risk of exercise-induced hypoglycemia in type 1 diabetic subjects. RESEARCH DESIGN AND METHODS—Eight male type 1 diabetic patients on a basal-bolus insulin regimen of ultralente (UL) as basal insulin and lispro (LP) as premeal insulin were tested in a randomized, crossover fashion during postprandial exercise at 25% Vo2max for 60 min, 50% Vo2max for 30 and 60 min, and 75% Vo2max for 30 min starting 90 min after a standardized mixed breakfast (600 kcal, 75 g carbohydrates). Each subject served as his own control and was tested after a full dose of insulin LP (LP 100%) and/or 50% (LP 50%) and/or 25% (LP 25%) of the current dose. RESULTS—At all intensities, the full premeal insulin dose was associated with an increased risk of hypoglycemia. At 25% Vo2max for 60 min, a 50% reduction in the premeal insulin dose resulted in plasma glucose of −0.62 mmol/l compared with baseline at the end of exercise. At 50% Vo2max for 30 and 60 min, 50 and 75% reductions of the premeal insulin dose were associated with plasma glucose of −0.39 and +0.49 mmol/l, respectively, at the end of the exercise. At 75% Vo2max, a 75% reduction of the premeal insulin dose was required to achieve appropriate postexercise plasma glucose (+0.71 mmol/l). Such reductions in the premeal insulin dose resulted in a 75% decrease in the incidence of exercise-induced hypoglycemia. CONCLUSIONS—In well-controlled type 1 diabetic subjects on intensive insulin therapy with the basal-bolus (UL-LP) insulin regimen, risk of hypoglycemia can be minimized during postprandial exercises of different intensities and different durations by appropriate reduction of premeal insulin LP.
Evolution of the Transposable Element Pokey in the Ribosomal DNA of Species in the Subgenus Daphnia (Crustacea: Cladocera)
Authors: Erin H. Penton, Teresa J. Crease
Journal: Molecular Biology and Evolution (2004)

Pokey is a member of the piggyBac (previously called the TTAA-specific) family of transposons and inserts into a conserved region of the large subunit ribosomal RNA gene. This location is a "hot spot" for insertional activity, as it is known to contain other arthropod transposable elements. However, Pokey is unique in that it is the first DNA transposon yet known to insert into this region. All other insertions are class I non-LTR retrotransposons. This study surveyed variation in Pokey elements through phylogenetic analysis of the 3′ ends of Pokey elements from ribosomal DNA (rDNA) in species from the nominate subgenus of the genus Daphnia (Crustacea: Cladocera). The results suggest that Pokey has been stably, vertically inherited within rDNA over long periods of evolutionary time. No evidence was found to support horizontal transfer, which commonly occurs in other DNA transposons, such as P and mariner. Furthermore, Pokey has diverged into sublineages that have persisted across speciation events in some groups. In addition, a new highly divergent paralogous Pokey element was discovered in the rDNA of one species.