tbuckley/cabot-search huggingface dataset:
Phase I/IIa Study of Cetuximab With Gemcitabine Plus Carboplatin in Patients With Chemotherapy-Naïve Advanced Non–Small-Cell Lung Cancer
Authors: Francisco Robert, George Blumenschein, Roy S. Herbst, Frank V. Fossella, Jennifer Tseng, Mansoor N. Saleh, Michael Needle
Journal: Journal of Clinical Oncology (2005)

Purpose This multicenter, open-label, phase I/IIa study was undertaken to establish the safety/toxicity profile of cetuximab in combination with gemcitabine and carboplatin in patients with chemotherapy-naïve, epidermal growth factor receptor–positive, stage IV non–small-cell lung cancer. Secondary objectives were to gather preliminary evidence of efficacy including tumor response rate, time to progression, and overall survival. Patients and Methods Thirty-five patients received a total of 264 3-week cycles of treatment with cetuximab, carboplatin, and gemcitabine. An initial dose of cetuximab 400 mg/m 2 intravenously was administered the first week, followed by weekly doses of 250 mg/m 2 . Carboplatin (area under the curve = 5, day 1) and gemcitabine 1,000 mg/m 2 on days 1 and 8 were administered every 3 weeks. Patients were evaluated for tumor response after every two cycles of therapy. Results The most frequently reported adverse events related to cetuximab included an acne-like rash (88.6%), dry skin (34.3%), asthenia and skin disorders (31.4%), mucositis/stomatitis (25.7%), fever/chills (20%), and nausea/vomiting (17.1%). The majority of these toxicities were mild to moderate. One patient withdrew from the study because of a grade 3 allergic reaction. Myelosuppression was the most frequently observed toxicity related to chemotherapy. Responses among 35 assessable patients included 10 partial responses (28.6%). Twenty-one patients had stable disease. The median time to progression was 165 days, and the median overall survival was 310 days. Conclusion The combination of cetuximab, carboplatin, and gemcitabine was well tolerated with an acceptable toxicity profile. Most grade 3 adverse events were attributable to chemotherapy. The response rate and median survival are encouraging and warrant additional investigation.
Myelopoietic enhancing effects of murine macrophage inflammatory proteins 1 and 2 on colony formation in vitro by murine and human bone marrow granulocyte/macrophage progenitor cells.
Authors: H E Broxmeyer, B Sherry, L Lu, S Cooper, C Carow, S D Wolpe, A Cerami
Journal: The Journal of Experimental Medicine (1989)

Two recently identified and purified murine macrophage inflammatory proteins MIP-1 and MIP-2 were tested in vitro both alone, and in combination with purified recombinant (r) murine (mu) GM-CSF, natural (n)muCSF-1, or rhuman (hu)G-CSF, for effects on mouse marrow CFU-GM, in combination with erythropoietin for effects on mouse marrow BFU-E, and in combination with rhuGM-CSF or rhuG-CSF for effects on human marrow CFU-GM. MIP-1 and MIP-2 did not stimulate, but did enhance by up to threefold, colony formation of mouse CFU-GM co-stimulated by rmuGM-CSF and nmuCSF-1, but not by rhuG-CSF, in the absence or presence of serum. MIP-1 and MIP-2 were maximally active at concentrations greater than or equal to 100 ng/ml and the actions appeared to be initiated during the DNA synthetic portion of the cell cycle. Neither MIP-1 nor MIP-2 at up to 1 microgram/ml had any effect on mouse BFU-E, in the absence or presence of erythropoietin. Both MIP-1 and MIP-2 had direct acting effects on purified mouse CFU-GM. The cloning efficiency of 200 purified cells plated with 50 U muCSF-1 was 82% with and 43% without MIP; the cloning efficiency with 50 U rmuGM-CSF was 65% with and 35% without MIP. MIP effects were not mimicked by bacterial LPS, rhuIL-1 alpha, rhuIL-6, or rmuIL-4, and were neutralized by their respective specific antibodies. MIP-1 and MIP-2 also enhanced endogenously stimulated and rhuGM-CSF-, but not rhuG-CSF-, stimulated colony formation by human marrow CFU-GM. These results demonstrate a new role for MIP-1 and MIP-2 in vitro as myelopoietic enhancing activities for CFU-GM.
Defining Phenotypic Causes of Obstructive Sleep Apnea. Identification of Novel Therapeutic Targets
Authors: Danny J. Eckert, David P. White, Amy S. Jordan, Atul Malhotra, Andrew Wellman
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Rationale: The pathophysiologic causes of obstructive sleep apnea (OSA) likely vary among patients but have not been well characterized.Objectives: To define carefully the proportion of key anatomic and nonanatomic contributions in a relatively large cohort of patients with OSA and control subjects to identify pathophysiologic targets for future novel therapies for OSA.Methods: Seventy-five men and women with and without OSA aged 20–65 years were studied on three separate nights. Initially, the apnea-hypopnea index was determined by polysomnography followed by determination of anatomic (passive critical closing pressure of the upper airway [Pcrit]) and nonanatomic (genioglossus muscle responsiveness, arousal threshold, and respiratory control stability; loop gain) contributions to OSA.Measurements and Main Results: Pathophysiologic traits varied substantially among participants. A total of 36% of patients with OSA had minimal genioglossus muscle responsiveness during sleep, 37% had a low arousal threshold, and 36% had high loop gain. A total of 28% had multiple nonanatomic features. Although overall the upper airway was more collapsible in patients with OSA (Pcrit, 0.3 [−1.5 to 1.9] vs. −6.2 [−12.4 to −3.6] cm H2O; P <0.01), 19% had a relatively noncollapsible upper airway similar to many of the control subjects (Pcrit, −2 to −5 cm H2O). In these patients, loop gain was almost twice as high as patients with a Pcrit greater than −2 cm H2O (−5.9 [−8.8 to −4.5] vs. −3.2 [−4.8 to −2.4] dimensionless; P = 0.01). A three-point scale for weighting the relative contribution of the traits is proposed. It suggests that nonanatomic features play an important role in 56% of patients with OSA.Conclusions: This study confirms that OSA is a heterogeneous disorder. Although Pcrit-anatomy is an important determinant, abnormalities in nonanatomic traits are also present in most patients with OSA.
Adjuvant antibiotic therapy in duodenal ulcers treated with colloidal bismuth subcitrate.
Authors: T O'Riordan, E Mathai, E Tobin, D McKenna, C Keane, E Sweeney, C O'Morain
Journal: Gut (1990)

Persistence of Helicobacter pylori after duodenal ulcer healing is associated with high rates of ulcer relapse. We compared colloidal bismuth subcitrate alone with CBS combined with one of four antibiotic regimens in the treatment of duodenal ulcers. Endoscopy and antral biopsies were performed before treatment and four weeks afterwards. Biopsy specimens were examined for histological evidence of gastritis and by Gram stain and culture for H pylori infection. Altogether 141 patients were allocated to one of five treatment groups. Giving CBS and metronidazole (400 mg tid for 7 days) with and without amoxycillin (500 mg tid) achieved higher clearance rates of H pylori than treatment with CBS alone (p less than 0.01). These two combinations also achieved higher rates of antral gastritis healing than CBS alone (p less than 0.01 and p less than 0.05 respectively). Susceptibility to metronidazole was tested in 29 isolates before and in seven isolates after treatment with metronidazole by disc diffusion test and minimum inhibitory concentration assay. Twenty seven (93%) of the isolates were sensitive before treatment while six of seven (86%) were resistant afterwards. Four of the six resistant strains had acquired resistance during treatment and one of these had acquired metronidazole resistance despite concomitant treatment with amoxycillin, to which it remained sensitive. CBS with adjuvant metronidazole at a dose of 400 mg tid for seven days significantly improves the eradication of H pylori compared with CBS alone. Acquired metronidazole resistance, however, seems to be an important cause of failure to eradicate H pylori.
Optical techniques for 3D surface reconstruction in computer-assisted laparoscopic surgery
Authors: L. Maier-Hein, P. Mountney, A. Bartoli, H. Elhawary, D. Elson, A. Groch, A. Kolb, M. Rodrigues, J. Sorger, S. Speidel, D. Stoyanov
Journal: Medical Image Analysis (2013)
Spain bans sale of unhealthy food in schools in bid to tackle obesity
Authors: M. de Lago
Journal: BMJ (2011)

Spain has banned the sale in schools of food and drinks that have high amounts of saturated fat, trans fats, salt, or sugar in an effort to tackle a rising prevalence of overweight and obesity, which has reached 27% in children and 56% in adults.

The measures are included in a new law on food safety and nutrition. The law also forbids doctors, scientists, and patients from recommending food products in advertisements. Promoting food products through pharmacies and promoting dietary substitutes, especially to breastfeeding women, is also banned. 

Some critics have complained that the law is a watered-down version of the initial proposals. The Spanish umbrella group of consumer …
An ANOCEF genomic and transcriptomic microarray study of the response to radiotherapy or to alkylating first-line chemotherapy in glioblastoma patients
Authors: François Ducray, Aurélien de Reyniès, Olivier Chinot, Ahmed Idbaih, Dominique Figarella-Branger, Carole Colin, Lucie Karayan-Tapon, Hervé Chneiweiss, Michel Wager, François Vallette, Yannick Marie, David Rickman, Emilie Thomas, Jean-Yves Delattre, Jérôme Honnorat, Marc Sanson, François Berger
Journal: Molecular Cancer (2010)

The molecular characteristics associated with the response to treatment in glioblastomas (GBMs) remain largely unknown. We performed a retrospective study to assess the genomic characteristics associated with the response of GBMs to either first-line chemotherapy or radiation therapy. The gene expression (n = 56) and genomic profiles (n = 67) of responders and non-responders to first-line chemotherapy or radiation therapy alone were compared on Affymetrix Plus 2 gene expression arrays and BAC CGH arrays.According to Verhaak et al.'s classification system, mesenchymal GBMs were more likely to respond to radiotherapy than to first-line chemotherapy, whereas classical GBMs were more likely to respond to first-line chemotherapy than to radiotherapy. In patients treated with radiation therapy alone, the response was associated with differential expression of microenvironment-associated genes; the expression of hypoxia-related genes was associated with short-term progression-free survival (< 5 months), whereas the expression of immune genes was associated with prolonged progression-free survival (> 10 months). Consistently, infiltration of the tumor by both CD3 and CD68 cells was significantly more frequent in responders to radiotherapy than in non-responders. In patients treated with first-line chemotherapy, the expression of stem-cell genes was associated with resistance to chemotherapy, and there was a significant association between response to treatment and p16 locus deletions. Consistently, in an independent data set of patients treated with either radiotherapy alone or with both radiotherapy and adjuvant chemotherapy, we found that patients with the p16 deletion benefited from adjuvant chemotherapy regardless of their MGMT promoter methylation status, whereas in patients without the p16 deletion, this benefit was only observed in patients with a methylated MGMT promoter.Differential expression of microenvironment genes and p16 locus deletion are associated with responses to radiation therapy and to first-line chemotherapy, respectively, in GBM. Recently identified transcriptomic subgroups of GBMs seem to respond differently to radiotherapy and to first-line chemotherapy.
MUC4 Is a Novel Prognostic Factor of Extrahepatic Bile Duct Carcinoma
Authors: Shugo Tamada, Hiroaki Shibahara, Michiyo Higashi, Masamichi Goto, Surinder K. Batra, Kohzoh Imai, Suguru Yonezawa
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Many of the patients with extrahepatic bile duct carcinoma (EHBDC) show a poor outcome. We have reported that MUC4 is a novel prognostic factor of pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma. The aim of this study is to evaluate the prognostic significance of MUC4 expression in EHBDC. Experimental Design: We examined the expression profile of MUC4 in EHBDC tissues from 70 patients using immunohistochemistry. MUC4 is a membrane mucin like MUC1. In addition, MUC4 is an intramembrane ligand for receptor tyrosine kinase ErbB2 and is related with regulation of p27. We compared the MUC4 expression with MUC1, ErbB2, or p27 expression in EHBDC. Results: MUC4 was expressed in 36 of the 70 patients with EHBDC. There was no significant correlation between the MUC4 expression and MUC1, ErbB2, or p27 expression. The survival of 19 patients with high MUC4 expression (≥20% of carcinoma cells stained) was significantly worse than that of the 51 patients with low MUC4 expression (under 20% of carcinoma cells stained; P = 0.0072). The univariate analysis showed that high MUC4 expression (P = 0.0072), high MUC1 expression (P = 0.0092), histologic grading (P = 0.0029), surgical margin involvement (P = 0.0137), and nodal metastasis (P = 0.0036) were statistically significant risk factors. The backward stepwise multivariate analysis showed that high MUC4 expression (P = 0.0195) and surgical margin involvement (P = 0.0358) were statistically significant independent risk factors. Conclusions: MUC4 expression in EHBDC is a new independent factor for poor prognosis and predicts the outcome of patients with EHBDC.
Abstract P2-09-05: The potent anti-androgen enzalutamide demonstrates broad anti-tumour activity across all androgen receptor-positive triple-negative breast cancer subtypes
Authors: L Denne, A Shia, E Komulainen, V Haley, C Lenihan, F Cavicchioli, K O'Leary, P Schmid
Journal: Cancer Research (2013)

Abstract Background: Up to 30% of triple-negative breast cancers (TNBC) show expression of the androgen receptor (AR) and may therefore be candidates for AR-targeted therapy. Molecular profiling of TNBC has identified the luminal AR (LAR) subset, which shares many aspects of ER-positive luminal cancers but is resistant to ER-targeted therapy. LAR cancers highly express the AR, are heavily enriched in hormone-regulated pathways and demonstrate tumour growth in response to androgen stimulation that can be inhibited by the mixed AR agonist/antagonist bicalutamide. The objective of this study was to investigate the role of AR signalling in TNBC in more detail and to evaluate the potential of the second generation anti-androgen Enzalutamide in this setting relative to bicalutamide. Methods: A panel of 13 TNBC breast cancer cell lines was selected, representing different molecular subtypes of TNBC (including 4 LAR cell lines). Baseline AR expression was determined using qPCR (Taqman) and Western-Blot (Antibody, Santa Cruz Biotechnology). The effects of enzalutamide and bicalumatide on cell proliferation and survival were determined using MTT assays with and without DHT stimulation. Comprehensive molecular profiling (including Illumina Human HT-12 v4 whole genome mRNA and Illumina Human 450K methylation microarrays) was applied before and after enzalutamide treatment to define the molecular signature associated with sensitivity to enzalutamide therapy. All statistical calculations and IC50 doses were calculated using Prism v6.0 (GraphPad). Results: A wide range of AR expression was confirmed across the cell line panel defining 3 groups with complete lack of AR expression, low/moderate AR expressions levels, or very high expression in the LAR subtype (with up to 100-fold greater AR expression compared to other TNBC subtypes). Enzalutamide demonstrated broad anti-tumour activity across all AR+ TNBC subtypes (but not in AR-negative subtypes), with IC50 values being similar in LAR and non-LAR cell lines. Treatment with enzalutamide resulted in more effective growth inhibition and a broader range of activity compared to bicalutamide. Data on molecular profiles of enzalutamide sensitivity will be presented at the meeting. Conclusion: AR inhibition is a promising therapeutic strategy for both LAR and non-LAR AR-expressing TNBC. The potent anti-androgen enzalutamide shows broad activity across all AR+ TNBC subtypes and warrants further clinical evaluation. A phase 2 study of enzalutamide in AR+ TNBC has been initiated. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-05.
Low Concentrations of Diindolylmethane, a Metabolite of Indole-3-Carbinol, Protect against Oxidative Stress in a BRCA1-Dependent Manner
Authors: Saijun Fan, Qinghui Meng, Tapas Saha, Fazlul H. Sarkar, Eliot M. Rosen
Journal: Cancer Research (2009)

Abstract The indole-3-carbinol (I3C) metabolite 3,3′-diindolylmethane (DIM) is a proposed cancer prevention agent for various tumor types, including breast cancer. Here, we show that DIM up-regulates expression of the tumor suppressor protein BRCA1 in carcinoma and normal cell types. Up-regulation of BRCA1 was dose and time dependent, and it was observed at physiologically relevant micromolar and submicromolar DIM concentrations when cells were exposed for 72 hours. Treatment with the parent compound (I3C) or DIM (1 μmol/L) protected against cell killing due to H2O2 and other oxidants, and the protection was abrogated by knockdown of BRCA1. DIM stimulated signaling by the antioxidant transcription factor NFE2L2 (NRF2) through the antioxidant response element in a BRCA1-dependent manner. We further showed that DIM rapidly stimulated phosphorylation of BRCA1 on Ser 1387 and Ser 1524 and that these phosphorylations are required for protection against oxidative stress. DIM-induced phosphorylation of BRCA1 on Ser 1387 was dependent on ataxia-telangiectasia mutated. Finally, in our assay systems, H2O2-induced cell death was not due to apoptosis. However, a significant component of cell death was attributable to autophagy, and both DIM and BRCA1 inhibited H2O2-induced autophagy. Our findings suggest that low concentrations of DIM protect cells against oxidative stress via the tumor suppressor BRCA1 by several distinct mechanisms. [Cancer Res 2009;69(15):6083–91]
Analysis of 14 BAC sequences from the Aedes aegypti genome: a benchmark for genome annotation and assembly
Authors: Neil F Lobo, Kathy S Campbell, Daniel Thaner, Becky deBruyn, Hean Koo, William M Gelbart, Brendan J Loftus, David W Severson, Frank H Collins
Journal: Genome biology (2007)

Aedes aegypti is the principal vector of yellow fever and dengue viruses throughout the tropical world. To provide a set of manually curated and annotated sequences from the Ae. aegypti genome, 14 mapped bacterial artificial chromosome (BAC) clones encompassing 1.57 Mb were sequenced, assembled and manually annotated using a combination of computational gene-finding, expressed sequence tag (EST) matches and comparative protein homology. PCR and sequencing were used to experimentally confirm expression and sequence of a subset of these transcripts. Of the 51 manual annotations, 50 and 43 demonstrated a high level of similarity to Anopheles gambiae and Drosophila melanogaster genes, respectively. Ten of the 12 BAC sequences with more than one annotated gene exhibited synteny with the A. gambiae genome. Putative transcripts from eight BAC clones were found in multiple copies (two copies in most cases) in the Aedes genome assembly, which point to the probable presence of haplotype polymorphisms and/or misassemblies. This study not only provides a benchmark set of manually annotated transcripts for this genome that can be used to assess the quality of the auto-annotation pipeline and the assembly, but it also looks at the effect of a high repeat content on the genome assembly and annotation pipeline.
Relationship of Ventricular Excitability Characteristics to Ventricular Arrhythmias in Dogs
Authors: KENICHI HARUMI, JOHN OWENS, MARY JO BURGESS, J. A. ABILDSKOV
Journal: Circulation Research (1974)

The relationship of the form of ventricular anodal strength-interval curves to the types of arrhythmias induced by trains of low-intensity stimuli was studied in 16 dogs. Strength-interval curves were determined after basic atrial driven beats and after induced premature ventricular depolarizations. The test stimuli for these determinations were 2-msec anodal square waves delivered in 1-msec decrements during the first half of the cardiac cycle and in 10-msec decrements during the last half of the cycle. At each time step, the stimulus intensity was increased in 5-µamp steps until a ventricular response occurred or a level of 1.2 mamp was reached. Three types of strength-interval curves were observed. Each form of the strength-interval curve was associated with a specific type of arrhythmia induced by a train of 50-Hz, 2-msec anodal stimuli of minimum threshold intensity which was applied for periods of up to several minutes. When the minimum threshold in the strength-interval curve following the basic driven beat was lower than the minimum threshold following the induced premature ventricular depolarization, the train of stimuli induced stable ventricular bigeminy. Accelerating ventricular tachycardia followed by ventricular fibrillation resulted if there were deep dips in the strength-interval curves following both the basic driven beats and the premature ventricular depolarizations. When the strength-interval curves following both the basic driven beats and the premature ventricular depolarizations smoothly approached diastolic levels without deep dips or supernormal periods, the train of stimuli caused either occasional premature ventricular depolarizations with long coupling intervals or slow ventricular tachycardia. These relationships may participate in the initiation and the maintenance of arrhythmias.
Increasing age at symptom onset is associated with worse radiological damage at presentation in patients with early inflammatory polyarthritis
Authors: M. Bukhari, M. Lunt, A. Barton, D. Bunn, A. Silman, D. Symmons
Journal: Annals of the Rheumatic Diseases (2006)

<b>Background:</b> Increasing age at onset has been associated with worse outcome in rheumatoid arthritis, although there are few data from unselected inception cohorts. <b>Hypothesis:</b> Increasing age is associated with a higher risk of erosions at presentation, and this increase is not explained by age-related disease confounders. <b>Subjects and methods:</b> 222 subjects (median onset age 59 years) were studied from a primary-care-based register of new-onset inflammatory polyarthritis. Patients had hand and feet radiographs taken within 12 months from symptom onset. Films were scored by two readers using the Larsen score. The risk of erosions in those aged 50–69 and ⩾70 years at onset was compared with the risk in those aged &lt;50 years both before and after adjustment for possible age-related disease confounders. <b>Result:</b> The prevalences of erosions were 22%, 52% and 71% in those aged &lt;50, 50–69 and ⩾70 years at onset equivalent to odds ratios (ORs) (95% confidence intervals (CIs)) of 3.5 (2.2 to 5.7) and 7.4 (4.5 to 12.1), respectively, in the two older age groups. Excluding those with proximal interphalangeal (PIP) erosions alone (due to possible osteoarthritis) did not alter these findings. Adjustments for disease characteristics using logistic regression did not attenuate these findings: adjusted ORs (95% CIs) 3.6 (2.1 to 6.1) and 6.9 (3.8 to 12.2) for age groups 50–69 and ⩾70 years, respectively. The influence of age was stronger than most of the disease-related variables in predicting erosions in this cohort. <b>Conclusion:</b> Increasing age at symptom onset is strongly associated with higher occurrence of erosions within the first year unexplained by greater disease severity.