tbuckley/cabot-search huggingface dataset:
Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway.
Authors: J Han, P Thompson, B Beutler
Journal: The Journal of Experimental Medicine (1990)

The induction of cachectin/tumor necrosis factor (TNF) synthesis by bacterial endotoxins is a process that entails activation at several levels. Cachectin/TNF gene transcription is accelerated, leading to rapid accumulation of mRNA within the macrophage cytosol. In addition, translational derepression occurs, leading to far more efficient message utilization. Through the use of posttranscriptional reporter constructs, we now demonstrate that certain agents capable of inhibiting cachectin/TNF biosynthesis operate through different mechanisms. In RAW 264.7 macrophages, pentoxifylline blocks cachectin/TNF mRNA accumulation but has no effect upon the efficiency of reporter mRNA translation. Dexamethasone, on the other hand, has only a modest effect on cachectin/TNF mRNA accumulation, but strongly impedes translational derepression. Combined application of dexamethasone and pentoxifylline to macrophages causes a greater suppression of cachectin/TNF biosynthesis that can be achieved by either agent alone. These findings suggest that the signaling pathway activated by endotoxin is branched, and that selective inhibition of different parts of the pathway may be achieved through the use of distinct agents.
Malignant pleural mesothelioma stage III and IV: Retrospective analysis of ten years in a central hospital
Authors: Claudia Lares dos Santos, Ines Sanches, Ligia Fernandes, Filipa Cruz e Costa, Fernando Barata
Journal: European Respiratory Journal (2012)

Introduction: Pleural mesothelioma (PM) is the most frequent malignant primary tumor of pleura. The incidence in Western Europe is still rising due to the prolonged latency of the disease.  Aims: Determine demographic, epidemiological, histological and therapeutical aspects of malignant PM in stage III and IV. Evaluate survival rates.  Methods: The study was conducted in an European central hospital covering approximately 475.000 inhabitants. We performed a retrospective analysis of cases diagnosed in our department over a period of 10 years. Survival analysis was performed using Kaplan Meier method and Cox regression.  Results: We diagnosed 32 cases in stages III/IV (91,5% of total), 84.4% men, mean age 65.5+-10.2 years, 50% with current or past exposure to tobacco. Exposure to asbestos was reported in 56.3% and had occurred, on average, 41.4+-10.8 years before. Approximately 56% of exposures were associated with building construction and mechanics. In 87.5% the diagnosis was obtained with video-assisted thoracic surgery. Histology was epithelioid in 84%. All patients received chemotherapy: 53.1% carboplatin+gemcitabine, 37.5% pemetrexed+cisplatin and 9.4% cisplatin+gemcitabine. Hematological toxicity occurred in 18.8% and non haematological toxicity in 12.5% (grade 3/4). Prophylactic local radiotherapy was performed in 75%. Median survival was 51.6+-9.4 weeks. There was no statistically significant difference according to chemotherapy regimen.  Conclusion: Malignant PM must be considered, particularly in men involved in mechanics, even with unrecognized or remote exposure to asbestos. In our series no difference was seen combining platinum analogs with gemcitabine or pemetrexed.
Vandetanib Improves Anti-Tumor Effects of L19mTNFα in Xenograft Models of Esophageal Cancer
Authors: Marika Crescenzi, Luca Persano, Giovanni Esposito, Elisabetta Zulato, Laura Borsi, Enrica Balza, Alberto Ruol, Ermanno Ancona, Stefano Indraccolo, Alberto Amadori
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Targeting the tumor vasculature by vascular disrupting agents (VDAs) has shown therapeutic activity in mouse models. In most cases, however, VDA efficacy is substantially compromised by the inability of these drugs to completely kill tumor cells located at the periphery of the tumor mass. In this study, we investigated anti-tumor effects of L19mTNFα, a fusion protein composed of L19 (scFv), specific for the angiogenesis-associated ED-B containing fibronectin isoform, and murine TNFα, in xenograft models of esophageal cancer. Experimental design: We evaluated ED-B expression in esophageal cancer samples. Subsequently, we generated subcutaneous xenografts from primary tumors, treated them with the L19mTNFα scFv, and determined effects on tumor vasculature, viability and proliferation, and VEGF expression and infiltration by hematopoietic cells. To overcome tumor resistance, L19mTNFα scFv was combined with vandetanib, a tyrosine kinase inhibitor of VEGF receptor, epidermal growth factor receptor, and RET signaling. Results: ED-B was broadly expressed by esophageal cancer cell lines, as well as xenografts and primary surgical samples of esophageal cancer. Administration of L19mTNFα acutely damaged tumor vasculature and increased necrosis, indicating a VDA-like activity of this immunoconjugate. This event was followed, however, by rapid tumor growth recovery associated with increased expression of VEGF and recruitment of CD11b+Gr1+ myeloid cells into tumors. Combination of L19mTNFα with vandetanib severely impaired vascular functions in tumors, leading to a reduction of cell proliferation and increased necrosis, without apparent signs of toxicity. Conclusion: These findings indicate that a combination of vascular damaging agents with anti-angiogenic drugs could represent a promising therapeutic strategy for esophageal cancer. Clin Cancer Res; 17(3); 447–58. ©2010 AACR.
Photoangioplasty
Authors: Stanley G. Rockson, David P. Lorenz, Wai-Fung Cheong, Kathryn W. Woodburn
Journal: Circulation (2000)

Abstract —Photodynamic therapy (PDT) has been studied and applied to various disease processes. The potential of PDT for selective destruction of target tissues is especially appealing in cardiovascular disease, in which other existing interventional tools are somewhat nonselective and carry substantial risk of damage to the normal arterial wall. Enthusiasm for photoangioplasty (PDT of vascular de novo atherosclerotic and, potentially, restenotic lesions) is fueled by more effective second-generation photosensitizers and technological advances in endovascular light delivery. This excitement revolves around at least 4 significant attributes of light-activated therapy: the putative selectivity and safety of photoangioplasty, the potential for atraumatic and effective debulking of atheromatous plaque through a biological mechanism, the postulated capability to reduce or inhibit restenosis, and the potential to treat long segments of abnormal vessel by simply using fibers with longer light-emitting regions. The available nonclinical data, coupled with the observations of a new phase I trial in human peripheral atherosclerosis, suggest a promising future for photoangioplasty in the treatment of primary atherosclerosis and prevention of restenosis.
Transcription factor MITF regulates cardiac growth and hypertrophy
Authors: S. Tshori
Journal: Journal of Clinical Investigation (2006)

High levels of microphthalmia transcription factor (MITF) expression have been described in several cell types, including melanocytes, mast cells, and osteoclasts. MITF plays a pivotal role in the regulation of specific genes in these cells. Although its mRNA has been found to be present in relatively high levels in the heart, its cardiac role has never been explored. Here we show that a specific heart isoform of MITF is expressed in cardiomyocytes and can be induced by β-adrenergic stimulation but not by paired box gene 3 (PAX3), the regulator of the melanocyte MITF isoform. In 2 mouse strains with different MITF mutations, heart weight/body weight ratio was decreased as was the hypertrophic response to β-adrenergic stimulation. These mice also demonstrated a tendency to sudden death following β-adrenergic stimulation. Most impressively, 15-month-old MITF-mutated mice had greatly decreased heart weight/body weight ratio, systolic function, and cardiac output. In contrast with normal mice, in the MITF-mutated mice, β-adrenergic stimulation failed to induce B-type natriuretic peptide (BNP), an important modulator of cardiac hypertrophy, while atrial natriuretic peptide levels and phosphorylated Akt were increased, suggesting a cardiac stress response. In addition, cardiomyocytes cultured with siRNA against MITF showed a substantial decrease in BNP promoter activity. Thus, for what we believe is the first time, we have demonstrated that MITF plays an essential role in β-adrenergic–induced cardiac hypertrophy.
Prospective Analysis of <i>TEL</i> Gene Rearrangements in Childhood Acute Lymphoblastic Leukemia: A Children's Oncology Group Study
Authors: Jeffrey E. Rubnitz, David Wichlan, Meenakshi Devidas, Jonathan Shuster, Stephen B. Linda, Joanne Kurtzberg, Beverly Bell, Stephen P. Hunger, Allen Chauvenet, Ching-Hon Pui, Bruce Camitta, Jeanette Pullen
Journal: Journal of Clinical Oncology (2008)

To prospectively determine the prognostic significance of the TEL-AML1 fusion in children with acute lymphoblastic leukemia (ALL).TEL gene status was determined for 926 patients with B-precursor ALL enrolled on the Pediatric Oncology Group ALinC 16 trials and patients were observed for a median time of 8 years.Rearrangements of the TEL gene were detected in 244 patients (26%). The estimated 5-year event-free survival rate (+/- SE) for patients with TEL rearrangements was 86% +/- 2%, compared with 72% +/- 2% for those with germline TEL (P < .0001). TEL rearrangements were associated with a superior outcome among patients with standard-risk ALL, high-risk ALL, and rapid early responses to therapy. In a multivariate analysis that included risk group, sex, and day 15 marrow status, TEL status was an independent predictor of outcome (P = .0002).We conclude that TEL gene status should be incorporated into risk classification schemes and suggest that patients who have standard-risk features, the TEL-AML1 fusion, and rapid early responses to therapy, should be treated with antimetabolite-based therapy designed to maintain their high cure rates and avoid late effects.
Deciphering the genetic basis of common diseases by integrated functional annotation of common and rare variants
Authors: Olivier Harismendy, Gaurav Bhatia, Nazli G Rahim, Vikas Bansal, Masakazu Nakano, Michael Scott, Xiaoyun Wang, Colette Dib, Edouard Turlotte, Nathaniel Heintzman, Sarah S Murray, Jean-Francois Deleuze, Jack C Sipe, Bing Ren, Vineet Bafna, Eric J Topol, Kelly A Frazer
Journal: Genome biology (2010)

Genome-wide associations studies (GWAS) have identified >400 loci associated with common human diseases. Despite the extraordinary achievement that these results represent, several questions remain unanswered: (i) What is the contribution of rare variants to common diseases not addressed by GWAS? (ii) What are the functional variants underlying the GWAS associations?

To answer these questions, we first explored the role of common and rare variants in morbid obesity (BMI>40) by identifying all the variants in the intervals of two endocannabinoid metabolic genes (MGLL and FAAH) using targeted sequencing. We used two different statistical approaches (single marker tests and collapsed markers tests) to identify variants in four intervals associated with high BMI. The majority of the associated variants are located in promoter sequences or in predicted transcriptional enhancers, suggesting their regulatory role. Additionally, we demonstrate that the set of rare variants in the FAAH promoter associated with BMI are also associated with an increased level of anandamide, a FAAH substrate, further suggesting a functional role in obesity. In a second study, we examined one of the most compelling GWAS that had identified SNPs in the 9p21 gene desert associated with coronary artery disease (CAD) and Type 2 diabetes (T2D). We identified 33 enhancers in 9p21; the interval is the second most dense gene-desert for predicted enhancers and is six times denser than the whole genome. The activity of three of these enhancers is affected by regulatory variants that show allelic differences in DNA-protein affinity and are strongly associated with either CAD or T2D. Some of these variants are predicted to disrupt the transcription-binding site relevant to CAD biology. Our study shows that the 9p21 gene desert is significantly enriched in enhancer elements and suggests the associations with CAD and T2D likely result from the cumulative contributions of multiple regulatory variants. 

Taken together, our studies show that a comprehensive approach of human genetics that integrates rare variants and functional knowledge, such as regulatory elements or metabolic and cell-specific effects, can leverage the findings of GWAS and lead to a deeper functional understanding of the role of genetic variation in human diseases.
Phase II Trial of a Single Weekly Intravenous Dose of Ranpirnase in Patients With Unresectable Malignant Mesothelioma
Authors: S. M. Mikulski
Journal: Journal of Clinical Oncology (2002)

PURPOSE: A multicenter phase II trial of ranpirnase (Onconase; Alfacell Corp, Bloomfield, NJ) as a single agent was conducted to further assess the safety and clinical efficacy of this novel antitumor ribonuclease. Patients with unresectable and histologically confirmed malignant mesothelioma (MM) were eligible. PATIENTS AND METHODS: One hundred five patients with Eastern Cooperative Oncology Group performance status 0 to 2 were enrolled onto the study. Thirty-seven percent of patients had not responded to prior chemotherapy. The primary end point of the study was survival. Tumor responses and time to progression were also assessed. The Cancer and Leukemia Group B (CALGB) prognostic group criteria were used to define a treatment target group (TTG). Both the intent-to-treat (ITT) and the TTG populations were analyzed for survival. RESULTS: Median survival times of 6 months for the ITT and 8.3 months for the TTG populations were observed. The 1- and 2-year survival rates were 34.3% and 21.6% for ITT, respectively, and 42% and 26.8% for TTG, respectively. Among the 81 patients assessable for tumor response, four had partial responses, two had minor regressions, and thirty-five experienced stabilization of previously progressive disease. Patients with responses and stable disease demonstrated markedly prolonged survival. Ranpirnase was well tolerated in the majority of patients, and there were no drug-related deaths. CONCLUSION: Ranpirnase demonstrated activity and a tolerable toxicity profile in patients with unresectable MM. The prognostic value of the CALGB groups was confirmed.
Group-level traits are not units of selection
Authors: Carlos Santana, Michael Weisberg
Journal: Behavioral and Brain Sciences (2014)

Abstract We argue that Smaldino has not established that group-level traits constitute a unit of selection distinct from selection on individuals, as group-level traits are neither replicators nor interactors. Moreover, we argue that Wimsatt's analysis of emergence and aggregativity supports an understanding of group-level and other emergent traits as explanatorily reducible to the individual level.
Protective Effect of Erythropoietin and Its Carbamylated Derivative in Experimental Cisplatin Peripheral Neurotoxicity
Authors: Roberto Bianchi, Michael Brines, Giuseppe Lauria, Costanza Savino, Alessandra Gilardini, Gabriella Nicolini, Virginia Rodriguez-Menendez, Norberto Oggioni, Annalisa Canta, Paola Penza, Raffaella Lombardi, Claudio Minoia, Anna Ronchi, Anthony Cerami, Pietro Ghezzi, Guido Cavaletti
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Antineoplastic drugs, such as cisplatin (CDDP), are severely neurotoxic, causing disabling peripheral neuropathies with clinical signs known as chemotherapy-induced peripheral neurotoxicity. Cotreatment with neuroprotective agents and CDDP has been proposed for preventing or reversing the neuropathy. Erythropoietin given systemically has a wide range of neuroprotective actions in animal models of central and peripheral nervous system damage. However, the erythropoietic action is a potential cause of side effects if erythropoietin is used for neuroprotection. We have successfully identified derivatives of erythropoietin, including carbamylated erythropoietin, which do not raise the hematocrit but retain the neuroprotective action exerted by erythropoietin. Experimental Design: We have developed previously an experimental chemotherapy-induced peripheral neurotoxicity that closely resembles CDDP neurotoxicity in humans. The present study compared the effects of erythropoietin and carbamylated erythropoietin (50 μg/kg/d thrice weekly) on CDDP (2 mg/kg/d i.p. twice weekly for 4 weeks) neurotoxicity in vivo. Results: CDDP given to Wistar rats significantly lowered their growth rate (P &amp;lt; 0.05), with slower sensory nerve conduction velocity (P &amp;lt; 0.001) and reduced intraepidermal nerve fibers density (P &amp;lt; 0.001 versus controls). Coadministration of CDDP and erythropoietin or carbamylated erythropoietin partially but significantly prevented the sensory nerve conduction velocity reduction. Both molecules preserved intraepidermal nerve fiber density, thus confirming their neuroprotective effect at the pathologic level. The protective effects were not associated with any difference in platinum concentration in dorsal root ganglia, sciatic nerve, or kidney specimens. Conclusions: These results widen the spectrum of possible use of erythropoietin and carbamylated erythropoietin as neuroprotectant drugs, strongly supporting their effectiveness.
Evolution of lung function during the first year of life in newborn screened cystic fibrosis infants
Authors: The Thanh-Diem Nguyen, Lena P Thia, Ah-Fong Hoo, Andrew Bush, Paul Aurora, Angie Wade, Jane Chudleigh, Sooky Lum, Janet Stocks
Journal: Thorax (2013)

<h3>Rationale</h3> Newborn screening (NBS) for cystic fibrosis (CF) allows early intervention. Design of randomised controlled trials (RCT) is currently impeded by uncertainty regarding evolution of lung function, an important trial end point in such infants. <h3>Objective</h3> To assess changes in pulmonary function during the first year of life in CF NBS infants. <h3>Methods</h3> Observational longitudinal study. CF NBS infants and healthy controls were recruited between 2009 and 2011. Lung Clearance Index (LCI), plethysmographic lung volume (plethysmographic functional residual capacity (FRC<sub>pleth</sub>)) and forced expired volume (FEV<sub>0.5</sub>) were measured at 3 months and 1 year of age. <h3>Main results</h3> Paired measurements were obtained from 72 CF infants and 44 controls. At 3 months, CF infants had significantly worse lung function for all tests. FEV<sub>0.5</sub> improved significantly (0.59 (95% CI 0.18 to 0.99) z-scores; p&lt;0.01) in CF infants between 3 months and 1 year, and by 1 year, FEV<sub>0.5</sub> was only 0.52 (0.89 to 0.15) z-scores less than in controls. LCI and FRC<sub>pleth</sub> remained stable throughout the first year of life, being on average 0.8 z-scores higher in infants with CF. Pulmonary function at 1 year was predicted by that at 3 months. Among the 45 CF infants with entirely normal LCI and FEV<sub>0.5</sub> at 3 months, 80% remained so at 1 year, while 74% of those with early abnormalities remained abnormal at 1 year. <h3>Conclusions</h3> This is the first study reporting improvements in FEV<sub>0.5</sub> over time in stable NBS CF infants treated with standard therapy. Milder changes in lung function occurred by 1 year than previously reported. Lung function at 3 months predicts a high-risk group, who should be considered for intensification of treatment and enrolment into RCTs.
Why some Africans stand out in a crowd: BokSmart for injury prevention and other SASMA-related jewels
Authors: Jon S Patricios
Journal: British Journal of Sports Medicine (2012)

The giraffe ( Giraffa camelopardalis ) pictured on the front cover has more similarities to us than we might think. Their necks, like ours, contain seven vertebra. The classical Darwinian explanation for the remarkable feat of biological engineering that is the elongated giraffe's neck being that it allowed them to reach higher branches. As a consequence, these giraffes were more reproductively successful since they had untouched food sources while giraffes of lesser stature perished due to competition.1 2 Giraffes can feed at a variety of levels but have the ability to reach high during times of tough competition – sound like a few sportsmen you know? The giraffe's cardiovascular adaptations to overcome massive gravitational forces include a bigger heart (a great exercise benefit!) said to be twice as powerful a pump as other animals', while the tight skin and tough fascia of their legs has been mimicked by National Aeronautics and Space Administration scientists in the design of astronauts' gravity suits.3 But perhaps the most interesting feature of the giraffe, as they gracefully stride across the African savannah, is its visibility – the ability to stand …
Response of psoriasis to twice weekly PUVA
Authors: A. SAKUNTABHAI, G.R. SHARPE, P.M. FARR
Journal: British Journal of Dermatology (1993)

In the U.K., PUVA treatment for psoriasis is usually given three times weekly, with the starting dose of UVA chosen according to the skin type of the patient. Observations on the time-course and dose-response characteristics of PUVA erythema suggest that larger doses of UVA could be used safely, provided that the frequency of PUVA treatment is reduced. We have examined this by treating 100 patients with chronic plaque-type psoriasis with a PUVA protocol in which treatment using oral 8-methoxypsoralen was given twice weekly, with the starting dose of UVA based on each patient's minimal phototoxic dose, and with weekly UVA dose increments calculated as a percentage of the dose used in the previous treatment. Clearance of psoriasis was achieved in 92% of patients. The median number of treatments required for clearance was 12, and the median cumulative UVA dose for clearance was 52J/cm2. Although erythema occurred at some stage during the course of PUVA in 48% of patients, in only 16% of cases was the erythema of sufficient intensity to result in more than one treatment being missed. These results compare favourably with previous studies in which treatment was given three or four times weekly. Thus, twice weekly PUVA treatment for psoriasis is at least as effective as treatment given more frequently, and may be safer, as lower cumulative UVA doses are required for clearance. It also allows for more efficient operation of a PUVA unit and is more convenient for patients.
A functional CFTR assay using primary cystic fibrosis intestinal organoids
Authors: Johanna F Dekkers, Caroline L Wiegerinck, Hugo R de Jonge, Inez Bronsveld, Hettie M Janssens, Karin M de Winter-de Groot, Arianne M Brandsma, Nienke W M de Jong, Marcel J C Bijvelds, Bob J Scholte, Edward E S Nieuwenhuis, Stieneke van den Brink, Hans Clevers, Cornelis K van der Ent, Sabine Middendorp, Jeffrey M Beekman
Journal: Nature Medicine (2013)