bluuebunny/crossref_metadata_2025_split huggingface dataset:
Initial diagnosis of Wegener’s granulomatosis mimicking severe ulcerative colitis: a case report
Authors: Timmermann Sonja , Perez Bouza Alberto , Junge Karsten , Neumann Ulf P , Binnebösel Marcel 
Published: May 2013

Abstract

Introduction
We describe the case of a woman with an unusual presentation of Wegener’s granulomatosis.

Case presentation
A 20-year old Caucasian woman presented with the principal feature of a pancolonic, superficial microulceration mimicking severe ulcerative colitis. Our patient was refractory to therapy and had persisting signs of septic shock as well as being at risk of perforation, so we performed a subtotal colectomy and a cholecystectomy due to the incipient necrosis of her gallbladder. Histologic analysis of her colon showed multiple superficial microulcera of the mucosa, lamina propria mucosae and, to a lesser extent, the lamina submucosa. The medium-sized arteries and arterioles of her entire colon, appendix and gallbladder showed acute vasculitic changes with fibrinoid necrosis of the walls and diffuse infiltration with neutrophil granulocytes, accompanied by a strong perivascular histiocyte-rich and partially granulomatous reaction. These findings strongly suggested an autoimmune multisystem disease like Wegener’s granulomatosis or microscopic polyangiitis. A diagnosis of Wegener’s granulomatosis was confirmed by the results of serologic antibody tests: her cytoplasmic antineutrophil cytoplasmic antibody titer was considerably elevated at 1:2560 specific for subclass proteinase 3 (>200kU/L). After the histopathological diagnosis and serological tests, immunosuppression with high doses of corticosteroids and plasmapheresis was started.

Conclusion
In critically ill patients with severe, therapy-refractory ulcerative colitis, Wegener´s granulomatosis should be considered and serologic antibody testing should be performed.
HPV Status and second primary tumours in Oropharyngeal Squamous Cell Carcinoma
Authors: Xu Caroline C , Biron Vincent L , Puttagunta Lakshmi , Seikaly Hadi 
Published: May 2013

Introductions The incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCCs) is rising in developed nations. Studies have shown that these virally mediated tumours are epidemiologically, clinically, and biologically different than other head and neck squamous cell carcinomas and traditional concepts of field cancerization may not apply to HPV-related oropharyngeal cancer. Objective The purpose of this study was to evaluate the rate of second primary tumors and the diagnostic yield of field cancerization work up in the upper aerodigestive tract in patients with HPV-related and HPV-unrelated oropharyngeal squamous cell carcinoma. Design Retrospective review. Setting Tertiary cancer care centers in Alberta. Methods Retrospective review of 406 patients diagnosed with OPSCC in Alberta between 2005 and 2009. HPV-status of tumours was determined by tissue microarray using immunohistochemistry staining for p16. Main outcome measures Primary outcome: incidence of upper aerodigestive tract second primary tumours in p16-positive versus p16-negative OPSCC. Secondary outcomes: diagnostic yield of traditional field cancerization work-up in p16-positive versus negative patients. Results The overall rate of SPTs was 7.4% (30/406). The incidence rate of SPTs was significantly lower in p16-positive patients (0.7 per 100 patient-yrs vs. 8.5 in p16-negative, p < 0.0001). Field cancerization work-up for synchronous lesions in the upper aerodigestive tract, including panendoscopy and whole-body PET-CT, had decreased diagnostic yield in p16-positive patients (2.8% vs. 10.2% in HPV-negative patients, p=0.02). Conclusions Patients with HPV-related OPSCC, who are non-smokers have decreased risk of developing second primary tumours in the upper aerodigestive tract and have low yield on field cancerization work-up. This study provides further evidence that virally mediated OPSCC are distinct and may benefit from alternate diagnostic pathways.
Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma
Authors: Cheng Javelin C , McBrayer Samuel K , Coarfa Cristian , Dalva-Aydemir Sevim , Gunaratne Preethi H , Carpten John D , Keats Jonathan K , Rosen Steven T , Shanmugam Mala 
Published: May 2013

Abstract

Background
Multiple myeloma (MM) is a fatal plasma cell malignancy exhibiting enhanced glucose consumption associated with an aerobic glycolytic phenotype (i.e., the Warburg effect). We have previously demonstrated that myeloma cells exhibit constitutive plasma membrane (PM) localization of GLUT4, consistent with the dependence of MM cells on this transporter for maintenance of glucose consumption rates, proliferative capacity, and viability. The purpose of this study was to investigate the molecular basis of constitutive GLUT4 plasma membrane localization in MM cells.

Findings
We have elucidated a novel mechanism through which myeloma cells achieve constitutive GLUT4 activation involving elevated expression of the Rab-GTPase activating protein AS160_v2 splice variant to promote the Warburg effect. AS160_v2-positive MM cell lines display constitutive Thr642 phosphorylation, known to be required for inactivation of AS160 Rab-GAP activity. Importantly, we show that enforced expression of AS160_v2 is required for GLUT4 PM translocation and activation in these select MM lines. Furthermore, we demonstrate that ectopic expression of a full-length, phospho-deficient AS160 mutant is sufficient to impair constitutive GLUT4 cell surface residence, which is characteristic of MM cells.

Conclusions
This is the first study to tie AS160 de-regulation to increased glucose consumption rates and the Warburg effect in cancer. Future studies investigating connections between the insulin/IGF-1/AS160_v2/GLUT4 axis and FDG-PET positivity in myeloma patients are warranted and could provide rationale for therapeutically targeting this pathway in MM patients with advanced disease.
Characterizing and measuring bias in sequence data
Authors: Ross Michael G , Russ Carsten , Costello Maura , Hollinger Andrew , Lennon Niall J , Hegarty Ryan , Nusbaum Chad , Jaffe David B 
Published: May 2013

Abstract
Background
DNA sequencing technologies deviate from the ideal uniform distribution of reads. These biases impair scientific and medical applications. Accordingly, we have developed computational methods for discovering, describing and measuring bias.

Results
We applied these methods to the Illumina, Ion Torrent, Pacific Biosciences and Complete Genomics sequencing platforms, using data from human and from a set of microbes with diverse base compositions. As in previous work, library construction conditions significantly influence sequencing bias. Pacific Biosciences coverage levels are the least biased, followed by Illumina, although all technologies exhibit error-rate biases in high- and low-GC regions and at long homopolymer runs. The GC-rich regions prone to low coverage include a number of human promoters, so we therefore catalog 1,000 that were exceptionally resistant to sequencing. Our results indicate that combining data from two technologies can reduce coverage bias if the biases in the component technologies are complementary and of similar magnitude. Analysis of Illumina data representing 120-fold coverage of a well-studied human sample reveals that 0.20% of the autosomal genome was covered at less than 10% of the genome-wide average. Excluding locations that were similar to known bias motifs or likely due to sample-reference variations left only 0.045% of the autosomal genome with unexplained poor coverage.

Conclusions
The assays presented in this paper provide a comprehensive view of sequencing bias, which can be used to drive laboratory improvements and to monitor production processes. Development guided by these assays should result in improved genome assemblies and better coverage of biologically important loci.
Results of an International Randomized Phase III Trial of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus Versus Placebo to Control Metastatic Sarcomas in Patients After Benefit From Prior Chemotherapy
Authors: Demetri George D. , Chawla Sant P. , Ray-Coquard Isabelle , Le Cesne Axel , Staddon Arthur P. , Milhem Mohammed M. , Penel Nicolas , Riedel Richard F. , Bui-Nguyen Binh , Cranmer Lee D. , Reichardt Peter , Bompas Emmanuelle , Alcindor Thierry , Rushing Daniel , Song Yang , Lee Ruey-min , Ebbinghaus Scot , Eid Joseph E. , Loewy John W. , Haluska Frank G. , Dodion Pierre F. , Blay Jean-Yves 
Published: May 2013

Purpose Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. Patients and Methods Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. Results A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). Conclusion Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.
Dasatinib in Children and Adolescents With Relapsed or Refractory Leukemia: Results of the CA180-018 Phase I Dose-Escalation Study of the Innovative Therapies for Children With Cancer Consortium
Authors: Zwaan C. Michel , Rizzari Carmelo , Mechinaud Francoise , Lancaster Donna L. , Lehrnbecher Thomas , van der Velden Vincent H.J. , Beverloo B. Berna , den Boer Monique L. , Pieters Rob , Reinhardt Dirk , Dworzak Michael , Rosenberg Julie , Manos George , Agrawal Shruti , Strauss Lewis , Baruchel André , Kearns Pamela R. 
Published: May 2013

PurposeDasatinib is a potent BCR-ABL inhibitor with proven efficacy in adults with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) and in imatinib-resistant/intolerant disease. This phase I study of the Innovative Therapies for Children with Cancer Consortium assessed dasatinib safety and efficacy in pediatric patients.Patients and MethodsEscalating once-daily dasatinib doses (60 to 120 mg/m2) were administered to children (n = 58) with (i) imatinib-pretreated CML or Philadelphia chromosome (Ph)–positive acute lymhoblastic leukemia (ALL) and (ii) treatment-refractory Ph-negative ALL or acute myeloid leukemia (AML).ResultsDasatinib safety and efficacy profiles compared favorably with those in adults. The most common drug-related nonhematologic adverse events were nausea (31%, all grades; 2%, grade 3 to 4), headache (22%, 3%), diarrhea (21%, 0%), and vomiting (17%, 2%). Of 17 patients with CML-CP, 14 (82%) achieved complete cytogenetic response (CCyR) and eight (47%) achieved major molecular response. After ≥ 24 months of follow-up, median complete hematologic response (CHR) and major cytogenetic response (MCyR) durations were not reached. Of 17 patients with advanced-phase CML or Ph-positive ALL, six (35%) achieved confirmed CHR and 11 (65%) achieved CCyR. Median MCyR duration was 4.6 months (95% CI, 2.1 to 17.4 months). No patient with Ph-negative ALL or AML responded. Dasatinib pediatric pharmacokinetic parameters were comparable with those in adult studies, showing rapid absorption (time to reach maximum concentration, 0.5 to 6.0 hours) and elimination (mean half-life, 3.0 to 4.4 hours).ConclusionDasatinib 60 mg/m2and 80 mg/m2once-daily dosing were selected for phase II studies in children with Ph-positive leukemias.
Research Resource: Preovulatory LH Surge Effects on Follicular Theca and Granulosa Transcriptomes
Authors: Christenson Lane K. , Gunewardena Sumedha , Hong Xiaoman , Spitschak Marion , Baufeld Anja , Vanselow Jens 
Published: May 2013

Abstract
The molecular mechanisms that regulate the pivotal transformation processes observed in the follicular wall following the preovulatory LH surge, are still not established, particularly for cells of the thecal layer. To elucidate thecal cell (TC) and granulosa cell (GC) type-specific biologic functions and signaling pathways, large dominant bovine follicles were collected before and 21 hours after an exogenous GnRH-induced LH surge. Antral GCs (aGCs; aspirated by follicular puncture) and membrane-associated GCs (mGCs; scraped from the follicular wall) were compared with TC expression profiles determined by mRNA microarrays. Of the approximately 11 000 total genes expressed in the periovulatory follicle, only 2% of thecal vs 25% of the granulosa genes changed in response to the LH surge. The majority of the 203 LH-regulated thecal genes were also LH regulated in GCs, leaving a total of 57 genes as LH-regulated TC-specific genes. Of the 57 thecal-specific LH-regulated genes, 74% were down-regulated including CYP17A1 and NR5A1, whereas most other genes are being identified for the first time within theca. Many of the newly identified up-regulated thecal genes (eg, PTX3, RND3, PPP4R4) were also up-regulated in granulosa. Minimal expression differences were observed between aGCs and mGCs; however, transcripts encoding extracellular proteins (NID2) and matrix modulators (ADAMTS1, SASH1) dominated these differences. We also identified large numbers of unknown LH-regulated GC genes and discuss their putative roles in ovarian function. This Research Resource provides an easy-to-access global evaluation of LH regulation in TCs and GCs that implicates numerous molecular pathways heretofore unknown within the follicle.
Lysosomal cell death at a glance
Authors: Aits Sonja , Jäättelä Marja 
Published: May 2013

Summary
Lysosomes serve as the cellular recycling centre and are filled with numerous hydrolases that can degrade most cellular macromolecules. Lysosomal membrane permeabilization and the consequent leakage of the lysosomal content into the cytosol leads to so-called “lysosomal cell death”. This form of cell death is mainly carried out by the lysosomal cathepsin proteases and can have necrotic, apoptotic or apoptosis-like features depending on the extent of the leakage and the cellular context. This article summarizes our current knowledge on lysosomal cell death with an emphasis on the upstream mechanisms that lead to lysosomal membrane permeabilization.
Limits to sustained energy intake. XVI. Body temperature and physical activity of female mice during pregnancy
Authors: Gamo Yuko , Bernard Amelie , Mitchell Sharon E. , Hambly Catherine , Al Jothery Aqeel , Vaanholt Lobke M. , Król Elzbieta , Speakman John R. 
Published: May 2013

SUMMARY
Lactation is the most energy-demanding phase of mammalian reproduction, and lactation performance may be affected by events during pregnancy. For example, food intake may be limited in late pregnancy by competition for space in the abdomen between the alimentary tract and fetuses. Hence, females may need to compensate their energy budgets during pregnancy by reducing activity and lowering body temperature. We explored the relationships between energy intake, body mass, body temperature and physical activity throughout pregnancy in the MF1 mouse. Food intake and body mass of 26 females were recorded daily throughout pregnancy. Body temperature and physical activity were monitored every minute for 23 h a day by implanted transmitters. Body temperature and physical activity declined as pregnancy advanced, while energy intake and body mass increased. Compared with a pre-mating baseline period, mice increased energy intake by 56% in late pregnancy. Although body temperature declined as pregnancy progressed, this served mostly to reverse an increase between baseline and early pregnancy. Reduced physical activity may compensate the energy budget of pregnant mice but body temperature changes do not. Over the last 3 days of pregnancy, food intake declined. Individual variation in energy intake in the last phase of pregnancy was positively related to litter size at birth. As there was no association between the increase in body mass and the decline in intake, we suggest the decline was not caused by competition for abdominal space. These data suggest overall reproductive performance is probably not constrained by events during pregnancy.
Limits to sustained energy intake. XVIII. Energy intake and reproductive output during lactation in Swiss mice raising small litters
Authors: Zhao Zhi-Jun , Song De-Guang , Su Zhen-Cheng , Wei Wen-Bo , Liu Xian-Bin , Speakman John R. 
Published: May 2013

SUMMARYLimits to sustained energy intake (SusEI) during lactation in Swiss mice have been suggested to reflect the secretory capacity of the mammary glands. However, an alternative explanation is that milk production and food intake are regulated to match the limited growth capacity of the offspring. In the present study, female Swiss mice were experimentally manipulated in two ways – litter sizes were adjusted to be between 1 and 9 pups and mice were exposed to either warm (21°C) or cold (5°C) conditions from day 10 of lactation. Energy intake, number of pups and litter mass, milk energy output (MEO), thermogenesis, mass of the mammary glands and brown adipose tissue cytochrome c oxidase activity of the mothers were measured. At 21 and 5°C, pup mass at weaning was almost independent of litter size. Positive correlations were observed between the number of pups, litter mass, asymptotic food intake and MEO. These data were consistent with the suggestion that in small litters, pup requirements may be the major factor limiting milk production. Pups raised at 5°C had significantly lower body masses than those raised at 21°C. This was despite the fact that milk production and energy intake at the same litter sizes were both substantially higher in females raising pups at 5°C. This suggests that pup growth capacity is lower in the cold, perhaps due to pups allocating ingested energy to fuel thermogenesis. Differences in observed levels of milk production under different conditions may then reflect a complex interplay between factors limiting maternal performance (peripheral limitation and heat dissipation: generally better when it is cooler) and factors influencing maximum pup growth (litter size and temperature: generally better when it is hotter), and may together result in an optimal temperature favouring reproduction.
Survival and arm abscission are linked to regional heterothermy in an intertidal sea star
Authors: Pincebourde Sylvain , Sanford Eric , Helmuth Brian 
Published: May 2013

SUMMARYBody temperature is a more pertinent variable to physiological stress than ambient air temperature. Modeling and empirical studies on the impacts of climate change on ectotherms usually assume that body temperature within organisms is uniform. However, many ectotherms show significant within-body temperature heterogeneity. The relationship between regional heterothermy and the response of ectotherms to sublethal and lethal conditions remains underexplored. We quantified within-body thermal heterogeneity in an intertidal sea star (Pisaster ochraceus) during aerial exposure at low tide to examine the lethal and sublethal effects of temperatures of different body regions. In manipulative experiments, we measured the temperature of the arms and central disc, as well as survival and arm abscission under extreme aerial conditions. Survival was related strongly to central disc temperature. Arms were generally warmer than the central disc in individuals that survived aerial heating, but we found the reverse in those that died. When the central disc reached sublethal temperatures of 31–35°C, arms reached temperatures of 33–39°C, inducing arm abscission. The absolute temperature of individual arms was a poor predictor of arm abscission, but the arms lost were consistently the hottest at the within-individual scale. Therefore, the vital region of this sea star may remain below the lethal threshold under extreme conditions, possibly through water movement from the arms to the central disc and/or evaporative cooling, but at the cost of increased risk of arm abscission. Initiation of arm abscission seems to reflect a whole-organism response while death occurs as a result of stress acting directly on central disc tissues.
Role of Dexmedetomidine for the Prevention and Treatment of Delirium in Intensive Care Unit Patients
Authors: Mo Yoonsun , Zimmermann Anthony E 
Published: May 2013

OBJECTIVE: To review recent clinical studies regarding the role of dexmedetomidine for prevention and treatment of delirium in intensive care unit (ICU) patients. DATA SOURCES: MEDLINE and PubMed searches (1988-Feburary 2013) were conducted, using the key words delirium, dexmedetomidine, Precedex, agitation, α-2 agonists, critical care, and intensive care. References from relevant articles were reviewed for additional information. STUDY SELECTION AND DATA EXTRACTION: Clinical trials comparing dexmedetomidine with other sedatives/analgesics or with antipsychotics for delirium were selected. Studies that evaluated the use of dexmedetomidine for sedation for more than 6 hours were included in this review. DATA SYNTHESIS: Dexmedetomidine is a highly selective α-2 receptor agonist that provides sedation, anxiolysis, and modest analgesia with minimal respiratory depression. Its mechanism of action is unique compared with that of traditional sedatives because it does not act on γ-aminobutyric acid receptors. In addition, dexmedetomidine lacks anticholinergic activity and promotes a natural sleep pattern. These pharmacologic characteristics may explain the possible antidelirium effects of dexmedetomidine. Eight clinical trials, including 5 double-blind randomized trials, were reviewed to evaluate the impact of dexmedetomidine on ICU delirium. CONCLUSIONS: Currently available evidence suggests that dexmedetomidine is a promising agent, not only for prevention but also for treatment of ICU-associated delirium. However, larger, well-designed trials are warranted to define the role of dexmedetomidine in preventing and treating delirium in the ICU.