bluuebunny/crossref_metadata_2025 huggingface dataset:
Osteomalacia with low alkaline phosphatase: a not so rare condition with important consequences
Authors: Belkhouribchia Jamal , Bravenboer Bert , Meuwissen Marije , Velkeniers Brigitte
Published: January 2016

Hypophosphatasia is a genetic disorder, characterised by a dysfunctional tissue-non-specific isoenzyme of alkaline phosphatase that impacts bone metabolism and predisposes to osteomalacia or rickets. The clinical presentation is very diverse, depending on the age of onset and the severity of the disease. Several forms of hypophosphatasia are recognised. We present a case of a 50-year-old woman with low impact fractures and loss of teeth at a young age. She also had a low alkaline phosphatase and was diagnosed with adult hypophosphatasia. Although the severe forms of hypophosphatasia are rather rare, the adult form is thought to occur quite frequently. As this condition is not well known by healthcare professionals, the time to diagnosis and initiation of adequate treatment is often postponed. When encountering a patient with low alkaline phosphatase, low bone density or a history of bone fractures, the possibility of hypophosphatasia should be considered.
A novel haemoglobin variant mimicking cyanotic congenital heart disease
Authors: Abecasis Francisco , Marques Inês , Bento Celeste , Ferrão Anabela
Published: January 2016

Screening for critical congenital heart defects in newborn babies can aid in early recognition, with the prospect of improved outcome. However, as this universal newborn screening is implemented, there will be an increasing number of false-positive results. In order to avoid multiple investigations and uncertainty, an haemoglobin (Hb) variant must be included in the differential diagnosis in otherwise well newborns with low oxygen saturation by pulse oximetry. We describe a novel fetal Hb variant (heterozygous γ-globin gene (HBG1) mutation in exon 2 c.202G>A (p.Val68Met)) identified in a newborn with positive pulse oximetry screening for congenital heart disease.
Colonic metastasis in mucoepidermoid carcinoma of the parotid: a rare occurrence
Authors: Jeba Jenifer , Suryawanshi Mayur , Gaikwad Pranay , Backianathan Selvamani
Published: January 2016

We present a case of intermediate-grade mucoepidermoid carcinoma of the parotid with late local recurrence and colonic metastasis. A 69-year-old man who had undergone right total conservative parotidectomy followed by adjuvant radiotherapy for intermediate-grade mucoepidermoid carcinoma 10 years prior, presented with a recurrent swelling in the postoperative site and cardiac failure. On evaluation, he was found to have severe anaemia with positive stool occult blood. Colonoscopic evaluation revealed a globular submucosal bulge with erosion 40 cm from the anal verge, the biopsy of which was consistent with mucoepidermoid carcinoma. The presentation, diagnostic details and management of this rare case are discussed.
Impact of point-of-care diagnostics on maternal outcomes in HIV-infected women: systematic review and meta-analysis protocol
Authors: Mashamba-Thompson T P , Sartorius B , Thabane L , Shi C X , Drain P K
Published: January 2016

Introduction

Studies indicate substandard diagnostic care, delayed and missed diagnosis as some of the contributing factors to maternal mortality. The clinical impact of point-of-care (POC) diagnostics has been shown in the monitoring and treatment of a variety of infectious diseases, including HIV/AIDS and tuberculosis. The objective of this systematic review is to investigate the impact of POC diagnostics on maternal outcomes for HIV-infected women.

Methods

We will conduct a systematic review to evaluate the impact of POC diagnostics for improving desired healthcare outcomes for HIV-infected women. The search strategy will involve electronic databases including: Cochrane Infectious Disease Group Specialised Register; Cochrane Central Register of Control Trials, published in The Cochrane Library; PubMed; EBSCOhost and LILACS. The studies will be mapped in 2 stages: stage 1 will map studies descriptively by focus and method; stage 2 will involve additional inclusion criteria, quality assessment and data extraction undertaken by 2 reviewers in parallel. Evidence will be synthesised using relevant systematic research tools: meta-analysis and subgroup analysis will be conducted usingRevManand Stata 13 will be used for meta-regressions. We will follow recommendations described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and the Cochrane Handbook for Intervention Reviews.

Ethics and dissemination

We anticipate finding a large number of studies on POC diagnostic interventions on maternal outcomes in HIV-infected women, which, once summarised, will be useful to guide future diagnostic interventions. The protocol for the systematic review has been registered in PROSPERO. The study will be disseminated electronically and in print. It will also be presented to conferences related to HIV/AIDS, POC diagnostics and maternal health.

Trial registration number

PROSPERO CRD42014015439.
Effect of the adjuvanted (AS03) A/H1N1 2009 pandemic influenza vaccine on the risk of rejection in solid organ transplant recipients in England: a self-controlled case series
Authors: Cohet Catherine , Haguinet François , Dos Santos Gaël , Webb Dave , Logie John , LC Ferreira Germano , Rosillon Dominique , Shinde Vivek
Published: January 2016

Objective

To assess the risk of solid organ transplant (SOT) rejection after vaccination with the adjuvanted (AS03) A/H1N1 2009 pandemic influenza vaccinePandemrix.

Design

Self-controlled case series (SCCS) in the UK Clinical Practice Research Datalink (CPRD) and its linked component of the Hospital Episodes Statistics (HES) inpatient database. Analyses were conducted using the SCCS method for censored, perturbed or curtailed post-event exposure.

Participants

Of the 184 transplant recipients having experienced at least one SOT rejection (liver, kidney, lung, heart or pancreas) during the study period from 1 October 2009 to 31 October 2010, 91 participants were included in the main analysis, of which 71 had been exposed toPandemrix.

Main outcome measures

Occurrence of SOT rejection during risk (30 and 60 days after anyPandemrixdose) and control periods. Covariates in the CPRD included time since transplantation, seasonal influenza vaccination, bacterial and viral infections, previous SOT rejections and malignancies.

Results

The relative incidence (RI) of rejection of any one of the five transplanted organs, adjusted for time since transplantation, was 1.05 (95% CI 0.52 to 2.14) and 0.80 (95% CI 0.42 to 1.50) within 30 and 60 days after vaccination, respectively. Similar estimates were observed for rejection of a kidney only, the most commonly transplanted organ (RI within 30 days after vaccination: 0.85 (95% CI 0.38 to 1.90)). Across various models and sensitivity analyses, RI estimates remained stable and within a consistent range around 1.0.

Conclusions

These results suggest a reassuring safety profile forPandemrixwith regard to the risk of rejection in SOT recipients in England and contribute to inform the benefit–risk of AS03-adjuvanted pandemic influenza vaccines in transplanted patients in the event of future pandemics.

Trial registration number

NCT01715792.
Did the use of the Guideliner V2TMguide catheter extension increase complications? A review of the incidence of complications related to the use of the V2 catheter, the influence of right brachiocephalic arterial anatomy and the redesign of the V3TMGuideliner and clinical outcomes
Authors: Alkhalil Mohammad , Smyth Alison , Walsh Simon J , McQuillan Conor , Spence Mark S , Owens Colum G , Hanratty Colm G
Published: January 2016

Objective

We sought to investigate the incidence of complications associated with V2 Guideliner, understand the mechanisms and evaluate the impact of alterations made to the V3 Guideliner.

Methods

Retrospective analysis of consecutive cases employing V2 Guideliner from two university teaching hospitals. Complications were identified, analysed and classified into major versus minor ones. To understand the potential anatomical mechanism of these complications, analysis of normal great vessel anatomy was undertaken in separate cohort of patients undergoing cardiac catheterisation via right radial approach. Further analysis of consecutive cases employing V3 Gudieliner took place and the incidence of complications were compared between V2 and V3 groups.

Results

Total of 188 cases of V2 Guideliner use were identified. One major complication was reported (coronary dissection). Proximal collar interaction and stent damage occurred in 19 cases (10%). Anatomical data suggest that extending the V2 Guideliner tubing sited the proximal collar of the device in the brachiocephalic/subclavian artery, a potential site of tortuosity and potential cause of the Guideliner proximal collar-stent interaction. Further analysis of 124 cases of V3 Guideliner use demonstrated no cases with proximal collar-stent interactions, one case of longitudinal stent deformation and two incidents of stent interaction with the distal edge of the V3 Guideliner.

Conclusions

We have demonstrated a higher incidence of V2 Guideliner complications compared to previous series. The change in design of the V2 Guideliner was a likely contributor but the modifications with V3 Guideliner appear to have ameliorated this issue.
Mapping regions in Ste5 that support Msn5-dependent and -independent nuclear export
Authors: Hu Zhenhua , Wang Yunmei , Yu Lu , Mahanty Sanjoy K. , Mendoza Natalia , Elion Elaine A.
Published: January 2016

Careful control of the available pool of the MAPK scaffold Ste5 is important for mating-pathway activation and the prevention of inappropriate mating differentiation in haploid Saccharomyces cerevisiae. Ste5 shuttles constitutively through the nucleus, where it is degraded by a ubiquitin-dependent mechanism triggered by G1 CDK phosphorylation. Here we narrow-down regions of Ste5 that mediate nuclear export. Four regions in Ste5 relocalize SV40-TAgNLS-GFP-GFP from nucleus to cytoplasm. One region is N-terminal, dependent on exportin Msn5/Ste21/Kap142, and interacts with Msn5 in 2 hybrid assays independently of mating pheromone, Fus3, Kss1, Ptc1, the NLS/PM, and RING-H2. A second region overlaps the PH domain and Ste11 binding site and 2 others are on the vWA domain and include residues essential for MAPK activation. We find no evidence for dependence on Crm1/Xpo1, despite numerous potential nuclear export sequences (NESs) detected by LocNES and NetNES1.1 predictors. Thus, Msn5 (homolog of human Exportin-5) and one or more exportins or adaptor molecules besides Crm1/Xpo1 may regulate Ste5 through multiple recognition sites.
Ventilation changes associated with hatching and maturation of an endothermic phenotype in the Pekin duck,Anas platyrhynchos domestica
Authors: Sirsat Tushar S. , Dzialowski Edward M.
Published: January 2016

Precocial birds begin embryonic life with an ectothermic metabolic phenotype and rapidly develop an endothermic phenotype after hatching. Switching to a high-energy, endothermic phenotype requires high-functioning respiratory and cardiovascular systems to deliver sufficient environmental oxygen to the tissues. We measured tidal volume (VT), breathing frequency (ƒ), minute ventilation (V̇e), and whole-animal oxygen consumption (V̇o2) in response to gradual cooling from 37.5°C (externally pipped paranates, EP) or 35°C (hatchlings) to 20°C along with response to hypercapnia during developmental transition from an ectothermic, EP paranate to endothermic hatchling. To examine potential eggshell constraints on EP ventilation, we repeated these experiments in artificially hatched early and late EP paranates. Hatchlings and artificially hatched late EP paranates were able to increase V̇o2significantly in response to cooling. EP paranates had high ƒ that decreased with cooling, coupled with an unchanging low VTand did not respond to hypercapnia. Hatchlings had significantly lower ƒ and higher VTand V̇e that increased with cooling and hypercapnia. In response to artificial hatching, all ventilation values quickly reached those of hatchlings and responded to hypercapnia. The timing of artificial hatching influenced the temperature response, with only artificially hatched late EP animals, exhibiting the hatchling ventilation response to cooling. We suggest one potential constraint on ventilatory responses of EP paranates is the rigid eggshell, limiting air sac expansion during inhalation and constraining VT. Upon natural or artificial hatching, the VTlimitation is removed and the animal is able to increase VT, V̇e, and thus V̇o2, and exhibit an endothermic phenotype.
In vivo and in vitro degradation of peptide YY3–36 to inactive peptide YY3–34 in humans
Authors: Toräng Signe , Bojsen-Møller Kirstine Nyvold , Svane Maria Saur , Hartmann Bolette , Rosenkilde Mette Marie , Madsbad Sten , Holst Jens Juul
Published: January 2016

Peptide YY (PYY) is a 36-amino-acid peptide released from enteroendocrine cells upon food intake. The NH2 terminally truncated metabolite, PYY3–36, exerts anorexic effects and has received considerable attention as a possible antiobesity drug target. The kinetics and degradation products of PYY metabolism are not well described. A related peptide, neuropeptide Y, may be degraded from the COOH terminus, and in vivo studies in pigs revealed significant COOH-terminal degradation of PYY. We therefore investigated PYY metabolism in vitro after incubation in human blood and plasma and in vivo after infusion of PYY1–36 and PYY3–36 in eight young, healthy men. A metabolite, corresponding to PYY3–34, was formed after incubation in plasma and blood and during the infusion of PYY. PYY3–34 exhibited no agonistic or antagonistic effects on the Y2 receptor. PYY1–36 infused with and without coadministration of sitagliptin was eliminated with half-lives of 10.1 ± 0.5 and 9.4 ± 0.8 min (means ± SE) and metabolic clearance rates of 15.7 ± 1.5 and 14.1 ± 1.1 ml·kg−1·min−1 after infusion, whereas PYY3–36 was eliminated with a significantly longer half-life of 14.9 ± 1.3 min and a metabolic clearance rate of 9.4 ± 0.6 ml·kg−1·min−1. We conclude that, upon intravenous infusion in healthy men, PYY is inactivated by cleavage of the two COOH-terminal amino acids. In healthy men, PYY3–36 has a longer half-life than PYY1–36.
Trastuzumab in Esophagogastric Cancer: HER2-Testing and Treatment Reality outside Clinical Studies in Germany
Authors: Merx Kirsten , Barreto Miranda Manuel , Kellermann Lenka , Mahlknecht Ulrich , Lange Oliver , Gonnermann Michael , Hofheinz Ralf-Dieter
Published: January 2016

We analysed trends over time in palliative first-line chemotherapy in patients with locally advanced or metastatic esophagogastric cancer. Special focus was on frequency and quality of HER2-testing and trends in drug use in combination with trastuzumab. Earlier published data about patients treated outside clinical studies showed a relatively low rate of HER2-testing and insufficient test quality. A total of 2,808 patients retrospectively documented in Therapiemonitor®from 2006 to 2013 were analysed regarding treatment intensity and trends in used drugs. Data on HER2-testing and therapies were analysed in two cohorts documented in 2010 and 2011 (1) compared to 2012 and 2013 (2). Treatment intensity increased: 49.3% of patients received at least a triplet in 2013 compared to 10.1% in 2006. In cohort 2 HER2 expression was tested in 79.1% of the cases. Still, in 26.9% testing was not done as requested by guidelines. Good performance status, multiple metastases, age ≤ 65 years, the objective “to prevent progression,” good cognitive capabilities, estimated good compliance, and social integration positively influenced the probability of HER2-testing; comorbidities negatively affected it. Usage of the combination of fluoropyrimidines and cisplatin with trastuzumab declined from 67% in cohort 1 to 50% in cohort 2.
The Influence of Aging on the Regenerative Potential of Human Adipose Derived Mesenchymal Stem Cells
Authors: Marędziak Monika , Marycz Krzysztof , Tomaszewski Krzysztof A. , Kornicka Katarzyna , Henry Brandon Michael
Published: January 2016

Tissue regeneration using human adipose derived mesenchymal stem cells (hASCs) has significant potential as a novel treatment for many degenerative bone and joint diseases. Previous studies have established that age negatively affects the proliferation status and the osteogenic and chondrogenic differentiation potential of mesenchymal stem cells. The aim of this study was to assess the age‐related maintenance of physiological function and differentiation potential of hASCs in vitro. hASCs were isolated from patients of four different age groups: (1) >20 years (n = 7), (2) >50 years (n = 7), (3) >60 years (n = 7), and (4) >70 years (n = 7). The hASCs were characterized according to the number of fibroblasts colony forming unit (CFU‐F), proliferation rate, population doubling time (PDT), and quantified parameters of adipogenic, chondrogenic, and osteogenic differentiation. Compared to younger cells, aged hASCs had decreased proliferation rates, decreased chondrogenic and osteogenic potential, and increased senescent features. A shift in favor of adipogenic differentiation with increased age was also observed. As many bone and joint diseases increase in prevalence with age, it is important to consider the negative influence of age on hASCs viability, proliferation status, and multilineage differentiation potential when considering the potential therapeutic applications of hASCs.
E2A Antagonizes PU.1 Activity through Inhibition of DNA Binding
Authors: Rogers Jason H. , Owens Kristin S. , Kurkewich Jeffrey , Klopfenstein Nathan , Iyer Sangeeta R. , Simon M. Celeste , Dahl Richard
Published: January 2016

Antagonistic interactions between transcription factors contribute to cell fate decisions made by multipotent hematopoietic progenitor cells. Concentration of the transcription factor PU.1 affects myeloid/lymphoid development with high levels of PU.1 directing myeloid cell fate acquisition at the expense of B cell differentiation. High levels of PU.1 may be required for myelopoiesis in order to overcome inhibition of its activity by transcription factors that promote B cell development. The B cell transcription factors, E2A and EBF, are necessary for commitment of multipotential progenitors and lymphoid primed multipotential progenitors to lymphocytes. In this report we hypothesized that factors required for early B cell commitment would bind to PU.1 and antagonize its ability to induce myeloid differentiation. We investigated whether E2A and/or EBF associate with PU.1. We observed that the E2A component, E47, but not EBF, directly binds to PU.1. Additionally E47 represses PU.1-dependent transactivation of theMCSFRpromoter through antagonizing PU.1’s ability to bind to DNA. Exogenous E47 expression in hematopoietic cells inhibits myeloid differentiation. Our data suggest that E2A antagonism of PU.1 activity contributes to its ability to commit multipotential hematopoietic progenitors to the lymphoid lineages.
Assessment of Newly Proposed Clinical Criteria to IdentifyHNF1AMODY in Patients with an Initial Diagnosis of Type 1 or Type 2 Diabetes Mellitus
Authors: Grzanka Malgorzata , Matejko Bartlomiej , Szopa Magdalena , Kiec-Wilk Beata , Malecki Maciej T. , Klupa Tomasz
Published: January 2016

The most common form of maturity-onset diabetes of the young (MODY) is caused by mutations in the hepatocyte nuclear factor 1A (HNF1A) gene. However, mostHNF1Amutation-carriers are initially misdiagnosed with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus; hence, they often receive nonoptimal treatment. The aim of our study was to test newly proposed clinical criteria for the identification ofHNF1AMODY in patients with a diagnosis of T1DM or T2DM. To achieve this, the following criteria to preselect patients for screening were used: for T1DM: TDIR (total daily insulin requirement) > 0.3 IU of insulin/kg and the percentage of basal insulin > 30% of TDIR; for T2DM: sulphonylurea- (SU-) based oral treatment (monotherapy or combined with Metformin) > 15 years and BMI < 30 kg/m2. We reviewed the clinical data of 140 patients with T1DM and 524 clinically diagnosed with T2DM. On the basis of these criteria, we found aHNF1Amutation in 1 out of 2 individuals with a diagnosis of T1DM and 1 out of 11 selected individuals with a diagnosis of T2DM. We believe that the simplicity of the proposed criteria might prove useful in clinical practice, as an alternative to more time-consuming classical diagnostic techniques.
DAS181 Treatment of Severe Parainfluenza Virus 3 Pneumonia in Allogeneic Hematopoietic Stem Cell Transplant Recipients Requiring Mechanical Ventilation
Authors: Dhakal B. , D’Souza A. , Pasquini M. , Saber W. , Fenske T. S. , Moss R. B. , Drobyski W. R. , Hari P. , Abidi M. Z.
Published: January 2016

Parainfluenza virus (PIV) may cause life-threatening pneumonia in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Currently, there are no proven effective therapies. We report the use of inhaled DAS181, a novel sialidase fusion protein, for treatment of PIV type 3 pneumonia in two allogeneic hematopoietic SCT recipients with respiratory failure.
A Review on Potential Mechanisms ofTerminalia chebulain Alzheimer’s Disease
Authors: Afshari Amir R. , Sadeghnia Hamid R. , Mollazadeh Hamid
Published: January 2016

The current management of Alzheimer’s disease (AD) focuses on acetylcholinesterase inhibitors (AChEIs) and NMDA receptor antagonists, although outcomes are not completely favorable. Hence, novel agents found in herbal plants are gaining attention as possible therapeutic alternatives. TheTerminalia chebula(Family: Combretaceae) is a medicinal plant with a wide spectrum of medicinal properties and is reported to contain various biochemicals such as hydrolysable tannins, phenolic compounds, and flavonoids, so it may prove to be a good therapeutic alternative. In this research, we reviewed published scientific literature found in various databases: PubMed, Science Direct, Scopus, Web of Science, Scirus, and Google Scholar, with the keywords:T. chebula, AD, neuroprotection, medicinal plant, antioxidant, ellagitannin, gallotannin, gallic acid, chebulagic acid, and chebulinic acid. This review shows thatT. chebulaextracts and its constituents have AChEI and antioxidant and anti-inflammatory effects, all of which are currently relevant to the treatment of Alzheimer’s disease.
Birth Size Characteristics and Risk of Brain Tumors in Early Adulthood: Results from a Swedish Cohort Study
Authors: Tettamanti Giorgio , Ljung Rickard , Mathiesen Tiit , Schwartzbaum Judith , Feychting Maria
Published: January 2016

Background: Despite extensive research on the effect of birth size characteristics on childhood brain tumors, very few studies have evaluated the effect of birth size characteristics on the risk of adult brain tumor, and they have provided inconsistent results.

Methods: All individuals born in Sweden between 1973 and 1995 who were still alive and cancer free at their 15th birthday were included in the study (n = 2,032,727). At the end of the study period (December 31, 2010), the study participants were 15 to 37 years old. Incident cases of primary brain tumors were identified through the Swedish Cancer Register.

Results: No association was observed between any birth size characteristics and glioma, although an indication of increased glioma risk associated with high birth weight, or being large for gestational age at birth, was found among men [relative risk (RR) = 1.36, 95% confidence interval (CI), 0.97–1.90; RR = 1.44, 95% CI, 0.99–2.09, respectively]. An increased risk of meningioma was observed among individuals born with a large head circumference (RR = 1.76, 95% CI, 1.01–3.05). Large head circumference was also associated with an elevated risk of neuroma (RR = 1.86, 95% CI, 0.94–3.68). Being born small for gestational age was also related to a higher risk of neuroma (RR = 2.50, 95% CI, 1.31–4.78).

Conclusion: Selected birth size characteristics were associated with increased risk of some brain tumor subtypes in young adults.

Impact: We have presented additional evidence suggesting that birth size characteristics are associated with subsequent primary brain tumor risk in young adults. Cancer Epidemiol Biomarkers Prev; 25(4); 678–85. ©2016 AACR.
Next-Generation Sequencing in Diffuse Large B-Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study
Authors: Dubois Sydney , Viailly Pierre-Julien , Mareschal Sylvain , Bohers Elodie , Bertrand Philippe , Ruminy Philippe , Maingonnat Catherine , Jais Jean-Philippe , Peyrouze Pauline , Figeac Martin , Molina Thierry J. , Desmots Fabienne , Fest Thierry , Haioun Corinne , Lamy Thierry , Copie-Bergman Christiane , Brière Josette , Petrella Tony , Canioni Danielle , Fabiani Bettina , Coiffier Bertrand , Delarue Richard , Peyrade Frédéric , Bosly André , André Marc , Ketterer Nicolas , Salles Gilles , Tilly Hervé , Leroy Karen , Jardin Fabrice
Published: January 2016

Purpose: Next-generation sequencing (NGS) has detailed the genomic characterization of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. We set out to design a clinically feasible NGS panel focusing on genes whose mutations hold potential therapeutic impact. Furthermore, for the first time, we evaluated the prognostic value of these mutations in prospective clinical trials.

Experimental Design: A Lymphopanel was designed to identify mutations in 34 genes, selected according to literature and a whole exome sequencing study of relapsed/refractory DLBCL patients. The tumor DNA of 215 patients with CD20+de novo DLBCL in the prospective, multicenter, and randomized LNH-03B LYSA clinical trials was sequenced to deep, uniform coverage with the Lymphopanel. Cell-of-origin molecular classification was obtained through gene expression profiling with HGU133+2.0 Affymetrix GeneChip arrays.

Results: The Lymphopanel was informative for 96% of patients. A clear depiction of DLBCL subtype molecular heterogeneity was uncovered with the Lymphopanel, confirming that activated B-cell–like (ABC), germinal center B-cell like (GCB), and primary mediastinal B-cell lymphoma (PMBL) are frequently affected by mutations in NF-κB, epigenetic, and JAK–STAT pathways, respectively. Novel truncating immunity pathway, ITPKB, MFHAS1, and XPO1 mutations were identified as highly enriched in PMBL. Notably, TNFAIP3 and GNA13 mutations in ABC patients treated with R-CHOP were associated with significantly less favorable prognoses.

Conclusions: This study demonstrates the contribution of NGS with a consensus gene panel to personalized therapy in DLBCL, highlighting the molecular heterogeneity of subtypes and identifying somatic mutations with therapeutic and prognostic impact. Clin Cancer Res; 22(12); 2919–28. ©2016 AACR.

See related commentary by Lim and Elenitoba-Johnson, p. 2829
Adjuvant Immunotherapy to Improve Outcome in High-Risk Pediatric Sarcomas
Authors: Merchant Melinda S. , Bernstein Donna , Amoako Martha , Baird Kristin , Fleisher Thomas A. , Morre Michel , Steinberg Seth M. , Sabatino Marianna , Stroncek Dave F. , Venkatasan Aradhana M. , Wood Bradford J. , Wright Matthew , Zhang Hua , Mackall Crystal L.
Published: January 2016

Purpose: Patients with metastatic or relapsed pediatric sarcomas receive cytotoxic regimens that induce high remission rates associated with profound lymphocyte depletion, but ultimately few survive long term. We administered adjuvant immunotherapy to patients with metastatic and recurrent pediatric sarcomas in an effort to improve outcomes.

Experimental Design: Mononuclear cells were collected via apheresis, and tumor lysate was acquired via percutaneous biopsy at enrollment. Participants received standard antineoplastic therapy, followed by autologous lymphocytes, tumor lysate/keyhole limpet hemocyanin–pulsed dendritic cell vaccinations ± recombinant human IL7. Primary outcomes were toxicity and vaccine responses. Secondary outcomes were immune reconstitution, event-free survival, and overall survival (OS).

Results: Forty-three patients enrolled and 29 received immunotherapy. The regimen was well tolerated. Intent-to-treat analysis demonstrated 5-year OS of 51% with significant differences based upon histologic group (63% vs. 0% for Ewing/rhabdomyosarcoma vs. other sarcomas) and response to standard therapy (74% no residual disease vs. 0% residual disease). Five-year intent-to-treat OS of patients with newly diagnosed metastatic Ewing/rhabdomyosarcoma was 77%, higher than previously reported in this population and higher than observed in a similar group treated with an earlier adjuvant immunotherapy regimen (25% 5-year OS). T-cell responses to autologous tumor lysate were identified in 62% of immunotherapy recipients, and survival was higher in those patients (73% 5-year OS with vs. 37% without immune response, P = 0.017). Immune reconstitution, measured by CD4 count recovery, was significantly enhanced in subjects treated with recombinant human IL7.

Conclusions: Adjuvant immunotherapy may improve survival in patients with metastatic pediatric sarcoma. Clin Cancer Res; 22(13); 3182–91. ©2016 AACR.
Modeling Therapy Response and Spatial Tissue Distribution of Erlotinib in Pancreatic Cancer
Authors: Grüner Barbara M. , Winkelmann Isabel , Feuchtinger Annette , Sun Na , Balluff Benjamin , Teichmann Nicole , Herner Alexander , Kalideris Evdokia , Steiger Katja , Braren Rickmer , Aichler Michaela , Esposito Irene , Schmid Roland M. , Walch Axel , Siveke Jens T.
Published: January 2016

Pancreatic ductal adenocarcinoma (PDAC) is likely the most aggressive and therapy-resistant of all cancers. The aim of this study was to investigate the emerging technology of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) as a powerful tool to study drug delivery and spatial tissue distribution in PDAC. We utilized an established genetically engineered mouse model of spontaneous PDAC to examine the distribution of the small-molecule inhibitor erlotinib in healthy pancreas and PDAC. MALDI IMS was utilized on sections of single-dose or long-term–treated mice to measure drug tissue distribution. Histologic and statistical analyses were performed to correlate morphology, drug distribution, and survival. We found that erlotinib levels were significantly lower in PDAC compared with healthy tissue (P = 0.0078). Survival of long-term–treated mice did not correlate with overall levels of erlotinib or with overall histologic tumor grade but did correlate both with the percentage of atypical glands in the cancer (P = 0.021, rs = 0.59) and the level of erlotinib in those atypical glands (P = 0.019, rs = 0.60). The results of this pilot study present MALDI IMS as a reliable technology to study drug delivery and spatial distribution of compounds in a preclinical setting and support drug imaging–based translational approaches. Mol Cancer Ther; 15(5); 1145–52. ©2016 AACR.
GSK-3β Governs Inflammation-Induced NFATc2 Signaling Hubs to Promote Pancreatic Cancer Progression
Authors: Baumgart Sandra , Chen Nai-Ming , Zhang Jin-San , Billadeau Daniel D. , Gaisina Irina N. , Kozikowski Alan P. , Singh Shiv K. , Fink Daniel , Ströbel Philipp , Klindt Caroline , Zhang Lizhi , Bamlet William R. , Koenig Alexander , Hessmann Elisabeth , Gress Thomas M. , Ellenrieder Volker , Neesse Albrecht
Published: January 2016

We aimed to investigate the mechanistic, functional, and therapeutic role of glycogen synthase kinase 3β (GSK-3β) in the regulation and activation of the proinflammatory oncogenic transcription factor nuclear factor of activated T cells (NFATc2) in pancreatic cancer. IHC, qPCR, immunoblotting, immunofluorescence microscopy, and proliferation assays were used to analyze mouse and human tissues and cell lines. Protein–protein interactions and promoter regulation were analyzed by coimmunoprecipitation, DNA pulldown, reporter, and ChIP assays. Preclinical assays were performed using a variety of pancreatic cancer cells lines, xenografts, and a genetically engineered mouse model (GEMM). GSK-3β–dependent SP2 phosphorylation mediates NFATc2 protein stability in the nucleus of pancreatic cancer cells stimulating pancreatic cancer growth. In addition to protein stabilization, GSK-3β also maintains NFATc2 activation through a distinct mechanism involving stabilization of NFATc2–STAT3 complexes independent of SP2 phosphorylation. For NFATc2–STAT3 complex formation, GSK-3β–mediated phosphorylation of STAT3 at Y705 is required to stimulate euchromatin formation of NFAT target promoters, such as cyclin-dependent kinase-6, which promotes tumor growth. Finally, preclinical experiments suggest that targeting the NFATc2–STAT3–GSK-3β module inhibits proliferation and tumor growth and interferes with inflammation-induced pancreatic cancer progression in KrasG12D mice. In conclusion, we describe a novel mechanism by which GSK-3β fine-tunes NFATc2 and STAT3 transcriptional networks to integrate upstream signaling events that govern pancreatic cancer progression and growth. Furthermore, the therapeutic potential of GSK-3β is demonstrated for the first time in a relevant Kras and inflammation-induced GEMM for pancreatic cancer. Mol Cancer Ther; 15(3); 491–502. ©2016 AACR.
Enhancing the Tumor Selectivity of a Picornavirus Virotherapy Promotes Tumor Regression and the Accumulation of Infiltrating CD8+ T Cells
Authors: Bell Michael P. , Pavelko Kevin D.
Published: January 2016

Picornaviruses have emerged as promising cancer therapies due to their ability to drive cytotoxic cellular immune responses and for promoting oncolysis. These properties include preferential replication in tumor cells, the induction of strong innate and adaptive immune responses, and the ease with which their genomes can be manipulated. We have developed Theiler's murine encephalomyelitis virus (TMEV) as an immunotherapy vector that promotes strong adaptive immune responses to tumor antigens embedded within its genome. To further explore its usefulness as cancer therapy, we investigated whether direct intratumoral delivery of TMEV could promote tumor regression. We generated several picornavirus hybrids using substrains of TMEV that have unique immunopathologic characteristics, despite their extensive sequence homology. These hybrids exhibit a unique propensity to infect and replicate in melanoma. We have identified GD7-KS1, a virus that is particularly effective at replicating and infecting B16 melanoma in vitro and provides benefit as an oncolytic therapy in vivo after intratumoral injection. In addition, this virus promotes the mobilization and accumulation of CD8+ T cells within treated tumors. Altogether, these findings demonstrate that picornavirus substrains can be used to rationally design virus hybrids that promote antitumor responses and add to the known strategies identified by us and others to further enhance the therapeutic potential of vectors used to treat cancer. Mol Cancer Ther; 15(3); 523–30. ©2016 AACR.
Tigecycline Inhibits Glioma Growth by Regulating miRNA-199b-5p–HES1–AKT Pathway
Authors: Yang Rui , Yi Liang , Dong Zhen , Ouyang Qing , Zhou Ji , Pang Yi , Wu Yanan , Xu Lunshan , Cui Hongjuan
Published: January 2016

Tigecycline is a broad-spectrum, first-in-class glycylcycline antibiotic currently used to treat complicated skin infections and community-acquired pneumonia. However, there is accumulating evidence showing that tigecycline has anticancer properties. In this study, we found tigecycline could inhibit cell proliferation by inducing cell-cycle arrest, but not apoptosis in glioma. To find the underlying mechanism of how tigecycline inhibits cell proliferation, the expression of miRNAs, which were related to regulating cell-cycle progression, was detected with miRNA assay. We found that miR-199b-5p expression was significantly increased after tigecycline treatment, and miR-199b-5p target gene HES1 was downregulated. In addition, the PI3K/AKT pathway was inhibited and p21 expression was increased. When treated with tigecycline and miR-199b-5p antagomir simultaneously in glioma cells, we found that miR-199b-5p antagomir could partly block the effects induced by tigecycline. Tigecycline effectively upregulated miR-199b-5p expression and inhibited tumor growth in the xenograft tumor model of U87 glioma cells. These results suggest that tigecycline may induce cell-cycle arrest and inhibit glioma growth by regulating miRNA-199b-5p–HES1–AKT pathway. Thus, tigecycline is a promising agent in the treatment of malignant gliomas. Mol Cancer Ther; 15(3); 421–9. ©2016 AACR.
SGK3 Sensitivity of Voltage Gated K+ Channel Kv1.5 (KCNA5)
Authors: Ahmed Musaab , Fezai Myriam , Uzcategui Nestor L. , Hosseinzadeh Zohreh , Lang Florian
Published: January 2016

Background: The serum & glucocorticoid inducible kinase isoform SGK3 is a powerful regulator of several transporters, ion channels and the Na+/K+ ATPase. Targets of SGK3 include the ubiquitin ligase Nedd4-2, which is in turn a known regulator of the voltage gated K+ channel Kv1.5 (KCNA5). The present study thus explored whether SGK3 modifies the activity of the voltage gated K+ channel KCNA5, which participates in the regulation of diverse functions including atrial cardiac action potential, activity of vascular smooth muscle cells, insulin release and tumour cell proliferation. Methods: cRNA encoding KCNA5 was injected into Xenopus oocytes with and without additional injection of cRNA encoding wild-type SGK3, constitutively active S419DSGK3, inactive K191NSGK3 and/or wild type Nedd4-2. Voltage gated K+ channel activity was quantified utilizing dual electrode voltage clamp. Results: Voltage gated current in KCNA5 expressing Xenopus oocytes was significantly enhanced by wild-type SGK3 and S419DSGK3, but not by K191NSGK3. SGK3 was effective in the presence of ouabain (1 mM) and thus did not require Na+/K+ ATPase activity. Coexpression of Nedd4-2 decreased the voltage gated current in KCNA5 expressing Xenopus oocytes, an effect largely reversed by additional coexpression of SGK3. Conclusion: SGK3 is a positive regulator of KCNA5, which is at least partially effective by abrogating the effect of Nedd4-2.
The Long Non-Coding RNA ENST00000537266 and ENST00000426615 Influence Papillary Thyroid Cancer Cell Proliferation and Motility
Authors: Xu Bo , Shao Qin , Xie Kaipeng , Zhang Yuqing , Dong Tianyu , Xia Yankai , Tang Wei
Published: January 2016

Background/Aims: Papillary thyroid cancer (PTC) is the most common histotype of Thyroid cancer (TC). Here, we detected the differentially expressed lncRNAs in tumor tissues and non-tumor tissues of PTC patients by lncRNA microarrays, and explored the function and molecular mechanisms of lncRNAs in the pathogenesis of PTC using a PTC cell line. Methods: CCK-8 assay, colony formation assay and EdU assay were used to detect the cell viability. Flow Cytometry was used to detect the cell cycle and apoptosis. Transwell and scratch assay were used to detect the cell motility. Results: CCK-8 assay, colony formation assay and EdU assay revealed that lncRNAs (ENST00000537266 and ENST00000426615) could inhibit cell proliferation. Cell cycle analysis showed that cell proportion was statistically significant increased in G1 phase and decreased in S phase and G2 phase in Si-266 transfected TPC-1 cells. In addition, a noteworthy increase of cell proportion in G1 phase accompanied by a decrease in S phase and unchanged G2 phase in Si-615 transfected TPC-1 cells were also observed. Meanwhile, transwell and scratch assay showed that ENST00000426615 could inhibit the cell motility while ENST00000537266 could not. Conclusion: Our results showed that lncRNAs (ENST00000426615 and ENST00000537266) might be important regulators of PTC cell proliferation and motility, which might provide new insight into the understanding of PTC pathogenesis.
Genomic Alteration During Metastasis of Lung Adenocarcinoma
Authors: Tan Qiang , Cui Jian , Huang Jia , Ding Zhengping , Lin Hao , Niu Xiaomin , Li Zhiming , Wang Guan , Luo Qingquan , Lu Shun
Published: January 2016

Background/Aims: Recurrent gene mutation has been identified by the analysis of exonic DNA from lung adenocarcinoma, but its progression has not been extensively profiled. The investigation of the mutational landscape of tumors provides new insights into cancer genome evolution and further discovers the interplay of somatic mutation, adaptation of clones to their environment and natural selection. Cancer development involves cycles of genomic damage, epigenetic deregulation, and increased cellular proliferation that eventually culminate in the carcinoma phenotype. Methods: Comparative whole exome sequencing of both primary and metastatic tumor tissues from four patients of stage IV lung adenocarcinoma patients with chest wall metastasis was performed. Both primary and metastatic tumors were diagnosed through biopsy followed by surgical resection. All tumor specimens were cut into several pieces to assess potential heterogenic clones within the tumor tissue. Adjacent normal lung tissue was also obtained to provide germline mutation background. Results: By modeling and analyzing progression of the cancer metastasis based on non-synonymous variants, we defined the extent of heterogeneity of cancer genomes and identified similar cancer evolution pattern in the four patients: metastasis was an early event occurring right after the primary cancer formation and evolution in the metastatic tumor was continuously and simultaneously in progression with that in the primary tumor. By characterizing the clonal hierarchy of genetic lesions, we further charted a pathway of oncogenic events along which genes may drive lung adenocarcinoma metastasis, such as TAS2R31 and UMODL1, involving in G-protein coupled receptor protein signaling pathway. Conclusion: The candidate genes identified in this study may become targets for the treatment of lung adenocarcinoma metastasis.
Evaluation of Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry in Identification of Nontuberculous Mycobacteria
Authors: Mareković Ivana , Bošnjak Zrinka , Jakopović Marko , Boras Zagorka , Janković Mateja , Popović-Grle Sanja
Published: January 2016

Background/Aims: Species-level identification of nontuberculous mycobacteria (NTM) is important in making decisions about the necessity and choice of antimicrobial treatment. The reason is predictable clinical significance and the susceptibility profile of specific NTM species. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is recognized as a diagnostic tool for routine identification of bacteria and yeasts in the clinical laboratory based on protein fingerprint analysis. The aim of the study was to evaluate MALDI-TOF MS in the identification of NTM. Methods: A total of 25 NTM isolates from liquid cultures were identified with both polymerase chain reaction (PCR)-based hybridization assay and MALDI-TOF MS at the University Hospital Center Zagreb. Results: PCR-based hybridization assay identified 96% (24/25) and MALDI-TOF MS 80% (20/25) of tested NTM isolates. Five isolates with no reliable MALDI-TOF MS identification belonged to the Mycobacterium avium-intracellulare complex. Seventy percent (14/20) of NTM isolates successfully identified with MALDI-TOF MS had a score higher than 2.0, indicating reliable species identification. Conclusion: MALDI-TOF MS is a promising tool for the identification of NTM. With a further improvement of the protein extraction protocol, especially regarding the M. avium-intracellulare complex, MALDI-TOF MS could be an additional standard method for identification of NTM.
The Heterogeneity Hidden in Allergic Rhinitis and Its Impact on Co-Existing Asthma in Adults: A Population-Based Survey
Authors: Antonicelli Leonardo , Marchetti Pierpaolo , Accordini Simone , Bono Roberto , Carosso Aurelia , Casali Lucio , Cazzoletti Lucia , Corsico Angelo , Ferrari Marcello , Fois Alessandro , Nicolini Gabriele , Olivieri Mario , Pirina Pietro , Verlato Giuseppe , Villani Simona , de Marco Roberto
Published: January 2016

Background: It has been suggested that there is some overlap between allergic rhinitis (AR), sinusitis and polyposis, but this has not been fully documented. The present study aimed to evaluate the prevalence of these co-existing diseases and their impact on bronchial asthma in the general population of Italy. Methods: Within the frame of the multicentre Gene Environment Interactions in Respiratory Diseases (GEIRD) study, a postal screening questionnaire including questions about self-reported symptoms of asthma, AR, AR with sinusitis without nasal polyps (AR + SsNP) and AR with sinusitis with nasal polyps (AR + SwNP) was administered. Random samples of subjects aged between 20 and 44 years (n = 5,162) answered the postal questionnaire in 4 Italian centres (Pavia, Sassari, Turin, Verona). In AR subjects, the association among AR only, AR + SsNP, AR + SwNP and bronchial asthma was estimated by the relative risk ratio (RRR) using multinomial regression models. Results: The prevalence of AR in the sample was 25.4% (95% CI 24.2-26.6). A self-reported diagnosis of AR + SsNP and AR + SwNP was reported by 5.7% (95% CI 5.0-6.3) and by 1.2% (95% CI 0.9-1.5) of the subjects, respectively. Current asthma was reported by 17.5% of the AR subjects. In the adjusted multivariate analysis, the risk of having current asthma (RRR = 2.31, 95% CI 1.29-4.15), of having at least 1 asthma attack per year (RRR = 2.30, 95% CI 1.19-4.46) and of having had an emergency department admission for respiratory diseases (RRR = 5.61, 95% CI 1.81-23.92) was higher for subjects with AR + SwNP than subjects with AR only. Conclusions: The diagnosis of AR in the epidemiological setting includes heterogeneous upper airway diseases that affect the clinical features of AR and its interactions with asthma.
Organ Specificity and Functional Relevance of the Arterial Structure: A Comparative Study in the Kidney and the Skeletal Muscle with Electron Microscopy
Authors: Hosoyamada Yasue , Ichimura Koichiro , Sakai Tatsuo
Published: January 2016

The differences in circulation among various organs are well known, but the structural differences have only been poorly investigated. In the present study the wall structure of arteries was observed with electron microscopy in rat kidney and skeletal muscle. The wall thickness was almost equal in both organs at about 40 μm in luminal diameter, while it was relatively thin in the larger arteries and thick in the smaller arteries in the kidney compared with that in the skeletal muscle. The smooth muscle cells were regularly arranged in parallel in circular or slightly spiral orientation in the kidney, whereas those in the skeletal muscle were irregularly arranged in heterogeneous orientations. Extracellular matrices were more abundant in the arterial media in the skeletal muscle than in the kidney. The inner elastic lamina was continuous in the kidney, and arranged in longitudinal bundles in the skeletal muscle. The adventitial collagen fibers were abundant and dense in the skeletal muscle, and were scattered in small bundles in the fluid-filled spaces in the kidney. While the arteries in the skeletal muscle are under severe mechanical stress during muscle contraction and dilate dramatically during exercise, those in the kidney regulate glomerular pressure almost constantly.