bluuebunny/crossref_metadata_2025_split huggingface dataset:
RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis
Authors: Brünker Peter , Wartha Katharina , Friess Thomas , Grau-Richards Sandra , Waldhauer Inja , Koller Claudia Ferrara , Weiser Barbara , Majety Meher , Runza Valeria , Niu Huifeng , Packman Kathryn , Feng Ningping , Daouti Sherif , Hosse Ralf J. , Mössner Ekkehard , Weber Thomas G. , Herting Frank , Scheuer Werner , Sade Hadassah , Shao Cuiying , Liu Bin , Wang Peng , Xu Gary , Vega-Harring Suzana , Klein Christian , Bosslet Klaus , Umaña Pablo 
Published: April 2016

Abstract
Dysregulated cellular apoptosis and resistance to cell death are hallmarks of neoplastic initiation and disease progression. Therefore, the development of agents that overcome apoptosis dysregulation in tumor cells is an attractive therapeutic approach. Activation of the extrinsic apoptotic pathway is strongly dependent on death receptor (DR) hyperclustering on the cell surface. However, strategies to activate DR5 or DR4 through agonistic antibodies have had only limited clinical success. To pursue an alternative approach for tumor-targeted induction of apoptosis, we engineered a bispecific antibody (BsAb), which simultaneously targets fibroblast-activation protein (FAP) on cancer-associated fibroblasts in tumor stroma and DR5 on tumor cells. We hypothesized that bivalent binding to both FAP and DR5 leads to avidity-driven hyperclustering of DR5 and subsequently strong induction of apoptosis in tumor cells but not in normal cells. Here, we show that RG7386, an optimized FAP-DR5 BsAb, triggers potent tumor cell apoptosis in vitro and in vivo in preclinical tumor models with FAP-positive stroma. RG7386 antitumor efficacy was strictly FAP dependent, was independent of FcR cross-linking, and was superior to conventional DR5 antibodies. In combination with irinotecan or doxorubicin, FAP-DR5 treatment resulted in substantial tumor regression in patient-derived xenograft models. FAP-DR5 also demonstrated single-agent activity against FAP-expressing malignant cells, due to cross-binding of FAP and DR5 across tumor cells. Taken together, these data demonstrate that RG7386, a novel and potent antitumor agent in both mono- and combination therapies, overcomes limitations of previous DR5 antibodies and represents a promising approach to conquer tumor-associated resistance to apoptosis. Mol Cancer Ther; 15(5); 946–57. ©2016 AACR.
Nanofluidic Digital PCR and Extended Genotyping of RAS and BRAF for Improved Selection of Metastatic Colorectal Cancer Patients for Anti-EGFR Therapies
Authors: Azuara Daniel , Santos Cristina , Lopez-Doriga Adriana , Grasselli Julieta , Nadal Marga , Sanjuan Xavier , Marin Fátima , Vidal Joana , Montal Robert , Moreno Victor , Bellosillo Beatriz , Argiles Guillem , Elez Elena , Dienstmann Rodrigo , Montagut Clara , Tabernero Josep , Capellá Gabriel , Salazar Ramon 
Published: April 2016

Abstract
The clinical significance of low-frequent RAS pathway–mutated alleles and the optimal sensitivity cutoff value in the prediction of response to anti-EGFR therapy in metastatic colorectal cancer (mCRC) patients remains controversial. We aimed to evaluate the added value of genotyping an extended RAS panel using a robust nanofluidic digital PCR (dPCR) approach. A panel of 34 hotspots, including RAS (KRAS and NRAS exons 2/3/4) and BRAF (V600E), was analyzed in tumor FFPE samples from 102 mCRC patients treated with anti-EGFR therapy. dPCR was compared with conventional quantitative PCR (qPCR). Response rates, progression-free survival (PFS), and overall survival (OS) were correlated to the mutational status and the mutated allele fraction. Tumor response evaluations were not available in 9 patients and were excluded for response rate analysis. Twenty-two percent of patients were positive for one mutation with qPCR (mutated alleles ranged from 2.1% to 66.6%). Analysis by dPCR increased the number of positive patients to 47%. Mutated alleles for patients only detected by dPCR ranged from 0.04% to 10.8%. An inverse correlation between the fraction of mutated alleles and radiologic response was observed. ROC analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value for all combinations of RAS and BRAF analysis. In addition, this threshold also optimized prediction both PFS and OS. We conclude that mutation testing using an extended gene panel, including RAS and BRAF with a threshold of 1% improved prediction of response to anti-EGFR therapy. Mol Cancer Ther; 15(5); 1106–12. ©2016 AACR.
Augmentation of CAR T-cell Trafficking and Antitumor Efficacy by Blocking Protein Kinase A Localization
Authors: Newick Kheng , O'Brien Shaun , Sun Jing , Kapoor Veena , Maceyko Steven , Lo Albert , Puré Ellen , Moon Edmund , Albelda Steven M. 
Published: April 2016

AbstractAntitumor treatments based on the infusion of T cells expressing chimeric antigen receptors (CAR T cells) are still relatively ineffective for solid tumors, due to the presence of immunosuppressive mediators [such as prostaglandin E2 (PGE2) and adenosine] and poor T-cell trafficking. PGE2 and adenosine activate protein kinase A (PKA), which then inhibits T-cell receptor (TCR) activation. This inhibition process requires PKA to localize to the immune synapse via binding to the membrane protein ezrin. We generated CAR T cells that expressed a small peptide called the “regulatory subunit I anchoring disruptor” (RIAD) that inhibits the association of PKA with ezrin, thus blunting the negative effects of PKA on TCR activation. After exposure to PGE2 or adenosine in vitro, CAR-RIAD T cells showed increased TCR signaling, released more cytokines, and showed enhanced killing of tumor cells compared with CAR T cells. When injected into tumor-bearing mice, the antitumor efficacy of murine and human CAR-RIAD T cells was enhanced compared with that of CAR T cells, due to resistance to tumor-induced hypofunction and increased T-cell infiltration of established tumors. Subsequent in vitro assays showed that both mouse and human CAR-RIAD cells migrated more efficiently than CAR cells did in response to the chemokine CXCL10 and also had better adhesion to various matrices. Thus, the intracellular addition of the RIAD peptide to adoptively transferred CAR T cells augments their efficacy by increasing their effector function and by improving trafficking into tumor sites. This treatment strategy, therefore, shows potential clinical application for treating solid tumors. Cancer Immunol Res; 4(6); 541–51. ©2016 AACR.
Global Climate Impacts of Fixing the Southern Ocean Shortwave Radiation Bias in the Community Earth System Model (CESM)
Authors: Kay Jennifer E. , Wall Casey , Yettella Vineel , Medeiros Brian , Hannay Cecile , Caldwell Peter , Bitz Cecilia 
Published: April 2016

Abstract
A large, long-standing, and pervasive climate model bias is excessive absorbed shortwave radiation (ASR) over the midlatitude oceans, especially the Southern Ocean. This study investigates both the underlying mechanisms for and climate impacts of this bias within the Community Earth System Model, version 1, with the Community Atmosphere Model, version 5 [CESM1(CAM5)]. Excessive Southern Ocean ASR in CESM1(CAM5) results in part because low-level clouds contain insufficient amounts of supercooled liquid. In a present-day atmosphere-only run, an observationally motivated modification to the shallow convection detrainment increases supercooled cloud liquid, brightens low-level clouds, and substantially reduces the Southern Ocean ASR bias. Tuning to maintain global energy balance enables reduction of a compensating tropical ASR bias. In the resulting preindustrial fully coupled run with a brighter Southern Ocean and dimmer tropics, the Southern Ocean cools and the tropics warm. As a result of the enhanced meridional temperature gradient, poleward heat transport increases in both hemispheres (especially the Southern Hemisphere), and the Southern Hemisphere atmospheric jet strengthens. Because northward cross-equatorial heat transport reductions occur primarily in the ocean (80%), not the atmosphere (20%), a proposed atmospheric teleconnection linking Southern Ocean ASR bias reduction and cooling with northward shifts in tropical precipitation has little impact. In summary, observationally motivated supercooled liquid water increases in shallow convective clouds enable large reductions in long-standing climate model shortwave radiation biases. Of relevance to both model bias reduction and climate dynamics, quantifying the influence of Southern Ocean cooling on tropical precipitation requires a model with dynamic ocean heat transport.
Variable Lifting Index for Manual-Lifting Risk Assessment
Authors: Battevi Natale , Pandolfi Monica , Cortinovis Ivan 
Published: April 2016

Objective: The aim of this study was to evaluate the efficacy of the new Variable Lifting Index (VLI) method, theoretically based on the Revised National Institute for Occupational Safety and Health [NIOSH] Lifting Equation (RNLE), in predicting the risk of acute low-back pain (LBP) in the past 12 months. Background: A new risk variable termed the VLI for assessing variable manual lifting has been developed, but there has been no epidemiological study that evaluates the relationship between the VLI and LBP. Method: A sample of 3,402 study participants from 16 companies in different industrial sectors was analyzed. Of the participants, 2,374 were in the risk exposure group involving manual materials handling (MMH), and 1,028 were in the control group without MMH. The VLI was calculated for each participant in the exposure group using a systematic approach. LBP information was collected by occupational physicians at the study sites. The risk of acute LBP was estimated by calculating the odds ratio (OR) between levels of the risk exposure and the control group using a logistic regression analysis. Both crude and adjusted ORs for body mass index, gender, and age were analyzed. Results: Both crude and adjusted ORs showed a dose-response relationship. As the levels of VLI increased, the risk of LBP increased. This risk relationship existed when VLI was greater than 1. Conclusion: The VLI method can be used to assess the risk of acute LBP, although further studies are needed to confirm the outcome and to define better VLI categories.
A 5-year analysis of semen parameters in Saudi Arabian men attending infertility clinics
Authors: Al-Turki Haifa A. 
Published: April 2016

Objective To evaluate semen parameters in infertile Saudi Arabian men. Methods In this retrospective study, semen analysis and other clinical data were extracted from medical records of men attending an infertility clinic. Patients were stratified according to smoking status and presence or absence of varicocele. Results The study included 425 patients. Nonsmokers ( n = 322) had significantly higher serum testosterone and sperm motility than smokers ( n = 194). Serum testosterone, semen volume, motility, morphology, sperm/ejaculation and sperm count were significantly higher in patients without varicocele ( n = 328) than in those with varicocele ( n = 188). Conclusions In this study, smoking and the presence of varicocele had negative effects on semen parameters in infertile men.
Association between ECE1 gene polymorphisms and risk of intracerebral haemorrhage
Authors: Zeng Yi , Ma Mingming , Liu Baoqiong , Xia Jian , Xu Hongwei , Liu Yunhai , Du Xiaoping , Hu Zhiping , Yang Qidong , Zhang Le 
Published: April 2016

Objective To determine whether endothelin converting enzyme-1 ( ECE1) gene polymorphisms contribute to susceptibility to intracerebral haemorrhage (ICH) by influencing blood pressure. Methods This case–control study enrolled patients with ICH and healthy control subjects from a Southern Han Chinese population. The ECE1 gene polymorphisms rs212528 and rs213045 were genotyped. The association between the genotypes and the risk of ICH was assessed. The effects of these two ECE1 gene polymorphisms on blood pressure were also analysed. Results A total of 389 patients with ICH and 404 healthy control subjects participated in the study. There was no significant association between the ECE1 rs212528 and rs213045 polymorphisms and ICH even after adjusting for different confounding variables. In patients with ICH, the systolic blood pressure of patients with the rs212528 AA genotype was significantly lower than that of patients with the AG/GG genotypes. Conclusions These results indicated that the ECE1 rs212528 and rs213045 polymorphisms had no major role to play in the genetic susceptibility to ICH, although rs212528 might influence blood pressure in patients with ICH.
Syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis presenting as acute neurological emergencies
Authors: Babi M-Alain , Applebee Angela , Shapiro Robert , Waheed Waqar 
Published: April 2016

Background The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) is a self-limited benign disorder of unclear pathogenesis, with diverse clinical manifestations. Cases We report two unusual presentations of this entity. The first case developed a catastrophic picture, characterized by acute elevation of intracranial pressure, necessitating emergency life support. The second case presented with hyperacute-onset mixed aphasia and facial droop, masquerading as acute ischemia of the middle cerebral artery territory. Both patients made full recoveries. Conclusion The possibility of HaNDL should be considered in individuals presenting with unusual patterns of headaches and transient neurological symptoms. Our report will expand the spectrum of this disorder, which will help physicians not only to recognize the unusual manifestations of this rare disorder, but also consider potential therapeutic interventions.
Pediatric Anterior Cruciate Ligament Reconstruction: A Systematic Review of Transphyseal Versus Physeal-Sparing Techniques
Authors: Pierce Todd P. , Issa Kimona , Festa Anthony , Scillia Anthony J. , McInerney Vincent K. 
Published: April 2016

Background: Anterior cruciate ligament reconstruction is becoming more common in skeletally immature individuals, and it may be performed with transphyseal or physeal-sparing techniques. A number of studies have assessed the outcomes of these techniques, but there is a need to systematically evaluate the pooled data from these studies. Purpose: To compare the differences in demographics and outcomes of transphyseal and physeal-sparing techniques by assessing (1) demographics, (2) incidence of growth disturbances, and (3) graft survivorship in the pediatric population. Study Design: Systematic review. Methods: A thorough review of 3 databases was performed to identify all studies that evaluated outcomes after pediatric reconstruction based on transphyseal or physeal-sparing techniques. After completing our search and cross-referencing for additional sources, 43 reports were identified for this review. Reports were analyzed for differences in demographics as well as incidence of leg-length discrepancies, angular deformities, and graft survivorship. After review of manuscripts, 27 studies were included for review (21 transphyseal and 6 physeal-sparing studies). Results: Those who had transphyseal reconstruction were more likely to be female (39% vs 20%; P = .0001), while those with the physeal-sparing surgery were younger (12 vs 13.5 years of age; P = .0001). The transphyseal and physeal-sparing cohorts demonstrated similar incidence rates of leg-length discrepancies (0.81% vs 1.2%, respectively; P = .64) and angular deformities (0.61% vs 0%, respectively; P = .36). The transphyseal and physeal-sparing cohorts also showed similar rates of rerupture (6.2% vs 3.1%, respectively; P = .11). Conclusion: Although the study groups were not well matched with regard to age and sex, our results show that these surgical techniques have no differences in incidence of growth disturbances or graft survivorship. Younger males tend to undergo physeal-sparing reconstruction. Future research should focus on long-term outcome metrics with the physeal-sparing techniques, as there remains a paucity of studies regarding them.
Mental Health Services for Students at Postsecondary Institutions: A National Survey
Authors: Jaworska Natalia , De Somma Elisea , Fonseka Bernice , Heck Emma , MacQueen Glenda M. 
Published: April 2016

Objective: Although the high prevalence of mental health issues among postsecondary students is well documented, comparatively little is known about the adequacy, accessibility, and adherence to best practices of mental health services (MHSs)/initiatives on postsecondary campuses. We evaluated existing mental health promotion, identification, and intervention initiatives at postsecondary institutions across Canada, expanding on our previous work in one Canadian province. Methods: A 54-question online survey was sent to potential respondents (mainly front-line workers dealing directly with students [e.g., psychologists/counsellors, medical professionals]) at Canada’s publicly funded postsecondary institutions. Data were analyzed overall and according to institutional size (small [<2000 students], medium [2000–10 000 students], large [>10 000 students]). Results: In total, 168 out of 180 institutions were represented, and the response rate was high (96%; 274 respondents). Most institutions have some form of mental health promotion and outreach programs, although most respondents felt that these were not a good use of resources. Various social supports exist at most institutions, with large ones offering the greatest variety. Most institutions do not require incoming students to disclose mental health issues. While counselling services are typically available, staff do not reliably have a diverse complement (e.g., gender or race diversity). Counselling sessions are generally limited, and follow-up procedures are uncommon. Complete diagnostic assessments and the use of standardized diagnostic systems are rare. Conclusions: While integral MHSs are offered at most Canadian postsecondary institutions, the range and depth of available services are variable. These data can guide policy makers and stakeholders in developing comprehensive campus mental health strategies.
Vancomycin Use: Room for Improvement Among Hospitalized Children
Authors: Gillon Jessica , Xu Meng , Slaughter James , Di Pentima M. Cecilia 
Published: April 2016

Introduction: The use of vancomycin is common among hospitalized children. We sought to evaluate the impact of prospective audit with real-time feedback on vancomycin use and pharmacy costs. Methods: Vancomycin use was evaluated at Monroe Carell Jr Children’s Hospital at Vanderbilt (MCJCHV) before and after the implementation of prospective audit with intervention and feedback to providers in 2012. Antibiotic use was compared to academic children’s hospitals with established antimicrobial stewardship programs (ASPs). Two similar pediatric academic institutions without an ASP were used as nonintervention controls. Analysis of monthly days of antibiotic therapy (DoT) per 1000 patient-days was performed by interrupted time series analysis. Results: Monthly vancomycin use decreased from 114 DoTs/1000 patient-days to 89 DoTs/1000 patient-days ( P < .0001). We did not find significant differences in the slope of change in vancomycin use between MCJCHV and institutions with ASPs either before or after the intervention ( P = .86 and P = .71, respectively). When compared to children’s hospitals without ASPs, the use of vancomycin was significantly lower at MCJCHV ( P < .001). Conclusion: The use of vancomycin at academic children’s hospitals with an ASP is declining. In our experience, prospective audit with real-time intervention and feedback to providers significantly reduced the use and costs associated with vancomycin.
Lurasidone: an antipsychotic with antidepressant effects in bipolar depression?
Authors: Keks Nicholas A , Hope Judy , Castle David 
Published: April 2016

Objective: Lurasidone is a new serotonin–dopamine antagonist atypical antipsychotic which also appears to be effective in bipolar depression. This paper will briefly review the evidence concerning lurasidone. Conclusions: Lurasidone is an antagonist at dopamine D2, serotonin 5-HT2 and 5-HT7, and partial agonist at 5HT1a receptors; it has no anticholinergic or antihistaminic activity. Rapidly absorbed, it has a half-life of 18 ± 7 hours, will reach steady state in five days and is taken at night with food (absorption is halved on an empty stomach). It is hepatically metabolised with some potential for interactions. Lurasidone is an effective antipsychotic in acute schizophrenia, and non-inferior to quetiapine but not risperidone in 12-month studies. Lurasidone may cause mild sedation, nausea, agitation, insomnia and akathisia (especially at initiation). Risks for weight gain, hyperprolactinaemia and QTc prolongation are low. Lurasidone has demonstrated antidepressant efficacy both as monotherapy and in addition to lithium or valproate in bipolar depression, of a comparable degree to that seen with the combination of olanzapine and fluoxetine. Lurasidone appears to be a “metabolically-friendly” antipsychotic for schizophrenia where weight gain and hyperprolactinaemia are of concern, and may also prove useful in bipolar depression (although not approved for this condition in Australia).
Immunological and pathological characterization of fatal rebound MS activity following natalizumab withdrawal
Authors: Larochelle Catherine , Metz Imke , Lécuyer Marc-André , Terouz Simone , Roger Michel , Arbour Nathalie , Brück Wolfgang , Prat Alexandre 
Published: April 2016

Background: Severe rebound multiple sclerosis (MS) activity is a life-threatening complication of natalizumab (NTZ) withdrawal, for which pathogenesis and treatment are still unclear. We report the immunological and pathological characterization of a case of central nervous system (CNS) inflammatory demyelination after NTZ discontinuation. Objective: To understand the pathophysiology of this neuroinflammatory condition. Methods: Antemortem blood and cerebrospinal fluid (CSF) analysis was compared with postmortem pathological studies, as well as with novel flow cytometry characterization of immune cells isolated from the CNS parenchyma. Results: Pathological analysis of the brain revealed the presence of innumerable active inflammatory demyelinating lesions typical of immunopathological pattern II. Monocytes/macrophages and B cells were enriched in the CNS parenchyma compared to the CSF. Numerous plasma cells were present in the lesions, but CD8 T lymphocytes were predominant in the parenchyma, as opposed to CD4 in the CSF. CNS-infiltrating lymphocytes expressed high levels of adhesion molecules, granzyme B (GzB), interferon-gamma (IFN-γ), and interleukin (IL)-17. Conclusions: Our results underline the differences in immune cell populations between the CSF and the CNS parenchyma, and suggest that aggressive immunosuppressive therapy targeting both T and B lymphocytes is warranted to control the overwhelming CNS inflammation.