bluuebunny/crossref_metadata_2025_split huggingface dataset:
HHLA2, a New Immune Checkpoint Member of the B7 Family, Is Widely Expressed in Human Lung Cancer and Associated with EGFR Mutational Status
Authors: Cheng Haiying , Janakiram Murali , Borczuk Alain , Lin Juan , Qiu Wanglong , Liu Huijie , Chinai Jordan M. , Halmos Balazs , Perez-Soler Roman , Zang Xingxing 
Published: August 2016

Abstract
Purpose: Immunotherapy with antibodies against B7/CD28 family members, including PD-1, PD-L1, and CTLA-4 has shifted the treatment paradigm for non–small cell lung carcinoma (NSCLC) with improved clinical outcome. HHLA2 is a newly discovered member of the family. By regulating T-cell function, HHLA2 could contribute to tumor immune suppression and thus be a novel target for cancer immunotherapy. There is limited information and critical need to characterize its expression profile and clinical significance in NSCLC.
Experimental Design: We performed IHC with an HHLA2-specific antibody (clone 566.1) using tissue microarrays constructed from 679 NSCLC tumor tissues, including 392 cases in the discovery set and 287 cases in the validation cohort. We also studied clinicopathologic characteristics of these patients.
Results: Overall, HHLA2 was not detected in most of normal lung tissue but expressed in 66% of NSCLC across different subtypes. In particular, EGFR-mutated NSCLC was significantly associated with higher tumor HHLA2 expression in both discovery (EGFR vs. WT: 76% vs. 53%, P = 0.01) and validation cohorts (89% vs. 69%, P = 0.01). In one of the two cohorts, HHLA2 expression was higher in lung adenocarcinoma as compared with squamous and large cell histology, non-Hispanic White versus Hispanics, and tumors with high tumor-infiltrating lymphocyte (TIL) density. In the multivariate analysis, EGFR mutation status and high TIL intensity were independently associated with HHLA2 expression in lung adenocarcinoma.
Conclusions: HHLA2 is widely expressed in NSCLC and is associated with EGFR mutation and high TILs in lung adenocarcinoma. It is potentially a novel target for lung cancer immunotherapy. Clin Cancer Res; 23(3); 825–32. ©2016 AACR.
PI3K–mTOR Pathway Inhibition Exhibits Efficacy Against High-grade Glioma in Clinically Relevant Mouse Models
Authors: Lin Fan , de Gooijer Mark C. , Hanekamp Diana , Chandrasekaran Gayathri , Buil Levi C.M. , Thota Nishita , Sparidans Rolf W. , Beijnen Jos H. , Würdinger Tom , van Tellingen Olaf 
Published: August 2016

Abstract
Purpose: The PI3K–AKT–mTOR signaling pathway is frequently activated in glioblastoma and offers several druggable targets. However, clinical efficacy of PI3K/mTOR inhibitors in glioblastoma has not yet been demonstrated. Insufficient drug delivery may limit the efficacy of PI3K/mTOR inhibitors against glioblastoma. The presence of the efflux transporters ABCB1/Abcb1 (P-glycoprotein, MDR1) and ABCG2/Abcg2 (BCRP) at the blood–brain barrier (BBB) restricts the brain penetration of many drugs.
Experimental Design: We used in vitro drug transport assays and performed pharmacokinetic/pharmacodynamic studies in wild-type and ABC-transporter knockout mice. The efficacy of PI3K-mTOR inhibition was established using orthotopic allograft and genetically engineered spontaneous glioblastoma mouse models.
Results: The mTOR inhibitors rapamycin and AZD8055 are substrates of ABCB1, whereas the dual PI3K/mTOR inhibitor NVP-BEZ235 and the PI3K inhibitor ZSTK474 are not. Moreover, ABCG2 transports NVP-BEZ235 and AZD8055, but not ZSTK474 or rapamycin. Concordantly, Abcb1a/b−/−;Abcg2−/− mice revealed increased brain penetration of rapamycin (13-fold), AZD8055 (7.7-fold), and NVP-BEZ235 (4.5-fold), but not ZSTK474 relative to WT mice. Importantly, ABC transporters limited rapamycin brain penetration to subtherapeutic levels, while the reduction in NVP-BEZ235 brain penetration did not prevent target inhibition. NVP-BEZ235 and ZSTK474 demonstrated antitumor efficacy with improved survival against U87 orthotopic gliomas, although the effect of ZSTK474 was more pronounced. Finally, ZSTK474 prolonged overall survival in Cre-LoxP conditional transgenic Pten;p16Ink4a/p19Arf;K-Rasv12;LucR mice, mainly by delaying tumor onset.
Conclusions: PI3K/mTOR inhibitors with weak affinities for ABC transporters can achieve target inhibition in brain (tumors), but have modest single-agent efficacy and combinations with (BBB penetrable) inhibitors of other activated pathways may be required. Clin Cancer Res; 23(5); 1286–98. ©2016 AACR.
Rnd3 in Cancer: A Review of the Evidence for Tumor Promoter or Suppressor
Authors: Paysan Lisa , Piquet Léo , Saltel Frédéric , Moreau Violaine 
Published: August 2016

Abstract
Rho-GTPases are members of the Ras superfamily of small GTPases and are general modulators of important cellular processes in tumor biology such as migration and proliferation. Among these proteins, Rnd3/RhoE, an atypical Rho-GTPase devoid of GTP hydrolytic activity, has recently been studied for its putative role in tumorigenesis. Indeed, Rnd3 is implicated in processes, such as proliferation and migration, whose deregulation is linked to cancer development and metastasis. The aim of this review is to provide an overview of the data surrounding Rnd3 deregulation in cancers, its origin, and consequences. Presented here is a comprehensive account of the expression status and biological output obtained in prostate, liver, stomach, colon, lung, and brain cancers as well as in melanoma and squamous cell carcinoma. Although there appears to be no general consensus about Rnd3 expression in cancers as this protein is differently altered according to the tumor context, these alterations overwhelmingly favor a protumorigenic role. Thus, depending on the tumor type, it may behave either as a tumor suppressor or as a tumor promoter. Importantly, the deregulation of Rnd3, in most cases, is linked to patient poor outcome.
Implications: Rnd3 has prognostic marker potential as exemplified in lung cancers and Rnd3 or Rnd3-associated signaling pathways may represent a new putative therapeutic target. Mol Cancer Res; 14(11); 1033–44. ©2016 AACR.
Glycemic Control for Patients With Type 2 Diabetes Mellitus: Our Evolving Faith in the Face of Evidence
Authors: Rodríguez-Gutiérrez René , Montori Victor M. 
Published: August 2016

Background—
We sought to determine the concordance between the accumulating evidence about the impact of tight versus less tight glycemic control in patients with type 2 diabetes mellitus since the publication of UKPDS (UK Prospective Diabetes Study) in 1998 until 2015 with the views about that evidence published in journal articles and practice guidelines.

Methods and Results—
We searched in top general medicine and specialty journals for articles referring to glycemic control appearing between 2006 and 2015 and identified the latest practice guidelines. To summarize the evidence, we included all published systematic reviews and meta-analyses of contemporary randomized trials of glycemic control measuring patient-important microvascular and macrovascular outcomes, and completed a meta-analysis of their follow-up extensions. We identified 16 guidelines and 328 statements. The body of evidence produced estimates warranting moderate confidence. This evidence reported no significant impact of tight glycemic control on the risk of dialysis/transplantation/renal death, blindness, or neuropathy. In the past decade, however, most published statements (77%–100%) and guidelines (95%) unequivocally endorsed benefit. There is also no significant effect on all-cause mortality, cardiovascular mortality, or stroke; however, there is a consistent 15% relative-risk reduction of nonfatal myocardial infarction. Between 2006 and 2008, most statements (47%–83%) endorsed the benefit; after 2008 (ACCORD), only a minority (21%–36%) did.

Conclusions—
Discordance exists between the research evidence and academic and clinical policy statements about the value of tight glycemic control to reduce micro- and macrovascular complications. This discordance may distort priorities in the research and practice agendas designed to improve the lives of patients with type 2 diabetes mellitus.
Sex Disparities in Ischemic Stroke Care
Authors: Asdaghi Negar , Romano Jose G. , Wang Kefeng , Ciliberti-Vargas Maria A. , Koch Sebastian , Gardener Hannah , Dong Chuanhui , Rose David Z. , Waddy Salina P. , Robichaux Mary , Garcia Enid J. , Gonzalez-Sanchez Juan A. , Burgin W. Scott , Sacco Ralph L. , Rundek Tatjana 
Published: August 2016

Background and Purpose—
Sex-specific disparities in stroke care including thrombolytic therapy and early hospital admission are reported. In a large registry of Florida and Puerto Rico hospitals participating in the Get With The Guidelines—Stroke program, we sought to determine sex-specific differences in ischemic stroke performance metrics and overall thrombolytic treatment.

Methods—
Around 51 317 (49% women) patients were included from 73 sites from 2010 to 2014. Multivariable logistic regression with generalized estimating equations evaluated sex-specific differences in the prespecified Get With The Guidelines—Stroke metrics for defect-free care in ischemic stroke, adjusting for age, race-ethnicity, insurance status, hospital characteristics, individual risk factors, and the presenting stroke severity.

Results—

As compared with men, women were older (73±15 versus 69±14 years;
P
<0.0001), more hypertensive (67% versus 63%,
P
<0.0001), and had more atrial fibrillation (19% versus 16%;
P
<0.0001). Defect-free care was slightly lower in women than in men (odds ratio, 0.96; 95% confidence interval, 0.93–1.00). Temporal trends in defect-free care improved substantially and similarly for men and women, with a 29% absolute improvement in women (
P
<0.0001) and 28% in men (
P
<0.0001), with
P
value of 0.13 for time-by-sex interaction. Women were less likely to receive thrombolysis (odds ratio, 0.92; 95% confidence interval, 0.86–0.99;
P
=0.02) and less likely to have a door-to-needle time <1 hour (odds ratio, 0.83; 95% confidence interval, 0.71–0.97;
P
=0.02) as compared with men.

Conclusions—
Women received comparable stroke care to men in this registry as measured by prespecified Get With The Guidelines metrics. However, women less likely received thrombolysis and had door-to-needle time <1 hour, an observation that calls for the implementation of interventions to reduce sex disparity in these measures.
Development of Orphan Drugs under European Regulatory Incentives and Patent Protection
Authors: Minn Mari 
Published: August 2016

AbstractThis article analyses how the regulatory incentives provided by Regulation 141/2000 affect orphan drug development and generic market entry. It seeks to find out how the regulatory incentives work in combination with patent protection, and whether in combination they foster orphan drug innovation and overall patient access, or rather hinder the latter. The article argues that even though the regulatory incentives are targeted to fostering innovation and early generic market access, when combined with patent protection, the generic entry is likely blocked or delayed.
The Peacock Spiders (Araneae: Salticidae: Maratus) of the Queensland Museum, including six new species
Authors: BAEHR BARBARA C. , WHYTE ROBERT 
Published: August 2016

Six new species of the peacock spider genus Maratus Karsch, 1878 are described from Australia: M. eliasi sp. nov., M. julianneae sp. nov., M. licunxini sp. nov., M. michaelorum sp. nov. and M. ottoi sp. nov. from Queensland, and M. kiwirrkurra sp. nov. from Western Australia. Five species groups are further documented within the genus and new records, detailed SEM and automontage images are provided for six previously described species: M. anomalus Karsch, 1878, M. chrysomelas (Simon, 1909), M. digitatus Otto & Hill, 2012, M. pavonis (Dunn, 1947), M. speciosus (O.P.-Cambridge, 1874) and M. volans (O.P.-Cambridge, 1874).
Topographic Influence on the Motion of Tropical Cyclones Landfalling on the Coast of China
Authors: Chen Xiaoyu , Wu Liguang 
Published: August 2016

Abstract
A few recent numerical studies investigated the influence of a continent, which is much larger in size than islands, on the track of a landfalling tropical cyclone. It has been found that land surface roughness and temperature tend to make a tropical cyclone move toward the continent. In this study, the effect of the elevated terrain on the western part of mainland China on landfall tracks is examined through idealized numerical experiments, in which an initially axisymmetric vortex is embedded into a monsoon trough and takes a landfall track across China’s mainland. It is found that the effect of the elevated terrain on the western part of mainland China can enhance the southerly environmental flows in the low and midtroposphere, leading to an additional landward component of tropical cyclone motion, suggesting that forecasts for tropical cyclone tracks over land should take into consideration the change in thermal condition over the continent. The study suggests that the increased duration of tropical cyclone overland tracks observed in China may be associated with the reduction of the thermal forcing over the Tibetan Plateau.
Climate Change Education and Knowledge among Nigerian University Graduates
Authors: Ayanlade Ayansina , Jegede Margaret Olusolape 
Published: August 2016

Abstract
The introduction of climate change studies in universities has a fundamental role in helping the general public, especially the next generations, to recognize the global challenges of climate change and to find ways of adapting to the changing climate. This study examined the level of climate change education and perception of Nigerian university graduates. A mixed method approach was used to obtain data relating to perceptions, understanding, and level at which climate change has been taught in Nigerian universities. The results from this study revealed that about 70.7% of university graduates received brief lectures in some special elective courses during their university education, while only 4.1% were taught more than three semesters/terms in some special elective courses. It was also revealed that graduates from departments of environmental sciences have more class experience on climate change than students in the humanities and other faculties. The major finding of this study is that students appear far more informed about climate change, usually from the Internet and international media, than the level of climate change education they were taught in university. These results show the need for the introduction of climate change studies in Nigerian universities, with over 71% of participants believing that climate change studies should be included as a required course in both undergraduate and postgraduate studies.
Elevated fasting and postprandial C-terminal telopeptide after Roux-en-Y gastric bypass
Authors: Maghsoodi Negar , Alaghband-Zadeh Jamshid , Cross Gemma F , Werling Malin , Fändriks Lars , Docherty Neil G , Olbers Torsten , Dew Tracy , Sherwood Roy A , Vincent Royce P , le Roux Carel W 
Published: August 2016

BackgroundRoux-en-Y gastric bypass increases circulating bile acid concentrations, known mediators of postprandial suppression of markers of bone resorption. Long-term data, however, indicate that Roux-en-Y gastric bypass confers an increased risk of bone loss on recipients.MethodsThirty-six obese individuals, median age 44 (26–64) with median body mass index at baseline of 42.5 (40.4–46) were studied before and 15 months after Roux-en-Y gastric bypass. After an overnight fast, patients received a 400 kcal mixed meal. Blood samples were collected premeal then at 30-min periods for 120 min. Pre and postmeal samples were analysed for total bile acids, parathyroid hormone and C-terminal telopeptide.ResultsBody weight loss post Roux-en-Y gastric bypass was associated with a median 4.9-fold increase in peak postprandial total bile acid concentration, and a median 2.4-fold increase in cumulative food evoked bile acid response. Median fasting parathyroid hormone, postprandial reduction in parathyroid hormone and total parathyroid hormone release over 120 min remained unchanged after surgery. After surgery, median fasting C-terminal telopeptide increased 2.3-fold, peak postprandial concentrations increased 3.8-fold and total release was increased 1.9-fold.ConclusionsFasting and postprandial total bile acids and C-terminal telopeptide are increased above reference range after Roux-en-Y gastric bypass. These changes occur in spite of improved vitamin D status with supplementation. These results suggest that post-Roux-en-Y gastric bypass increases in total bile acids do not effectively oppose an ongoing resorptive signal operative along the gut–bone axis. Serial measurement of C-terminal telopeptide may be of value as a risk marker for long-term skeletal pathology in patients post Roux-en-Y gastric bypass.
Best practice guidelines on first-line laboratory testing for porphyria
Authors: Woolf Jacqueline , Marsden Joanne T , Degg Timothy , Whatley Sharon , Reed Paul , Brazil Nadia , Stewart M Felicity , Badminton Michael 
Published: August 2016

The porphyrias are disorders of haem biosynthesis which present with acute neurovisceral attacks or disorders of sun-exposed skin. Acute attacks occur mainly in adults and comprise severe abdominal pain, nausea, vomiting, autonomic disturbance, central nervous system involvement and peripheral motor neuropathy. Cutaneous porphyrias can be acute or chronic presenting at various ages. Timely diagnosis depends on clinical suspicion leading to referral of appropriate samples for screening by reliable biochemical methods. All samples should be protected from light. Investigation for an acute attack: • Porphobilinogen (PBG) quantitation in a random urine sample collected during symptoms. Urine concentration must be assessed by measuring creatinine, and a repeat requested if urine creatinine <2 mmol/L. • Urgent porphobilinogen testing should be available within 24 h of sample receipt at the local laboratory. Urine porphyrin excretion (TUP) should subsequently be measured on this urine. • Urine porphobilinogen should be measured using a validated quantitative ion-exchange resin-based method or LC-MS. • Increased urine porphobilinogen excretion requires confirmatory testing and clinical advice from the National Acute Porphyria Service. • Identification of individual acute porphyrias requires analysis of urine, plasma and faecal porphyrins. Investigation for cutaneous porphyria: • An EDTA blood sample for plasma porphyrin fluorescence emission spectroscopy and random urine sample for TUP. • Whole blood for porphyrin analysis is essential to identify protoporphyria. • Faeces need only be collected, if first-line tests are positive or if clinical symptoms persist. Investigation for latent porphyria or family history: • Contact a specialist porphyria laboratory for advice. Clinical, family details are usually required.
Socioeconomic disparities in psychological distress in a nationally representative sample of Japanese adolescents: A time trend study
Authors: Kachi Yuko , Abe Aya , Ando Emiko , Kawada Tomoyuki 
Published: August 2016

Objective: Socioeconomic status as a determinant of mental health problems has received scant attention in Japan, which has long been considered an egalitarian society. This study examined the association between socioeconomic status and psychological distress and its trends over 6 years among Japanese adolescents. Methods: We used data from a nationally representative sample of 9491 adolescents aged 12–18 years who participated in three repeated cross-sectional surveys between 2007 and 2013. The K6 scale was used to assess psychological distress. Socioeconomic status indicators included household income, parental education, parental working status and household structure. Results: Psychological distress prevalence decreased significantly from 2007 (10.7%) to 2013 (7.6%). However, the socioeconomic status patterns of psychological distress were consistent through the study period. Adolescents living in both lower (odds ratio = 1.61; 95% confidence interval = [1.27, 2.05]) and higher income households (odds ratio = 1.30; 95% confidence interval = [1.03, 1.62]) were more likely to report psychological distress than their middle-income counterparts. Adolescents with low household income were more likely to feel stress from interpersonal relationships and less likely to have help-seeking behaviors, while those with high household income were more likely to feel stress about school achievement. Psychological distress was also associated with parental poor education and single parenthood. Conclusions: Socioeconomic status disparities in adolescent psychological distress were evident and consistent during the 6-year period. There is a unique U-shaped relationship between household income and psychological distress among adolescents in Japan, unlike those from other countries. However, the underlying mechanisms may differ by income status. Future prevention efforts should consider socioeconomic status as a determinant of adolescent mental health problems.
From System Collapse to Chavista Hegemony
Authors: Hetland Gabriel 
Published: August 2016

During the 14 years Hugo Chávez was in office, Venezuela’s party system experienced a 180-degree shift. When Chávez was elected in 1998, Venezuela’s party system had collapsed because of a two-decade-long economic-cum-political crisis. His initial appeal was built, in large part, on his antiparty message, a stance that continued through the first half of his time in office. A series of factors, principally the need for a more cohesive organization to combat an intransigent opposition, led to the creation of the Partido Socialista Unido de Venezuela (United Socialist Party of Venezuela—PSUV) in 2007. The PSUV quickly became Venezuela’s largest party and the linchpin of a new hegemonic system. The contradictions of that system are manifested in the split between the PSUV’s right and left wings, and the hegemony of Chavismo is now in doubt. Durante los 14 años de la presidencia de Hugo Chávez, el sistema de partidos de Venezuela sufrió un giro de 180°. Cuando Chávez fue elegido en 1998, el sistema ya había colapsado debido a la larga crisis económica y política que ya llevaba dos décadas. Su llamamiento inicial se fundamentó, en gran parte, en un mensaje antipartido, una postura que continuó durante la primera mitad de su mandato. Una serie de factores—principalmente, la necesidad de una organización más cohesiva para combatir a la oposición intransigente — llevó a la creación del Partido Socialista Unido de Venezuela (PSUV) en 2007. El PSUV rápidamente se convirtió en el partido más grande de Venezuela y en la pieza esencial de un nuevo sistema hegemónico. Las contradicciones del sistema se manifiestan en la brecha entre el ala izquierdista y el ala derechista del PSUV y la hegemonía del chavismo ahora está en entredicho.