bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined BRAF and HSP90 Inhibition in Patients with Unresectable BRAFV600E-Mutant Melanoma
Authors: Eroglu Zeynep , Chen Y. Ann , Gibney Geoffrey T. , Weber Jeffrey S. , Kudchadkar Ragini R. , Khushalani Nikhil I. , Markowitz Joseph , Brohl Andrew S. , Tetteh Leticia F. , Ramadan Howida , Arnone Gina , Li Jiannong , Zhao Xiuhua , Sharma Ritin , Darville Lancia N.F. , Fang Bin , Smalley Inna , Messina Jane L. , Koomen John M. , Sondak Vernon K. , Smalley Keiran S.M. 
Published: April 2018

Abstract
Purpose: BRAF inhibitors are clinically active in patients with advanced BRAFV600-mutant melanoma, although acquired resistance remains common. Preclinical studies demonstrated that resistance could be overcome using concurrent treatment with the HSP90 inhibitor XL888.
Patients and Methods: Vemurafenib (960 mg p.o. b.i.d.) combined with escalating doses of XL888 (30, 45, 90, or 135 mg p.o. twice weekly) was investigated in 21 patients with advanced BRAFV600-mutant melanoma. Primary endpoints were safety and determination of a maximum tolerated dose. Correlative proteomic studies were performed to confirm HSP inhibitor activity.
Results: Objective responses were observed in 15 of 20 evaluable patients [75%; 95% confidence interval (CI), 51%–91%], with 3 complete and 12 partial responses. Median progression-free survival and overall survival were 9.2 months (95% CI, 3.8–not reached) and 34.6 months (6.2–not reached), respectively. The most common grade 3/4 toxicities were skin toxicities, such as rash (n = 4, 19%) and cutaneous squamous cell carcinomas (n = 3, 14%), along with diarrhea (n = 3, 14%). Pharmacodynamic analysis of patients' peripheral blood mononuclear cells (PBMC) showed increased day 8 HSP70 expression compared with baseline in the three cohorts with XL888 doses ≥45 mg. Diverse effects of vemurafenib-XL888 upon intratumoral HSP client protein expression were noted, with the expression of multiple proteins (including ERBB3 and BAD) modulated on therapy.
Conclusions: XL888 in combination with vemurafenib has clinical activity in patients with advanced BRAFV600-mutant melanoma, with a tolerable side-effect profile. HSP90 inhibitors warrant further evaluation in combination with current standard-of-care BRAF plus MEK inhibitors in BRAFV600-mutant melanoma. Clin Cancer Res; 24(22); 5516–24. ©2018 AACR.
See related commentary by Sullivan, p. 5496
Antigen Presentation Keeps Trending in Immunotherapy Resistance
Authors: Kalbasi Anusha , Ribas Antoni 
Published: April 2018

Abstract
Through a gain-of-function kinome screen, MEX3B was identified as a mediator of resistance to T-cell immunotherapy not previously identified using CRISPR-based screens. MEX3B is a posttranscriptional regulator of HLA-A, validating the critical role of tumor-intrinsic antigen presentation in T-cell immunotherapy and indicating a new putative molecular target. Clin Cancer Res; 24(14); 3239–41. ©2018 AACR.
See related article by Huang et al., p. 3366
Tamoxifen Resistance Trumped and Oral Selective Estrogen Receptor Degraders Arrive
Authors: Jordan V. Craig 
Published: April 2018

Abstract
Predictive tests, to refine the estrogen receptor assay, for the adjuvant treatment of breast cancer with tamoxifen and oral selective estrogen receptor degraders (SERD) are required. A splice variant of the corepressor NCOR2, BQ2313636.1 predicts tamoxifen resistance to adjuvant tamoxifen and AZ9496, the first oral SERD, completes phase I studies. Clin Cancer Res; 24(15); 3480–2. ©2018 AACR.
See related articles by Gong et al., p. 3681 and Hamilton et al., p. 3510
Risk of Infective Endocarditis After Invasive Dental Treatments
Authors: Chen Tzu-Ting , Yeh Yi-Chun , Chien Kuo-Liong , Lai Mei-Shu , Tu Yu-Kang 
Published: April 2018

Background:
Invasive dental treatments (IDTs) can yield temporary bacteremia and have therefore been considered a potential risk factor of infective endocarditis (IE). It is hypothesized that, through the trauma caused by IDTs, bacteria gain entry to the bloodstream and may attach to abnormal heart valves or damaged heart tissue, giving rise to IE. However, the association between IDTs and IE remains controversial. The aim of this study is to estimate the association between IDTs and IE.

Methods:
The data in this study were obtained from the Health Insurance Database in Taiwan. We selected 2 case-only study designs, case-crossover and self-controlled case series, to analyze the data. The advantage of these methods is that confounding factors that do not vary with time are adjusted for implicitly. In the case-crossover design, a conditional logistic regression model with exposure to IDTs was used to estimate the risks of IE following an IDT with 4, 8, 12, and 16 weeks delay, respectively. In the self-controlled case series design, a conditional Poisson regression model was used to estimate the risk of IE for the risk periods of 1 to 4, 5 to 8, 9 to 12, and 13 to 16 weeks following an IDT.

Results:
In total, 9120 and 8181 patients with IE were included in case-crossover design and self-controlled case series design, respectively. In the case-crossover design, 277 cases and 249 controls received IDTs during the exposure period, and the odds ratio was 1.12 (95% confidence interval, 0.94–1.34) for 4 weeks. In the self-controlled case series design, we observed that 407 IEs occurred during the first 4 weeks after IDTs, and the age-adjusted incidence rate ratio was 1.14 (95% confidence interval, 1.02–1.26) for 1 to 4 weeks after IDTs.

Conclusions:
In both study designs, we did not observe a clinically larger risk for IE in the short periods after IDTs. We also found no association between IDTs and IE among patients with a high risk of IE. Therefore, antibiotic prophylaxis for the prevention of IE is not required for the Taiwanese population.
Contrasting Impacts of Radiative Forcing in the Southern Ocean versus Southern Tropics on ITCZ Position and Energy Transport in One GFDL Climate Model
Authors: Xiang Baoqiang , Zhao Ming , Ming Yi , Yu Weidong , Kang Sarah M. 
Published: April 2018

Abstract
Most current climate models suffer from pronounced cloud and radiation biases in the Southern Ocean (SO) and in the tropics. Using one GFDL climate model, this study investigates the migration of the intertropical convergence zone (ITCZ) with prescribed top-of-the-atmosphere (TOA) shortwave radiative heating in the SO (50°–80°S) versus the southern tropics (ST; 0°–20°S). Results demonstrate that the ITCZ position response to the ST forcing is twice as strong as the SO forcing, which is primarily driven by the contrasting sea surface temperature (SST) gradient over the tropics; however, the mechanism for the formation of the SST pattern remains elusive. Energy budget analysis reveals that the conventional energetic constraint framework is inadequate in explaining the ITCZ shift in these two perturbed experiments. For both cases, the anomalous Hadley circulation does not contribute to transport the imposed energy from the Southern Hemisphere to the Northern Hemisphere, given a positive mean gross moist stability in the equatorial region. Changes in the cross-equatorial atmospheric energy are primarily transported by atmospheric transient eddies when the anomalous ITCZ shift is most pronounced during December–May. The partitioning of energy transport between the atmosphere and ocean shows latitudinal dependence: the atmosphere and ocean play an overall equivalent role in transporting the imposed energy for the extratropical SO forcing, while for the ST forcing, the imposed energy is nearly completely transported by the atmosphere. This contrast originates from the different ocean heat uptake and also the different meridional scale of the anomalous ocean circulation.
Human Articular Chondrocytes Retain Their Phenotype in Sustained Hypoxia While Normoxia Promotes Their Immunomodulatory Potential
Authors: Mennan Claire , Garcia John , McCarthy Helen , Owen Sharon , Perry Jade , Wright Karina , Banerjee Robin , Richardson James B. , Roberts Sally 
Published: April 2018

Objective To assess the phenotype of human articular chondrocytes cultured in normoxia (21% O2) or continuous hypoxia (2% O2). Design Chondrocytes were extracted from patients undergoing total knee replacement ( n = 5) and cultured in ~21% (normoxic chondrocytes, NC) and 2% (hypoxic chondrocytes, HC) oxygen in both monolayer and 3-dimensional (3D) pellet culture and compared with freshly isolated chondrocytes (FC). Cells were assessed by flow cytometry for markers indicative of mesenchymal stromal cells (MSCs), chondrogenic-potency and dedifferentiation. Chondrogenic potency and immunomodulatory gene expression was assessed in NC and HC by reverse transcription quantitative polymerase chain reaction. Immunohistochemistry was used to assess collagen II production following 3D pellet culture. Results NC were positive (>97%, n = 5) for MSC markers, CD73, CD90, and CD105, while HC demonstrated <90% positivity ( n = 4) and FC ( n = 5) less again (CD73 and CD90 <20%; CD105 <40%). The markers CD166 and CD151, indicative of chondrogenic de-differentiation, were significantly higher on NC compared with HC and lowest on FC. NC also produced the highest levels of CD106 and showed the greatest levels of IDO expression, following interferon-γ stimulation, indicating immunomodulatory potential. NC produced the highest levels of CD49c (>60%) compared with HC and FC in which production was <2%. Hypoxic conditions upregulated expression of SOX9, frizzled-related protein ( FRZB), fibroblast growth factor receptor 3 ( FGFR3), and collagen type II ( COL2A1) and downregulated activin receptor-like kinase 1 ( ALK1) in 3 out of 4 patients compared with normoxic conditions for monolayer cells. Conclusions Hypoxic conditions encourage retention of a chondrogenic phenotype with some immunomodulatory potential, whereas normoxia promotes dedifferentiation of chondrocytes toward an MSC phenotype with loss of chondrogenic potency but enhanced immunomodulatory capacity.
Fiscal Decentralization and Economic Growth: Evidence from Indian States
Authors: Ganaie Aadil Ahmad , Bhat Sajad Ahmad , Kamaiah Bandi , Khan N. A. 
Published: April 2018

This study examines the relationship between fiscal decentralization and economic growth in the case of India using panel data for 14 non-specialized states for the period 1981–2014. The results revealed from panel cointegration, and dynamic ordinary least squares (DOLS) framework indicate that spending decentralization has a positive and significant impact on the state domestic product. On the other hand, revenue decentralization has a negative and significant effect on state domestic product. The overall measure of fiscal decentralization is found positively associated with the state income. This study is consistent with the divergence hypothesis in opposite to convergence hypothesis of Oates (1972). JEL: E62, H71, H72
Conservative Treatment Versus Repair Deltoid in SER Type IV Equivalent Ankle Fracture
Authors: Rungprai Chamnanni 
Published: April 2018

Category: Trauma Introduction/Purpose: There remains a controversy to repair deltoid ligament in SER type IV equivalence of acute ankle fracture. Some surgeons prefer conservative treatment with casting while others prefer to repair deltoid ligament after distal fibular fixation. However, there is a little evidence to report comparative outcomes between the two methods. There remains a controversy to repair deltoid ligament in SER type IV equivalence of acute ankle fracture. Some surgeons prefer conservative treatment with casting while others prefer to repair deltoid ligament after distal fibular fixation. However, there is a little evidence to report comparative outcomes between the two methods. The purpose of this study was to report clinical and functional outcomes including complications between the two methods. Methods: A prospective, randomized collected data of 41 consecutive patients who were diagnosed with SER type IV equivalence acute ankle fracture and underwent either conservative treatment (20 patients) or deltoid repair (21 patients) between 2015 and 2017. A minimum follow up to be included in the study was 6 months (mean, 13.2 months; range, 6 to 30 months). The primary outcome was visual analogue scale (VAS), Short Form-36 (SF-36); physical and mental component scores, and FAAM; ADL and Sport. Pre- and post-operative SF-36, FAAM, and pain (Visual Analog Scale) were obtained and compared between the two groups using independent t-test. The secondary outcomes were time to return to activity of daily living, sports, work, and complications. Results: There were 41 patients (30 male and 11 female) with mean age of 29.7 years (range, 18-70 years) and mean BMI of 26.7 kg/m2 (range, 18.3-33.6 kg/m2). Both methods demonstrated significant improvement of post-operative functional outcomes (FAAM, SF-36, and VAS (p < 0.05 all)) compared to pre-operative period; however, there was no significant different between the two groups. Functional outcomes between casting and deltoid repair groups were time to return to activity of daily living (10.4 vs 11.7 weeks), works (12.1 vs 12.9 weeks), sport (25.9 vs 23.7 weeks), weight bearing medial clear space (2.9 vs 3.9 mm), and complications included medial side ankle pain (57 vs 15%) and painful scar (0 vs 15%) for cast and deltoid repair respectively. Conclusion: Both casting and deltoid repair were demonstrated significant improvement in terms of functional outcomes as measured with the FAAM, SF-36, and VAS in patients with SER IV equivalent ankle fracture. Although there was no significant difference of functional outcome in short term of follow-up, deltoid repair group was better in term of medial side ankle pain and lesser medial clear space widening.
Midfoot Charcot Reconstruction with Intramedullary Beaming
Authors: Ford Samuel , Davis W. Hodges , Cohen Bruce , Jones Carroll P. 
Published: April 2018

Category: Midfoot/Forefoot Introduction/Purpose: Midfoot Charcot osteoarthropathy is characterized by non-infectious osteolysis that often leads to midfoot collapse and resultant ulceration. Deformity and ulceration often lead to deep infection and amputation. Midfoot reconstruction with intramedullary screws (beams) is a recently described technique that provides deformity correction and a stable construct without the extensive exposure required for plate fixation. The purpose of this study is to examine the clinical outcomes and complications of patients with midfoot Charcot managed with midfoot osteotomy, realignment arthrodesis, and stabilization using intramedullary beams. Methods: A surgical database query of a tertiary-care foot and ankle center was performed from January 2013 to July 2016 to identify patients with midfoot Charcot who underwent corrective osteotomy with internal beam fixation. 24 patients (Median Age: 60; Median BMI: 32.5; Diabetic: 79%; Insulin Dependent: 74%) were identified and included in the final analysis. Patients with minimum one-year follow-up were evaluated with physical examination, weight-bearing radiographs, and patient-reported outcome measures (FAAM and VR-12). The primary outcome measure was defined as restoration of a stable, plantigrade, ulcer- free foot. Secondary outcome measures include quantitative angular correction, rates of reoperation, post-operative infection, and amputation. Results: The lateral Meary’s angle median improved from -29° preoperatively to -21° on final postoperative radiographs (p<0.001). Likewise, the AP Meary’s angle median improved from 17° to 2° (p<0.001). 43% of midfoot osteotomies were united on final radiographs. An ulcer-free, stable, plantigrade foot was obtained in 83% of patients. Deep infection developed in six (25%) patients. The presence of a preoperative ulcer was found to be predictive of postoperative infection (p=0.04); all six deep infections occurred in patients with preoperative ulceration. 63% of patients required reoperation. Three (13%) patients progressed to amputation at a median nine postoperative months, all for deep infection. The final postoperative median FAAM score was 21. The VR-12 median score was also 21 (PCS: 32, MCS: 67). Conclusion: Results from the FAAM indicate that patients with midfoot Charcot are severely disabled overall, moderately disabled with ADLs, and mostly unable to participate in sport. Results from the VR-12 indicate that patients continue to have poor healthcare quality of life, even following Charcot reconstruction. Midfoot Charcot reconstruction with intramedullary beaming allows for restoration of an ulcer-free, plantigrade foot in most patients, but the complication rates are high, especially in patients with pre-operative ulceration. Despite a low bony union rate, improvement in both the lateral and AP Meary’s angle and clinical success is often obtainable with a relatively low amputation rate.
RETRACTED ARTICLE: Dose selection of central or peripheral administration of sufentanil affect opioid induced cough?: a prospective, randomized, controlled trial
Authors: He Jiabei , Zhu Ling , Zhu Huichen , Gu Xinyu , Li Peiying , Yang Yuting , Yang Liqun 
Published: April 2018

Abstract
Background
Opioid-induced cough (OIC) is one of the most common complications of opioids during anesthesia induction. This study was designed to assess the incidence of OIC mediated by different intravenous route.

Methods
A total of 102(ASA I-II) scheduled for elective surgery under general anesthesia were randomly allocated into two groups: central vein group (group CV, n = 51) and peripheral vein group (group PV, n = 51). The incidence, onset time and severity of OIC were evaluated within 1 min just after sufentanil injection during induction. Meanwhile, heart rate (HR) and blood pressure (BP) were also recorded to assess the hemodynamic changes.

Results
The incidence of OIC was 10/51 (20.4%) in group CV and 16/51 (32%) in group PV, patients received central venous administration of sufentanil experienced less OIC compared with those injected by peripheral venous route (P < 0.05), as well as a significantly lower incidence of severe OIC (P < 0.05). Nevertheless, the onset of OIC and hemodynamic data were comparable between two groups (P > 0.05).

Conclusion
Our study indicates that sufentanil administration by central venous route reduces the incidence and severity of OIC, but without significant changes in hemodynamic status.

Trial registration
Chinese Clinical Trial Registry with registration number ChiCTR-IOR-15006075. Registered 28 February 2015.
Genetic analysis of Wnt/PCP genes in neural tube defects
Authors: Chen Zhongzhong , Lei Yunping , Cao Xuanye , Zheng Yufang , Wang Fang , Bao Yihua , Peng Rui , Finnell Richard H. , Zhang Ting , Wang Hongyan 
Published: April 2018

Abstract
Background
Mouse homozygous mutants in Wnt/planar cell polarity (PCP) pathway genes have been shown to cause neural tube defects (NTDs) through the disruption of normal morphogenetic processes critical to neural tube closure (NTC). Knockout mice that are heterozygotes of single PCP genes likely fail to produce NTD phenotypes, yet damaging variants detected in human NTDs are almost always heterozygous, suggesting that other deleterious interacting variants are likely to be present. Nonetheless, the Wnt/PCP pathway remains a genetic hotspot. Addressing these issues is essential for understanding the genetic etiology of human NTDs.

Methods
We performed targeted next-generation sequencing (NGS) on 30 NTD-predisposing Wnt/PCP pathway genes in 184 Chinese NTD cases. We subsequently replicated our findings for the CELSR1 gene in an independent cohort of 292 Caucasian NTD samples from the USA. Functional validations were confirmed using in vitro assays.

Results
CELSR1, CELSR2 and CELSR3 genes were significantly clustered with rare driver coding mutations (q-value< 0.05) demonstrated by OncodriveCLUST. During the validation stage, the number of rare loss of function (LoF) variants in CELSR1 was significantly enriched in NTDs compared with the LoF counts in the ExAC database (p < 0.001). Functional studies indicated compound heterozygote variants of CELSR2 p.Thr2026Met and DVL3 p.Asp403Asn result in down regulation of PCP signals.

Conclusions
These data indicate rare damaging variants of the CELSR genes, identified in ~ 14% of NTD cases, are expected to be driver genes in the Wnt/PCP pathway. Compound damaging variants of CELSR genes and other Wnt/PCP genes, which were observed in 3.3% of the studied NTD cohort, are also expected to amplify these effects at the pathway level.
Real-Time Genomic Characterization of Metastatic Pancreatic Neuroendocrine Tumors Has Prognostic Implications and Identifies Potential Germline Actionability
Authors: Raj Nitya , Shah Ronak , Stadler Zsofia , Mukherjee Semanti , Chou Joanne , Untch Brian , Li Janet , Kelly Virginia , Osoba Muyinat , Saltz Leonard B. , Mandelker Diana , Ladanyi Marc , Berger Michael F. , Klimstra David S. , Reidy-Lagunes Diane 
Published: April 2018

PurposeWe assessed the usefulness of real-time molecular profiling through next-generation sequencing (NGS) in predicting the tumor biology of advanced pancreatic neuroendocrine tumors (panNETs) and in characterizing genomic evolution.MethodsPatients with metastatic panNETs were recruited in the routine clinical practice setting (between May 2014 and March 2017) for prospective NGS of their tumors as well as for germline analysis using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing platform. When possible, NGS was performed at multiple time points.ResultsNGS was performed in 96 tumor samples from 80 patients. Somatic alterations were identified in 76 of 80 patients (95%). The most commonly altered genes were MEN1 (56%), DAXX (40%), ATRX (25%), and TSC2 (25%). Alterations could be defined in pathways that included chromatin remodeling factors, histone methyltransferases, and mammalian target of rapamycin pathway genes. Somatic loss of heterozygosity was particularly prevalent (55 of 95 tested samples [58%]), and the presence of loss of heterozygosity resulted in improved overall survival (P = .06). Sequencing of pre- and post-treatment samples revealed tumor-grade progression; clonal evolution patterns were also seen (molecular resistance mechanisms and chemotherapy-associated mutagenesis). Germline genetic analysis identified clinically actionable pathogenic or likely pathogenic variants in 14 of 88 patients (16%), including mutations in high-penetrance cancer susceptibility genes ( MEN1, TSC2, and VHL).ConclusionA clinical NGS platform reveals pertubations of biologic pathways in metastatic panNETs that may inform prognosis and direct therapies. Repeat sequencing at disease progression reveals increasing tumor grade and genetic evolution, demonstrating that panNETs adopt a more aggressive behavior through time and therapies. In addition to frequent somatic mutations in MEN1 and TSC2, germline mutations in these same genes underlie susceptibility to panNETs and highlight the need to re-evaluate whether germline genetic analysis should be performed for all patients with panNETs.
Further miniaturisation of the Thermochron iButton to create a thermal bio-logger weighing 0.3 g
Authors: Virens Evelyn , Cree Alison 
Published: April 2018

ABSTRACT
Thermochron iButtons are commonly used by thermal biologists to continuously measure body temperature from animals. However, if unmodified, these devices are of a size that limits their use with very small animals. To allow iButtons to be used to study smaller species, methods to miniaturise them by 61% have been previously described. We present a method to reduce iButton mass by a further 71%. The modified devices have a shorter battery life, but the minimum size of vertebrates able to carry the devices is reduced from 28.9 g to 6.6 g, if the arbitrary, yet widely cited, maximum of 5% body mass for attached devices is adhered to. We demonstrate the application of our method by recording surface temperatures of captive and wild skinks and show that captive cockroaches weighing 0.8 g are also able to carry the device. We believe this to be the first time that temperature data have been recorded from an insect in this way.