bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactive K-Means Clustering Method Based on User Behavior for Different Analysis Target in Medicine
Authors: Lei Yang , Yu Dai , Bin Zhang , Yang Yang
Published: October 2017

Clustering algorithm as a basis of data analysis is widely used in analysis systems. However, as for the high dimensions of the data, the clustering algorithm may overlook the business relation between these dimensions especially in the medical fields. As a result, usually the clustering result may not meet the business goals of the users. Then, in the clustering process, if it can combine the knowledge of the users, that is, the doctor’s knowledge or the analysis intent, the clustering result can be more satisfied. In this paper, we propose an interactive K-means clustering method to improve the user’s satisfactions towards the result. The core of this method is to get the user’s feedback of the clustering result, to optimize the clustering result. Then, a particle swarm optimization algorithm is used in the method to optimize the parameters, especially the weight settings in the clustering algorithm to make it reflect the user’s business preference as possible. After that, based on the parameter optimization and adjustment, the clustering result can be closer to the user’s requirement. Finally, we take an example in the breast cancer, to testify our method. The experiments show the better performance of our algorithm.
Computational Exploration for Lead Compounds That Can Reverse the Nuclear Morphology in Progeria
Authors: Rampogu Shailima , Baek Ayoung , Son Minky , Zeb Amir , Park Chanin , Kumar Raj , Lee Gihwan , Kim Donghwan , Choi Yeonuk , Cho Yeongrae , Park Yohan , Park Seok Ju , Lee Keun Woo
Published: October 2017

Progeria is a rare genetic disorder characterized by premature aging that eventually leads to death and is noticed globally. Despite alarming conditions, this disease lacks effective medications; however, the farnesyltransferase inhibitors (FTIs) are a hope in the dark. Therefore, the objective of the present article is to identify new compounds from the databases employing pharmacophore based virtual screening. Utilizing nine training set compounds along with lonafarnib, a common feature pharmacophore was constructed consisting of four features. The validated Hypo1 was subsequently allowed to screen Maybridge, Chembridge, and Asinex databases to retrieve the novel lead candidates, which were then subjected to Lipinski’s rule of 5 and ADMET for drug-like assessment. The obtained 3,372 compounds were forwarded to docking simulations and were manually examined for the key interactions with the crucial residues. Two compounds that have demonstrated a higher dock score than the reference compounds and showed interactions with the crucial residues were subjected to MD simulations and binding free energy calculations to assess the stability of docked conformation and to investigate the binding interactions in detail. Furthermore, this study suggests that the Hits may be more effective against progeria and further the DFT studies were executed to understand their orbital energies.
Risk Evaluation of Debris Flow Hazard Based on Asymmetric Connection Cloud Model
Authors: Xu Xinyu , Wang Mingwu , Li Yafeng , Zhang Libiao
Published: October 2017

Risk assessment of debris flow is a complex problem involving various uncertainty factors. Herein, a novel asymmetric cloud model coupled with connection number was described here to take into account the fuzziness and conversion situation of classification boundary and interval nature of evaluation indicators for risk assessment of debris flow hazard. In the model, according to the classification standard, the interval lengths of each indicator were first specified to determine the digital characteristic of connection cloud at different levels. Then the asymmetric connection clouds in finite intervals were simulated to analyze the certainty degree of measured indicator to each evaluation standard. Next, the integrated certainty degree to each grade was calculated with corresponding indicator weight, and the risk grade of debris flow was determined by the maximum integrated certainty degree. Finally, a case study and comparison with other methods were conducted to confirm the reliability and validity of the proposed model. The result shows that this model overcomes the defect of the conventional cloud model and also converts the infinite interval of indicators distribution into finite interval, which makes the evaluation result more reasonable.
Comparison of Turkey’s Geographical Regions in terms of Stand-Alone PV System Design and Cost Parameters
Authors: Onat Nevzat
Published: October 2017

Stand-alone photovoltaic (SAPV) systems are widely used in rural areas where there is no national grid or as a precaution against power outages. In this study, technical and economic analysis of a SAPV system was carried out using meteorological data for 75 province centers in seven geographical regions of Turkey. Obtained results for each province center were separated by geographical area. The averages of the centers for each region are taken as output. A calculation algorithm based on MsExcel has been established for these operations. The analyses made with the developed algorithm are repeated for five different scenarios that they cover periods of time when a constant strong load is active for all seasons (winter, spring, summer, and autumn) and all year round. The developed algorithm calculates the life-cycle cost, the unit energy cost, the electrical capacity utilization rate, the amount of generated/excess energy per month, the initial investment/replacement, and operating and maintenance (O&M) costs of each element. As a result, geographical regions of Turkey are compared in terms of these outputs graphically. Further investigations may include the sale of excess energy generated, small-scale PV system cost factors parallel to the grid, and the effects of government incentives.
Iterative Learning Control Experimental Results in Twin‐Rotor Device
Authors: Mascaró Palliser R. , Costa-Castelló Ramon , Ramos G. A.
Published: October 2017

This paper presents the results of applying the Iterative Learning Control algorithms to a Twin‐Rotor Multiple‐Input Multiple‐Output System (TRMS) in order to achieve high performance in repetitive tracking of trajectories. The plant, which is similar to a prototype of helicopter, is characterized by its highly nonlinear and cross‐coupled dynamics. In the first phase, the system is modelled using the Lagrangian approach and combining theoretical and experimental results. Thereafter, a hierarchical control architecture which combines a baseline feedback controller with an Iterative Learning Control algorithm is developed. Finally, the responses of the real device and a complete analysis of the learning behaviour are exposed.
Digital Closed-Loop Driving Technique Using the PFD-Based CORDIC Algorithm for a Biaxial Resonant Microaccelerometer
Authors: Yang Bo , Wu Lei , Wang Binlong , Wang Qiuhua
Published: October 2017

A digital closed-loop driving technique is presented in this paper that uses the PFD- (phase frequency detector-) based CORDIC (coordinate rotation digital computer) algorithm for a biaxial resonant microaccelerometer. A conventional digital closed-loop self-oscillation system based on the CORDIC algorithm is implemented and simulated using Simulink software to verify the system performance. The system performance simulations reveal that the incompatibility between the sampling frequency and effective bits of AD and DA convertors limits further performance improvements. Therefore, digital, closed-loop self-oscillation using the PFD-based CORDIC algorithm is designed to further optimize the system performance. The system experimental results illustrate that the optimized system using the PFD-based CORDIC improves the bias stability of the resonant microaccelerometer by more than 5.320 times compared to the conventional system. This demonstrates that the optimized digital closed-loop driving technique using the PFD-based CORDIC for the biaxial resonant microaccelerometer is effective.
TGFβ Promotes Genomic Instability after Loss of RUNX3
Authors: Krishnan Vaidehi , Chong Yu Lin , Tan Tuan Zea , Kulkarni Madhura , Bin Rahmat Muhammad Bakhait , Tay Lavina Sierra , Sankar Haresh , Jokhun Doorgesh S. , Ganesan Amudha , Chuang Linda Shyue Huey , Voon Dominic C. , Shivashankar GV , Thiery Jean-Paul , Ito Yoshiaki
Published: October 2017

Studies of genomic instability have historically focused on intrinsic mechanisms rather than extrinsic mechanisms based in the tumor microenvironment (TME). TGFβ is the most abundantly secreted cytokine in the TME, where it imparts various aggressive characteristics including invasive migration, drug resistance, and epithelial-to-mesenchymal transition (EMT). Here we show that TGFβ also promotes genomic instability in the form of DNA double strand breaks (DSB) in cancer cells that lack the tumor suppressor gene RUNX3. Loss of RUNX3 resulted in transcriptional downregulation of the redox regulator heme oxygenase-1 (HO-1 or HMOX1). Consequently, elevated oxidative DNA damage disrupted genomic integrity and triggered cellular senescence, which was accompanied by tumor-promoting inflammatory cytokine expression and acquisition of the senescence-associated secretory phenotype (SASP). Recapitulating the above findings, tumors harboring a TGFβ gene expression signature and RUNX3 loss exhibited higher levels of genomic instability. In summary, RUNX3 creates an effective barrier against further TGFβ-dependent tumor progression by preventing genomic instability. These data suggest a novel cooperation between cancer cell–extrinsic TGFβ signaling and cancer cell–intrinsic RUNX3 inactivation as aggravating factors for genomic instability.

Significance: RUNX3 inactivation in cancer removes an antioxidant barrier against DNA double strand breaks induced by TGFβ expressed in the tumor microenvironment. Cancer Res; 78(1); 88–102. ©2017 AACR.
Type I IFN Receptor Signaling Controls IL7-Dependent Accumulation and Activity of Protumoral IL17A-Producing γδT Cells in Breast Cancer
Authors: Patin Emmanuel C. , Soulard Daphnée , Fleury Sébastien , Hassane Maya , Dombrowicz David , Faveeuw Christelle , Trottein François , Paget Christophe
Published: October 2017

The protumoral activity of γδT17 cells has recently emerged in a wide variety of solid malignancies, including breast cancer. These cells exert their detrimental functions by promoting tumor growth, angiogenesis, and subsequent metastasis development. However, the intratumoral factors that regulate the biology of γδT17cells within the tumor microenvironment are less well understood. Here, using two experimental models of breast cancer, we reinforced the concept that tumor-infiltrating γδT17 cells are endowed with protumoral functions, which promote tumor progression and metastasis development. More importantly, we demonstrated a critical role for type I IFN signaling in controlling the preferential accumulation in the tumor bed of a peculiar subset of γδT17 cells displaying a CD27− CD3bright phenotype (previously associated with the invariant Vγ6Vδ1+ TCR). Interestingly, this effect was indirect and partially relied on the IFNAR1-dependent control of IL7 secretion, a factor that triggers proliferation and activating functions of deleterious γδT17 cells. Our work therefore identifies a key role of the type I IFN/IL7 axis in the regulation of intratumoral γδT17-cell functions and in the development of primary breast tumor growth and metastasis.

Significance: Tumor-derived IL7 can represent a therapeutic target to prevent accumulation of immune cells endowed with potent protumoral activities. Cancer Res; 78(1); 195–204. ©2017 AACR.
Mitochondrial Haplotype Alters Mammary Cancer Tumorigenicity and Metastasis in an Oncogenic Driver–Dependent Manner
Authors: Brinker Amanda E. , Vivian Carolyn J. , Koestler Devin C. , Tsue Trevor T. , Jensen Roy A. , Welch Danny R.
Published: October 2017

Using a novel mouse model, a mitochondrial-nuclear exchange model termed MNX, we tested the hypothesis that inherited mitochondrial haplotypes alter primary tumor latency and metastatic efficiency. Male FVB/N-Tg(MMTVneu)202Mul/J (Her2) transgenic mice were bred to female MNX mice having FVB/NJ nuclear DNA with either FVB/NJ, C57BL/6J, or BALB/cJ mtDNA. Pups receiving the C57BL/6J or BALB/cJ mitochondrial genome (i.e., females crossed with Her2 males) showed significantly (P < 0.001) longer tumor latency (262 vs. 293 vs. 225 days), fewer pulmonary metastases (5 vs. 7 vs. 15), and differences in size of lung metastases (1.2 vs. 1.4 vs. 1.0 mm diameter) compared with FVB/NJ mtDNA. Although polyoma virus middle T–driven tumors showed altered primary and metastatic profiles in previous studies, depending upon nuclear and mtDNA haplotype, the magnitude and direction of changes were not the same in the HER2-driven mammary carcinomas. Collectively, these results establish mitochondrial polymorphisms as quantitative trait loci in mammary carcinogenesis, and they implicate distinct interactions between tumor drivers and mitochondria as critical modifiers of tumorigenicity and metastasis. Cancer Res; 77(24); 6941–9. ©2017 AACR.
PTEN Is Fundamental for Elimination of Leukemia Stem Cells Mediated by GSK126 Targeting EZH2 in Chronic Myelogenous Leukemia
Authors: Zhou Jingfeng , Nie Danian , Li Juan , Du Xin , Lu Yuhong , Li Yangqiu , Liu Chang , Dai Wei , Wang Yun , Jin Yanli , Pan Jingxuan
Published: October 2017

Purpose: Leukemia stem cells (LSCs) are an important source of tyrosine kinase inhibitor resistance and disease relapse in patients with chronic myelogenous leukemia (CML). Targeting LSCs may be an attractive strategy to override this thorny problem. Given that EZH2 was overexpressed in primary CML CD34+ cells, our purpose in this study was to evaluate the effects of targeting EZH2 on CML LSCs and clarify its underlying mechanism.

Experimental Design: Human primary CML CD34+ cells and retrovirally BCR–ABL-driven CML mouse models were employed to evaluate the effects of suppression of EZH2 by GSK126- or EZH2-specific shRNA in vitro and in vivo. Recruitment of EZH2 and H3K27me3 on the promoter of tumor-suppressor gene PTEN in CML cells was measured by chromatin immunoprecipitation assay.

Results: Our results showed that pharmacologic inhibition of EZH2 by GSK126 not only elicited apoptosis and restricted cell growth in CML bulk leukemia cells, but also decreased LSCs in CML CD34+ cells while sparing those from normal bone marrow CD34+ cells. Suppression of EZH2 by GSK126 or specific shRNA prolonged survival of CML mice and reduced the number of LSCs in mice. EZH2 knockdown resulted in elevation of PTEN and led to impaired recruitment of EZH2 and H3K27me3 on the promoter of PTEN gene. The effect of EZH2 knockdown in the CML mice was at least partially reversed by PTEN knockdown.

Conclusions: These findings improve the understanding of the epigenetic regulation of stemness in CML LSCs and warrant clinical trial of GSK126 in refractory patients with CML. Clin Cancer Res; 24(1); 145–57. ©2017 AACR.
Concurrent Inhibition of Pim and FLT3 Kinases Enhances Apoptosis of FLT3-ITD Acute Myeloid Leukemia Cells through Increased Mcl-1 Proteasomal Degradation
Authors: Kapoor Shivani , Natarajan Karthika , Baldwin Patrick R. , Doshi Kshama A. , Lapidus Rena G. , Mathias Trevor J. , Scarpa Mario , Trotta Rossana , Davila Eduardo , Kraus Manfred , Huszar Dennis , Tron Adriana E. , Perrotti Danilo , Baer Maria R.
Published: October 2017

Purpose: fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in 30% of acute myeloid leukemia (AML), and these patients have short disease-free survival. FLT3 inhibitors have limited and transient clinical activity, and concurrent treatment with inhibitors of parallel or downstream signaling may improve responses. The oncogenic serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD and also promotes its signaling in a positive feedback loop, suggesting benefit of combined Pim and FLT3 inhibition.

Experimental Design: Combinations of clinically active Pim and FLT3 inhibitors were studied in vitro and in vivo.

Results: Concurrent treatment with the pan-Pim inhibitor AZD1208 and FLT3 inhibitors at clinically applicable concentrations abrogated in vitro growth of FLT3-ITD, but not wild-type FLT3 (FLT3-WT), cell lines. AZD1208 cotreatment increased FLT3 inhibitor–induced apoptosis of FLT3-ITD, but not FLT3-WT, cells measured by sub-G1 fraction, annexin V labeling, mitochondrial membrane potential, and PARP and caspase-3 cleavage. Concurrent treatment with AZD1208 and the FLT3 inhibitor quizartinib decreased growth of MV4-11 cells, with FLT3-ITD, in mouse xenografts, and prolonged survival, enhanced apoptosis of FLT3-ITD primary AML blasts, but not FLT3-WT blasts or remission marrow cells, and decreased FLT3-ITD AML blast colony formation. Mechanistically, AZD1208 and quizartinib cotreatment decreased expression of the antiapoptotic protein Mcl-1. Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML.

Conclusions: The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML. Clin Cancer Res; 24(1); 234–47. ©2017 AACR.
Extracellular Vesicles Released by Cardiomyocytes in a Doxorubicin-Induced Cardiac Injury Mouse Model Contain Protein Biomarkers of Early Cardiac Injury
Authors: Yarana Chontida , Carroll Dustin , Chen Jing , Chaiswing Luksana , Zhao Yanming , Noel Teresa , Alstott Michael , Bae Younsoo , Dressler Emily V. , Moscow Jeffrey A. , Butterfield D. Allan , Zhu Haining , St. Clair Daret K.
Published: October 2017

Purpose: Cardiac injury is a major cause of death in cancer survivors, and biomarkers for it are detectable only after tissue injury has occurred. Extracellular vesicles (EV) remove toxic biomolecules from tissues and can be detected in the blood. Here, we evaluate the potential of using circulating EVs as early diagnostic markers for long-term cardiac injury.

Experimental Design: Using a mouse model of doxorubicin (DOX)-induced cardiac injury, we quantified serum EVs, analyzed proteomes, measured oxidized protein levels in serum EVs released after DOX treatment, and investigated the alteration of EV content.

Results: Treatment with DOX caused a significant increase in circulating EVs (DOX_EV) compared with saline-treated controls. DOX_EVs exhibited a higher level of 4-hydroxynonenal adducted proteins, a lipid peroxidation product linked to DOX-induced cardiotoxicity. Proteomic profiling of DOX_EVs revealed the distinctive presence of brain/heart, muscle, and liver isoforms of glycogen phosphorylase (GP), and their origins were verified to be heart, skeletal muscle, and liver, respectively. The presence of brain/heart GP (PYGB) in DOX_EVs correlated with a reduction of PYGB in heart, but not brain tissues. Manganese superoxide dismutase (MnSOD) overexpression, as well as pretreatment with cardioprotective agents and MnSOD mimetics, resulted in a reduction of EV-associated PYGB in mice treated with DOX. Kinetic studies indicated that EVs containing PYGB were released prior to the rise of cardiac troponin in the blood after DOX treatment, suggesting that PYGB is an early indicator of cardiac injury.

Conclusions: EVs containing PYGB are an early and sensitive biomarker of cardiac injury. Clin Cancer Res; 24(7); 1644–53. ©2017 AACR.

See related commentary by Zhu and Gius, p. 1516
Low PD-1 Expression in Cytotoxic CD8+ Tumor-Infiltrating Lymphocytes Confers an Immune-Privileged Tissue Microenvironment in NSCLC with a Prognostic and Predictive Value
Authors: Mazzaschi Giulia , Madeddu Denise , Falco Angela , Bocchialini Giovanni , Goldoni Matteo , Sogni Francesco , Armani Giovanna , Lagrasta Costanza Annamaria , Lorusso Bruno , Mangiaracina Chiara , Vilella Rocchina , Frati Caterina , Alfieri Roberta , Ampollini Luca , Veneziani Michele , Silini Enrico Maria , Ardizzoni Andrea , Urbanek Konrad , Aversa Franco , Quaini Federico , Tiseo Marcello
Published: October 2017

Purpose: The success of immune checkpoint inhibitors strengthens the notion that tumor growth and regression are immune regulated. To determine whether distinct tissue immune microenvironments differentially affect clinical outcome in non–small cell lung cancer (NSCLC), an extended analysis of PD-L1 and tumor-infiltrating lymphocytes (TIL) was performed.

Experimental Design: Samples from resected adenocarcinoma (ADC 42), squamous cell carcinoma (SCC 58), and 26 advanced diseases (13 ADC and 13 SCC) treated with nivolumab were analyzed. PD-L1 expression and the incidence of CD3, CD8, CD4, PD-1, CD57, FOXP3, CD25, and Granzyme B TILs were immunohistochemically assessed.

Results: PD-L1 levels inversely correlated with N involvement, although they did not show a statistically significant prognostic value in resected patients. The incidence and phenotype of TILs differed in SCC versus ADC, in which EGFR and KRAS mutations conditioned a different frequency and tissue localization of lymphocytes. NSCLC resected patients with high CD8pos lymphocytes lacking PD-1 inhibitory receptor had a longer overall survival (OS: HR = 2.268; 95% CI, 1.056–4.871, P = 0.03). PD-1-to-CD8 ratio resulted in a prognostic factor both on univariate (HR = 1.952; 95% CI, 1.34–3.12, P = 0.001) and multivariate (HR = 1.943; 95% CI, 1.38–2.86, P = 0.009) analysis. Moreover, low PD-1 incidence among CD8pos cells was a distinctive feature of nivolumab-treated patients, showing clinical benefit with a prolonged progression-free survival (PFS: HR = 4.51; 95% CI, 1.45–13.94, P = 0.004).

Conclusions: In the presence of intrinsic variability in PD-L1 expression, the reservoir of PD-1–negative effector T lymphocytes provides an immune-privileged microenvironment with a positive impact on survival of patients with resected disease and response to immunotherapy in advanced NSCLC. Clin Cancer Res; 24(2); 407–19. ©2017 AACR.
Interleukin-12 from CD103+ Batf3-Dependent Dendritic Cells Required for NK-Cell Suppression of Metastasis
Authors: Mittal Deepak , Vijayan Dipti , Putz Eva M. , Aguilera Amelia R. , Markey Kate A. , Straube Jasmin , Kazakoff Stephen , Nutt Stephen L. , Takeda Kazuyoshi , Hill Geoffrey R. , Waddell Nicola , Smyth Mark J.
Published: October 2017

Several host factors may affect the spread of cancer to distant organs; however, the intrinsic role of dendritic cells (DC) in controlling metastasis is poorly described. Here, we show in several tumor models that although the growth of primary tumors in Batf3-deficient mice, which lack cross-presenting DCs, was not different from primary tumors in wild-type (WT) control mice, Batf3-deficient mice had increased experimental and spontaneous metastasis and poorer survival. The increased metastasis was independent of CD4+ and CD8+ T lymphocytes, but required NK cells and IFNγ. Chimeric mice in which Batf3-dependent DCs uniformly lacked the capacity to produce IL12 had metastatic burdens similar to the Batf3-deficient mice, suggesting that Batf3+ DCs were the only cell type whose IL12 production was critical for controlling metastasis. We found that IL12-YFP reporter mice, whose lungs were injected with B16F10 melanoma, had increased numbers of IL12-expressing CD103+ DCs with enhanced CD86 expression. Bone-marrow–derived DCs from WT, but not Batf3-deficient, mice activated NK cells to produce IFNγ in an IL12-dependent manner and therapeutic injection of recombinant mouse IL12 decreased metastasis in both WT and Batf3-deficient mice. Analysis of TCGA datasets revealed an association between high expression of BATF3 and IRF8 and improved survival of breast cancer patients; BATF3 expression also significantly correlated with NK-cell receptor genes, IL12, and IFNG. Collectively, our findings show that IL12 from CD103+ DCs is critical for NK cell–mediated control of tumor metastasis. Cancer Immunol Res; 5(12); 1098–108. ©2017 AACR.
Congenital Malformations of the Reproductive Tract in a Patient with Poland Syndrome: Is There a Connection
Authors: Meng Tian , Bai Ming , Zhao Ru
Published: October 2017

Background: Poland syndrome and Müllerian duct agenesis (Mayer-Rokitansky-Küster-Hauser(MRKH)-like syndrome) are two rare congenital anomalies with unclear etiology. Case Report: An 18-year-old female presented with hypoplasia of the left pectoralis muscles and subcutaneous tissue, hypoplasia of the left breast and nipple, and dextrocardia, typical in those with a severe form of Poland syndrome. She also showed aplasia of the vagina and uterus, bilateral ovarian agenesis, and hyperandrogenism, presenting as MRKH-like syndrome. Conclusion: It is plausible to assume that these two congenital anomalies which arose from distant sites may be interrelated. More cases and further studies will certainly help delineate the pathogenesis of these syndromes.
Huntington's Disease: Premotor Phase
Authors: Ramos Ana Rita Saldanha , Garrett Carolina
Published: October 2017

Huntington's disease (HD) is an incurable, neurodegenerative disease, which manifests via a triad of progressive symptoms: motor impairment, psychiatric disorders, and cognitive decline. Conventionally, the HD diagnosis is based on the presence of involuntary choreiform movements and a positive genetic test for the CAG-expanded allele gene. Although the diagnosis focuses on the motor part of the triad, there is increasing evidence that both cognitive and neuropsychiatric symptoms can, and often do, present decades before the onset of motor symptoms. In this paper, we review the evidence regarding the symptoms in the HD premotor phase and summarize the most relevant and robust studies in the last few years. Regarding neuropsychiatric symptoms, higher levels of depression, anxiety, apathy, irritability, psychosis, disinhibition, hostility, and sleeping problems were found. In terms of cognition, there was impairment in attention, working memory, episodic memory, language, recognition of facial emotions, empathy, and theory of mind. These early symptoms of HD can be very debilitating and are often disregarded by doctors. It is necessary to acknowledge them so that they can be treated or alleviated. Moreover, an earlier diagnosis can lead to the implementation of neurodegenerative prevention therapies, which may slow the progression of the disease and prolong overall functioning. This will improve the patient's independence and their quality of life.
Impact of the FloTrac/VigileoTM Monitoring on Intraoperative Fluid Management and Outcome after Liver Resection
Authors: Giustiniano Enrico , Procopio Fabio , Ruggieri Nadia , Grimaldi Stefania , Torzilli Guido , Raimondi Ferdinando
Published: October 2017

Backgrounds: Perioperative fluid-therapy is a still a debated issue. In hepatic surgery, volume load must be strictly monitored to assure both a safe hemodynamics and low central venous pressure (CVP) to limit the backflow bleeding. Retrospectively, we compared intraoperative fluid management before and after the adoption of a semi-invasive hemodynamic monitoring. Methods: We compared patients submitted to liver resection monitored by FloTrac/VigileoTM (group A) vs. patients who did not (group B). We searched for differences about hemodynamics, fluid therapy and outcome. Results: Three hundred fifty-five patients underwent hepatic resection due to neoplasm: group A – n = 179 and group B – n = 176. At the end of the resection, patients of group A showed a higher mean arterial pressure (MAP) than group B (74 ± 12 vs. 49.4 ± 8 mm Hg, respectively; p < 0.001). Cardiac index and stroke volume variation in group A were within a normal range. Fluid input was higher in group B than in group A (12.0 ± 3.4 vs. 7.6 ± 3.1 mL/kg/h, respectively; p < 0.001) and fluid balance was significantly different: group A –400 ± 1,527 vs. group B 326 ± 1,527 mL (p < 0.001). Group B showed a greater number of cases complicated outcomes (36 vs. 20; p = 0.014). Considering only those subjects who were able to reach their hemodynamic targets (MAP ≥65 mm Hg and CVP ≤7 mm Hg), we found similar data. Conclusions: Patients who received a monitored fluid therapy experienced a safer outcome.
Early Cognitive Impairment after Intracerebral Hemorrhage in the INTERACT1 Study
Authors: You Shoujiang , Wang Xia , Lindley Richard I. , Robinson Thompson , Anderson Craig S. , Cao Yongjun , Chalmers John
Published: October 2017

Background: Data on cognitive impairment after acute intracerebral hemorrhage (ICH) are limited. This study is aimed at determining the frequency and predictors of cognitive impairment among participants of the pilot phase, Intensive Blood Pressure (BP) Reduction in Acute Cerebral Hemorrhage Trial (INTERACT1). Methods: INTERACT1 was an open randomized trial of early intensive (target systolic BP <140 mm Hg) compared with contemporaneous guideline-recommended BP lowering in 404 patients with elevated systolic BP (150–220 mm Hg) within 6 h of ICH onset. Cognitive impairment was defined by scores ≤24 on the Mini-Mental State Examination (MMSE) assessed by interview on follow-up at 90 days. Results: A total of 231 (64.5%) of 358 90-day survivors had MMSE scores for analyses, and 75 (32.5%) had cognitive impairment. In multivariable analysis, older age (OR 2.48, 95% CI 1.73–3.56 per 10-year increase; p < 0.001), female sex (OR 2.06, 95% CI 1.00–4.23; p = 0.049), prior ICH (OR 2.87, 95% CI 1.08–7.65; p = 0.035), high baseline National Institute of Health Stroke Scale score (OR 1.06, 95% CI 1.00–1.13; p = 0.044), and high mean systolic BP over the first 24 h post-randomization (OR 1.34, 95% CI 1.07–1.68/10 mm Hg increase; p = 0.011) were independently associated with cognitive impairment. Conclusions: One third of patients have significant cognitive impairment early after ICH, which is more frequent in the elderly, females, those with prior ICH, and more severe initial neurological deficit and with persistently high early systolic BP.
Serum 1,5-Anhydroglucitol: Risk Factor of Acute Ischemic Stroke and Transient Ischemic Attack in Well-Controlled Diabetes
Authors: Shiga Yuji , Kuriyama Masaru , Kanaya Yuhei , Takeshima Shinichi , Takemaru Makoto , Takamatsu Kazuhiro , Shimoe Yutaka , Fujikawa Yasunori , Nishigaki Masakazu
Published: October 2017

Background: Serum 1,5-anhydroglucitol (1,5-AG) levels are a measure that provides information on daily glycemic variations. We evaluated whether 1,5-AG could be a possible marker of acute ischemic stroke (AIS) or transient ischemic attacks (TIA) in patients with diabetes mellitus (DM). Methods: We retrospectively reviewed electronic medical records of 5,294 AIS/TIA patients. Of the 5,294, 1,898 had diabetes and in 1,246, serum 1,5-AG levels were measured (group S). Group S was divided into 2 subgroups: hemoglobin A1c (HbA1c) <7% (S-low) and >7% (S-high). As controls, 394 outpatients with diabetes (group C) without AIS/TIA were likewise divided into subgroups, C-low and C-high according to HbA1c level. In each HbA1c subgroup, the association between serum 1,5-AG (≥14 vs. <14 µg/mL) and stroke was examined using multivariable logistic regression (MLR) with stepwise variable selection. In model 1, the OR and 95% CI was examined adjusted for age and gender. Known risk factors for stroke; hypertension, dyslipidemia, alcohol consumption, smoking, and estimated glomerular filtration rate were included in model 2. Results: Overall, serum 1,5-AG levels were lower in group S than in group C. Serum 1,5-AG levels were low in subgroups S-high and C-high, showing no differences in mean values. However, mean serum 1,5-AG levels in S-low was statistically lower than that in C-low. MLR analysis showed that the OR for low (<14 µg/mL) 1,5-AG for stroke was statistically significant only in well-controlled diabetes (OR [95% CI] 2.19 [1.54–3.10]) in model 1 and (2.26 [1.56–3.28]) model 2. Conclusions: Low serum 1,5-AG levels could be a possible marker for AIS/TIA risk in patients with well-controlled DM.
Inhibitory Effect of Afatinib on Platelet Activation and Apoptosis
Authors: Cao Hang , Bhuyan Abdulla Al Mamun , Umbach Anja T. , Bissinger Rosi , Gawaz Meinrad , Lang Florian
Published: October 2017

Background/Aims: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor afatinib is used for the treatment of several malignancies. Afatinib is at least partially effective by triggering apoptosis of tumor cells. Platelets may similarly undergo apoptosis, which is characterized by caspase 3 activation, cell shrinkage and phosphatidylserine translocation. However, an effect of afatinib on platelets has never been reported. The present study explored whether treatment of platelets with afatinib modifies platelet activation and apoptosis in the absence and presence of platelet activators thrombin or collagen related peptide (CRP). Methods: Platelets isolated from wild-type mice were exposed for 30 minutes to afatinib (18 µg/ml) without or with subsequent treatment with thrombin (0.005 U/ml or 0.01 U/ml) or CRP (2 µg/ml or 5 µg/ml). Flow cytometry was employed to estimate Orai1 abundance at the platelet surface with specific antibodies, cytosolic Ca2+-activity ([Ca2+]i) from Fluo-3 fluorescence, platelet degranulation from P-selectin abundance, integrin activation from αIIbβ3 integrin abundance, caspase activity utilizing an Active Caspase-3 Staining kit, phosphatidylserine abundance from annexin-V-binding, platelet volume from forward scatter and aggregation utilizing staining with CD9-APC and CD9-PE. Results: In the absence of thrombin and CRP, the administration of afatinib (18 µg/ml) slightly, but significantly, increased [Ca2+]i and annexin-V-binding, but did not significantly modify Orai1 abundance, P-selectin abundance, activated αIIbβ3 integrin, cell volume, caspase activity and aggregation. Exposure of platelets to 0.005 U/ml or 0.01 U/ml thrombin or 2 µg/ml or 5 µg/ ml CRP was followed by a significant increase of Orai1 abundance, increase of [Ca2+]i, P-selectin abundance, αIIbβ3 integrin activity, annexin-V-binding, caspase activity, and aggregation, as well as a significant decrease of forward scatter, all effects significantly blunted (thrombin) or virtually abolished (CRP) by afatinib. Conclusions: Afatinib is a powerful inhibitor of platelet activation, platelet apoptosis and platelet aggregation.
Gene Expression and Apoptosis Levels in Cumulus Cells of Patients with Polymorphisms of FSHR and LHB Undergoing in Vitro Fertilization Program
Authors: Bosco Liana , Ruvolo Giovanni , Luparello Claudio , Ferrari Stefania , Valerio Domenico , Santi Daniele , Piomboni Paola , Sarcina Elena , Lispi Monica , Roccheri Maria Carmela
Published: October 2017

Background/Aims: FSH receptor (FSHR) Ala307Thr and Asn680Ser and LHβ chain (LHB) Trp28Arg and Ile35Thr polymorphisms affect the response to pharmacological ovarian stimulation with r-FSH in women undergoing assisted reproductive treatment (ART). Here, we evaluated the expression level of selected genes involved in follicle maturation and the possible onset of apoptosis in cumulus cells of patients with single and double FSHR and LHB polymorphisms, as potential markers of oocyte competence. Methods: Cumulus cells from 36 stimulated patients were collected and SNP genotyping performed by PCR. Gene expression was evaluated through real-time PCR, and apoptosis estimated via TUNEL assay, and cleaved caspase-3 and pAKT immunostaining. Results: The cumulative data show significant correlations indicating that the genetic alteration of FSHR and/or LHB genes may lead to perturbations of the signaling network programmed to granulosa cell survival and follicle development. Notably, when double heterozygotes were compared to the rest of the patients, a higher level of apoptosis in terms of both DNA fragmentation index and amount of active caspase-3 was observed in cumulus cells. Conclusions: These results may help to define personalized stimulation protocols in ART programs, to increase the success rate of ICSI procedures in accordance with the polymorphic condition of the individual patient.
Lenin Studies: Method and Organisation
Authors: Le Blanc Paul
Published: October 2017

The growing field of Lenin Studies has been nurtured by the growth of crises and struggles in our own time and may contribute to present-day activists’ efforts at developing revolutionary strategy, organisation and struggle. Surveying this field, it is worth focusing on three recent studies by Antonio Negri, Tamás Krausz and Alan Shandro which give attention to the methodological core of what can be called ‘Leninism’. All three distinguish Lenin’s approach to Marxism from that of such prominent Marxists as Kautsky. The result, highlighted by aspects of Lenin’s functioning in the early Communist International, provides a more consistent activist- and revolutionary edge that might have relevance for future struggles, particularly in relation to the question of organisation.
When a Spiel is not a Game
Authors: Wintjes Jorit
Published: October 2017

The nineteenth century saw dramatic changes in military technology that profoundly changed the nature of warfare, and integrating the performance of that new technology into the existing operational and tactical thinking became hugely important. In Prussia, from 1824 onwards, the Kriegsspiel, the world’s first professional conflict simulation in official use, became a key element for learning how to make best use of the new technology. Between 1824 and 1871, the rules went through several different editions, each one revised according to the latest technological and tactical developments. The paper will provide a brief historical introduction, then concentrate on the impact of technological innovations on the rules, and finally show that the Kriegsspiel and its non-Prussian counterparts are essential for understanding how military establishments in and beyond Europe reacted to the impact of technology on war.
Description of Rhamma dawkinsi (Lepidoptera: Lycaenidae) a new mountain butterfly from Colombia
Authors: PRIETO CARLOS , LORENC-BRUDECKA JADWIGA
Published: October 2017

A preliminary assessment of barcode data for the genus Rhamma suggests the presence of several cryptic species in Colombia. Based on morphology and barcodes, we were able to diagnose one of these lineages as a new species that is described herein as Rhamma dawkinsi, sp. nov. Adult specimens and the genitalia of both sexes are illustrated and compared with R. adunca (Draudt, 1919) and R. comstocki (Johnson, 1992), the most closely related species based on phenotypic appearance.
Jelinekius prisniyi sp. nov., new species of genus Jelinekius Majer, 1990 (Coleoptera: Dasytidae: Rhadalinae) from Tajikistan
Authors: KOVALENKO YAKOV N.
Published: October 2017

The genus Jelinekius Majer, 1990, previously known only from Iran, is reported from Tajikistan for the first time. A new species, J. prisniyi sp. nov., is described as new to science.
Annotated catalogue of South American Dalodesmidae (Diplopoda, Polydesmida)
Authors: MESIBOV ROBERT
Published: October 2017

All published names for genera and species of South American Dalodesmidae are presented with annotated synonymies. Semnosoma chilense (Silvestri, 1903) comb. nov. is introduced for the "orphan" species Iulidesmus chilensis Silvestri, 1903.
Climate Similarity Search: GeoWeb Tool for Exploring Climate Variability
Authors: Netzel Pawel , Stepinski Tomasz
Published: October 2017

Climate and climate change are among the scientific topics most widely recognized by the public. Thus, climatologists seek out effective ways of communicating results of their research to various constituencies—a task made difficult by the complexity of the concept of climate. The current standard for communicated variability of climate on the global scale is a map based on the Köppen-Geiger classification (KGC) of climates, and maps of change in average annual temperatures and total annual precipitation for communicating climate change. The ClimateEx (Climate Explorer) project (http://sil.uc.edu/webapps/climateex/) communicates spatial variability and temporal change of global climate in a novel way by using the data science concept of similarity-based query. ClimateEx is implemented as a web-based visual spatial search tool. Users select a location (query), and ClimatEx returns a similarity map that visually communicates locations of places in the world having climates similar to the climate at a query location. ClimateEx can also inform about magnitude of temporal climate change by calculating a global map of local magnitudes of climate change. It offers personalized means of communicating climate heterogeneity and conveying magnitude of climate change in a single map. It has the advantage of relating climate to a user’s own experience, and is well-suited for communicating character of global climate to specialists and nonspecialists alike.
A New Radiative Transfer Method for Solar Radiation in a Vertically Internally Inhomogeneous Medium
Authors: Zhang Feng , Yan Jia-Ren , Li Jiangnan , Wu Kun , Iwabuchi Hironobu , Shi Yi-Ning
Published: October 2017

The problem of solar spectral radiation is considered in a layer-based model, with scattering and absorption parallel to the plane for each medium (cloud, ocean, or aerosol layer) and optical properties assumed to be vertically inhomogeneous. A new radiative transfer (RT) method is proposed to deal with the variation of vertically inhomogeneous optical properties in the layers of a model for solar spectral radiation. This method uses the standard perturbation method to include the vertically inhomogeneous RT effects of cloud and snow. The accuracy of the new inhomogeneous RT solution is investigated systematically for both an idealized medium and realistic media of cloud and snow. For the idealized medium, the relative errors in reflection and absorption calculated by applying the homogeneous solution increase with optical depth and can exceed 20%. However, the relative errors when applying the inhomogeneous RT solution are limited to 4% in most cases. Observations show that stratocumulus clouds are vertically inhomogeneous. In the spectral band of 0.25–0.69 μm, the relative error in absorption with the inhomogeneous solution is 1.4% at most, but that with the homogeneous solution can be up to 7.4%. The effective radius of snow varies vertically. In the spectral band of 0.25–0.69 μm, the relative error in absorption with the homogeneous solution can be as much as 72% but is reduced to less than 40% by using the inhomogeneous solution. At the spectral wavelength of 0.94 μm, the results for reflection and absorption with the inhomogeneous solution are also more accurate than those with the homogeneous solution.
Assessment of MERRA-2 Land Surface Energy Flux Estimates
Authors: Draper Clara S. , Reichle Rolf H. , Koster Randal D.
Published: October 2017

In the Modern-Era Retrospective Analysis for Research and Applications version 2 (MERRA-2) system the land is forced by replacing the model-generated precipitation with observed precipitation before it reaches the surface. This approach is motivated by the expectation that the resultant improvements in soil moisture will lead to improved land surface latent heating (LH). Here aspects of the MERRA-2 land surface energy budget and 2-m air temperatures [Formula: see text] are assessed. For global land annual averages, MERRA-2 appears to overestimate the LH (by 5 W m−2), the sensible heating (by 6 W m−2), and the downwelling shortwave radiation (by 14 W m−2) while underestimating the downwelling and upwelling (absolute) longwave radiation (by 10–15 W m−2each). These results differ only slightly from those for NASA’s previous reanalysis, MERRA. Comparison to various gridded reference datasets over boreal summer (June–August) suggests that MERRA-2 has particularly large positive biases (>20 W m−2) where LH is energy limited and that these biases are associated with evaporative fraction biases rather than radiation biases. For time series of monthly means during boreal summer, the globally averaged anomaly correlations [Formula: see text] with reference data were improved from MERRA to MERRA-2, for LH (from 0.39 to 0.48 vs Global Land Evaporation Amsterdam Model data) and the daily maximum T2m(from 0.69 to 0.75 vs Climatic Research Unit data). In regions where [Formula: see text] is particularly sensitive to the precipitation corrections (including the central United States, the Sahel, and parts of South Asia), the changes in the [Formula: see text] [Formula: see text] are relatively large, suggesting that the observed precipitation influenced the [Formula: see text] performance.
Northern Westerlies during the Last Glacial Maximum: Results from CMIP5 Simulations
Authors: Wang Na , Jiang Dabang , Lang Xianmei
Published: October 2017

Based upon simulations from phase 5 of the Coupled Model Intercomparison Project (CMIP5), the vertical and regional characteristics of the northern westerlies during the Last Glacial Maximum (LGM) are investigated in this study. At the Northern Hemispheric scale, all nine available models simulate a poleward shift of the 200-hPa jet, and eight models simulate an equatorward shift of the 850-hPa jet compared to the preindustrial period; these shifts are of approximately 2°–3° latitude for the arithmetic multimodel mean. The upper-tropospheric cooling in the tropics, possibly due to reduced latent heat release, is expected to account for the poleward shift of the 200-hPa jet through the thermal wind relationship. Changes in the midlatitude baroclinic instability in response to the amplified polar cooling are associated with the jet stream in the lower troposphere through anomalous eddy activity. In particular, the types of predominant baroclinic eddies are regionally dependent. The behavior of the 850-hPa jet over the North Pacific is steered by transient eddies and characterized by a southward displacement during the LGM. By contrast, the remarkable enhancement of the North Atlantic jet stream throughout the troposphere is associated with the notably increased stationary eddy momentum convergence, presumably due to the presence of the Laurentide ice sheet over North America. In comparison with the proxy records, although there is no observational evidence explicitly indicating changes of the upper-level northern westerlies, the simulated LGM 850-hPa westerly wind field is indirectly concordant with the reconstructed moisture conditions over the Mediterranean region and southwestern North America.
Comparative Evaluation of Three Schaake Shuffle Schemes in Postprocessing GEFS Precipitation Ensemble Forecasts
Authors: Wu Limin , Zhang Yu , Adams Thomas , Lee Haksu , Liu Yuqiong , Schaake John
Published: October 2017

Natural weather systems possess certain spatiotemporal variability and correlations. Preserving these spatiotemporal properties is a significant challenge in postprocessing ensemble weather forecasts. To address this challenge, several rank-based methods, the Schaake Shuffle and its variants, have been developed in recent years. This paper presents an extensive assessment of the Schaake Shuffle and its two variants. These schemes differ in how the reference multivariate rank structure is established. The first scheme (SS-CLM), an implementation of the original Schaake Shuffle method, relies on climatological observations to construct rank structures. The second scheme (SS-ANA) utilizes precipitation event analogs obtained from a historical archive of observations. The third scheme (SS-ENS) employs ensemble members from the Global Ensemble Forecast System (GEFS). Each of the three schemes is applied to postprocess precipitation ensemble forecasts from the GEFS for its first three forecast days over the mid-Atlantic region of the United States. In general, the effectiveness of these schemes depends on several factors, including the season (or precipitation pattern) and the level of gridcell aggregation. It is found that 1) the SS-CLM and SS-ANA behave similarly in spatial and temporal correlations; 2) by a measure for capturing spatial variability, the SS-ENS outperforms the SS-ANA, which in turn outperforms the SS-CLM; and 3), overall, the SS-ANA performs better than the SS-CLM. The study also reveals that it is important to choose a proper size for the postprocessed ensembles in order to capture extreme precipitation events.