bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic Features of Exceptional Response in Vemurafenib ± Cobimetinib–treated Patients with BRAFV600-mutated Metastatic Melanoma
Authors: Yan Yibing , Wongchenko Matthew J. , Robert Caroline , Larkin James , Ascierto Paolo A. , Dréno Brigitte , Maio Michele , Garbe Claus , Chapman Paul B. , Sosman Jeffrey A. , Shi Zhen , Koeppen Hartmut , Hsu Jessie J. , Chang Ilsung , Caro Ivor , Rooney Isabelle , McArthur Grant A. , Ribas Antoni
Published: March 2019

Purpose: Previous investigations identified transcriptional signatures associated with innate resistance to anti–programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for BRAFV600-mutated metastatic melanoma.

Patients and Methods: This exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with cobimetinib combined with vemurafenib or vemurafenib alone. Associations of gene expression with progression-free survival or overall survival were assessed by Cox proportional hazards modeling.

Results: Whole-exome sequencing showed that MITF and TP53 alterations were more frequent in tumors from patients with rapid progression, while NF1 alterations were more frequent in tumors from patients with complete response. However, the low frequency of alterations in any one gene precluded their characterization as drivers of response/resistance. Analysis of RNA profiles showed that expression of immune response–related genes was enriched in tumors from patients with complete response, while expression of keratinization-related genes was enriched in tumors from patients who experienced rapid progression.

Conclusions: These findings suggest that enriched immune infiltration might be a shared feature favoring response to both targeted and immune therapies, while features of innate resistance to targeted and immune therapies were distinct.
L-Type Cav 1.2 Calcium Channel-α-1C Regulates Response to Rituximab in Diffuse Large B-Cell Lymphoma
Authors: Zhang Jiu-Yang , Zhang Pei-Pei , Zhou Wen-Ping , Yu Jia-Yu , Yao Zhi-Hua , Chu Jun-Feng , Yao Shu-Na , Wang Cheng , Lone Waseem , Xia Qing-Xin , Ma Jie , Yang Shu-Jun , Liu Kang-Dong , Dong Zi-Gang , Guo Yong-Jun , Smith Lynette M. , McKeithan Timothy W. , Chan Wing C. , Iqbal Javeed , Liu Yan-Yan
Published: March 2019

Purpose:

One third of patients with diffuse large B-cell lymphoma (DLBCL) succumb to the disease partly due to rituximab resistance. Rituximab-induced calcium flux is an important inducer of apoptotic cell death, and we investigated the potential role of calcium channels in rituximab resistance.

Experimental Design:

The distinctive expression of calcium channel members was compared between patients sensitive and resistant to rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone (RCHOP) regimen. The observation was further validated through mechanistic in vitro and in vivo studies using cell lines and patient-derived xenograft mouse models.

Results:

A significant inverse correlation was observed between CACNA1C expression and RCHOP resistance in two independent DLBCL cohorts, and CACNA1C expression was an independent prognostic factor for RCHOP resistance after adjusting for International Prognostic Index, cell-of-origin classification, and MYC/BCL2 double expression. Loss of CACNA1C expression reduced rituximab-induced apoptosis and tumor shrinkage. We further demonstrated direct interaction of CACNA1C with CD20 and its role in CD20 stabilization. Functional modulators of L-type calcium channel showed expected alteration in rituximab-induced apoptosis and tumor suppression. Furthermore, we demonstrated that CACNA1C expression was directly regulated by miR-363 whose high expression is associated with worse prognosis in DLBCL.

Conclusions:

We identified the role of CACNA1C in rituximab resistance, and modulating its expression or activity may alter rituximab sensitivity in DLBCL.
EPHA2 Is a Predictive Biomarker of Resistance and a Potential Therapeutic Target for Improving Antiepidermal Growth Factor Receptor Therapy in Colorectal Cancer
Authors: Martini Giulia , Cardone Claudia , Vitiello Pietro Paolo , Belli Valentina , Napolitano Stefania , Troiani Teresa , Ciardiello Davide , Della Corte Carminia Maria , Morgillo Floriana , Matrone Nunzia , Sforza Vincenzo , Papaccio Gianpaolo , Desiderio Vincenzo , Paul Mariel C. , Moreno-Viedma Veronica , Normanno Nicola , Rachiglio Anna Maria , Tirino Virginia , Maiello Evaristo , Latiano Tiziana Pia , Rizzi Daniele , Signoriello Giuseppe , Sibilia Maria , Ciardiello Fortunato , Martinelli Erika
Published: March 2019

The EPHA2 tyrosine kinase receptor is implicated in tumor progression and targeted therapies resistance. We evaluated EPHA2 as a potential resistance marker to the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in colorectal cancer. We studied activation of EPHA2 in a panel of human colorectal cancer cell lines sensitive or resistant to anti-EGFR drugs. The in vitro and in vivo effects of ALW-II-41-27 (an EPHA2 inhibitor) and/or cetuximab treatment were tested. Formalin-fixed paraffin-embedded tumor specimens from 82 RAS wild-type (WT) metastatic colorectal cancer patients treated with FOLFIRI + cetuximab as first-line therapy in the CAPRI-GOIM trial were assessed for EPHA2 expression by immunohistochemistry and correlated with treatment efficacy. EPHA2 was differentially activated in colorectal cancer cell lines. Combined treatment with ALW-II-41-27 plus cetuximab reverted primary and acquired resistance to cetuximab, causing cell growth inhibition, inducing apoptosis and cell-cycle G1–G2 arrest. In tumor xenograft models, upon progression to cetuximab, ALW-II-41-27 addition significantly inhibited tumor growth. EPHA2 protein expression was detected in 55 of 82 tumor samples, frequently expressed in less-differentiated and left-sided tumors. High levels of EPHA2 significantly correlated with worse progression-free survival [8.6 months; confidence interval (CI) 95%, 6.4–10.8; vs. 12.3 months; CI 95%, 10.4–14.2; P = 0.03] and with increased progression rate (29% vs. 9%, P = 0.02). A specific EPHA2 inhibitor reverts in vitro and in vivo primary and acquired resistance to anti-EGFR therapy. EPHA2 levels are significantly associated with worse outcome in patients treated with FOLFIRI + cetuximab. These results highlight EPHA2 as a potential therapeutic target in metastatic colorectal cancer.
Nanobody Targeting of Epidermal Growth Factor Receptor (EGFR) Ectodomain Variants Overcomes Resistance to Therapeutic EGFR Antibodies
Authors: Tintelnot Joseph , Baum Natalie , Schultheiß Christoph , Braig Friederike , Trentmann Marie , Finter Johannes , Fumey William , Bannas Peter , Fehse Boris , Riecken Kristoffer , Schuetze Kerstin , Bokemeyer Carsten , Rösner Thies , Valerius Thomas , Peipp Matthias , Koch-Nolte Friedrich , Binder Mascha
Published: March 2019

Epidermal growth factor receptor (EGFR) ectodomain variants mediating primary resistance or secondary treatment failure in cancer patients treated with cetuximab or panitumumab support the need for more resistance-preventive or personalized ways of targeting this essential pathway. Here, we tested the hypothesis that the EGFR nanobody 7D12 fused to an IgG1 Fc portion (7D12-hcAb) would overcome EGFR ectodomain–mediated resistance because it targets a very small binding epitope within domain III of EGFR. Indeed, we found that 7D12-hcAb bound and inhibited all tested cell lines expressing common resistance-mediating EGFR ectodomain variants. Moreover, we assessed receptor functionality and binding properties in synthetic mutants of the 7D12-hcAb epitope to model resistance to 7D12-hcAb. Because the 7D12-hcAb epitope almost completely overlaps with the EGF-binding site, only position R377 could be mutated without simultaneous loss of receptor functionality, suggesting a low risk of developing secondary resistance toward 7D12-hcAb. Our binding data indicated that if 7D12-hcAb resistance mutations occurred in position R377, which is located within the cetuximab and panitumumab epitope, cells expressing these receptor variants would retain sensitivity to these antibodies. However, 7D12-hcAb was equally ineffective as cetuximab in killing cells expressing the cetuximab/panitumumab-resistant aberrantly N-glycosylated EGFR R521K variant. Yet, this resistance could be overcome by introducing mutations into the Fc portion of 7D12-hcAb, which enhanced immune effector functions and thereby allowed killing of cells expressing this variant. Taken together, our data demonstrate a broad range of activity of 7D12-hcAb across cells expressing different EGFR variants involved in primary and secondary EGFR antibody resistance.
Cholesterol Sulfotransferase SULT2B1b Modulates Sensitivity to Death Receptor Ligand TNFα in Castration-Resistant Prostate Cancer
Authors: Vickman Renee E. , Yang Jiang , Lanman Nadia A. , Cresswell Gregory M. , Zheng Faye , Zhang Chi , Doerge R. W. , Crist Scott A. , Mesecar Andrew D. , Hu Chang-Deng , Ratliff Timothy L.
Published: March 2019

Cholesterol sulfotransferase, SULT2B1b, has been demonstrated to modulate both androgen receptor activity and cell growth properties. However, the mechanism(s) by which SULT2B1b alters these properties within prostate cancer cells has not been described. Furthermore, specific advantages of SULT2B1b expression in prostate cancer cells are not understood. In these studies, single-cell mRNA sequencing was conducted to compare the transcriptomes of SULT2B1b knockdown (KD) versus Control KD LNCaP cells. Over 2,000 differentially expressed genes were identified along with alterations in numerous canonical pathways, including the death receptor signaling pathway. The studies herein demonstrate that SULT2B1b KD increases TNFα expression in prostate cancer cells and results in NF-κB activation in a TNF-dependent manner. More importantly, SULT2B1b KD significantly enhances TNF-mediated apoptosis in both TNF-sensitive LNCaP cells and TNF-resistant C4-2 cells. Overexpression of SULT2B1b in LNCaP cells also decreases sensitivity to TNF-mediated cell death, suggesting that SULT2B1b modulates pathways dictating the TNF sensitivity capacity of prostate cancer cells. Probing human prostate cancer patient datasets further supports this work by providing evidence that SULT2B1b expression is inversely correlated with TNF-related genes, including TNF, CD40LG, FADD, and NFKB1. Together, these data provide evidence that SULT2B1b expression in prostate cancer cells enhances resistance to TNF and may provide a growth advantage. In addition, targeting SULT2B1b may induce an enhanced therapeutic response to TNF treatment in advanced prostate cancer.

Implications:

These data suggest that SULT2B1b expression enhances resistance to TNF and may promote prostate cancer.
Acceptability of Localized Cancer Risk Reduction Interventions Among Individuals at Average or High Risk for Cancer
Authors: Samimi Goli , Heckman-Stoddard Brandy M. , Kay Shelley S. , Bloodgood Bonny , Coa Kisha I. , Robinson Jennifer L. , Tennant Bethany , Ford Leslie G. , Szabo Eva , Minasian Lori
Published: March 2019

Individuals at high risk for cancer, including those already diagnosed with premalignant lesions, can potentially benefit from chemopreventive interventions to reduce cancer risk. However, uptake and acceptability have been hindered due to the risk of systemic toxicity and other adverse effects. Locally delivered chemopreventive agents, where direct action on the primary organ may limit systemic toxicity, are emerging as an option for high-risk individuals. While a number of clinical trials support the development of chemopreventive agents, it is crucial to understand the factors and barriers that influence their acceptability and use. We conducted 36 focus groups with 198 individuals at average and high risk of breast/ovarian, gynecologic, and head/neck/oral and lung cancers to examine the perceptions and acceptability of chemopreventive agents. Participants' willingness to use chemopreventive agents was influenced by several factors, including perceived risk of cancer, skepticism around prevention, previous knowledge of chemopreventive agents, support from trusted sources of health information, participation in other cancer-related risk-reduction activities, previous experience with similar modalities, cost, regimen, side effects, and perceived effectiveness of the preventive intervention. Our findings indicate that individuals may be more receptive to locally delivered chemopreventive agents if they perceive themselves to be at high risk for cancer and are given the necessary information regarding regimen and side effects to make an informed decision. Clinical trials that collect additional patient-centered data including side effects and how these interventions fit into an individual's lifestyle are imperative to improve uptake of chemopreventive agents.
Gly101Val BCL2 Mutation: One Step Closer to Understanding Venetoclax Resistance in CLL
Authors: Thangavadivel Shanmugapriya , Byrd John C.
Published: March 2019

In this issue, Blombery and colleagues show that the chronic lymphocytic leukemia (CLL) cells bearing Gly101Val mutation confer resistance to venetoclax by reducing the affinity of BCL2 for venetoclax by 180-fold in cell lines and in patient cells. Detection of this mutation provides a potential biomarker for impending disease progression and an opportunity for targeted and combinational therapy to treat CLL.

See related article by Blombery et al., p. 342.
Iridescent Life Course: LGBTQ Aging Research and Blueprint for the Future – A Systematic Review
Authors: Fredriksen Goldsen Karen I. , Jen Sarah , Muraco Anna
Published: March 2019

Background: LGBTQ* (lesbian, gay, bisexual, trans, and queer) older adults are demographically diverse and growing populations. In an earlier 25-year review of the literature on sexual orientation and aging, we identified four waves of research that addressed dispelling negative stereotypes, psychosocial adjustment to aging, identity development, and social and community-based support in the lives of LGBTQ older adults. Objectives: The current review was designed to develop an evidence base for the field of LGBTQ aging as well as to assess the strengths and limitations of the existing research and to articulate a blueprint for future research. Methods: Using a life course framework, we applied a systematic narrative analysis of research on LGBTQ aging. The review included 66 empirical peer-reviewed journal articles (2009–2016) focusing on LGBTQ adults aged 50 years and older, as well as age-based comparisons (50 years and older with those younger). Results: A recent wave of research on the health and well-being of LGBTQ older adults was identified. Since the prior review, the field has grown rapidly. Several findings were salient, including the increas­ed application of theory (with critical theories most often used) and more varied research designs and methods. While ­existing life course theory provided a structure for the investigation of the social dimensions of LGBTQ aging, it was limited in its attention to intersectionality and the psychological, behavioral, and biological work emerging in the field. There were few studies addressing the oldest in these ­communities, bisexuals, gender non-binary older adults, intersex, ­older adults of color, and those living in poverty. ­Conclusions: The Iridescent Life Course framework highlights the interplay of light and environment, creating dynamic and fluid colors as perceived from different angles and perspectives over time. Such an approach incorporates both queering and trans-forming the life course, capturing intersectionality, fluidity over time, and the psychological, behavioral, and biological as well as social dimensions of LGBTQ aging. Work is needed that investigates trauma, differing configurations of risks and resources over the life course, inequities and opportunities in representation and capital as LGBTQ adults age, and greater attention to subgroups that remain largely invisible in existing research. More depth than breadth is imperative for the field, and multilevel, longitudinal, and global initiatives are needed.
Germ Cell Tumors with Malignant Somatic Transformation: A Mayo Clinic Experience
Authors: Scheckel Caleb J. , Kosiorek Heidi E. , Butterfield Richard , Ho Thai H. , Hilal Talal
Published: March 2019

Background: Germ cell tumors (GCTs) with malignant somatic transformation (MST) represent an uncommon variant of what is typically a curable malignancy. There is a paucity of data on time of somatic transformation, response to conventional therapy, and survival outcomes of different somatic subtypes. Methods: After obtaining institutional review board (IRB) approval, we searched our institutional database from 1982 to 2017 and identified patients with GCTs with MST. Patient characteristics, pathologic description, treatment, and clinical outcomes were extracted from the medical records. Results: We identified 24 cases of GCTs with MST; the MST was adenocarcinoma in 50% and sarcoma in 50%. Median age at diagnosis was 27. Alpha-fetoprotein and beta-human chorionic gonadotropin were undetectable in 44%, both were elevated in 54%. The majority were advanced stage (71% stage III), and International Germ Cell Cancer Collaborative Group (IGCCCG) risk was classified as ‘good' in 60%. Median follow-up was 41 months (range 10-346 months). Median progression-free survival was 84 months (95% confidence interval (CI) 56-232), and median overall survival was 219 months (95% CI 165-not reported). Conclusion: Patients with GCTs with an MST appear to have poor responses to cisplatin-based chemotherapy, suggesting that somatic component-driven therapies should be considered. Furthermore, resection of residual disease when feasible is an essential component of management.
Diagnostik und Therapie von Spontanpneumothorax und postinterventionellem Pneumothorax - die deutsche S3-Leitlinie
Authors: Hekmat Khosro
Published: February 2019

In Germany, 10,000 cases of spontaneous pneumothorax are treated inpatient every year. The German Society for Thoracic Surgery, in co-operation with the German Society for Pulmonology, the German Radiological Society, and the German Society of Internal Medicine has developed an S3 guideline on spontaneous pneumothorax and post-interventional pneumothorax moderated by the German Association of Scientific Medical Societies. Method: Based on the source guideline of the British Thoracic Society (2010) for spontaneous pneumothorax, a literature search on spontaneous pneumothorax was carried out from 2008 onwards, for post-interventional pneumothorax from 1960 onwards. Evidence levels according to the Oxford Center for Evidence-Based Medicine (2011) were assigned to the relevant studies found. Recommendations according to grade (A: «we recommend»/«we do not recommend,» B: «we suggest»/«we do not suggest») were determined in 3 consensus conferences by the nominal group process. Results: The algorithms for primary and secondary pneumothorax differ in the indication for CT scan as well as in the indication for chest drainage application and video-assisted thoracic surgery. Indication for surgery is recommended individually taking into account the risk of recurrence, life circumstances, patient preferences, and procedure risks. For some forms of secondary pneumothorax, a reserved indication for surgery is recommended. Therapy of post-interventional spontaneous pneumothorax is similar to that of primary spontaneous pneumothorax. Discussion: The recommendations of the S3 Guideline provide assistance in managing spontaneous pneumothorax and post-interventional pneumothorax. Whether this will affect existing deviant diagnostic and therapeutic measures will be demonstrated by future epidemiological studies.
Besteht ein Zusammenhang zwischen Lungenkrebs und obstruktiver Schlafapnoe?
Authors: Galetke Wolfgang
Published: February 2019

Background: Obstructive sleep apnea (OSA) has been linked to tumorigenesis and tumor progression. Objectives: The Sleep Apnea in Lung Cancer (SAIL) study (NCT02764866) was designed to determine the prevalence of OSA in patients with lung cancer. Methods: Cross-sectional study including consecutive patients with newly diagnosed lung cancer. All patients were offered home sleep apnea testing (HSAT) and administered a sleep-specific questionnaire prior to initiating oncologic treatment. Sleep study-related variables, symptoms, and epidemiologic data as well as cancer related variables were recorded. Results: Eighty-three patients were enrolled in the SAIL study. Sixty-six completed HSAT. The mean age was 68 ± 11 years and 58% were male with a mean body mass index of 28.1 ± 5.4. Forty-seven percent were current smokers, 42% former smokers, and 11% never smokers with a median tobacco consumption of 51 pack-years. Fifty percent had COPD with a mean FEV1 of 83 ± 22.6% of predicted and a mean DLCO of 85.5 ± 20.1%. Adenocarcinoma was the most common histologic type (46.7%), followed by squamous cell (16.7%) and small cell (16.7%). Most patients were diagnosed at an advanced stage (65% in stages III-IV). The vast majority (80%) had OSA (apnea-hypopnea index [AHI] > 5), and 50% had moderate to severe OSA (AHI > 15) with a mean Epworth Sleepiness Score of 7.43 ± 3.85. Significant nocturnal hypoxemia was common (Median T90: 10.9% interquartile range 2.4-42.2). Conclusions: Sleep apnea and nocturnal hypoxemia are highly prevalent in patients with lung cancer.
Benign Metastasizing Leiomyoma to the Lung and Spine: A Case Report and Literature Review
Authors: Barber Emily , Eapen Ann , Mehta Rita , Lin Erin , Lane Karen , Cheng Yu , Parajuli Ritesh
Published: March 2019

Benign metastasizing leiomyomas (BML) represent a rare phenomenon consisting of the extra-uterine spread of smooth muscle cells with similar histological, immunological, and molecular patterns to those of benign uterine leiomyomas. They are considered benign based off their low mitotic activity, lack of anaplasia or necrosis, and limited vascularization. This condition represents an interesting diagnostic and treatment challenge based on their rarity and indolent nature. Our case represents a unique finding of BML in the thoracic spine in a postmenopausal woman many years after hysterectomy and partial oophorectomy. There are currently no standard guidelines for treatment of BML, given the rare nature of this condition, with most patients treated with a combination of surgical resection and radiotherapy, followed by hormonal treatment and radiological surveillance serving as the primary backbone of current management plans. Given that these patients present a unique clinical challenge in terms of diagnosis and management, it is important to delineate and further examine these rare entities.
Simplified Criteria Using Pleural Fluid Cholesterol and Lactate Dehydrogenase to Distinguish between Exudative and Transudative Pleural Effusions
Authors: Lépine Pierre-Alexis , Thomas Rajesh , Nguyen Sébastien , Lacasse Yves , Cheah Hui Min , Creaney Jenette , Muruganandan Sanjeevan , Martel Simon , Lee Y.C. Gary , Delage Antoine
Published: March 2019

Background: An important part of the investigation of pleural effusion is the identification of markers that help separate exudate from transudate. Objectives: The purposes of this study were to compare the accuracy of published and new sets of criteria to distinguish between exudative and transudative pleural effusions, and to determine whether serum biochemical analysis is necessary. Methods: An externally validated cohort study was performed. Pleural effusions were determined to be transudative or exudative on the basis of an assessment of the medical record by two clinicians blinded to biochemical results. Sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and area under the receiver operating characteristic curve were determined for each proposed combination of criteria. Results: Pleural fluid analysis was available for 311 thoracenteses in the main cohort and for 112 thoracenteses in the validation cohort. The best sensitivity (97% [95% CI 94–99]) and negative likelihood ratio (0.04 [95% CI 0.02–0.08]) for identifying exudative effusions were observed with criteria combining pleural fluid lactate dehydrogenase greater than 0.6 the upper limit of normal serum lactate dehydrogenase and pleural fluid cholesterol greater than 1.04 mmol/L (40 mg/dL). The overall diagnostic accuracy was similar to Light’s criteria. Findings were similar in the validation cohort. Conclusions: Our proposed criteria using simultaneously pleural fluid lactate dehydrogenase and pleural fluid cholesterol can identify an exudate with a sensitivity and an overall diagnostic accuracy similar to Light’s criteria. It avoids simultaneous blood sampling, thus reducing patient discomfort and potential costs.
Sensory Specializations of Mormyrid Fish Are Associated with Species Differences in Electric Signal Localization Behavior
Authors: Vélez Alejandro , Ryoo Da Yeon , Carlson Bruce A.
Published: March 2019

The ability to localize communication signals plays a fundamental role in social interactions. For signal localization to take place, the sensory system of the receiver must extract information about distance and direction to the sender from physical characteristics of the signal. In many sensory systems, information from multiple peripheral receptors must be integrated by central sensory pathways to determine the sender location. Here, we asked whether evolutionary divergence in the electrosensory and visual systems of mormyrid fish is associated with signal localization behavior. In mormyrids, differences in the distribution of electroreceptors on the surface of the skin are associated with differences in the midbrain exterolateral nucleus (EL). Species with electroreceptors clustered in three rosettes on both sides of the head have a small and undifferentiated EL. In contrast, EL is enlarged and subdivided into anterior (ELa) and posterior (ELp) regions in species that have electroreceptors broadly ­distributed throughout the body. Interestingly, species with EL and clustered electroreceptors also have larger visual systems and higher visual acuity than species with ELa/ELp and broadly distributed electroreceptors. Species with broadly distributed electroreceptors and ELa/ELp approached a simulated conspecific by following the curved electric field lines generated by the electrosensory stimulus. In contrast, a species with small EL and clustered electroreceptors, but an enlarged visual system, followed shorter and straighter paths to the stimulus source. In the central electrosensory system, evoked field potentials in response to stimuli delivered from the left versus the right differed more in EL than in ELa/ELp. Our results suggest that signal localization behavior is associated with differences in sensory specializations. We propose that the distribution of electroreceptors on the body affects the ability of individuals to align parallel to electric field lines and maintain such alignment while approaching the signal source. The spatial resolution of sensory information relayed from the periphery to the midbrain in species with clustered electroreceptors may allow for gross, but not fine, processing of sender location. Furthermore, visual information may play an important role in localizing signaling individuals in species with small EL and clustered electroreceptors. In line with previous studies, we suggest that the physiological and behavioral differences associated with signal localization reflect adaptations to different habitats and social environments.
Platelet Function Testing in Neurovascular Procedures: Tool or Gimmick?
Authors: Cheung Nicholas K. , Carr Michael W. , Ray Udayan , McKenzie Duncan , Froelich Jens J.
Published: March 2019

Background: Platelet inhibitors are used to prevent thromboembolic complications related to neurovascular stenting (NVS) procedures. Despite substantial inter-individual variability of functional platelet inhibition, the value of platelet function tests (PFT) to assess inhibition remains controversial. Objective: This study was conducted to compare differences in thromboembolic complication rates associated with NVS in platelet-inhibited patients with and without PFT. Clinical neurological outcomes were assessed by differences in the modified Rankin Scale (mRS). Materials and Methods: One hundred seventeen consecutive patients underwent elective NVS procedures within a 7-year period. All patients received aspirin and clopidogrel 8 days before the procedure. Fifty-two patients were treated without assessment of platelet inhibition, and 65 patients were tested for clopidogrel resistance. When clopidogrel resistance was revealed, corresponding patients were converted to ticagrelor. Changes in mRS and thromboembolic event rates were compared between the 2 cohorts. Results: Thirty-five percent of patients from the cohort subjected to PFT tests showed inadequate platelet inhi­bition under clopidogrel and were converted to ticagrelor. Compared to the non-PFT test ­cohort, neurological deficits were significantly reduced (12 vs. 0%; p = 0.009) and a lower number of thromboembolic events was found (12 vs. 3%; p > 0.05) within the test cohort. Conclusion: PFT appears to identify patients with clopidogrel resistance prior to NVS procedures. When non-responders are converted to alternative platelet inhibitors, neurological outcomes and thromboembolic complication rates may improve. Consequently, this study provides preliminary evidence that PFT may be a useful clinical tool to enhance procedural safety and improve clinical outcomes in NVS procedures.
Ferroptosis and Brain Injury
Authors: Magtanong Leslie , Dixon Scott J.
Published: March 2019

Ferroptosis is a nonapoptotic form of cell death characterized by the iron-dependent accumulation of toxic lipid reactive oxygen species. Small-molecule screening and subsequent optimization have yielded potent and specific activators and inhibitors of this process. These compounds have been employed to dissect the lethal mechanism and implicate this process in pathological cell death events observed in many tissues, including the brain. Indeed, ferroptosis is emerging as an important mechanism of cell death during stroke, intracerebral hemorrhage, and other acute brain injuries, and may also play a role in certain degenerative brain disorders. Outstanding issues include the practical need to identify molecular markers of ferroptosis that can be used to detect and study this process in vivo, and the more basic problem of understanding the relationship between ferroptosis and other forms of cell death that can be triggered in the brain during injury.
Hemobilia Derived from Cystic Artery Pseudoaneurysm
Authors: Tanaka Takayuki , Takakura Kazuki , Maruyama Yuki , Hidaka Akihisa , Nakano Masanori , Torisu Yuichi , Saruta Masayuki
Published: February 2019

Cystic artery pseudoaneurysm (CAP) is a rare disease, with small number of previous reports related to CAP. Besides, it is frequently prone to critical condition due to arterial bleeding. Here, we presented a case of ruptured CAP with acute calculus cholecystitis and its subsequent successful management with temporary endoscopic biliary drainage for obstructive jaundice and embolization for the culprit artery without cholecystectomy. Since CAP is at high risk of bleeding, intravascular treatment, which is only one currently available therapeutic option, is urgently required in the clinical sites.
Aortic-Brachial Stiffness Mismatch and Mortality in Peritoneal Dialysis Patients
Authors: Bao WenHan , Wang FangYu , Tang Wen
Published: February 2019

Background/Aims: Possible predictive value of aortic-brachial arterial stiffness mismatch assessed by pulse wave velocity PWV ratio in peritoneal dialysis patients’ outcomes need to be further elucidated. The aim of this study is to investigate the predictor value of PWV ratio on peritoneal dialysis (PD) patients’ outcomes in China. Methods: In this longitudinal cohort study, patients who started PD during September 20, 2005, to February 05, 2008, were included. All the patients were followed until January 31, 2018. Aortic-brachial arterial stiffness mismatch was assessed using carotid-femoral pulse wave velocity divided by carotid-radial pulse wave velocity (PWV ratio). Results: A total of 181 incident PD patients were included. The median survival of patients in PWV ratio above median group (4.03 years, 95% CI 4.64-7.99 years) was shorter than that of PWV ratio below median group (10.43 years, 95% CI 9.74-11.12 years, p< 0.001). The cardiovascular mortality rate in PWV ratio above median group were significantly higher than that of PWV below median group (log rank test, p< 0.001). Univariate Cox regression analysis showed that both PWV ratio (HR 2.42, 95% CI 1.80-3.25, p< 0.001) and CF-PWV (HR 1.27, 95% CI 1.16-1.38, p< 0.001) were associated with high patients’ all-cause mortality. Multivariable Cox regression analysis showed that the PWV ratio was a strong and significantly predictor of cardiovascular mortality (HR 2.08 95% CI 1.16-3.71, p=0.014) after adjusting for coronary heart disease history (HR 2.39, 95% CI 1.20-4.76, p=0.013), diabetes mellitus history (HR 2.84, 95% CI 1.51-5.33, p=0.001). However, the CF-PWV was failed to be included as a significant predictor for both all-cause and CVD mortality in the multivariable Cox regression model. Conclusion: Aortic-brachial arterial stiffness mismatch as assessed by PWV ratio, a new arteries stiffness risk parameter, is a significant prognostic indicator of CVD mortality in PD patients. We demonstrated that the discriminative power of the PWV ratio for both all-cause and CVD mortality was better than that CF-PWV.
High‐Sensitivity Cardiac Troponin I Improves Cardiovascular Risk Prediction in Older Men: HIMS (The Health in Men Study)
Authors: Lan Nick S. R. , Bell Damon A. , McCaul Kieran A. , Vasikaran Samuel D. , Yeap Bu B. , Norman Paul E. , Almeida Osvaldo P. , Golledge Jonathan , Hankey Graeme J. , Flicker Leon
Published: March 2019

Background

The Framingham Risk Score estimates the 10‐year risk of cardiovascular events. However, it performs poorly in older adults. We evaluated the incremental benefit of adding high‐sensitivity cardiac troponin I (hs‐cTnI) to the Framingham Risk Score.

Methods and Results

The HIMS (Health in Men Study) is a cohort study of community‐dwelling men aged 70 to 89 years in Western Australia. Participants were identified from the electoral roll, with a subset undergoing plasma analysis. Hs‐
cTnI
(Abbott Architect i2000
SR
) was measured in 1151 men without prior cardiovascular disease. The Western Australia Data Linkage System was used to identify incident cardiovascular events. After 10 years of follow‐up, 252 men (22%) had a cardiovascular event (
CVE
+) and 899 did not (CVE–). The Framingham Risk Score placed 148 (59%)
CVE
+ and 415 (46%)
CVE–
in the high‐risk category. In
CVE
– men, adding hs‐
cTnI
affected the risk categories of 244 (27.2%) men, with 64.8% appropriately reclassified to a lower and 35.2% to a higher category, which decreased the number of high‐risk men in the
CVE–
to 39%. In
CVE
+ men, adding hs‐
cTnI
affected the risk categories of 61 (24.2%), with 50.8% appropriately reclassified to a higher and 49.2% to a lower category and 82.5% remaining above the 15% risk treatment threshold. The net reclassification index was 0.305 (
P
<0.001). Adding hs‐
cTnI
increased the C‐statistic modestly from 0.588 (95%
CI
, 0.552–0.624) to 0.624 (95%
CI
, 0.589–0.659) and improved model fit (likelihood ratio test,
P
<0.001).

Conclusions

Adding hs‐
cTnI
to the Framingham Risk Score provided incremental prognostic benefit in older men, especially aiding reclassification of individuals into a lower risk category.
The Labor Productivity Gap between the Agricultural and Nonagricultural Sectors, and Poverty and Inequality Reduction in Asia
Authors: Imai Katsushi , Gaiha Raghav , Bresciani Fabrizio
Published: March 2019

The objective of this paper is to examine how agricultural and nonagricultural labor productivities have grown over time and whether the growth pattern affected poverty in low- and middle-income economies in Asia. We first examine whether labor productivities in the agricultural and nonagricultural sectors have converged, finding evidence that they did not as the latter have grown faster. We then confirm that both agricultural and nonagricultural labor productivities have converged across economies and that the convergence effect is stronger for the nonagricultural sector. We have also observed that, despite the relatively slower growth in agricultural labor productivity, the agricultural sector played an important role in promoting nonagricultural labor productivity and thus in nonagricultural growth. Finally, we have found some evidence that the labor productivity gap reduces rural and urban poverty, as well as national-level inequality.
The Long-Run Determinants of Indian Government Bond Yields
Authors: Akram Tanweer , Das Anupam
Published: March 2019

This paper investigates the long-term determinants of the nominal yields of Indian government bonds (IGBs). It examines whether John Maynard Keynes’ supposition that the short-term interest rate is the key driver of the long-term government bond yield holds over the long run, after controlling for key economic factors. It also appraises if the government fiscal variable has an adverse effect on government bond yields over the long run. The models estimated in this paper show that in India the short-term interest rate is the key driver of the long-term government bond yield over the long run. However, the government debt ratio does not have any discernible adverse effect on IGB yields over the long run. These findings will help policy makers to (i) use information on the current trend of the short-term interest rate and other key macro variables to form their long-term outlook about IGB yields, and (ii) understand the policy implications of the government's fiscal stance.
Visualizing the Middle Passage: The Brooks and the Reality of Ship Crowding in the Transatlantic Slave Trade
Authors: Radburn Nicholas , Eltis David
Published: March 2019

Crowding on slave ships was much more severe than historians have recognized, worsening in the nineteenth century during the illegal phase of the traffic. An analysis of numerous illustrations of slave vessels created by then-contemporary artists, in conjunction with new data, demonstrates that the 1789 diagram of the British slave ship Brooks—the most iconic of these illustrations—fails to capture the degree to which enslaved people were crowded on the Brooks, as well as on most other British slaving vessels of the eighteenth century. Five other images of slave ships sailing under different national colors in different eras further reveal the realities of ship crowding in different periods. The most accurate representation of ship-board conditions in the eighteenth-century slave trade is in the paintings of the French slave ship Marie-Séraphique.
Mind the GAP: A Balanced Corpus of Gendered Ambiguous Pronouns
Authors: Webster Kellie , Recasens Marta , Axelrod Vera , Baldridge Jason
Published: March 2019

Coreference resolution is an important task for natural language understanding, and the resolution of ambiguous pronouns a longstanding challenge. Nonetheless, existing corpora do not capture ambiguous pronouns in sufficient volume or diversity to accurately indicate the practical utility of models. Furthermore, we find gender bias in existing corpora and systems favoring masculine entities. To address this, we present and release GAP, a gender-balanced labeled corpus of 8,908 ambiguous pronoun–name pairs sampled to provide diverse coverage of challenges posed by real-world text. We explore a range of baselines that demonstrate the complexity of the challenge, the best achieving just 66.9% F1. We show that syntactic structure and continuous neural models provide promising, complementary cues for approaching the challenge.
Integrating Weakly Supervised Word Sense Disambiguation into Neural Machine Translation
Authors: Pu Xiao , Pappas Nikolaos , Henderson James , Popescu-Belis Andrei
Published: March 2019

This paper demonstrates that word sense disambiguation (WSD) can improve neural machine translation (NMT) by widening the source context considered when modeling the senses of potentially ambiguous words. We first introduce three adaptive clustering algorithms for WSD, based on k-means, Chinese restaurant processes, and random walks, which are then applied to large word contexts represented in a low-rank space and evaluated on SemEval shared-task data. We then learn word vectors jointly with sense vectors defined by our best WSD method, within a state-of-the-art NMT system. We show that the concatenation of these vectors, and the use of a sense selection mechanism based on the weighted average of sense vectors, outperforms several baselines including sense-aware ones. This is demonstrated by translation on five language pairs. The improvements are more than 1 BLEU point over strong NMT baselines, +4% accuracy over all ambiguous nouns and verbs, or +20% when scored manually over several challenging words.
DNA barcoding and integrative taxonomy of Macrobiotus hufelandi C.A.S. Schultze 1834, the first tardigrade species to be described, and some related species
Authors: BERTOLANI ROBERTO , REBECCHI LORENA , GIOVANNINI ILARIA , CESARI MICHELE
Published: February 2019

Within the framework of a DNA barcoding project on tardigrade species, a study was carried out on Macrobiotus hufelandi C.A.S. Schultze 1834, the first formally described tardigrade species. We used samples collected from the type locality and additional material from other European sites containing species of the “M. hufelandi group”. The study was performed by integrating morphological, karyological and molecular (mt-DNA cox1) information and comparing these data with morphological data from the type material. Several species from this group were found in the type locality of M. hufelandi (near Freiburg, Black Forest, Germany) and these were all barcoded. One was M. hufelandi, the other two were: Macrobiotus sandrae Bertolani & Rebecchi 1993 (originally described from the same locality), and Macrobiotus vladimiri Bertolani, Biserov, Rebecchi & Cesari in press (type locality Andalo, Italy), all with interspecific genetic distances of more than 19%. A fourth cryptic species, which had the same morphology as M. hufelandi but a genetic distance of 6.7%, was not described as a new taxon but named M. cf. hufelandi sp.1 for this study. Macrobiotus sandrae and M. vladimiri were also present (and barcoded) in Italy (Alps). Additional individuals (animals and eggs) were also found, and barcoded, in Italy (Apennines) and Switzerland that belonged to the haplogroup Macrobiotus cf. hufelandi sp. 1. These data together with other recent studies on tardigrade DNA barcoding represent a starting point for further studies on tardigrade biogeography, phylogeography and diversity.
Description of Barbus teugelsi sp. nov. (Cypriniformes: Cyprinidae) from the Little Scarcies basin in Guinea, Africa
Authors: BAMBA MAMADOU , VREVEN EMMANUEL J. , SNOEKS JOS
Published: February 2019

Barbus teugelsi, a new African cyprinid, is described from the Mongo River at Marela (Guinea). It is morphologically similar to the syntopically occurring ‘B.’ bigornei Lévêque et al. 1988, with which it has been confounded in the past. However, the scale meristics of the new species differ from those of ‘B.’ bigornei, but are similar in all but one to those of ‘B.’ ablabes (Bleeker 1863) and ‘B.’ parablabes Daget 1957. Barbus teugelsi sp. nov. is clearly distinguished from both these species by the following unique combination of characters: a lower total number of gill rakers on the first gill arch (3–6); the presence of long barbels, with the anterior barbels reaching the vertical passing through the middle of the eye and the posterior barbels extending beyond the vertical passing through the posterior edge of the eye and reaching the pre-operculum. In addition, the cephalic sensory canals are highly reduced or even absent. Furthermore, small differences between the new species and the other three species were found for several measurements. A short discussion on the taxonomic value of some diagnostic characters in small barbs is included.
Observed Variations of the Atmospheric Boundary Layer and Stratocumulus over a Warm Eddy in the Kuroshio Extension
Authors: Wang Qian , Zhang Su-Ping , Xie Shang-Ping , Norris Joel R. , Sun Jian-Xiang , Jiang Yu-Xi
Published: March 2019

A research vessel sailing across a warm eddy in the Kuroshio Extension on 13 April 2016 captured an abrupt development of stratocumulus under synoptic high pressure. Shipboard observations and results from regional atmospheric model simulations indicate that increased surface heat flux over the ocean eddy lowered surface pressure and thereby accelerated southeasterly winds. The southeasterly winds transported moisture toward the low pressure and enhanced the air–sea interface heat flux, which in turn deepened the low pressure and promoted low-level convergence and rising motion over the warm eddy. The lifting condensation level lowered and the top of the marine atmospheric boundary layer (MABL) rose, thereby aiding the development of the stratocumulus. Further experiments showed that 6°C sea surface temperature anomalies associated with the 400-km-diameter warm eddy accounted for 80% of the total ascending motion and 95% of total cloud water mixing ratio in the marine atmospheric boundary layer during the development of stratocumulus. The synthesis of in situ soundings and modeling contributes to understanding of the mechanism by which the MABL and marine stratocumulus respond to ocean eddies.
Evolving Climate Services into Knowledge–Action Systems
Authors: Weichselgartner Juergen , Arheimer Berit
Published: March 2019

The current landscape of climate services represents a highly diverse and still growing range of programs, projects, and portals involved in developing and/or providing climate services at different administrative levels and spatial–temporal scales. The diversity of service producers, users, and policy arenas has created a highly heterogeneous data- and information-oriented service landscape, and the authors contend that the domain of climate services requires efforts toward agreed structures and forms of conceptualization, operationalization, and evaluation. It is proposed here that qualitative classification be applied into climate change adaptation products, services, and systems to better guide research, policy, and practice with a clear terminology and analysis framework. This differentiation allows the pinpointing of critical challenges associated with the production and application of climate-relevant information, as well as the identification of suitable metrics to assess the impact of climate services. The article concludes with recommendations to advance climate services into knowledge–action systems and increase their sustainability.