bluuebunny/crossref_metadata_2025 huggingface dataset:
A Phase I/II Study of Evofosfamide, A Hypoxia-activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma
Authors: Laubach Jacob P. , Liu Chia-Jen , Raje Noopur S. , Yee Andrew J. , Armand Philippe , Schlossman Robert L. , Rosenblatt Jacalyn , Hedlund Jacquelyn , Martin Michael , Reynolds Craig , Shain Kenneth H. , Zackon Ira , Stampleman Laura , Henrick Patrick , Rivotto Bradley , Hornburg Kalvis T.V. , Dumke Henry J. , Chuma Stacey , Savell Alexandra , Handisides Damian R. , Kroll Stew , Anderson Kenneth C. , Richardson Paul G. , Ghobrial Irene M.
Published: October 2018

Purpose:

The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma. Evofosfamide (formerly TH-302) is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard, which is selectively activated under hypoxia. This trial was designed as a phase I/II study investigating evofosfamide in combination with dexamethasone, and in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma.

Patients and Methods:

Fifty-nine patients initiated therapy, 31 received the combination of evofosfamide and dexamethasone, and 28 received the combination of evofosfamide, bortezomib, and dexamethasone. Patients were heavily pretreated with a median number of prior therapies of 7 (range: 2–15). All had previously received bortezomib and immunomodulators. The MTD, treatment toxicity, and efficacy were determined.

Results:

The MTD was established at 340 mg/m2 evofosfamide + dexamethasone with dose-limiting mucositis at higher doses. For the combination of evofosfamide, bortezomib, and dexamethasone, no patient had a dose-limiting toxicity (DLT) and the recommended phase II dose was established at 340 mg/m2. The most common ≥grade 3 adverse events (AE) were thrombocytopenia (25 patients), anemia (24 patients), neutropenia (15 patients), and leukopenia (9 patients). Skin toxicity was reported in 42 (71%) patients. Responses included 1 very good partial response (VGPR), 3 partial response (PR), 2 minor response (MR), 20 stable disease (SD), and 4 progressive disease (PD) for evofosfamide + dexamethasone and 1 complete response (CR), 2 PR, 1 MR, 18 SD, and 5 PD for evofosfamide + bortezomib + dexamethasone. Disease stabilization was observed in over 80% and this was reflective of the prolonged overall survival of 11.2 months.

Conclusions:

Evofosfamide can be administered at 340 mg/m2 twice a week with or without bortezomib. Clinical activity has been noted in patients with heavily pretreated relapsed refractory multiple myeloma.
Age-Related Changes in HAPLN1 Increase Lymphatic Permeability and Affect Routes of Melanoma Metastasis
Authors: Ecker Brett L. , Kaur Amanpreet , Douglass Stephen M. , Webster Marie R. , Almeida Filipe V. , Marino Gloria E. , Sinnamon Andrew J. , Neuwirth Madalyn G. , Alicea Gretchen M. , Ndoye Abibatou , Fane Mitchell , Xu Xiaowei , Sim Myung Shin , Deutsch Gary B. , Faries Mark B. , Karakousis Giorgos C. , Weeraratna Ashani T.
Published: October 2018

Older patients with melanoma have lower rates of sentinel lymph node (LN) metastases yet paradoxically have inferior survival. Patient age correlated with an inability to retain Technetium radiotracer during sentinel LN biopsy in more than 1,000 patients, and high Technetium counts correlated to better survival. We hypothesized that loss of integrity in the lymphatic vasculature due to extracellular matrix (ECM) degradation might play a role. We have implicated HAPLN1 in age-dependent ECM degradation in the dermis. Here, we queried whether HAPLN1 could be altered in the lymphatic ECM. Lymphatic HAPLN1 expression was prognostic of long-term patient survival. Adding recombinant HAPLN1 to aged fibroblast ECMs in vitro reduced endothelial permeability via modulation of VE-cadherin junctions, whereas endothelial permeability was increased following HAPLN1 knockdown in young fibroblasts. In vivo, reconstitution of HAPLN1 in aged mice increased the number of LN metastases, but reduced visceral metastases. These data suggest that age-related changes in ECM can contribute to impaired lymphatics.

Significance:

Our studies reveal that changes in the stroma during aging may influence the way tumor cells traffic through the lymphatic vasculature. Aging may dictate the route of metastatic dissemination of tumor cells, and understanding these changes may help to reveal targetable moieties in the aging tumor microenvironment.

See related commentary by Marie and Merlino, p. 19.

This article is highlighted in the In This Issue feature, p. 1
Shipping Out MEK Inhibitor Resistance with SHP2 Inhibitors
Authors: Torres-Ayuso Pedro , Brognard John
Published: October 2018

Summary: RAS is one of the most frequently altered oncogenes, yet RAS-driven tumors are largely refractory to anticancer therapies. Fedele and colleagues demonstrate that SHP2 inhibitors prevent adaptive MEK inhibitor resistance; therefore, combining MEK and SHP2 inhibitors represents an exciting new therapeutic approach for the treatment of RAS-driven cancers. Cancer Discov; 8(10); 1210–2. ©2018 AACR.

See related article by Fedele et al., p. 1237.
Different Originating Cells Underlie Intertumoral Heterogeneity in Lung Neuroendocrine Tumors
Authors: Pozo Karine , Kelenis Demetra P. , Minna John D. , Johnson Jane E.
Published: October 2018

Summary: Studies in genetically engineered mouse models of neuroendocrine lung cancer suggest that differences in cells of origin underlie subtype variations in this class of cancers. These findings highlight the concept that the same driver mutations introduced into different cells of origin lead to tumors with the same histology but dramatically different metastatic programs and potentially different therapeutic responses. Cancer Discov; 8(10); 1216–8. ©2018 AACR.

See related article by Yang et al., p. 1316.
Stay Gathered Rather than Scattered: Strategies of Common Marmosets during Agonistic Interactions with Birds in the Atlantic Rain Forest
Authors: Borges Sawana C.A. , Oliveira Fernanda G.S. , Guerra Rafael , Oliveira Tina Gunhold-de , Pesendorfer Mario B. , Bezerra Bruna M. , Souto Antonio S. , Schiel Nicola
Published: October 2018

To reduce the vulnerability of their small body size, common marmosets live in large and cohesive social groups. Thus, we hypothesized that in order to compensate for small body size and predation risk, individuals of common marmosets will stay gathered rather than scattered when foraging for eggs and/or nestling birds. Furthermore, in order to avoid costly injuries and eventual predation risks, for both sides, the majority of interactions among common marmosets and small birds will not involve direct physical contact. The study was developed in a small fragment of Atlantic Forest in the northeast of Brazil. We recorded a total of 115 interactions between common marmosets (Callithrix jacchus) with 7 different bird species. As expected, agonistic interactions were significantly more frequent when the marmosets were gathered. Also, most agonistic interactions by the birds toward common marmosets involved overflights without physical contact. Apparently, the set of avoidance behavior leads to a reduced predation risk for both sides. It appears that dispersed marmosets do not represent an imminent threat that justifies an agonistic reaction by the birds as the latter appear to avoid exposing themselves to unnecessary danger during agonistic interactions, especially when the marmosets are gathered.
Secondary Adrenal Insufficiency after Treatment with Budesonide for Autoimmune Hepatitis
Authors: De Maeyer Filip , Lapauw Bruno , Hoorens Anne , Geerts Anja , Van Vlierberghe Hans , Verhelst Xavier
Published: October 2018

Autoimmune hepatitis (AIH) is a rare cause of chronic liver disease. The backbone of treatment is immunosuppressive medication, typically prednisolone as induction therapy and azathioprine as a maintenance therapy. Side effects of the long-term use of systemic corticosteroids are well known and have led to the use of alternative induction regimens. An attractive alternative is budesonide, a nonhalogenated glucocorticosteroid characterized by a high first-pass effect in the liver (90%), resulting in a high topical anti-inflammatory activity and a low systemic activity. It should be stressed that budesonide is contraindicated in patients with established cirrhosis with portal hypertension and portocaval shunting. In this case report, we present the first case of adrenal insufficiency following treatment with budesonide for AIH.
Hepatitis E Virus Genotype 1 and Hepatitis A Virus Dual Infection in Pediatric Patients with a Low Socioeconomic Status from Mexico
Authors: Realpe-Quintero Mauricio , Mirazo Santiago , Viera-Segura Oliver , Copado-Villagrana Edgar D. , Panduro Arturo , Roman Sonia , Arbiza Juan , Fierro Nora A.
Published: October 2018

Objective: We aimed to detect and characterize hepatitis E virus (HEV) RNA in sera samples from a pediatric population infected with the hepatitis A virus (HAV) exhibiting acute hepatitis and to correlate the infection status with the clinical outcome. Methods: Seventy-five ELISA-positive samples from children containing anti-HAV and anti-HEV IgM were used to amplify and characterize partial regions within HEV ORF2. A statistical comparison of clinical data between HEV IgM-positive/HEV RNA-positive patients and HEV IgM-positive/HEV RNA-negative patients was performed. Results: Thirteen out of 75 IgM-positive samples provided amplification of discrete regions of the HEV genome. Nested RT-PCR-based detection and subsequent sequencing of 5 samples confirmed the identity of HEV genotype 1 (G1), which had not been previously reported in Mexico. Though not significant, a trend towards exacerbated clinical manifestations was found in HEV RNA-positive patients relative to HEV RNA-negative patients. Conclusions: An elevated rate of G1 RNA was detected. Hepatitis E seems to be a neglected disease in Mexico and epidemic strains of HEV are likely to play a role as causative agents of acute hepatitis in highly exposed children. Although HAV is endemic in Mexico, an HEV-RNA detection rate of 17% in co-infected samples shows the need for screening for HEV as a part of future vaccination strategies.
Evaluation of an Intubation Readiness Score to Assess Neonatal Sedation before Intubation
Authors: de Kort Ellen H.M. , Andriessen Peter , Reiss Irwin K.H. , van Dijk Monique , Simons Sinno H.P.
Published: October 2018

Background: Premedication for neonatal intubation facilitates the procedure and reduces stress and physiological disturbances. However, no validated scoring system to assess the effect of premedication prior to intubation is available. Objective: To evaluate the usefulness of an Intubation Readiness Score (IRS) to assess the effect of premedication prior to intubation in newborn infants. Methods: Two-center prospective study in neonates who needed endotracheal intubation. Intubation was performed using a standardized procedure with propofol 1–2 mg/kg as premedication. The level of sedation was assessed with the IRS by evaluating the motor response to a firm stimulus (1 = spontaneous movement; 2 = movement on slight touch; 3 = movement on firm stimulus; 4 = no movement). Intubation was proceeded if an adequate effect, defined as an IRS of 3 or 4, was reached. IRS was compared to the quality of intubation measured with the Viby-Mogensen intubation score. Results: A total of 115 patients, with a median gestational age of 27.7 weeks (interquartile range 5.3) and a median birth weight of 1,005 g (interquartile range 940), were included. An adequate IRS was achieved in 105 patients, 89 (85%) of whom also had a good Viby-Mogensen intubation score and 16 (15%) had an inadequate Viby-Mogensen intubation score. The positive predictive value of the IRS was 85%. Conclusions: Preintubation sedation assessment using the IRS can adequately predict optimal conditions during intubation in the majority of neonates. We suggest using the IRS in routine clinical care. Further research combining the IRS with other parameters could further improve the predictability of adequate sedation during intubation.
Overstaged Rectal Cancer by MRI due to Fibrosis Induced by Tattoo Marker
Authors: Gasljevic Gorana , Boc Nina , Brecelj Erik , But Hadzic Jasna , Klancic Marko , Mlakar Jernej
Published: October 2018

Endoscopic colorectal tattooing with carbon-based dyes is commonly employed in order to assist with later localization of the lesion. Although carbon is thought to be nontoxic, there usually is some inflammatory reaction with fibrosis and granuloma formation after tissue injection. The aim of this report is to alert to a possible underestimated, late consequence of colorectal carbon-based marker tattooing, namely pronounced fibrosis at the site of the injection that could lead to a blurring and misinterpretation of changes evaluated by radiological techniques. We describe a case of cT stage overestimation due to fibrosis of the rectal wall and perirectal fat, induced by carbon-based dye injection in a 66-year-old patient. In our case it was an overestimation of MR evaluation in the case of early invasive carcinoma. Although there have been some studies on tissue effect of carbon-based dyes, the possible scenario consequence of cancer stage overestimation due to fibrosis has not yet been described. Such a mistake could lead to inappropriate overtreatment. Clinicians must be aware of the possible consequences of dye injection and resultant overestimation of T stage of colorectal cancer. More histological studies concerning histological changes after carbon-based marker tattooing are needed to establish the extent of its significance.
Validity of Laparoscopic Gastrectomy in the Elderly
Authors: Wakahara Tomoyuki , Kanemitsu Kiyonori , Maeda Tetsuo , Yoshikawa Takuro , Tsuchida Shinobu , Ueno Nozomi , Toyokawa Akihiro
Published: October 2018

Objectives: This study aimed to investigate the validity of laparoscopic gastric cancer surgery in elderly patients. Methods: A total of 202 patients who underwent laparoscopic gastrectomy for gastric cancer between January 2007 and December 2016 were divided into an elderly group (age ≥75 years, n = 36) and a control group (age < 75 years, n = 166). The patients’ clinicopathological data were reviewed. Results: The overall morbidity rate was relatively higher in the elderly group (16.7 vs. 11.4%, p = 0.389), whereas the incidence of serious complications ≥grade III according to the Clavien-Dindo classification did not increase significantly in the elderly group (8.3 vs. 7.8%, p = 0.920). Univariate and multivariate analyses revealed that age ≥75 years was not a significant predictive factor of postoperative morbidity (p = 0.568). There was no significant difference in the 5-year overall survival rate of patients with pathological stage I gastric cancer between the groups (97.1 vs. 96.1%, p = 0.704; hazard ratio, 0.669; 95% confidence interval, 0.036–3.692). Conclusions: Laparoscopic gastrectomy has an acceptable morbidity rate in elderly patients, and the long-term outcome of patients with stage I gastric cancer was similar to that of the control group.
Micropapular Cutaneous Sarcoidosis Reviewed
Authors: Labadie Jessica G. , Florek Aleksandra G. , VandenBoom Timothy , Yazdan Pedram , Krunic Aleksandar L.
Published: October 2018

Background: Micropapular cutaneous sarcoidosis (MPCS) is a rare variant of sarcoidosis. Herein we review the literature and include a recent case of MPCS discussing pathogenesis, diagnosis, treatment, and prognosis. Method: A review was conducted using the terms “micropapular sarcoidosis” and “micropapular sarcoid.” A recent case of a 50-year-old male patient with biopsy-identified MPCS was also included in the review. Results: In total, 12 cases with an aggregate of 18 patients were included in the review. Presentation among all patients was consistent, with scattered, occasionally pruritic, faintly erythematous shiny white papules. Skin biopsy demonstrated noncaseating granulomas. Systemic prednisone, oxytetracycline, and hydroxychloroquine, as well as topical betamethasone, were used for therapy. Conclusion: In our review there does not seem to be a clear link as to the definite cause of the MPCS. While the relationships to tuberculosis and autoimmunity seem to be often emphasized, there was no clear association with either etiology.
Comparison of Bubble CPAP Devices Using RAM Cannula for Extubation Failure in Very Low Birth Weight Infants: Randomized and Cohort Studies
Authors: Claassen Colleen C. , Hillman Noah H. , Brown Kimberly , Williams Howard L. , Strand Marya L.
Published: October 2018

Introduction: Bubble continuous positive airway pressure (bCPAP) generates a variable pressure due to bubble size and frequency, and these pressure oscillations may contribute to lung recruitment and gas exchange. Single-outlet bCPAP devices generate larger pressure fluctuation than bCPAP devices with diffusers, but clinical efficacy is unclear. Our hypothesis was that a single-outlet bCPAP device (B&B Bubbler©) would decrease extubation failure and improve oxygenation compared with a bCPAP device with a diffuser (BabiPlus©). Methods: Bench testing of bCPAP devices with the RAM© cannula determined pressure averages, fluctuations, and CPAP transmission at prongs. The B&B Bubbler© and the BabiPlus© devices were compared for oxygenation and bCPAP failure within 72 h of extubation in a randomized trial in infants less than 1,250 g (n = 43). Additionally, a cohort study with infants extubated to BabiPlus© (n = 128), B&B Bubbler© (n = 119), and noninvasive positive pressure ventilation (NIPPV) (n = 107) were compared. Results: Small differences in pressure fluctuations between bCPAP devices are attenuated by the RAM© cannula. Pressures at RAM© prongs are 62% of set pressure. The bCPAP extubation failure rate (35%) and oxygenation were similar between the bCPAP devices. bCPAP success was associated with lower FiO2 at extubation and decreased need for additional FiO2 in both groups. In the setting of the RAM© cannula, there were no differences in extubation failure rate for infants extubated to bCPAP or NIPPV. Conclusions: There were no clinical differences at extubation between the B&B Bubbler© and BabiPlus© devices. Oxygenation may predict bCPAP failure. The use of the RAM© cannula as a bCPAP interface should be more closely examined.
Liver Maximum Capacity: A Novel Test to Accurately Diagnose Different Stages of Liver Fibrosis
Authors: Buechter Matthias , Thimm Jonas , Baba Hideo A. , Bertram Stefanie , Willuweit Katharina , Gerken Guido , Kahraman Alisan
Published: October 2018

Aim: To assess the diagnostic accuracy of liver maximum capacity (LiMAx®) test compared to transient elastography (TE) and serum biomarkers for the noninvasive detection of different stages of liver fibrosis and cirrhosis. Patients and Methods: We retrospectively correlated LiMAx®, TE, aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR), AST-to-platelet ratio index (APRI), and fibrosis-4 (FIB-4) score with histological specimens in 102 patients with chronic liver disease (CLD) who underwent liver biopsy (either percutaneously or via mini-laparoscopy) at the University Clinic of Essen between 10/2016 and 12/2017. Results: Median LiMAx® values showed a tendency to decrease in accordance with increasing histological degree of fibrosis based on the Desmet scoring system (F0: 446.5 [381.0–592.5] µg/h/kg, F1: 405.0 [343.0–547.0] µg/h/kg, F2: 337.0 [250.0–394.0] µg/h/kg, F3: 281.0 [262.0–364.0] µg/h/kg, and F4: 181.5 [130.0–256.5] µg/h/kg. Furthermore, ­LiMAx® was superior to TE, FIB-4, AAR, and APRI in detecting different stages of fibrosis, while Spearman’s rank correlation test showed a statistically significant association of –0.68, 0.62, 0.61, 0.46, and 0.42, respectively. However, the combination of TE and LiMAx® had the highest diagnostic accuracy in detecting liver cirrhosis (sensitivity 88.9%, specificity 84.6%, Youden index 0.735). Conclusion: Enzymatic liver function measured by LiMAx® showed strong correlation with histology in patients with CLD irrespective of its underlying etiology and was superior to TE and serum biomarkers, possibly making it useful as a novel and noninvasive tool for the determination of hepatic disease severity.
Circular RNA Expression in the Brain of a Neonatal Rat Model of Periventricular White Matter Damage
Authors: Zhu Lihua , Zhao Ruibin , Huang Li , Mo Sisi , Yu Zhangbin , Jiang Li , Qiao Lixing
Published: October 2018

Background/Aims: Periventricular white matter damage (PWMD) is the predominant neurologic lesion in preterm infants who survive brain injury. In this study, we assessed the global changes in and characteristics of the transcriptome of circular RNAs (circRNAs) in the brain tissues of rats with PWMD. Methods: We compared the expression profiles of circRNAs in brain samples from three rats with PWMD and three paired control tissues using deep RNA sequencing. Bioinformatics analysis was applied to investigate these differentially expressed circRNAs, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis was performed to confirm the results. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict associated cell signaling pathways and functions. Network analysis was performed to predict circRNAs-microRNAs, and target genes related to PWMD. Results: A total of 2151 more reliable circRNAs were dysregulated in the brain tissues of rats with PWMD, indicating a potential role in the condition. Of the 98 circRNAs significantly differentially expressed in rat brains with PWMD (P< 0.05), 52 were significantly over-expressed and 46 were significantly under-expressed. The expression profiles of seven of 10 randomly selected circRNAs were confirmed by qRT-PCR analysis. The glutamatergic synapse pathway and the VEGF signaling pathway, both associated with hypoxia/ischemia induced brain damage, were inriched. Relationship between miRNA (rno-miR-433-3p and rno-miR-206-3p) and HIF-1α were evident and potential associations between chr6: 48820833|48857932 and their target genes (rno-miR-433-3p and rno-miR-206-3p) were identified. Conclusion: The distinct expression patterns of circRNAs in the brain tissues of rats with PWMD suggest that circRNAs actively respond to hypoxia-ischemia. These findings could assist the development of novel diagnostic and therapeutic targets for PWMD therapy.
Total Saponins of Aralia Elata (Miq) Seem Alleviate Calcium Homeostasis Imbalance and Endoplasmic Reticulum Stress-Related Apoptosis Induced by Myocardial Ischemia/Reperfusion Injury
Authors: Wang Ruiying , Yang Minghua , Wang Min , Liu Xuesong , Xu Huibo , Xu Xudong  , Sun Guibo , Sun Xiaobo
Published: October 2018

Background/Aims: Total saponins of Aralia elata (Miq) Seem (AS) from the Chinese traditional herb Long ya Aralia chinensis L. reportedly provide cardioprotective effects, but the exact mechanisms require further study. Previous studies have showed that myocardial ischemia/ reperfusion injury (MIRI) was related to calcium homeostasis imbalance and endoplasmic reticulum stress (ERS). Thus, this study aimed to demonstrate protective effects of AS on MIRI. Methods: After administrating AS for 5 days, the left anterior descending artery coronary artery of Sprague-Dawley (SD) rats was ligated for 30 min. After 48 h of reperfusion, haemodynamics, Evans blue/ 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (HE) staining, masson staining and the levels of lactate dehydrogenase (LDH) and creatine kinase (CK), superoxide dismutase (SOD), malondialdehyde (MDA) were detected to assess MIRI. ATPase activity and Western Blot were used to study the mechanisms. Results: Compared with IR group, AS treatment groups could significantly reduce myocardial infarct size; improve myocardial pathologic progress; decrease content of LDH, CK, and MDA; increase content of SOD; and restore the activities of Ca2+-Mg2+-ATPase, Na+-K+-ATPase, sarcoplasmic reticulum Ca2+-ATPases (SERCA), and calcineurin (CaN). AS treatment groups also significantly up-regulated the expression of GRP78, C/EBP homologous protein (CHOP), and Bax, and down-regulated the expression of Bcl-2, all similar to the effects of ERS. Conclusion: These findings illustrated that AS could prevent myocardial ischemia/reperfusion injury and reduce calcium homeostasis imbalance and ERS-related apoptosis.
Prognostic Role of High Stathmin 1 Expression in Patients with Solid Tumors: Evidence from a Meta-Analysis
Authors: Mao Qingyan , Chen Zhen , Wang Kun , Xu Renfang , Lu Hao , He Xiaozhou
Published: October 2018

Background/Aims: Several recent studies have demonstrated that Stathmin 1expression may be closely associated with prognosis in patients with various types of cancers. In the present study, we conducted a meta-analysis of all available studies in the English literature to assess the prognostic value of Stathmin 1expression in patients with solid cancers. Methods: The online databases PubMed, Embase, and Web of Science were searched for literature regarding Stathmin 1 and its association with patient outcomes associated with solid cancers. Results: A total of 23 articles including 26 studies that contained 5 335 patients were retrieved and analyzed. Our results indicated that high Stathmin 1 expression yielded a worse overall survival (OS) (hazard ratio [HR] = 2.17, 95% confidence interval [CI]: 1.81–2.60), disease-free survival (DFS) (HR = 2.46, 95% CI: 2.00–3.02), disease-specific survival (DSS) (HR = 1.98, 95% CI: 1.58– 2.47) and progression-free survival (PFS)/recurrence-free survival (RFS) (HR = 2.09, 95% CI: 1.51–2.89). Furthermore, the association of high Stathmin 1 expression with poor survival was significant even for sub-group analyses of different tumor types, ethnicities, methods used to calculate HRs, detected methods, and analysis types. Conclusion: In summary, this meta-analysis determined that high Stathmin 1 expression is associated with poor prognosis in patients with solid cancers and expression of this protein could be a clinically useful prognostic biomarker.
miR-449a Suppresses Tamoxifen Resistance in Human Breast Cancer Cells by Targeting ADAM22
Authors: Li Jun , Lu Mingjie , Jin Jiao , Lu Xiyi , Xu Tongpeng , Jin Shidai
Published: October 2018

Background/Aims: Most of estrogen receptor positive breast cancer patients respond well initially to endocrine therapies, but often develop resistance during treatment with selective estrogen receptor modulators (SERMs) such as tamoxifen. Altered expression and functions of microRNAs (miRNAs) have been reportedly associated with tamoxifen resistance. Thus, it is necessary to further elucidate the function and mechanism of miRNAs in tamoxifen resistance. Methods: Tamoxifen sensitivity was validated by using Cell Counting Kit-8 in tamoxifen-sensitive breast cancer cells (MCF-7, T47D) and tamoxifen-resistant cells (MCF-7/TAM, T47D/ TAM). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression level of miR-449a in tamoxifen-sensitive/-resistant cells and patient serums. Dual-luciferase assay was used to identify the binding of miR-449a and predicted gene ADAM22. The expression level of ADAM22 was determined by qRT-PCR and western blotting in miR-449a +/- breast cancer cells. Subsequently, rescue experiments were carried out to identify the function of ADAM22 in miR-449a-reduced tamoxifen resistance. Finally, Gene ontology (GO) and Protein-protein interaction analyses were performed to evaluate the potential mechanisms of ADAM22 in regulating tamoxifen resistance. Results: MiR-449a levels were downregulated significantly in tamoxifen-resistant breast cancer cells when compared with their parental cells, as well as in clinical breast cancer serum samples. Overexpression of miR-449a re-sensitized the tamoxifen-resistant breast cancer cells, while inhibition of miR-449a conferred tamoxifen resistance in parental cells. Luciferase assay identified ADAM22 as a direct target gene of miR-449a. Additionally, silencing of ADAM22 could reverse tamoxifen resistance induced by miR-449a inhibition in ER-positive breast cancer cells. GO analysis results showed ADAM22 was mainly enriched in the biological processes of cell adhesion, cell differentiation, gliogenesis and so on. Protein-protein interaction analyses appeared that ADAM22 might regulate tamoxifen resistance through PPARG, LGI1, KRAS and LYN. Conclusion: Decreased miR-449a causes the upregulation of ADAM22, which induces tamoxifen resistance of breast cancer cells. These results suggest that miR-449a, functioning by targeting ADAM22, contributes to the mechanisms underlying breast cancer endocrine resistance, which may provide a potential therapeutic strategy in ER-positive breast cancers.
The Profile of Genetic Mutations in Papillary Thyroid Cancer Detected by Whole Exome Sequencing
Authors: Fang Yi , Ma Xiao , Zeng Jing , Jin Yanwen , Hu Yong , Wang Jinjing , Liu Ran , Cao Cheng
Published: October 2018

Background/Aims: The purpose of the study was to investigate the altered driver genes and signal pathways during progression of papillary thyroid cancer (PTC) via next-generation sequencing technology. Methods: The DNA samples for whole exome sequencing (WES) analyses were extracted from 11 PTC tissues and adjacent normal tissues samples. Direct Sanger sequencing was applied to validate the identified mutations. Results: Among the 11 pairs of tissues specimens, 299 single nucleotide variants (SNVs) in 75 genes were identified. The most common pattern of base pair substitutions was T:A>C:G (49.83%), followed by C:G>T:A (18.06%) and C:G>G:C (15.05%). The altered genes were mainly implicated in MAPK (mitogen-activated protein kinase), PPAR (peroxisome proliferator-activated receptors), and p53 signaling pathways. In addition, 12 novel identified driver genes were validated by Sanger sequencing. The mutations of FAM133A, DPCR1, JAK1, C10orf10, EPB41L3, GPRASP1 and IWS1 exhibited in multiple PTC cases. Furthermore, the PTC cases exhibited individual mutational signature, even the same gene might present different mutational status in different cases. Conclusion: Multiple PTC-related somatic mutations and signal pathways are identified via WES and Sanger sequencing methods. The novel identified mutations in genes such as FAM133A, DPCR1, and JAK1 may be potential therapeutic targets for PTC patients.
Diet and Lifestyle Role in Homocysteine Metabolism in Turner Syndrome
Authors: Calcaterra Valeria , Larizza Daniela , De Giuseppe Rachele , De Liso Federica , Klersy Catherine , Albertini Riccardo , Pozzebon Irene , Princis Maria Pilar , Montalbano Chiara , Madè Alexandra , Cena Hellas
Published: October 2018

Objective: Patients with Turner syndrome (TS) have an unfavorable cardiometabolic profile. Hyperhomocysteinemia is a potential cardiovascular risk factor influenced by genetic and environmental factors, therapies, unbalanced diets and other lifestyle factors. We retrospectively studied the relationship between total plasma homocysteine (Hcy), serum vitamin B12 (B12) and folate concentration in TS patients, taking into account the genetic profile, diet, smoking habits, hormonal therapies and dietary supplements of the subjects. Patients and Methods: We evaluated 50 TS patients (31.5 ± 12.5 years). Medication, including vitamin supplementation, was obtained. Eating habits, cigarette smoking, alcohol and coffee consumption were investigated using phone interviews. Levels of Hcy metabolism parameters were classified by using the relevant cutoff value for an adult population and compared with a reference sample drawn from the general population. Results: Inadequate Hcy and B12 levels were noted, despite vitamin supplementation. Holotranscobalamin (HoloTC) was above the relevant cutoff in the population, and supplemented subjects showed mean levels lower than nonsupplemented subjects (p = 0.005). Dietary supplementation (p = 0.038), lifestyle (coffee consumption, p = 0.01) and hormonal replacement therapy (p = 0.02) are important factors for Hcy metabolism. No genetic influence on Hcy levels was noted. Multivariable regression analysis identified vitamin supplementation (p = 0.045) as the only independent predictor of increased Hcy levels. Conclusion: Cardiovascular risk in TS can be reduced using educational approaches to a healthy lifestyle with dietary guidelines. Besides this, we also recommend measuring HoloTC for the prompt detection of B12 deficiency and to consider hormone replacement therapy in the biochemical assessment of homocysteine in TS.
Textual Anxiety: Reading (and Misreading) the Draft Constitution in China, 1954
Authors: Diamant Neil J. , Xiaocai Feng
Published: October 2018

This article uses comments, questions, and conversations about the PRC's draft constitution of 1954 to assess state legitimacy and how people felt more generally about the Communist regime. Taking advantage of untapped archival sources in Hong Kong and the mainland—including classified intraparty reports and transcripts from meetings in factories, police stations, universities, and villages—this article challenges the conventional view that the constitution bolstered support for the Chinese Communist Party (CCP). Instead, the document generated a great deal of anxiety among ordinary citizens, as well as among CCP officials and the regime's favored classes. This “text-based” cause of emotional turmoil was a supplement to the classic forms of political terror that dominate the literature on Communist dictatorships. Despite widespread confusion, people's identification of problematic sections of the constitution turned out to be remarkably prescient in light of political disasters in the 1950s and 1960s and ongoing constitutional controversies in the era after Mao Zedong.
The Sources of Dual-task Costs in Multisensory Working Memory Tasks
Authors: Katus Tobias , Eimer Martin
Published: October 2018

We investigated the sources of dual-task costs arising in multisensory working memory (WM) tasks, where stimuli from different modalities have to be simultaneously maintained. Performance decrements relative to unimodal single-task baselines have been attributed to a modality-unspecific central WM store, but such costs could also reflect increased demands on central executive processes involved in dual-task coordination. To compare these hypotheses, we asked participants to maintain two, three, or four visual items. Unimodal trials, where only this visual task was performed, and bimodal trials, where a concurrent tactile WM task required the additional maintenance of two tactile items, were randomly intermixed. We measured the visual and tactile contralateral delay activity (CDA/tCDA components) as markers of WM maintenance in visual and somatosensory areas. There were reliable dual-task costs, as visual CDA components were reduced in size and visual WM accuracy was impaired on bimodal relative to unimodal trials. However, these costs did not depend on visual load, which caused identical CDA modulations in unimodal and bimodal trials, suggesting that memorizing tactile items did not reduce the number of visual items that could be maintained. Visual load did not also affect tCDA amplitudes. These findings indicate that bimodal dual-task costs do not result from a competition between multisensory items for shared storage capacity. Instead, these costs reflect generic limitations of executive control mechanisms that coordinate multiple cognitive processes in dual tasks. Our results support hierarchical models of WM, where distributed maintenance processes with modality-specific capacity limitations are controlled by a central executive mechanism.
The Holistic Interpretation of Treaties at the International Court of Justice
Authors: Popa Liliana E.
Published: October 2018

This article revises the topic of treaty interpretation at the International Court of Justice and focuses on what judges at this Court do in terms of treaty interpretation. The main argument developed in the article, based on an extended analysis of case-law at the ICJ, prior to and after the adoption of the 1969 Vienna Convention on the Law of Treaties, is that the ICJ’s approaches to interpretation after the VCLT was adopted are consistent with the canons of treaty interpretation which this Court has greatly developed and applied with consistency since its inception. The case-law analysis reveals a preference of the PCIJ/ICJ for holistic interpretation, and thus for the use of more rules and methods of interpretation than initially declared by the Court as sufficient to solve the issue of interpretation before it, in an interpretative approach which could be termed ‘overbuilding’.
The Disjunctive Structure of Positive Rights under the European Convention on Human Rights
Authors: Stoyanova Vladislava
Published: October 2018

The European Court of Human Rights (ECtHR) has reiterated that states have discretion regarding what means to use to fulfil their positive obligations under the European Convention on Human Rights (ECHR). Given the “wide range of possible measures” that could be taken to ensure compliance with positive rights, these rights have a disjunctive structure since an omission has no definitive counterpart. This article examines how the ECtHR deals with the disjunctive structure of positive rights and how it addresses alternative protective measures that could have been extended. In order to identify the main points of contention, I first draw on legal-theoretical literature that has grappled with the structure of positive rights. I then examine what the Court actually does when it adjudicates positive obligation cases under qualified and unqualified rights. I analyse how and why the review endorsed in the ECtHR’s judgments diverges from or converges with the theoretical model.
Towards an Intersectional Understanding of Conflict-Related Sexual Violence: Gender, Sexuality, and Ethnicity at the ICTY
Authors: Isaac Maike , Jurasz Olga
Published: October 2018

In the past 25 years, the International Criminal Tribunal for the former Yugoslavia (ICTY) has contributed significantly to a more sophisticated understanding of conflict-related sexual violence (CRSV) in international criminal law. The ICTY’s jurisprudence has broken new ground in relation to the prosecution of CRSV, but also has brought to light the multifaceted challenges associated with the prosecution of such crimes at an international level. Whilst cases heard by the ICTY have addressed both CRSV committed against women and men, there exist significant differences in the ways in which the ICTY has approached the experiences of male victims of sexual violence during the Yugoslav Wars. We therefore analyse the extent to and ways in which the ICTY has fostered the understanding of CRSV as gender-based violence that is embedded into the socio-cultural dynamics of the community within which the violence occurs.
Three new Hantzschia species (Bacillariophyta) from the Maritime Antarctic Region
Authors: BULÍNOVÁ MARIE , KOCHMAN-KĘDZIORA NATALIA , KOPALOVÁ KATEŘINA , VAN DE VIJVER BART
Published: October 2018

Following an earlier revision of the genus Hantzschia (Bacillariophyta) in the Maritime Antarctic Region, several at present unidentified or poorly known taxa of this aerophilic genus have been investigated using both light and scanning electron microscopy. Based on the morphological analysis of the observations, three new species are currently described: Hantzschia australabundans sp. nov., H. zidarovae sp. nov. and H. zikmundiana sp. nov. The new species differ from comparable taxa in valve outline, structure of the internal proximal raphe endings and structure of the striae and areolae. Additional observations are presented on Hantzschia amphioxys and its forma muelleri, H. abundans and H. incognita, based on observations of Antarctic populations from the South Shetland Islands, Vega Island and James Ross Island. Brief notes on the ecology of all reported species are added.
Macro- and micro-morphological study of fruits and seeds in the genus Geranium (Geraniaceae)
Authors: KESHAVARZI MARYAM , ESFANDANI-BOZCHALOYI SOMAYEH
Published: October 2018

Geranium (Geraniaceae) is a genus with 325 species worldwide. In present study fruit and seed morphology of 832 individuals from 23 taxa of Geranium were collected from different habitats in Iran. Samples were examined by use of light and scanning electron microscopy (SEM). The morphometric study involved 8 quantitative and 11 qualitative characters. Statistical analysis employed PAST software. Principal Component Analysis defined the most variable characters. Features as mericarp shape, mericarp and seed color, hair density, mericarp ornamentations and seed coat pattern were of diagnostic importance. Taxa of two subgenera are clearly separated based on selected fruit and seed characters. Seed macro and micro morphological characters were found useful for the taxonomic delimitations. Despite separation of the subgenera, some sections are mixed.
Additional morphological features of the epiphytic diatom Cocconeis sawensis Al-Handal & Riaux-Gobin (Cocconeidaceae, Bacillariophyta) from a coastal lagoon, Southern Brazil
Authors: DONADEL LETÍCIA , TORGAN LEZILDA CARVALHO , AL-HANDAL ADIL Y.
Published: October 2018

Cocconeis sawensis Al-Handal & Riaux-Gobin (2014: 217), first described from a saline lake in Southern Iraq (Middle East), is observed for the first time in South America attached on Cladophora sp. from Peixe lagoon in Southern Brazil. Specimens were examined with light and electron microscopy and some morphometric variations were observed in relation to the type material. Valves from Peixe lagoon exhibit rhombo-elliptic outline with broadly cuneate to rounded apices with slightly smaller dimensions. The number of striae shows a broader range of variation on both valves and areolae density in the raphe valve is lesser. The fimbria of the raphe valva valvocopula are elongated with unequal length and shape. Different arrangement of the hymenes were also observed in the sternum valve. More information on the environment where the species was found and its relation to the populations of the species from Florida and Napuka Atoll are provided.
A Cloud Microphysics Parameterization for Shallow Cumulus Clouds Based on Lagrangian Cloud Model Simulations
Authors: Noh Yign , Oh Donggun , Hoffmann Fabian , Raasch Siegfried
Published: October 2018

Cloud microphysics parameterizations for shallow cumulus clouds are analyzed based on Lagrangian cloud model (LCM) data, focusing on autoconversion and accretion. The autoconversion and accretion rates, A and C, respectively, are calculated directly by capturing the moment of the conversion of individual Lagrangian droplets from cloud droplets to raindrops, and it results in the reproduction of the formulas of A and C for the first time. Comparison with various parameterizations reveals the closest agreement with Tripoli and Cotton, such as and , where and are the mixing ratio and the number concentration of cloud droplets, is the mixing ratio of raindrops, is the threshold volume radius, and H is the Heaviside function. Furthermore, it is found that increases linearly with the dissipation rate and the standard deviation of radius and that decreases rapidly with while disappearing at > 3.5 μm. The LCM also reveals that and increase with time during the period of autoconversion, which helps to suppress the early precipitation by reducing A with smaller and larger in the initial stage. Finally, is found to be affected by the accumulated collisional growth, which determines the drop size distribution.
Distinguishing Trends and Shifts from Memory in Climate Data
Authors: Beaulieu Claudie , Killick Rebecca
Published: October 2018

The detection of climate change and its attribution to the corresponding underlying processes is challenging because signals such as trends and shifts are superposed on variability arising from the memory within the climate system. Statistical methods used to characterize change in time series must be flexible enough to distinguish these components. Here we propose an approach tailored to distinguish these different modes of change by fitting a series of models and selecting the most suitable one according to an information criterion. The models involve combinations of a constant mean or a trend superposed to a background of white noise with or without autocorrelation to characterize the memory, and are able to detect multiple changepoints in each model configuration. Through a simulation study on synthetic time series, the approach is shown to be effective in distinguishing abrupt changes from trends and memory by identifying the true number and timing of abrupt changes when they are present. Furthermore, the proposed method is better performing than two commonly used approaches for the detection of abrupt changes in climate time series. Using this approach, the so-called hiatus in recent global mean surface warming fails to be detected as a shift in the rate of temperature rise but is instead consistent with steady increase since the 1960s/1970s. Our method also supports the hypothesis that the Pacific decadal oscillation behaves as a short-memory process rather than forced mean shifts as previously suggested. These examples demonstrate the usefulness of the proposed approach for change detection and for avoiding the most pervasive types of mistake in the detection of climate change.
Employee service performance and collective turnover: Examining the influence of initiating structure leadership, service climate and meaningfulness
Authors: Walumbwa Fred O , Hsu I-Chieh , Wu Cindy , Misati Everlyne , Christensen-Salem Amanda
Published: October 2018

Organizations typically rely on their employees to provide high-quality service as a strategy for sustaining a competitive advantage. However, service-related jobs can have deleterious effects on employees—including negative health and attitudinal outcomes, such as burnout and decreased motivation—which also carry ramifications for organizations, including turnover. How might organizations mitigate these consequences? We posit that organizations can equip managers to create work environments conducive to employee motivation and performance because managers have substantial influence over the context within which service-oriented behaviors occur. Thus, drawing on social information processing theory and theory on work motivation, we build and test a path model that explains how and why an important type of leadership behavior—initiating structure leadership—enhances employees’ service performance and reduces collective turnover. Our multilevel analyses using multisource lagged data reveal that initiating structure leader behavior creates a high-quality service climate, which then influences meaningfulness at the individual and work-unit levels. At the individual level, our results show that employee motivation of meaningfulness positively relates to supervisor-rated employee service performance. Finally, results show that collective meaningfulness negatively relates to objective collective turnover as obtained from company archival records. Theoretical and practical implications of our study are discussed.