bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metastasis Suppressors NME1 and NME2 Promote Dynamin 2 Oligomerization and Regulate Tumor Cell Endocytosis, Motility, and Metastasis
Authors: Khan Imran , Gril Brunilde , Steeg Patricia S. 
Published: July 2019

AbstractNM23 (NME) is a metastasis suppressor that significantly reduces metastasis without affecting primary tumor size, however, the precise molecular mechanisms are not completely understood. We examined the role of dynamin (DNM2), a GTPase regulating membrane scission of vesicles in endocytosis, in NME1 and NME2 regulation of tumor cell motility and metastasis. Overexpression of NMEs in MDA-MB-231T and MDA-MB-435 cancer cell lines increased endocytosis of transferrin and EGF receptors (TfR and EGFR) concurrent with motility and migration suppression. The internalized vesicles, costained with Rab5, had AP2 depleted from the cell surface and exhibited increased Rab5-GTP levels, consistent with endocytosis. Dynamin inhibitors Iminodyn-22 and Dynole-34-2, or shRNA-mediated downregulation of DNM2, impaired NME's ability to augment endocytosis or suppress tumor cell motility. In a lung metastasis assay, NME1 overexpression failed to significantly suppress metastasis in the DNM2 knockdown MDA-MB-231T cells. Using the EGF–EGFR signaling axis as a model in MDA-MB-231T cells, NME1 decreased pEGFR and pAkt expression in a DNM2-dependent manner, indicating the relevance of this interaction for downstream signaling. NME–DNM2 interaction was confirmed in two-way coimmunoprecipitations. Transfection of a NME1 site–directed mutant lacking histidine protein kinase activity but retaining nucleoside diphosphate kinase (NDPK) activity showed that the NDPK activity of NME was insufficient to promote endocytosis or inhibit EGFR signaling. We show that addition of NME1 or NME2 to DNM2 facilitates DNM2 oligomerization and increases GTPase activity, both required for vesicle scission. NME–DNM2 interaction may contribute to metastasis suppression by altering tumor endocytic and motility phenotypes.Significance:NME1 suppresses metastasis via changes in tumor endocytosis and motility, mediated by dynamin (DNM2) GTPase activity.
MALAT1 rs664589 Polymorphism Inhibits Binding to miR-194-5p, Contributing to Colorectal Cancer Risk, Growth, and Metastasis
Authors: Wu Shenshen , Sun Hao , Wang Yajie , Yang Xi , Meng Qingtao , Yang Hongbao , Zhu Haitao , Tang Weiyan , Li Xiaobo , Aschner Michael , Chen Rui 
Published: July 2019

Abstract

Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) is an evolutionarily highly conserved lncRNA that contributes to colorectal cancer development. However, the exact molecular mechanisms connecting MALAT1 to colorectal cancer have not been fully elucidated. Here, we performed a case–control study in 1,078 patients with colorectal cancer and 1,175 healthy controls to evaluate the association between potentially functional genetic variants of MALAT1 and survival outcomes in patients with colorectal cancer. MALAT1 rs664589 CG/GG genotypes significantly increased the associated risk and decreased overall survival of patients with colorectal cancer compared with the CC genotype. In vitro and in vivo experiments showed that the rs664589 C to G mutation facilitated carcinogenesis and metastasis of colorectal cancer. Mechanistically, the miRNA miR-194-5p targeted MALAT1 for degradation in the nucleus in an Ago2-dependent manner; the rs664589 G allele altered the binding of MALAT1 to miR-194-5p, resulting in increased expression of MALAT1. Colorectal cancer cells and human tissues with the rs664589 CG/GG genotype expressed significantly higher MALAT1 than those with the rs664589 CC genotype. Multivariate Cox regression analysis showed that MALAT1 was a poor prognostic factor of colorectal cancer. In summary, MALAT1 with the rs664589 G allele demonstrates altered binding to miR-194-5p in the nucleus, leading to increased MALAT1 expression and enhanced colorectal cancer development.

Significance:
These findings highlight the functional role of MALAT1 polymorphism in colorectal cancer metastasis and survival as well as the underlying mechanism.
Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-Mediated Targeted Protein Degradation
Authors: Burslem George M. , Schultz Anna Reister , Bondeson Daniel P. , Eide Christopher A. , Savage Stevens Samantha L. , Druker Brian J. , Crews Craig M. 
Published: July 2019

Abstract

Although the use of ATP-competitive tyrosine kinase inhibitors of oncoprotein BCR-ABL1 has enabled durable responses in patients with chronic myeloid leukemia (CML), issues of drug resistance and residual leukemic stem cells remain. To test whether the degradation of BCR-ABL1 kinase could offer improved response, we developed a series of proteolysis-targeting chimera (PROTAC) that allosterically target BCR-ABL1 protein and recruit the E3 ligase Von Hippel-Lindau, resulting in ubiquitination and subsequent degradation of the oncogenic fusion protein. In both human CML K562 cells and murine Ba/F3 cells expressing BCR-ABL1, lead compound GMB-475 induced rapid proteasomal degradation and inhibition of downstream biomarkers, such as STAT5, and showed increased sensitivity compared with diastereomeric controls lacking degradation activity. Notably, GMB-475 inhibited the proliferation of certain clinically relevant BCR-ABL1 kinase domain point mutants and further sensitized Ba/F3 BCR-ABL1 cells to inhibition by imatinib, while demonstrating no toxicity toward Ba/F3 parental cells. Reverse phase protein array analysis suggested additional differences in levels of phosphorylated SHP2, GAB2, and SHC associated with BCR-ABL1 degradation. Importantly, GMB-475 reduced viability and increased apoptosis in primary CML CD34+ cells, with no effect on healthy CD34+ cells at identical concentrations. GMB-475 degraded BCR-ABL1 and reduced cell viability in primary CML stem cells. Together, these findings suggest that combined BCR-ABL1 kinase inhibition and protein degradation may represent a strategy to address BCR-ABL1–dependent drug resistance, and warrant further investigation into the eradication of persistent leukemic stem cells, which rely on neither the presence nor the activity of the BCR-ABL1 protein for survival.

Significance:
Small-molecule–induced degradation of BCR-ABL1 in CML provides an advantage over inhibition and provides insights into CML stem cell biology.
Enduring Connections?
Authors: Sobocinska Agnieszka , Purdey Jemma 
Published: July 2019

Abstract
Since 2013, the Australian government has funded Australian students to undertake short periods of study abroad with an emphasis on Asia, including Indonesia. Universities, too, have been enhancing their study-abroad options as part of broader internationalization campaigns. In a short time, the number of Australian higher-education students undertaking study abroad as part of their undergraduate degrees has doubled, to one in five students. This significant investment follows from two beliefs: that Australia’s relations with Asia are significantly impacted by people-to people relations; and that formal, experiential learning is a particularly effective pedagogical method. But is this investment warranted? Do periods of short-term study in Indonesia enrich students’ understanding of the region, and of Australia’s relations with Asia? And do current undergraduates, who have unprecedented access to mobility through travel and tourism, gain anything from a formal and guided people-to-people experience? This article explores these questions through an in-depth investigation of the intensive-mode undergraduate unit ‘Australia and Asia’ run by the Faculty of Arts at Monash University from 2014 to 2017. It suggests that, for many students, study tours facilitate a short-term period of emotional involvement and self-reflection, rather than forging enduring connections.
Seasonal Prediction of Midsummer Extreme Precipitation Days over Northeast China
Authors: Han Tingting , Wang Huijun , Hao Xin , Li Shangfeng 
Published: July 2019

AbstractNortheast China (NEC) has sustained economic losses in recent years because of extreme precipitation events. Despite many efforts, it remains very difficult to predict these extreme events. In this study, we documented the characteristics of extreme precipitation days (EPD) over NEC and established a seasonal prediction model using a year-to-year increment (DY) approach. The results show that most of the EPD over NEC occurred during midsummer, along with large values concentrated over the Greater and Lesser Khingan Mountains and Changbai Mountain. Two variables—the preceding early spring soil moisture DY over central Asia and the sea surface temperature DY in the tropical Atlantic Ocean—were used to construct the statistical model to predict the EPD DY over NEC. These two factors influenced the EPD by modulating the moisture transport over NEC. Cross-validation tests for the period from 1962 to 2016 and independent hindcasts for the period from 1997 to 2016 indicated that the two variables gave good predictions of the EPD over NEC. The observed and predicted year-to-year increments in EPD were well correlated, with a correlation coefficient of 0.65 for the period from 1962 to 2016 in the cross-validation test. In addition, the EPD DY covaried coherently with the midsummer precipitation amount DY over NEC, and those two predictors also gave good predictions for the midsummer precipitation amount over NEC. The correlation coefficient is 0.68 between the observed and predicted year-to-year increment in the amount of midsummer precipitation from 1962 to 2016 in a cross-validation test.
Revisiting the Cross-Equatorial Flows and Asian Summer Monsoon Precipitation Associated with the Maritime Continent
Authors: Zhuang Moran , Duan Anmin 
Published: July 2019

Abstract
This study uses an atmospheric general circulation model to examine the relative effects of Maritime Continent (MC) orography, surface roughness, and land–sea contrast on the three cross-equatorial flows (CEF) north of Australia, including the South China Sea (SCS), Celebes-Moluccas (CM), and New Guinea (NG) CEFs, and Asian monsoon precipitation during boreal summer. Four experiments are conducted: with islands, with islands without orography, with islands with ocean roughness and no orography, and with ocean only in the MC region. At the approximately 1° horizontal resolution of these sensitivity experiments, results indicate that the land–sea contrast and orography in the MC have complicated impacts on the CEFs. The land–sea contrast creates the three CEFs. The orography is dominant in deepening, concentrating, and strengthening the CM CEF and modulating the longitudinal location of the NG CEF. For the intensity and depth of the SCS and NG CEFs, the surface roughness over the flat MC and orography are both important. In addition, the MC modulates the monsoon rainfall in tropical Asia. The decreased rainfall (by roughly 57% and 21.4% over South Asia and the SCS, respectively) is dominated by the reduced moisture availability resulting from the presence of the land–sea contrast, thereby intercepting the westward propagating quasi-biweekly convection. The surface roughness over the MC is key in reducing precipitation through reducing moisture convergence over Sumatra, Borneo, and northeastern New Guinea. However, the orography controls the intense precipitation over southwestern New Guinea and the adjacent seas through enhancing the moisture transport carried by the CM and NG CEFs.
Long‐term Effects of Conservative Management of Vestibular Schwannoma on Dizziness, Balance, and Caloric Function
Authors: Nilsen Kathrin Skorpa , Lund‐Johansen Morten , Nordahl Stein Helge Glad , Finnkirk Monica , Goplen Frederik Kragerud 
Published: July 2019

ObjectivesTo study the development of dizziness, caloric function, and postural sway during long‐term observation of untreated vestibular schwannoma patients.Study DesignRetrospective review of a prospectively maintained longitudinal cohort.SettingTertiary referral hospital.Subjects and MethodsPatients with vestibular schwannoma undergoing wait‐and‐scan management were included—specifically, those who did not require treatment during a minimum radiologic follow‐up of 1 year. Baseline data and follow‐up included magnetic resonance imaging, posturography, bithermal caloric tests, and a dizziness questionnaire. Main outcomes were prevalence of moderate to severe dizziness, canal paresis, and postural instability at baseline and follow‐up, as compared with McNemar’s test.ResultsOut of 433 consecutive patients with vestibular schwannoma, 114 did not require treatment during follow‐up and were included. Median radiologic follow‐up was 10.2 years (interquartile range, 4.5 years). Age ranged from 31 to 78 years (mean, 59 years; SD, 10 years; 62% women). Median tumor volume at baseline was 139 mm3 (interquartile range, 314 mm3). This did not change during follow‐up (P =. 446). Moderate to severe dizziness was present in 27% at baseline and 19% at follow‐up (P =. 077). Postural unsteadiness was present in 17% at baseline and 21% at follow‐up (P =. 424). Canal paresis was present in 51% at baseline and 56% at follow‐up (P =. 664).ConclusionsThere was no significant change in the prevalence of dizziness, postural sway, or canal paresis during conservative management of vestibular schwannoma, while tumor volume remained unchanged. This indicates a favorable prognosis in these patients with regard to vestibular symptoms.
Does Surgical Volume and Complexity Affect Cost and Mortality in Otolaryngology–Head and Neck Surgery?
Authors: Redmann Andrew J. , Yuen Sonia N. , VonAllmen Douglas , Rothstein Adam , Tang Alice , Breen Joseph , Collar Ryan 
Published: July 2019

Objectives(1) To evaluate whether admission volume and case complexity are associated with mortality rates and (2) evaluate whether admission volume and case complexity are associated with cost per admission.Study DesignRetrospective case series.SettingTertiary academic hospital.Subjects and MethodsThe Vizient database was queried for inpatient admissions between July 2015 and March 2017 to an otolaryngology–head and neck surgery service. Data collected included admission volume, length of stay, intensive care unit (ICU) status, complication rates, case mix index (CMI), and cost data. Regression analysis was performed to evaluate the relationship between cost, CMI, admission volume, and mortality rate.ResultsIn total, 338 hospitals provided data for analysis. Mean hospital admission volume was 182 (range, 1‐1284), and mean CMI was 1.69 (range, 0.66‐6.0). A 1‐point increase in hospital average CMI was associated with a 40% increase in odds for high mortality. Admission volume was associated with lower mortality, with 1% lower odds for each additional case. A 1‐point increase in CMI produces a $4624 higher total cost per case (95% confidence interval, $4550‐$4700), and for each additional case, total cost per case increased by $6.ConclusionFor otolaryngology inpatient services at US academic medical centers, increasing admission volume is associated with decreased mortality rates, even after controlling for CMI and complication rates. Increasing CMI levels have an anticipated correlation with higher total costs per case, but admission volume is unexpectedly associated with a significant increase in average cost per case.
Multi-disciplinary palliative care is effective in people with symptomatic heart failure: A systematic review and narrative synthesis
Authors: Datla Sushma , Verberkt Cornelia Antonia , Hoye Angela , Janssen Daisy J.A. , Johnson Miriam J 
Published: July 2019

Background: Despite recommendations, people with heart failure have poor access to palliative care. Aim: To identify the evidence in relation to palliative care for people with symptomatic heart failure. Design: Systematic review and narrative synthesis. (PROSPERO CRD42016029911) Data sources: Databases (Medline, Cochrane database, CINAHL, PsycINFO, HMIC, CareSearch Grey Literature), reference lists and citations were searched and experts contacted. Two independent reviewers screened titles and abstracts and retrieved papers against inclusion criteria. Data were extracted from included papers and studies were critically assessed using a risk of bias tool according to design. Results: Thirteen interventional and 10 observational studies were included. Studies were heterogeneous in terms of population, intervention, comparator, outcomes and design rendering combination inappropriate. The evaluation phase studies, with lower risk of bias, using a multi-disciplinary specialist palliative care intervention showed statistically significant benefit for patient-reported outcomes (symptom burden, depression, functional status, quality of life), resource use and costs of care. Benefit was not seen in studies with a single component/discipline intervention or with higher risk of bias. Possible contamination in some studies may have caused under-estimation of effect and missing data may have introduced bias. There was no apparent effect on survival. Conclusion: Overall, the results support the use of multi-disciplinary palliative care in people with advanced heart failure but trials do not identify who would benefit most from specialist palliative referral. There are no sufficiently robust multi-centre evaluation phase trials to provide generalisable findings. Use of common population, intervention and outcomes in future research would allow meta-analysis.
Percutaneous antegrade nailing with reductor-T tape pin is effective and well tolerated in patients with ipsilateral multisegmental femoral shaft fractures
Authors: Wang Wei , Liu Jianning , Li Zhiyong , Xu Guohui , Wei Rongling , Li Xu , Qi Xiangbei 
Published: July 2019

Objective This study was performed to investigate the efficacy and safety of percutaneous antegrade nailing with a reductor-T tape pin in the treatment of ipsilateral multisegmental femoral shaft fractures (IMFSFs). Methods Nineteen patients with IMFSFs underwent antegrade nailing with a reductor-T tape pin by percutaneous techniques. The operation time, reduction time, fluoroscopy time, blood loss, fracture union time, and complications were recorded. Results All 19 patients (100%) achieved technical success. The mean and median operation time were 62.42±16.27 and 60 (range, 40–105) minutes, respectively; the mean and median reduction time were 11.47±3.78 and 10 (range, 8–22) minutes, respectively; the mean and median fluoroscopy time were 16.63±6.10 and 15 (range, 10–35) s, respectively; and the mean and median blood loss were 185.26±62.75 and 180 (range, 110–350) mL, respectively. Additionally, all 19 patients (100%) achieved fracture union within a mean and median time of 3.95±1.75 and 3 (range, 3–9) months, respectively; most patients [n=14 (73.7%)] achieved fracture union within 3 months. No obvious complications occurred during the study. Conclusion Antegrade nailing with a reductor-T tape pin by a percutaneous technique is effective and well tolerated in patients with IMFSFs.
Stroke knowledge among middle and high school students
Authors: Umar Abdullah B. , Koehler Tracy J. , Zhang Reian , Gilbert Veronica , Farooq Muhammad U. , Davis Alan T. , Nyenhuis David , Gorelick Philip B. 
Published: July 2019

Objective To determine the awareness of stroke symptoms and risk factors in middle and high school students at a single institution. Methods An 11-question multiple-choice stroke awareness survey was administered to students in grades 7 to 12 at City High Middle School in Grand Rapids, Michigan, United States. Summary statistics were calculated. Results A total of 603/608 surveys were analyzed. Only 8% of respondents correctly identified stroke as the fifth leading cause of death in the United States. Half (50.1%) recognized that a stroke occurred in the brain. Sixty-seven students (11.1%) correctly identified all 11 stroke risk factors. Only 5.1% correctly selected all four correct stroke symptoms. Two-thirds (64.5%) recognized stroke as an immediate medical emergency. Slightly more than half (55.9%) knew the acronym FAST (face, arms, speech, time). Conclusions Most students in our study were unaware of all the risk factors and symptoms related to stroke. Although this study was limited because data were collected from only one school, the findings suggest a need to educate middle and high school students about stroke risk factors, symptoms and acute interventions.
Opinion: psychiatry formal education courses have been lost in transition
Authors: McKay Roderick 
Published: July 2019

Objective: With reference to relevant literature, this article explores the impact of moving to a competency-based training programme upon psychiatry formal education courses (FECs). Conclusions: In the context of major changes in psychiatry training, FECs have lost clarity of role, alignment and governance. Strategic decisions made with key stakeholders are required to continue to train psychiatrists best able to meet future community needs.
Dietary protein and exercise for preservation of lean mass and perspectives on type 2 diabetes prevention
Authors: de Sousa Maysa Vieira , da Silva Soares Diana Bento , Caraça Elaine Reis , Cardoso Ronaldo 
Published: July 2019

Sedentary lifestyle and aging favor the increasing prevalence of obesity and type 2 diabetes and their comorbidities. The loss of lean body mass reduces muscle strength, resulting in impaired functional capacity and leading to increased risks of chronic diseases with advancing age. Besides aging, conditions such as inappetence, social isolation, and inadequate dietary intake cause the loss of lean body mass and increased abdominal fatty mass, resulting in sarcopenic obesity and predisposition to type 2 diabetes. Compared to younger people, this condition is more common in the elderly owing to natural changes in body composition associated with aging. Lifestyle changes such as increased physical activity and improved dietary behaviors are effective for preventing the occurrence of comorbidities. Regarding muscle nutrition, besides caloric adequacy, meeting the requirements for the consumption of dietary amino acids and proteins is important for treating sarcopenia and sarcopenic obesity because muscle tissue mainly consists of proteins and is, therefore, the largest reservoir of amino acids in the body. Thus, this review discusses the effects of dietary protein on the preservation of lean body mass, improvements in the functional capacity of muscle tissue, and prevention of chronic diseases such as type 2 diabetes. In addition, we address the effects of regular physical training associated with dietary protein strategies on lean body mass, body fat loss, and muscle strength in the elderly at a risk for type 2 diabetes development. Impact statement Diabetes mellitus is a worldwide health problem associated with obesity and sedentary lifestyle, which predisposes affected individuals to mortality and morbidity. Additionally, aging and unhealthy lifestyle behaviors increase inflammation and insulin resistance, contributing to the reduction of cytokines related to muscle nutrition and the suppression of lipogenesis, resulting in the development of sarcopenic obesity. One strategy for the prevention of T2D is the avoidance of secondary aging by participating in healthy action programs, including exercise and nutritional interventions. This minireview of several studies demonstrates the impact of physical activity and nutritional interventions on gaining or preserving muscle mass and on the functional aspects of muscles with aging. It provides information on the effect of protein, leucine, β-hydroxy-β-methylbutyrate (HMB), and creatine supplementation on muscle mass, strength, and volume gain and on the prevention of the progressive decrease in muscle mass with aging in combination with maintaining regular physical activity.