bluuebunny/crossref_metadata_2025_split huggingface dataset:
Critical Function for Nuclear Envelope Protein TMEM209 in Human Pulmonary Carcinogenesis
Authors: Fujitomo Takashi , Daigo Yataro , Matsuda Koichi , Ueda Koji , Nakamura Yusuke 
Published: June 2012

AbstractTherapeutic targets for more effective and less toxic treatments of lung cancer remain important. Here we report the identification of the integral nuclear envelope protein TMEM209 as a critical driver of human lung cancer growth and survival. TMEM209 expression was normally limited to testis, but we found that it was widely expressed in lung cancer, in which it localized to the nuclear envelope, Golgi apparatus, and the cytoplasm of lung cancer cells. Ectopic overexpression of TMEM209 promoted cell growth, whereas TMEM209 attenuation was sufficient to block growth. Mass spectrometric analysis identified the nucleoporin protein NUP205 as a TMEM209-interacting protein, stabilizing NUP205 and increasing the level of c-Myc in the nucleus. Taken together, our findings indicate that TMEM209 overexpression and TMEM209–NUP205 interaction are critical drivers of lung cancer proliferation, suggesting a promising new target for lung cancer therapy. Cancer Res; 72(16); 4110–8. ©2012 AACR.
Epithelial Plasticity, Cancer Stem Cells, and the Tumor-Supportive Stroma in Bladder Carcinoma
Authors: van der Horst Geertje , Bos Lieke , van der Pluijm Gabri 
Published: June 2012

Abstract
High recurrence rates and poor survival rates of metastatic bladder cancer emphasize the need for a drug that can prevent and/or treat bladder cancer progression and metastasis formation. Accumulating evidence suggests that cancer stem/progenitor cells are involved in tumor relapse and therapy resistance in urothelial carcinoma. These cells seem less affected by the antiproliferative therapies, as they are largely quiescent, have an increased DNA damage response, reside in difficult-to-reach, protective cancer stem cell niches and express ABC transporters that can efflux drugs from the cells. Recent studies have shown that epithelial-to-mesenchymal transition (EMT), a process in which sessile, epithelial cells switch to a motile, mesenchymal phenotype may render cancer cells with cancer stem cells properties and/or stimulate the expansion of this malignant cellular subpopulation. As cancer cells undergo EMT, invasiveness, drug resistance, angiogenesis, and metastatic ability seem to increase in parallel, thus giving rise to a more aggressive tumor type. Furthermore, the tumor microenvironment (tumor-associated stromal cells, extracellular matrix) plays a key role in tumorigenesis, tumor progression, and metastasis formation. Taken together, the secret for more effective cancer therapies might lie in developing and combining therapeutic strategies that also target cancer stem/progenitor cells and create an inhospitable microenvironment for highly malignant bladder cancer cells. This review will focus on the current concepts about the role of cancer stem cells, epithelial plasticity, and the supportive stroma in bladder carcinoma. The potential implications for the development of novel bladder cancer therapy will be discussed. Mol Cancer Res; 10(8); 995–1009. ©2012 AACR.
The HIF-1α Hypoxia Response in Tumor-Infiltrating T Lymphocytes Induces Functional CD137 (4-1BB) for Immunotherapy
Authors: Palazón Asís , Martínez-Forero Iván , Teijeira Alvaro , Morales-Kastresana Aizea , Alfaro Carlos , Sanmamed Miguel F. , Perez-Gracia Jose Luis , Peñuelas Iván , Hervás-Stubbs Sandra , Rouzaut Ana , Landázuri Manuel Ortiz de , Jure-Kunkel Maria , Aragonés Julian , Melero Ignacio 
Published: June 2012

AbstractThe tumor microenvironment of transplanted and spontaneous mouse tumors is profoundly deprived of oxygenation as confirmed by positron emission tomographic (PET) imaging. CD8 and CD4 tumor-infiltrating T lymphocytes (TIL) of transplanted colon carcinomas, melanomas, and spontaneous breast adenocarcinomas are CD137 (4-1BB)-positive, as opposed to their counterparts in tumor-draining lymph nodes and spleen. Expression of CD137 on activated T lymphocytes is markedly enhanced by hypoxia and the prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG). Importantly, hypoxia does not upregulate CD137 in hypoxia-inducible factor (HIF)-1α–knockout T cells, and such HIF-1α–deficient T cells remain CD137-negative even when becoming TILs, in clear contrast to co-infiltrating and co-transferred HIF-1α–sufficient T lymphocytes. The fact that CD137 is selectively expressed on TILs was exploited to confine the effects of immunotherapy with agonist anti-CD137 monoclonal antibodies to the tumor tissue. As a result, low-dose intratumoral injections avoid liver inflammation, achieve antitumor systemic effects, and permit synergistic therapeutic effects with PD-L1/B7-H1 blockade.Significance: CD137 (4-1BB) is an important molecular target to augment antitumor immunity. Hypoxia in the tumor microenvironment as sensed by the HIF-1α system increases expression of CD137 on tumor-infiltrating lymphocytes that thereby become selectively responsive to the immunotherapeutic effects of anti-CD137 agonist monoclonal antibodies as those used in ongoing clinical trials. Cancer Discov; 2(7); 608–23. ©2012 AACR.Read the Commentary on this article by Melief, p. 586.This article is highlighted in the In This Issue feature, p. 569.
Chimeric Transcript Generated by cis-Splicing of Adjacent Genes Regulates Prostate Cancer Cell Proliferation
Authors: Zhang Yanmei , Gong Mei , Yuan Huiling , Park Hong G. , Frierson Henry F. , Li Hui 
Published: June 2012

Abstract
Gene fusion is a common event in cancer. The fusion RNA and protein products often play causal roles in tumorigenesis and therefore represent ideal diagnostic and therapeutic targets. Formerly, fusion chimeric products in cancer were thought to be produced solely by chromosomal translocation. Here, we show that a chimeric SLC45A3-ELK4 RNA is generated in the absence of chromosomal rearrangement. We showed that it is not a product of RNA trans-splicing, but formed by cis-splicing of adjacent genes/read-through. The binding of CCCTC-binding factor (CTCF) to the insulator sequences inversely correlates with the expression of the chimera transcript. The SLC45A3-ELK4 fusion, but not wild-type, ELK4 plays important roles in regulating cell growth in both androgen-dependent and -independent prostate cancer cells. The level of the chimeric transcript correlates with disease progression, with the highest levels in prostate cancer metastases. Our results suggest that gene fusions can arise from cis-splicing of adjacent genes without corresponding DNA changes.
Significance: With the absence of corresponding DNA rearrangement, chimeric fusion SLC45A3-ELK4 transcript in prostate cancer cells is generated by cis-splicing of adjacent genes/gene read-through instead of trans-splicing. SLC45A3-ELK4 controls prostate cancer cell proliferation, and the chimera level correlates with prostate cancer disease progression. Cancer Discov; 2(7); 598–607. ©2012 AACR.
Read the Commentary on this article by Kumar-Sinha et al., p. 582.
This article is highlighted in the In This Issue feature, p. 569.
Interplay of Coronary Artery Calcification and Traditional Risk Factors for the Prediction of All-Cause Mortality in Asymptomatic Individuals
Authors: Nasir Khurram , Rubin Jonathan , Blaha Michael J. , Shaw Leslee J. , Blankstein Ron , Rivera Juan J. , Khan Atif N. , Berman Daniel , Raggi Paolo , Callister Tracy , Rumberger John A. , Min James , Jones Steve R. , Blumenthal Roger S. , Budoff Matthew J. 
Published: June 2012

Background—
Current guidelines recommend the use of coronary artery calcium (CAC) scoring for intermediate-risk patients; however, the potential role of CAC among individuals who have no risk factors (RFs) is less established. We sought to examine the relationship between the presence and burden of traditional RFs and CAC for the prediction of all-cause mortality.

Methods and Results—
The study cohort consisted of 44 052 consecutive asymptomatic individuals free of known coronary heart disease referred for computed tomography for the assessment of CAC. The following RFs were considered: (1) current cigarette smoking, (2) dyslipidemia, (3) diabetes mellitus, (4) hypertension, and (5) family history of coronary heart disease. Patients were followed for a mean of 5.6±2.6 years for the primary end point of all-cause mortality. Among individuals who had no RF, Cox proportional model adjusted for age and sex identified that increasing CAC scores were associated with 3.00- to 13.38-fold higher mortality risk. The lowest survival rate was observed in those with no CAC and no RF, whereas those with CAC≥400 and ≥3 RFs had the highest all-cause fatality rate. Notably, individuals with no RF and CAC≥400 had a substantially higher mortality rate compared with individuals with ≥3 RFs in the absence of CAC (16.89 versus 2.72 per 1000 person-years).

Conclusions—
By highlighting that individuals without RFs but elevated CAC have a substantially higher event rates than those who have multiple RFs but no CAC, these findings challenge the exclusive use of traditional risk assessment algorithms for guiding the intensity of primary prevention therapies.
Polyvascular Disease and Long-Term Cardiovascular Outcomes in Older Patients With Non–ST-Segment–Elevation Myocardial Infarction
Authors: Subherwal Sumeet , Bhatt Deepak L. , Li Shuang , Wang Tracy Y. , Thomas Laine , Alexander Karen P. , Patel Manesh R. , Ohman E. Magnus , Gibler W. Brian , Peterson Eric D. , Roe Matthew T. 
Published: June 2012

Background—
The impact of polyvascular disease (peripheral arterial disease [PAD] and cerebrovascular disease [CVD]) on long-term cardiovascular outcomes among older patients with acute myocardial infarction has not been well studied.

Methods and Results—
Patients with non–ST-segment–elevation myocardial infarction aged ≥65 years from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines) registry who survived to hospital discharge were linked to longitudinal data from the Centers for Medicare & Medicaid Services (n=34 205). All patients were presumed to have coronary artery disease (CAD) and were classified into the following 4 groups: 10.7% with prior CVD (CAD+CVD group); 11.5% with prior PAD (CAD+PAD); 3.1% with prior PAD and CVD (CAD+PAD+CVD); and 74.7% with no polyvascular disease (CAD alone). Cox proportional hazards modeling was used to examine the hazard of long-term mortality and composite of death or readmission for myocardial infarction or stroke (median follow-up, 35 months; interquartile range, 17–49 months). Compared with the CAD alone group, patients with polyvascular disease had greater comorbidities, were less likely to undergo revascularization, and received less often recommended discharge interventions. Three-year mortality rates increased with number of arterial bed involvement as follows: 33% for CAD alone, 49% for CAD+PAD, 52% for CAD+CVD, and 59% for CAD+PAD+CVD. Relative to the CAD alone group, patients with all 3 arterial beds involved had the highest risk of long-term mortality (adjusted hazard ratio [95% CI], 1.49 [1.38–1.61]; CAD+CVD, 1.38 [1.31–1.44]; CAD+PAD, 1.29 [1.23–1.35]). Similarly, the risk of long-term composite ischemic events was highest among patients in the CAD+PAD+CVD group.

Conclusions—
Among older patients with non–ST-segment–elevation myocardial infarction, those with polyvascular disease have substantially higher long-term risk for recurrent events or death. Future studies targeting greater adherence to secondary prevention strategies and novel therapies are needed to help to reduce long-term cardiovascular events in this vulnerable population.
Effects of Repetitive Transcranial Magnetic Stimulation on Motor Functions in Patients With Stroke
Authors: Hsu Wan-Yu , Cheng Chia-Hsiung , Liao Kwong-Kum , Lee I-Hui , Lin Yung-Yang 
Published: June 2012

Background and Purpose—
The purpose of this study was to perform a meta-analysis of studies that investigated the effects of repetitive transcranial magnetic stimulation (rTMS) on upper limb motor function in patients with stroke.

Methods—
We searched for randomized controlled trials published between January 1990 and October 2011 in PubMed, Medline, Cochrane, and CINAHL using the following key words: stroke, cerebrovascular accident, and repetitive transcranial magnetic stimulation. The mean effect size and a 95% CI were estimated for the motor outcome and motor threshold using fixed and random effect models.

Results—
Eighteen of the 34 candidate articles were included in this analysis. The selected studies involved a total of 392 patients. A significant effect size of 0.55 was found for motor outcome (95% CI, 0.37–0.72). Further subgroup analyses demonstrated more prominent effects for subcortical stroke (mean effect size, 0.73; 95% CI, 0.44–1.02) or studies applying low-frequency rTMS (mean effect size, 0.69; 95% CI, 0.42–0.95). Only 4 patients of the 18 articles included in this analysis reported adverse effects from rTMS.

Conclusions—
rTMS has a positive effect on motor recovery in patients with stroke, especially for those with subcortical stroke. Low-frequency rTMS over the unaffected hemisphere may be more beneficial than high-frequency rTMS over the affected hemisphere. Recent limited data suggest that intermittent theta-burst stimulation over the affected hemisphere might be a useful intervention. Further well-designed studies in a larger population are required to better elucidate the differential roles of various rTMS protocols in stroke treatment.
Neural Stem Cells Genetically Modified to Overexpress Cu/Zn-Superoxide Dismutase Enhance Amelioration of Ischemic Stroke in Mice
Authors: Sakata Hiroyuki , Niizuma Kuniyasu , Wakai Takuma , Narasimhan Purnima , Maier Carolina M. , Chan Pak H. 
Published: June 2012

Background and Purpose—
The harsh host brain microenvironment caused by production of reactive oxygen species after ischemic reperfusion injury offers a significant challenge to survival of transplanted neural stem cells (NSCs) after ischemic stroke. Copper/zinc-superoxide dismutase (SOD1) is a specific antioxidant enzyme that counteracts superoxide anions. We have investigated whether genetic manipulation to overexpress SOD1 enhances survival of grafted stem cells and accelerates amelioration of ischemic stroke.

Methods—
NSCs genetically modified to overexpress or downexpress SOD1 were administered intracerebrally 2 days after transient middle cerebral artery occlusion. Histological and behavioral tests were examined from Days 0 to 28 after stroke.

Results—
Overexpression of SOD1 suppressed production of superoxide anions after ischemic reperfusion injury and reduced NSC death after transplantation. In contrast, downexpression of SOD1 promoted superoxide generation and increased oxidative stress-mediated NSC death. Transplantation of SOD1-overexpressing NSCs enhanced angiogenesis in the ischemic border zone through upregulation of vascular endothelial growth factor. Moreover, grafted SOD1-overexpressing NSCs reduced infarct size and improved behavioral performance compared with NSCs that were not genetically modified.

Conclusions—
Our findings reveal a strong involvement of SOD1 expression in NSC survival after ischemic reperfusion injury. We propose that conferring antioxidant properties on NSCs by genetic manipulation of SOD1 is a potential approach for enhancing the effectiveness of cell transplantation therapy in ischemic stroke.
Massively multiplayer online role-playing games (MMORPG): Association between its addiction, self-control and mental disorders among young people in Vietnam
Authors: Son Dinh Thai , Yasuoka Junko , Poudel Krishna C. , Otsuka Keiko , Jimba Masamine 
Published: June 2012

Aims: To explore the association between MMORPG addiction and mental health status, and between self-control ability and mental health status among young male MMORPG players in Hanoi, Vietnam. Methods: In this cross-sectional study, 10 computer game rooms were randomly selected out of 77 in five communes in Hanoi. From these game rooms, 350 MMORPG players were purposively recruited as a study group, of whom 344 completed the questionnaire. In the same five communes, 344 non-players were selected as a control group. An online game addiction scale, a self-control scale and the Vietnamese SRQ-20 were used to measure the degree of MMORPG addiction, self-control ability and level of mental disorders. Results: MMORPG players had significantly higher mental disorders scale scores than non-players ( p < .001). The strongest positive correlation was detected between MMORPG addiction scale scores and mental disorders scale scores ( r = 0.730, p < .001). Self-control scale scores were negatively associated with mental disorders scale scores ( r = -0.345, p < .001). The average amount of money spent on games per month, MMORPG addiction scale score and self-control scale score were considered the best predictors of a higher mental disorders scale score. Conclusion: Young, male MMORPG players with higher addiction scores were more likely to have higher mental disorders scale scores, and such mental status was negatively associated with the level of self-control in Hanoi, Vietnam. Closer attention should be paid to prevent mental disorders among MMORPG players.
Self-stigma and attitudes about treatment in depressed patients in a hospital setting
Authors: Gaudiano Brandon A , Miller Ivan W 
Published: June 2012

Aims: Many patients have stigma about depression, which may inhibit treatment seeking. However, most previous research in this area has been conducted in outpatient samples. The current study investigated self-stigma and its relationship with treatment beliefs in depressed patients receiving psychiatric hospital treatment. Method: The sample consisted of 55 hospitalized patients with depressive disorders who completed measures of self-stigma, medication beliefs, psychotherapy beliefs and depression. Results: Multiple regression analyses controlling for demographic variables demonstrated that higher depression severity was associated with increased self-stigma related to treatment and having depression. Higher self-stigma about treatment was associated with more negative beliefs about psychiatric medications, but more positive beliefs about psychotherapy. In contrast, self-stigma about depression was associated with negative beliefs about medications, but not psychotherapy. Conclusions: Psychiatric hospital treatment, particularly in the USA, emphasizes medication treatment while de-emphasizing evidence-based psychosocial interventions. Individuals with negative views about psychiatric medications and positive views about the value of psychotherapy have higher treatment self-stigma, which may discourage them from seeking hospital treatment when needed or negatively affect their treatment response.
From self-care to hospitalization: Bipolar patients’ health care practices in Mexico
Authors: Vargas-Huicochea Ingrid , Berenzon-Gorn Shoshana 
Published: June 2012

Background: New research is continually improving the comprehension of bipolar disorder (BD). However, many challenges remain to be addressed, such as understanding the health care practices (HCPs) chosen by bipolar patients and the determinants of seeking treatment. Material: Using a qualitative approach, we studied the HCPs of six patients with BD through focused interviews. Discussion: Even patients who report using primarily allopathic care usually test out and combine different HCPs. Conclusion: Pathways to care in BD are composed of a combination of HCPs because patients need to develop a stock of potential treatment alternatives to deal with the suffering involved in living with BD.
Managing Diabetes From First Diagnosis
Authors: Kruger Davida F. 
Published: June 2012

Purpose A review of the pathophysiologic features of early type 2 diabetes mellitus, the benefits of early glycemic control, the concerns of patients that may influence treatment adherence, and how the use of newer treatment options are addressed. Conclusion Given the multifactorial nature of diabetes pathophysiology, early combination therapy incorporating agents with different mechanisms of action is advocated. Medication side effects and risks influence patients’ treatment choices. These concerns include hypoglycemia, weight gain, and fears of treatment failure. With the increasing complexity of therapy regimens for diabetes, the role of diabetes educators includes recommending therapy, counseling about adverse effects, monitoring for contraindications, identifying therapeutic duplication, as well as discussion of new agents to optimize patient outcomes. A case study is used to describe the process of choosing well-tolerated therapies at first diagnosis.
Managing Diabetes in the Middle-Aged Patient When Loss of Glycemic Control Occurs
Authors: Peters Anne 
Published: June 2012

Purpose The purpose of this article is to review the treatment of a patient with type 2 diabetes who is commonly seen in practice—specifically, a middle-aged obese patient with micro- and macrovascular complications whose A1C rises after therapeutic intervention. Discussion of glucose management, as well as hypertension, dyslipidemia, and obesity comorbidities, is included. Conclusion The key to successful treatment is individualization of targets and therapeutic choices. GLP-1 receptor agonists have been shown to be effective in the treatment of type 2 diabetes, including aiding with A1C reduction and weight loss. Using a combination of old and new treatments for the management of diabetes can help to improve outcomes.
Preeclampsia and angiotensin converting enzyme (ACE) I/D and angiotensin II type-1 receptor (AT1R) A1166C polymorphisms: association with ACE I/D polymorphism
Authors: Rahimi Zohreh , Rahimi Ziba , Mozafari Hadi , Parsian Abbas 
Published: June 2012

Background: The aim of the present study was to investigate the association between angiotensin converting enzyme (ACE) insertion/deletion (I/D) and angiotensin II type-1 receptor (AT1R) A1166C polymorphisms with the risk of preeclampsia and lipid peroxidation in preeclamptic women from Western Iran. Methods: One hundred and ninety-eight preeclamptic women (128 women with mild and 70 with severe forms) and 100 age- and parity-matched controls were enrolled in this case-control study. Results: The presence of D allele of ACE was associated with a 1.8-fold increased risk of preeclampsia ( p=0.002) in total preeclamptic patients. The frequency of AT1R AC+CC genotypes was higher in mild preeclamptic women (32%) compared to controls (27.2%) ( p>0.05). In mild preeclamptic women with ID genotype, the level of total antioxidant capacity (TAC) was significantly decreased compared to those with II genotype. Also, there was a trend toward increasing malondialdehyde (MDA) and decreasing TAC levels in mild and severe preeclamptic women with AT1R AA through CC genotypes. Conclusions: Our study indicates that lipid peroxidation and oxidative stress are involved in the development of preeclampsia that might be influenced by polymorphism in the renin-angiotensin-aldosterone system genes.