bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intracellular Signalling Pathways Associated with the Glucose-Lowering Effect of St36 Electroacupuncture in Streptozotocin-Induced Diabetic Rats
Authors: Tzeng Chung-Yuh , Lee Yu-Chen , Ho Tin-Yun , Chen Ying-I , Hsu Tai-Hao , Lin Jaung-Geng , Lee Kuan-Rong , Chang Shih-Liang 
Published: May 2015

Background and Aim Previous animal studies have reported a glucose-lowering effect of electroacupuncture (EA) and suggested that the mechanisms are closely related to intracellular signalling pathways. The aim of this study was to screen for potential intracellular signalling pathways that are upregulated by EA at ST36 bilaterally in rats with diabetes mellitus (DM) using microarray analysis. Methods Streptozotocin (STZ)-induced diabetic rats were randomly assigned to experimental (EA, n=8) or control (non-EA, n=8) groups. Plasma glucose levels were measured at baseline and after 30 and 60 min, and microarray analysis was performed on samples of gastrocnemius muscle. Results Relative to baseline values, EA significantly reduced plasma levels of glucose at 30 and 60 min. The microarray pathway analysis showed that cell adhesion molecules and type 1 DM gene sets were both upregulated in EA versus non-EA groups (p<0.05). Conclusions Cell adhesion molecules might be related to the glucose-lowering effect induced by EA in rats with STZ-induced type 1 diabetes. Further research will be required to examine the involvement of related intracellular signalling pathways.
Electroacupuncture plus Metformin Lowers Glucose Levels and Facilitates Insulin Sensitivity by Activating Mapk in Steroid-Induced Insulin-Resistant Rats
Authors: Liao Hsien-Yin , Sun Mao-Feng , Lin Jaung-Geng , Chang Shih-Liang , Lee Yu-Chen 
Published: May 2015

Background Type 2 diabetes mellitus is the predominant form of diabetes. Although metformin is the preferred first-line drug for treatment of the disease, it is associated with a risk of secondary failure. Electroacupuncture (EA) can enhance insulin sensitivity and reduce blood glucose levels. Objectives To examine, in an animal study, whether EA combined with metformin (EA–metformin) results in a better glucose-lowering effect and greater insulin sensitivity than metformin alone in steroid-induced insulin-resistant rats. Methods Adult Wistar rats were injected with dexamethasone to induce diabetes and subsequently treated with EA plus metformin or metformin alone. Variations in plasma glucose, plasma insulin, and plasma free fatty acid levels were studied at the midpoint and end of the experimental course. Insulin receptor substrate 1 (IRS-1) and peroxisome proliferator-activated receptor γ (PPAR-γ), which are associated with glucose transporter type 4 (GLUT4) translocation, and mitogen-activated protein kinase (MAPK), which is related to GLUT4 activation, were measured after EA treatment. Results We found that EA–metformin resulted in a better glucose-lowering effect, greater insulin sensitivity, lower plasma free fatty acid levels and higher levels of MAPK than metformin alone (p<0.05). There were no significant differences between treatment groups in expression of IRS-1 or PPAR-γ. Conclusions The glucose-lowering effect and increased insulin sensitivity associated with EA–metformin administration is governed, at least in part, by its ability to stimulate the activation of GLUT4 via upregulation of MAPK expression.
Transcutaneous Electrical Acupuncture Stimulation as a Countermeasure against Cardiovascular Deconditioning during 4 days of Head-Down Bed Rest in Humans
Authors: Sun Jing , Li Xiaotao , Yang Changbin , Wang Yongchun , Shi Fei , Gao Yuan , Luan Qi , Zhu Yongsheng , Sun Xiqing 
Published: May 2015

Objective Spaceflight is associated with cardiovascular deregulation. However, the influence of microgravity on the cardiovascular system and its mechanisms and countermeasures remain unknown. Our previous studies have demonstrated that transcutaneous electrical acupuncture stimulation (TEAS) is effective in improving orthostatic tolerance (OT). The purpose of this study was to determine if TEAS treatment can attenuate cardiovascular deconditioning induced by a 4-day −6° head-down bed rest (HDBR). Methods Fourteen healthy male subjects were randomly allocated to a control group (control, n=6, 4 days HDBR without countermeasures) and a TEAS treatment group (TEAS, n=8, 4 days HDBR with TEAS at Neiguan (PC6) for 30 min each day for 4 consecutive days during HDBR). OT, plasma hormones, plasma volume and heart rate variability were assessed before and after HDBR. Cardiac function and cerebral blood flow were measured before, during and after HDBR. Results The data showed that TEAS treatment mitigated the decrease in OT that was observed in the control group and cardiac function, alleviated autonomic dysfunction, and partially prevented plasma volume reduction after HDBR. Angiotensin II and aldosterone were significantly increased by 129.3% and 133.3% after HDBR in the TEAS group (p<0.05). Conclusions These results indicate that 30 min of daily TEAS treatment at PC6 is partially effective in maintaining OT, probably due to increased plasma volume-regulating hormones and activation of the peripheral sympathetic nervous system. TEAS treatment appears effective at reducing cardiovascular deconditioning induced by HDBR for 4 days. Trial Registration Number NCT02300207.
Influence of renal complications on the efficacy and adverse events of tacrolimus combination therapy in patients with systemic lupus erythematosus (SLE) during a maintenance phase: a single-centre, prospective study
Authors: Ishii Sho , Miwa Yusuke , Otsuka Kumiko , Nishimi Shinichiro , Nishimi Airi , Saito Mayu , Miura Yoko , Oguro Nao , Tokunaga Takahiro , Takahashi Ryo , Kasama Tsuyoshi 
Published: May 2015

ObjectivesThe study investigated whether renal complications affected the efficacy and safety of tacrolimus combination therapy in patients with systemic lupus erythematosus (SLE) during a maintenance phase.MethodsFifty-seven patients with SLE (A: 30 cases with renal complication, B: 27 cases without renal complications) were included. The presence of renal complications was defined as proteinuria ≥0.5 g/day and lupus nephritis on renal biopsy. Major outcome measures included SLE disease activity index (SLEDAI), steroid dose, serum anti-dsDNA Ab, C3 and creatinine (Cr) levels and estimated glomerular filtration rate (eGFR). The patient's background factors included age, gender, disease duration and ACE-I/angiotensin II receptor blocker and statin therapies. We compared these outcome measures pre treatment and after 1 year of treatment.ResultsThe SLEDAI and serum C3 levels improved in both groups from pretreatment period to post-treatment period: from 7.2±5.0 to 2.8±2.3 in A and 6.4±3.8 to 2.4±2.2 in B, p<0.001, and from 65.9±24.6 to 77.7±18.2 mg/dL in A and 81.8±23.0 to 90.6±19.4 mg/dL in B, p=0.002, respectively. The anti-dsDNA antibody level was reduced, and the serum Cr and eGFR levels were slightly elevated. No patients developed end-stage renal failure that required artificial dialysis.ConclusionsTacrolimus combination therapy had additive beneficial effects on reduced proteinuria and increased serum C3 levels in patients with SLE with renal complications during a maintenance phase.
Initial experience with a new distal intermediate and aspiration catheter in the treatment of acute ischemic stroke: clinical safety and efficacy
Authors: Stampfl Sibylle , Kabbasch Christoph , Müller Marguerite , Mpotsaris Anastasios , Brockmann Marc , Liebig Thomas , Wiesmann Martin , Bendszus Martin , Möhlenbruch Markus A 
Published: May 2015

PurposeTo describe our initial experience with the novel 5 F SOFIA (Soft Torqueable catheter Optimized For Intracranial Access) intermediate and aspiration catheter for endovascular treatment of patients with acute ischemic stroke.MethodsA retrospective review was performed in three centers of prospectively collected data of all stroke patients who underwent endovascular therapy using the SOFIA catheter. Patients were enrolled between November 2013 and December 2014. The primary endpoint of the study was accessibility of the thrombus with the SOFIA catheter. As a secondary endpoint, the study assessed recanalization success (Thrombolysis In Cerebral Infarction (TICI) ≥2b). Clinical presentation on admission and discharge was also documented. In addition, catheter- and procedure-related complications (particularly thromboembolic complications) were recorded.ResultsThe SOFIA catheter was used in 115 acute stroke procedures. In 110 cases (96%) the catheter could be advanced to the occlusion site. After mechanical thrombectomy, successful recanalization (TICI ≥2b) was documented in 86.9%. There were no complications related to positioning of the catheter. Distal thrombus migration into a new vascular territory occurred in three patients following thrombectomy with a stent retriever (2.6%). The mean NIH Stroke Scale (NIHSS) score on admission was 16.8±6 and at discharge the mean NIHSS score was 8.2±7.7. Sixteen patients died.ConclusionsThe SOFIA catheter is a safe and efficient catheter for endovascular stroke therapy.
Incidental findings on chest CT imaging are associated with increased COPD exacerbations and mortality
Authors: Jairam Pushpa M , van der Graaf Yolanda , Lammers Jan-Willem J , Mali Willem P Th M , de Jong Pim A 
Published: May 2015

BackgroundThis study aimed to evaluate whether incidental CT findings of emphysema, airway thickening and bronchiectasis, as seen on CT scans performed for other non-pulmonary clinical indications, are associated with future acute exacerbations of COPD resulting in hospitalisation or death.MethodsThis multicentre prospective case–cohort study comprised 6406 subjects who underwent routine diagnostic chest CT for non-pulmonary indications. Using a case–cohort approach, we visually graded CT scans from cases and a random sample of ∼10% of the baseline cohort (n=704) for emphysema severity (range 0–20), airway thickening (range 0–5) and bronchiectasis (range 0–5). We used weighted Cox proportional hazards analysis to assess the independent association between CT findings and hospitalisation or death due to COPD exacerbation.ResultsDuring a median follow-up of 4.4 years (maximum 5.2 years), 338 COPD events were identified. The risk of experiencing a future acute exacerbation of COPD resulting in hospitalisation or death was significantly increased in subjects with severe emphysema (score ≥7) and severe airway thickening (score ≥3). The respective HRs were 4.6 (95% CI 3.0 to 7.1) and 5.9 (95% CI 3.4 to 10.5). Severe bronchiectasis (score ≥3) was not significantly associated with increased risk of adverse events (HR 1.5; 95% CI 0.9 to 2.5).ConclusionsMorphological correlates of COPD such as emphysema and airway thickening detected on CT scans obtained for other non-pulmonary indications are strong independent predictors of subsequent development of acute exacerbations of COPD resulting in hospitalisation or death.
Longitudinal shape irregularity of airway lumen assessed by CT in patients with bronchial asthma and COPD
Authors: Oguma Tsuyoshi , Hirai Toyohiro , Fukui Motonari , Tanabe Naoya , Marumo Satoshi , Nakamura Hajime , Ito Hisao , Sato Susumu , Niimi Akio , Ito Isao , Matsumoto Hisako , Muro Shigeo , Mishima Michiaki 
Published: May 2015

BackgroundAirway remodelling in bronchial asthma (BA) and COPD has been quantitatively assessed by analysing the airway wall area and the luminal area on cross-sectional CT images. To date, there have been no reports on assessment of the longitudinal structure of the airway lumen.MethodsQuantitative airway analysis using CT was performed on three groups consisting of 29 patients with BA, 58 patients with COPD and 59 healthy controls. To assess the longitudinal shape irregularity of the airway lumen, new quantitative CT parameters, validated by a phantom study, were established. The internal radii of imaginary inscribed spheres in the airway lumen were measured as a function of distance from the level of the carina to the fifth-order branches of the right posterior basal bronchus. The gaps of these radii from the regression line were calculated as parameters to reflect the longitudinal airway lumen shape irregularity. These new parameters were compared among the study groups as well as with the conventional parameters of airway wall thickening and luminal area.ResultsLongitudinal airway lumen shape irregularity was significantly greater in patients with COPD than in those with BA and healthy controls. Wall thickening was significantly greater, and luminal area smaller, in patients with BA than in those with COPD and healthy controls. These results were consistent even among the BA and COPD subgroups with similar airflow limitation.ConclusionsThe combination of cross-sectional and longitudinal airway structure analyses using CT images may suggest differences in the characteristics of airway remodelling between COPD and asthma.
Minor Changes in Expression of the Mismatch Repair Protein MSH2 Exert a Major Impact on Glioblastoma Response to Temozolomide
Authors: McFaline-Figueroa José L. , Braun Christian J. , Stanciu Monica , Nagel Zachary D. , Mazzucato Patrizia , Sangaraju Dewakar , Cerniauskas Edvinas , Barford Kelly , Vargas Amanda , Chen Yimin , Tretyakova Natalia , Lees Jacqueline A. , Hemann Michael T. , White Forest M. , Samson Leona D. 
Published: May 2015

Abstract
Glioblastoma (GBM) is often treated with the cytotoxic drug temozolomide, but the disease inevitably recurs in a drug-resistant form after initial treatment. Here, we report that in GBM cells, even a modest decrease in the mismatch repair (MMR) components MSH2 and MSH6 have profound effects on temozolomide sensitivity. RNAi-mediated attenuation of MSH2 and MSH6 showed that such modest decreases provided an unexpectedly strong mechanism of temozolomide resistance. In a mouse xenograft model of human GBM, small changes in MSH2 were sufficient to suppress temozolomide-induced tumor regression. Using The Cancer Genome Atlas to analyze mRNA expression patterns in tumors from temozolomide-treated GBM patients, we found that MSH2 transcripts in primary GBM could predict patient responses to initial temozolomide therapy. In recurrent disease, the absence of microsatellite instability (the standard marker for MMR deficiency) suggests a lack of involvement of MMR in the resistant phenotype of recurrent disease. However, more recent studies reveal that decreased MMR protein levels occur often in recurrent GBM. In accordance with our findings, these reported decreases may constitute a mechanism by which GBM evades temozolomide sensitivity while maintaining microsatellite stability. Overall, our results highlight the powerful effects of MSH2 attenuation as a potent mediator of temozolomide resistance and argue that MMR activity offers a predictive marker for initial therapeutic response to temozolomide treatment. Cancer Res; 75(15); 3127–38. ©2015 AACR.
Does It MEK a Difference? Understanding Immune Effects of Targeted Therapy
Authors: Cooper Zachary A. , Reuben Alexandre , Austin-Breneman Jacob , Wargo Jennifer A. 
Published: May 2015

Abstract
BRAF inhibitor (BRAFi) treatment enhances antitumor immunity, but is associated with increased intratumoral PD-L1 expression. MEK inhibitors (MEKi) may alter T-cell function; however, recent studies demonstrate preserved T-cell infiltrate during treatment with BRAFi/MEKi. These data have important implications for combining BRAFi/MEKi and checkpoint blockade in the treatment of melanoma. Clin Cancer Res; 21(14); 3102–4. ©2015 AACR.
See related article by Kakavand et al., p. 3140
The TMPRSS2–ERG Gene Fusion Blocks XRCC4-Mediated Nonhomologous End-Joining Repair and Radiosensitizes Prostate Cancer Cells to PARP Inhibition
Authors: Chatterjee Payel , Choudhary Gaurav S. , Alswillah Turkeyah , Xiong Xiahui , Heston Warren D. , Magi-Galluzzi Cristina , Zhang Junran , Klein Eric A. , Almasan Alexandru 
Published: May 2015

Abstract
Exposure to genotoxic agents, such as ionizing radiation (IR), produces DNA damage, leading to DNA double-strand breaks (DSB); IR toxicity is augmented when the DNA repair is impaired. We reported that radiosensitization by a PARP inhibitor (PARPi) was highly prominent in prostate cancer cells expressing the TMPRSS2–ERG gene fusion protein. Here, we show that TMPRSS2–ERG blocks nonhomologous end-joining (NHEJ) DNA repair by inhibiting DNA-PKcs. VCaP cells, which harbor TMPRSS2–ERG and PC3 cells that stably express it, displayed γH2AX and 53BP1 foci constitutively, indicating persistent DNA damage that was absent if TMPRSS2–ERG was depleted by siRNA in VCaP cells. The extent of DNA damage was enhanced and associated with TMPRSS2–ERG's ability to inhibit DNA-PKcs function, as indicated by its own phosphorylation (Thr2609, Ser2056) and that of its substrate, Ser1778-53BP1. DNA-PKcs deficiency caused by TMPRSS2–ERG destabilized critical NHEJ components on chromatin. Thus, XRCC4 was not recruited to chromatin, with retention of other NHEJ core factors being reduced. DNA-PKcs autophosphorylation was restored to the level of parental cells when TMPRSS2–ERG was depleted by siRNA. Following IR, TMPRSS2–ERG-expressing PC3 cells had elevated Rad51 foci and homologous recombination (HR) activity, indicating that HR compensated for defective NHEJ in these cells, hence addressing why TMPRSS2–ERG alone did not lead to radiosensitization. However, the presence of TMPRSS2–ERG, by inhibiting NHEJ DNA repair, enhanced PARPi-mediated radiosensitization. IR in combination with PARPi resulted in enhanced DNA damage in TMPRSS2–ERG-expressing cells. Therefore, by inhibiting NHEJ, TMPRSS2–ERG provides a synthetic lethal interaction with PARPi in prostate cancer patients expressing TMPRSS2–ERG. Mol Cancer Ther; 14(8); 1896–906. ©2015 AACR.
Structure-Based Screen Identifies a Potent Small Molecule Inhibitor of Stat5a/b with Therapeutic Potential for Prostate Cancer and Chronic Myeloid Leukemia
Authors: Liao Zhiyong , Gu Lei , Vergalli Jenny , Mariani Samanta A. , De Dominici Marco , Lokareddy Ravi K. , Dagvadorj Ayush , Purushottamachar Puranik , McCue Peter A. , Trabulsi Edouard , Lallas Costas D. , Gupta Shilpa , Ellsworth Elyse , Blackmon Shauna , Ertel Adam , Fortina Paolo , Leiby Benjamin , Xia Guanjun , Rui Hallgeir , Hoang David T. , Gomella Leonard G. , Cingolani Gino , Njar Vincent , Pattabiraman Nagarajan , Calabretta Bruno , Nevalainen Marja T. 
Published: May 2015

Abstract
Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl–driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain–mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic myeloid leukemia (CML). The lead compound inhibitor of Stat5-002 (IST5-002) prevented both Jak2 and Bcr-Abl–mediated phosphorylation and dimerization of Stat5a/b, and selectively inhibited transcriptional activity of Stat5a (IC50 = 1.5μmol/L) and Stat5b (IC50 = 3.5 μmol/L). IST5-002 suppressed nuclear translocation of Stat5a/b, binding to DNA and Stat5a/b target gene expression. IST5-002 induced extensive apoptosis of prostate cancer cells, impaired growth of prostate cancer xenograft tumors, and induced cell death in patient-derived prostate cancers when tested ex vivo in explant organ cultures. Importantly, IST5-002 induced robust apoptotic death not only of imatinib-sensitive but also of imatinib-resistant CML cell lines and primary CML cells from patients. IST5-002 provides a lead structure for further chemical modifications for clinical development for Stat5a/b-driven solid tumors and hematologic malignancies. Mol Cancer Ther; 14(8); 1777–93. ©2015 AACR.
Inhibition of mTORC2 Induces Cell-Cycle Arrest and Enhances the Cytotoxicity of Doxorubicin by Suppressing MDR1 Expression in HCC Cells
Authors: Chen Bryan Wei , Chen Wei , Liang Hui , Liu Hao , Liang Chao , Zhi Xiao , Hu Li-qiang , Yu Xia-Zhen , Wei Tao , Ma Tao , Xue Fei , Zheng Lei , Zhao Bin , Feng Xin-Hua , Bai Xue-li , Liang Ting-bo 
Published: May 2015

Abstract
mTOR is aberrantly activated in hepatocellular carcinoma (HCC) and plays pivotal roles in tumorigenesis and chemoresistance. Rapamycin has been reported to exert antitumor activity in HCC and sensitizes HCC cells to cytotoxic agents. However, due to feedback activation of AKT after mTOR complex 1 (mTORC1) inhibition, simultaneous targeting of mTORC1/2 may be more effective. In this study, we examined the interaction between the dual mTORC1/2 inhibitor OSI-027 and doxorubicin in vitro and in vivo. OSI-027 was found to reduce phosphorylation of both mTORC1 and mTORC2 substrates, including 4E-BP1, p70S6K, and AKT (Ser473), and inhibit HCC cell proliferation. Similar to OSI-027 treatment, knockdown of mTORC2 induced G0–G1 phase cell-cycle arrest. In contrast, rapamycin or knockdown of mTORC1 increased phosphorylation of AKT (Ser473), yet had little antiproliferative effect. Notably, OSI-027 synergized with doxorubicin for the antiproliferative efficacy in a manner dependent of MDR1 expression in HCC cells. The synergistic antitumor effect of OSI-027 and doxorubicin was also observed in a HCC xenograft mouse model. Moreover, AKT was required for OSI-027–induced cell-cycle arrest and downregulation of MDR1. Our findings provide a rationale for dual mTORC1/mTORC2 inhibitors, such as OSI-027, as monotherapy or in combination with cytotoxic agents to treat HCC. Mol Cancer Ther; 14(8); 1805–15. ©2015 AACR.
STAT3 in CD8+ T Cells Inhibits Their Tumor Accumulation by Downregulating CXCR3/CXCL10 Axis
Authors: Yue Chanyu , Shen Shudan , Deng Jiehui , Priceman Saul J. , Li Wenzhao , Huang Austin , Yu Hua 
Published: May 2015

Abstract
One of the obstacles for cancer immunotherapy is the inefficiency of CD8+ T-cell recruitment to tumors. STAT3 has been shown to suppress CD8+ T-cell antitumor functions in various cancer models, in part by restricting accumulation of CD8+ T cells. However, the underlying molecular mechanism by which STAT3 in CD8+ T cells inhibits their accumulation in tumors remains to be defined. Here, we show that STAT3 signaling in CD8+ T cells inhibits chemokine CXCL10 production by tumor-associated myeloid cells by reducing IFNγ expression by T cells. We further demonstrate that ablating STAT3 in T cells allows expression of CXCR3, the receptor of CXCL10, on CD8+ T cells, resulting in efficient accumulation of CD8+ T cells at tumor sites. Blocking IFNγ or CXCR3 impairs the accumulation of STAT3-deficient CD8+ T cells in tumor and their antitumor effects. Together, our study reveals a negative regulation by STAT3 signaling in T cells on cross-talk between myeloid cells and T cells through IFNγ/CXCR3/CXCL10, which is important for CD8+ T cells homing to tumors. Our results thus provide new insights applicable to cancer immunotherapy and adoptive T-cell strategies. Cancer Immunol Res; 3(8); 864–70. ©2015 AACR.