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Background/purpose Several long non-coding RNAs (lncRNAs) harbor miRNA in their genome. MIR31HG harbors miR-31 in its intron and it is speculated that they are co-expressed in tumors. This study addressed whether frequent miR-31 and MIR31HG co-upregulation occurred in oral squamous cell carcinoma (OSCC) and its clinical implications. Materials and methods Microarray was performed to retrieve dis-regulated lncRNAs from tissue sample. The ectopic gene expression was carried out to specify the phenotypic influences of selected lncRNA screened from bioinformatic algorithms. The expression of miR-31 and MIR31HG in tissues or scrapped samples was analyzed using qRT-PCR. The implications of gene expression as related to metastasis or survival were further dissected. Results Microarray identified disrupted transcripts including MIR31HG and other 152 lncRNAs aberrantly expressed in OSCC tissues. In silico algorithms annotated an eminent involvement of aberrant transcripts in the regulation of cell cycle, extracellular modulation, adhesion, and wound healing. The enhancement of proliferation, wound healing, invasion and anchorage-independent colony formation mediated by MIR31HG was ascertained by ectopic expression in OECM1 cells. Besides, co-upregulation of miR-31 and MIR31HG was conspicuous in OSCC tissues. High expression of miR-31 and MIR31HG designated a trend of worse OSCC prognosis. Interestingly, high MIR31HG expression defined a very poor survival in stage IV diseases. By contrast, high miR-31 expression predicted nodal metastasis in stage I–III diseases. Conclusion Assessment of miR-31 and MIR31HG expression in OSCC may enable the prognostic prediction. The candidate lncRNAs isolated from this work can be further validated as crucial factors contributing to OSCC pathogenesis.

Background The optimal posttreatment surveillance strategy for nasopharyngeal carcinoma (NPC) remains unclear. Circulating cell-free Epstein-Barr virus (cfEBV) DNA has been recognized as a promising biomarker to facilitate early detection of NPC recurrence. Therefore, we aim to determine whether integrating circulating cfEBV DNA into NPC follow-up is cost-effective. Methods For each stage of asymptomatic nonmetastatic NPC patients after complete remission to primary NPC treatment, we developed a Markov model to compare the cost-effectiveness of the following surveillance strategies: routine follow-up strategy, i.e., (1) routine clinical physical examination; routine imaging strategies, including (2) routine magnetic resonance imaging plus computed tomography plus bone scintigraphy (MRI + CT + BS); and (3) routine 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT); cfEBV DNA-guided imaging strategies, including (4) cfEBV DNA-guided MRI + CT + BS and (5) cfEBV DNA-guided PET/CT. Clinical probabilities, utilities, and costs were derived from published studies or databases. Sensitivity analyses were performed. Results For all disease stages, cfEBV DNA-guided imaging strategies demonstrated similar survival benefits but were considerably more economical than routine imaging strategies. They only required approximately one quarter of the number of imaging studies compared with routine imaging strategies to detect one recurrence. Specifically, cfEBV DNA-guided MRI + CT + BS was most cost-effective for stage II (incremental cost-effectiveness ratio [ICER] $57,308/quality-adjusted life-year [QALY]) and stage III ($46,860/QALY) patients, while cfEBV DNA-guided PET/CT was most cost-effective for stage IV patients ($62,269/QALY). However, routine follow-up was adequate for stage I patients due to their low recurrence risk. Conclusions The cfEBV DNA-guided imaging strategies are effective and cost-effective follow-up methods in NPC. These liquid biopsy-based strategies offer evidence-based, stage-specific surveillance modalities for clinicians and reduce disease burden for patients.

Arginine methylation is an important posttranslational modification catalyzed by protein arginine methyltransferases (PRMTs). However, the role of PRMTs in colorectal cancer (CRC) progression is not well understood. Here we report that non-POU domain-containing octamer-binding protein (NONO) is overexpressed in CRC tissue and is a potential marker for poor prognosis in CRC patients. NONO silencing resulted in decreased proliferation, migration, and invasion of CRC cells, whereas overexpression had the opposite effect. In a xenograft model, tumors derived from NONO-deficient CRC cells were smaller than those derived from wild-type (WT) cells, and PRMT1 inhibition blocked CRC xenograft progression. A mass spectrometry analysis indicated that NONO is a substrate of PRMT1. R251 of NONO was asymmetrically dimethylated by PRMT1 in vitro and in vivo. Compared to NONO WT cells, NONO R251K mutant-expressing CRC cells showed reduced proliferation, migration, and invasion, and PRMT1 knockdown or pharmacological inhibition abrogated the malignant phenotype associated with NONO asymmetric dimethylation in both KRAS WT and mutant CRC cells. Compared to adjacent normal tissue, PRMT1 was highly expressed in the CRC zone in clinical specimens, which was correlated with poor overall survival in patients with locally advanced CRC. These results demonstrate that PRMT1-mediated methylation of NONO at R251 promotes CRC growth and metastasis, and suggest that PRMT1 inhibition may be an effective therapeutic strategy for CRC treatment regardless of KRAS mutation status.

Background Conditional survival (CS) provides dynamic prognostic estimates by considering the patients existing survival time. Since CS for endemic nasopharyngeal carcinoma (NPC) is lacking, we aimed to assess the CS of endemic NPC and establish a web‐based calculator to predict individualized, conditional site‐specific recurrence risk. Methods Using an NPC‐specific database with a big‐data intelligence platform, 10,058 endemic patients with non‐metastatic stage I–IVA NPC receiving intensity‐modulated radiotherapy with or without chemotherapy between April 2009 and December 2015 were investigated. Crude CS estimates of conditional overall survival (COS), conditional disease‐free survival (CDFS), conditional locoregional relapse‐free survival (CLRRFS), conditional distant metastasis‐free survival (CDMFS), and conditional NPC‐specific survival (CNPC‐SS) were calculated. Covariate‐adjusted CS estimates were generated using inverse probability weighting. A prediction model was established using competing risk models and was externally validated with an independent, non‐metastatic stage I–IVA NPC cohort undergoing intensity‐modulated radiotherapy with or without chemotherapy (n = 601) at another institution. Results The median follow‐up of the primary cohort was 67.2 months. The 5‐year COS, CDFS, CLRRFS, CDMFS, and CNPC‐SS increased from 86.2%, 78.1%, 89.8%, 87.3%, and 87.6% at diagnosis to 87.3%, 87.7%, 94.4%, 96.0%, and 90.1%, respectively, for an existing survival time of 3 years since diagnosis. Differences in CS estimates between prognostic factor subgroups of each endpoint were noticeable at diagnosis but diminished with time, whereas an ever‐increasing disparity in CS between different age subgroups was observed over time. Notably, the prognoses of patients that were poor at diagnosis improved greatly as patients survived longer. For individualized CS predictions, we developed a web‐based model to estimate the conditional risk of local (C‐index, 0.656), regional (0.667), bone (0.742), lung (0.681), and liver (0.711) recurrence, which significantly outperformed the current staging system (P < 0.001). The performance of this web‐based model was further validated using an external validation cohort (median follow‐up, 61.3 months), with C‐indices of 0.672, 0.736, 0.754, 0.663, and 0.721, respectively. Conclusions We characterized the CS of endemic NPC in the largest cohort to date. Moreover, we established a web‐based calculator to predict the CS of site‐specific recurrence, which may help to tailor individualized, risk‐based, time‐adapted follow‐up strategies.

We aimed to investigate the prognostic value of radiation interruptions at different times on the overall survival (OS) and disease‐free survival (DFS) of patients with nasopharyngeal carcinoma receiving intensity‐modulated radiation therapy. Totally, 4510 patients were identified from a well‐established big‐data intelligence platform. Optimal interruption thresholds were identified using Recursive partitioning analyses. Actuarial rates were plotted using the Kaplan–Meier method and were compared using the log‐rank test. Patients with preceding interruptions ≥1 d (5‐year OS, 89.6% vs. 85.7%, p, Our findings suggest that radiation interruptions longer than 3 days that occurred in the latter period of treatment with IMRT were independent factors in poorer survival. Efforts are needed to minimize radiation interruptions and improve the timely provision of treatment.

Objectives: Achievement of patients’ preferred place of death is recognized as a component of a good death. This study aimed to investigate the symptom burden in advanced cancer patients, achievement of their place of death preferences and factors associated with home death. Methods: In this retrospective review of 287 patient deaths, we examined patients’ symptom prevalence, preferred and actual place of death and achievement of their place of death preferences using descriptive statistics. Associations between patient factors, home death preference and actual home death were further analyzed using multivariate logistic regression. Results: The most prevalent symptoms were weakness, pain and poor appetite, with a mean of 5.77(SD: 2.37) symptoms per patient. The median interval from palliative care referral to death was 21 (IQR: 74) days. Of the 253 patients with documented place of death preference, 132 (52.1%) preferred home death, 111(43.9%) preferred hospital death, 1 (0.4%) preferred to die at a temple and 9(3.6%) expressed no preference. Overall, 221 of 241(91.7%) patients with known actual place of death achieved their preference. Older patients were more likely to prefer home death (OR 1.021; 95% CI 1.004-1.039, p = 0.018) and die at home (OR 1.023; 95% CI 1.005-1.041, p = 0.014). Gender, marital status, cancer diagnosis and symptoms were not associated with preference for or actual home death. Conclusion: Despite a high symptom burden, most patients preferred and achieved a home death. Late palliative care referral and difficult symptom management contributed to failure to fulfill home death preference. Preference for home death should be considered when managing terminally ill geriatric patients.

Key Points Question What are the associations of cancer stage at time of diagnosis, treatment, and marital status with cancer-specific survival? Findings This cohort study of 1.7 million adults with cancer found that stage at diagnosis mediated the association of marriage with cancer-specific survival in breast, colorectal, and endometrial cancers as well as melanoma; receiving surgery mediated the association in lung, pancreatic, and prostate cancers; and receiving chemotherapy mediated the association in lung and pancreatic cancers. Meaning These findings suggest that promoting the early diagnosis of breast, colorectal, and endometrial cancers and melanoma and providing definitive treatment for lung, pancreatic, and prostate cancers could improve cancer-specific survival among unmarried patients with cancer., This cohort study evaluates the extent to which marriage is associated with cancer-specific survival, stage at diagnosis, and treatment among patients with 9 common solid cancers and recommends methods for reducing the survival gap., Importance Married patients with cancer have better cancer-specific survival than unmarried patients. Increasing the early diagnosis and definitive treatment of cancer among unmarried patients may reduce the survival gap. Objectives To evaluate the extent to which marriage is associated with cancer-specific survival, stage at diagnosis, and treatment among patients with 9 common solid cancers and to recommend methods for reducing the survival gap. Design, Setting, and Participants This retrospective, population-based cohort study included patients older than 18 years who were diagnosed with 1 of 9 common cancers between January 1, 2007, and December 31, 2016. Patient data were retrieved from the Surveillance, Epidemiology, and End Results Program. Statistical analyses were performed from August 1 to October 1, 2020. Exposures Marital status, classified as married and unmarried (including single, separated, divorced, widowed, and unmarried patients or domestic partners). Main Outcomes and Measures The primary outcome was the time ratio (TR) of cancer-specific survival (married vs unmarried). Mediation analyses were conducted to determine the extent to which the association of marriage with cancer-specific survival was mediated by stage at diagnosis and treatment. Results This study included 1 733 906 patients (894 379 [51.6%] women; 1 067 726 [61.6%] married; mean [SD] age, 63.76 [12.60] years). Multivariate analyses found that those who were married were associated with better cancer-specific survival than unmarried patients (TR, 1.36; 95% CI, 1.35-1.37). Early diagnosis in breast cancer, colorectal cancer, endometrial cancer, and melanoma mediated the association between marital status and cancer-specific survival (breast cancer: proportion mediated [PM], 11.4%; 95% CI, 11.2%-11.6%; colorectal cancer: PM, 10.9%; 95% CI, 10.7%-11.2%; endometrial cancer: PM, 12.9%; 95% CI, 12.5%-13.3%; melanoma: PM, 12.0%; 95% CI, 11.7-12.4%). Surgery mediated the association between marital status and cancer-specific survival in lung (PM, 52.2%; 95% CI, 51.9%-52.4%), pancreatic (PM, 28.9%; 95% CI, 28.6%-29.3%), and prostate (PM, 39.3%; 95% CI, 39.0%-39.6%) cancers. Chemotherapy mediated the association of marital status with cancer-specific survival in lung (PM, 37.7%; 95% CI, 37.6%-37.9%) and pancreatic (PM, 28.6%; 95% CI, 28.4%-28.9%) cancers. Improved cancer-specific survival associated with marriage was greater among men than women (men: TR, 1.27; 95% CI, 1.25-1.28; women: TR, 1.20; 95% CI, 1.19-1.21). The contribution of receiving an early diagnosis and treatment with surgery or chemotherapy to the association between marital status and cancer-specific survival was greater among men than women (early diagnosis: PM, 21.7% [95% CI, 21.5%-21.9%] vs PM, 20.3% [95% CI, 20.2%-20.4%]; surgery: PM, 26.6% [95% CI, 26.4%-26.7%] vs PM, 11.1% [95% CI, 11.0%-11.2%]; chemotherapy: PM, 6.8% [95% CI, 6.7%-6.8%] vs PM, 5.1% [95% CI, 5.0%-5.2%]). Conclusions and Relevance In this study, survival disparities associated with marital status were attributable to early diagnosis in breast, colorectal, and endometrial cancers as well as melanoma and to treatment-related variables in lung, pancreatic, and prostate cancers. The findings also suggest that marriage may play a greater protective role in the cancer-specific survival of men than of women.

Backgroud: The optimal treatment strategy for elderly patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) remains unclear. We aimed to develop individualized treatment strategies for such patients according to their pretreatment risk stratification and the degree of comorbidities.Methods: A total of 583 elderly LA-NPC patients diagnosed between January 2011 and January 2018 were retrospectively studied. Based on prognostic factors confirmed by multivariate analysis, we constructed a nomogram for disease-free survival (DFS). The entire cohort was then divided into two groups according to the nomogram cutoff value determined by X-tile analysis. The degree of comorbidities was assessed by Charlson Comorbidity Index (CCI). We performed subgroup analysis based on the degree of complications in the low- and high-risk groups to compare the survival outcomes of different treatment regimens using the Kaplan-Meier method and the log-rank test.Results: A nomogram for DFS was constructed with T/N classification, Epstein-Barr virus DNA and albumin. The high-risk group had significantly poorer survival compared with the low-risk group. The 3-year DFS and overall survival (OS) of the low-risk group and the high-risk group were 76.7% vs. 44.6%, 81.5% vs. 51.0% (both P 2) would not have.Conclusion: We constructed a prognostic nomogram for DFS and generated two risk groups. Combining risk stratification and degree of comorbidities can better guide individualized treatment for elderly LA-NPC patients.

Objective The now standard cortical stimulation approach of inhibiting contralesional primary motor cortex (cM1) disrupts bimanual coordination while facilitating ipsilesional M1 (iM1) fails to enhance paretic arm function, in severely impaired individuals. We propose an alternative target, enhancing contralesional dorsal premotor cortex (cPMd) to improve bimanual coordination and compare its effects to iM1. Methods Fourteen participants with stroke received 5-Hz repetitive transcranial magnetic stimulation (rTMS) on cPMd or iM1 in a repeated cross-over design. Bimanual force/neuromuscular coordination and cortical excitability were assessed. We also examined the relationship of baseline motor function/interhemispheric inhibition (IHI) to participant’s responses to each stimulation target. Results We identified two patterns of responses. Participants with more severe impairment and weaker IHI improved bimanual force/neuromuscular coordination, ipsilesional activations and reduced IHI after cPMd-rTMS; whereas, those with milder impairment and stronger IHI improved only after iM1-rTMS. Conclusions Cortical stimulation protocols could be tailored to the types of tasks and to individuals’ severity of impairment. Facilitation of cPMd may improve bimanual coordination especially for individuals with limited arm/hand function. Significance Our study is the first to identify cortical stimulation strategies for improving bimanual coordination for individuals with different level of severity of stroke.

Programmed death ligand-1 (PD-L1) is involved in inhibiting of T lymphocyte proliferation, producing cytokine, cytolytic activity, and suppressing of the immune response. Genes with molecular alterations involved in DNA mismatch repair promote cancer initiation and tumor progression. Clinical studies show that colorectal cancer (CRC) patients harboring microsatellite instability (MSI) have a higher anti-programmed cell death protein 1/PD-L1 immunotherapy response ratio compared with microsatellite stable subgroup patients. The underlying mechanism has however remained unclear. Here, we found that compared with microsatellite stable samples, PD-L1 was glycosylated and highly expressed both in MSI CRC cell lines and tissue samples. Specifically, PD-L1 was N-glycosylated at its N35, N192, N200, and N219 sites, and the four glycosylation sites were all responsible for PD-L1 degradation. Additionally, non-glycosylated PD-L1 underwent rapid degradation compared with glycosylated PD-L1 through the 26S proteasome pathway. The faster degradation of the non-glycosylated PD-L1 was ascribed to its binding to glycogen synthase kinase 3β via ubiquitination. This degradation phenotype was, however, not observed for glycosylated PD-L1. Significantly, glycosylated PD-L1 was up-regulated by activated epidermal growth factor receptor in MSI CRC cells. Together, our results indicate that epidermal growth factor receptor stabilized PD-L1 via glycosylation in MSI CRC cells, uncovering a novel role of PD-L1 in MSI CRC immunosuppression and disease progression. The study was approved by the Clinical Ethics Review Committee at the Six Affiliated Hospital of Sun Yat-sen University, China (Approval No. 2019ZSLYEC-005). Key words: epidermal growth factor receptor; glycogen synthase kinase 3β; glycosylation; microsatellite instability; microsatellite stability; programmed death ligand-1

Background and Purpose: Increasing evidence suggests systemic inflammation-caused skeletal muscle atrophy as a major clinical feature of cachexia. Triptolide obtained from Tripterygium wilfordii Hook F possesses potent anti-inflammatory and immunosuppressive effects. The present study aims to evaluate the protective effects and molecular mechanisms of triptolide on inflammation-induced skeletal muscle atrophy. Experimental Approach: The effects of triptolide on skeletal muscle atrophy were investigated in LPS-treated C2C12 myotubes and C57BL/6 mice. Protein expressions and mRNA levels were analysed by western blot and qPCR, respectively. Skeletal muscle mass, volume and strength were measured by histological analysis, micro-CT and grip strength, respectively. Locomotor activity was measured using the open field test. KEY RESULTS: Triptolide (10–100 fM) up-regulated protein synthesis signals (IGF-1/p-IGF-1R/IRS-1/p-Akt/p-mTOR) and down-regulated protein degradation signal atrogin-1 in C2C12 myotubes. In LPS (100 ng·ml−1)-treated C2C12 myotubes, triptolide up-regulated MyHC, IGF-1, p-IGF-1R, IRS-1 and p-Akt. Triptolide also down-regulated ubiquitin-proteasome molecules (n-FoxO3a/atrogin-1/MuRF1), proteasome activity, autophagy-lysosomal molecules (LC3-II/LC3-I and Bnip3) and inflammatory mediators (NF-κB, Cox-2, NLRP3, IL-1β and TNF-α). However, AG1024, an IGF-1R inhibitor, suppressed triptolide-mediated effects on MyHC, myotube diameter, MuRF1 and p62 in LPS-treated C2C12 myotubes. In LPS (1 mg·kg−1, i.p.)-challenged mice, triptolide (5 and 20 μg·kg−1·day−1, i.p.) decreased plasma TNF-α levels and it increased skeletal muscle volume, cross-sectional area of myofibers, weights of the gastrocnemius and tibialis anterior muscles, forelimb grip strength and locomotion. Conclusions and Implications: These findings reveal that triptolide prevented LPS-induced inflammation and skeletal muscle atrophy and have implications for the discovery of novel agents for preventing muscle wasting.

Background Accurate prediction of motor recovery after stroke is critical for treatment decisions and planning. Machine learning has been proposed to be a promising technique for outcome prediction because of its high accuracy and ability to process large volumes of data. It has been used to predict acute stroke recovery; however, whether machine learning would be effective for predicting rehabilitation outcomes in chronic stroke patients for common contemporary task-oriented interventions remains largely unexplored. This study aimed to determine the accuracy and performance of machine learning to predict clinically significant motor function improvements after contemporary task-oriented intervention in chronic stroke patients and identify important predictors for building machine learning prediction models. Methods This study was a secondary analysis of data using two common machine learning approaches, which were the k-nearest neighbor (KNN) and artificial neural network (ANN). Chronic stroke patients (N = 239) that received 30 h of task-oriented training including the constraint-induced movement therapy, bilateral arm training, robot-assisted therapy and mirror therapy were included. The Fugl-Meyer assessment scale (FMA) was the main outcome. Potential predictors include age, gender, side of lesion, time since stroke, baseline functional status, motor function and quality of life. We divided the data set into a training set and a test set and used the cross-validation procedure to construct machine learning models based on the training set. After the models were built, we used the test data set to evaluate the accuracy and prediction performance of the models. Results Three important predictors were identified, which were time since stroke, baseline functional independence measure (FIM) and baseline FMA scores. Models for predicting motor function improvements were accurate. The prediction accuracy of the KNN model was 85.42% and area under the receiver operating characteristic curve (AUC-ROC) was 0.89. The prediction accuracy of the ANN model was 81.25% and the AUC-ROC was 0.77. Conclusions Incorporating machine learning into clinical outcome prediction using three key predictors including time since stroke, baseline functional and motor ability may help clinicians/therapists to identify patients that are most likely to benefit from contemporary task-oriented interventions. The KNN and ANN models may be potentially useful for predicting clinically significant motor recovery in chronic stroke.

Background The timing of transcranial direct current stimulation (tDCS) with neurorehabilitation interventions may affect its modulatory effects. Motor function has been reported to be modulated by the timing of tDCS; however, whether the timing of tDCS would also affect restoration of daily function and upper extremity motor control with neurorehabilitation in stroke patients remains largely unexplored. Mirror therapy (MT) is a potentially effective neurorehabilitation approach for improving paretic arm function in stroke patients. This study aimed to determine whether the timing of tDCS with MT would influence treatment effects on daily function, motor function and motor control in individuals with chronic stroke. Methods This study was a double-blinded randomized controlled trial. Twenty-eight individuals with chronic stroke received one of the following three interventions: (1) sequentially combined tDCS with MT (SEQ), (2) concurrently combined tDCS with MT (CON), and (3) sham tDCS with MT (SHAM). Participants received interventions for 90 min/day, 5 days/week for 4 weeks. Daily function was assessed using the Nottingham Extended Activities of Daily Living Scale. Upper extremity motor function was assessed using the Fugl-Meyer Assessment Scale. Upper extremity motor control was evaluated using movement kinematic assessments. Results There were significant differences in daily function between the three groups. The SEQ group had greater improvement in daily function than the CON and SHAM groups. Kinematic analyses showed that movement time of the paretic hand significantly reduced in the SEQ group after interventions. All three groups had significant improvement in motor function from pre-intervention to post-intervention. Conclusion The timing of tDCS with MT may influence restoration of daily function and movement efficiency of the paretic hand in chronic stroke patients. Sequentially applying tDCS prior to MT seems to be advantageous for enhancing daily function and hand movement control, and may be considered as a potentially useful strategy in future clinical application. Trial registration ClinicalTrials.gov Identifier: NCT02827864 . Registered on 29th June, 2016.

Purpose To develop predictive models with dosimetric and clinical variables for temporal lobe injury (TLI) in nasopharyngeal carcinoma (NPC) after intensity-modulated radiotherapy (IMRT). Materials and methods Data of 8194 NPC patients who received IMRT-based treatment were retrospectively reviewed. TLI was diagnosed by magnetic resonance imaging. Dosimetric factors were selected by penalized regression and machine learning, with area under the receiver operating curve (AUC) calculated. Cox proportional hazards models containing the most predictive dosimetric factor with/without clinical variables were performed. A nomogram was generated as a visualization of Cox regression for predicting TLI-free survival. Results During median follow-up of 66.8 months (interquartile range [IQR] 54.2–82.2 months), 12.1% of patients (989/8194) developed TLI. Median latency from IMRT to TLI was 36 months (IQR 28–47 months). D0.5cc (dose delivered to 0.5-cm3 temporal-lobe volume) was the most predictive dosimetric factor (AUC: 0.799). Tolerance dose for 5% and 50% probabilities to develop TLI in 5 years were 65.06 Gy (95% confidence interval [CI]: 64.19–65.92) and 89.75 Gy (95% CI: 87.39–92.11), respectively. A nomogram comprising age, T stage, and D0.5cc significantly outperformed the model with only D0.5cc in predicting TLI (C-index: 0.78 vs. 0.737 in train set; 0.775 vs. 0.73 in test set; both P Conclusions D0.5cc of 65.06 Gy was the tolerance dose of the temporal lobe. Reducing D0.5cc decreased risk of TLI, especially in older patients with advanced T stage. The nomogram could predict TLI precisely and allow individualized follow-up management.

Objectives To screen subgroup potentially benefiting from cumulative cisplatin dose (CCD) ≥ 200 mg/m2 during concurrent chemoradiotherapy (CCRT) of patients with locoregionally-advanced nasopharyngeal carcinoma (LA-NPC) receiving induction chemotherapy (IC) and CCRT. Materials and Methods In total, 2 063 patients with non-disseminated LA-NPC diagnosed from 2009 to 2015 receiving IC plus CCRT were enrolled. Patients were restaged based on proposed stage groupings and risk groupings was established. After propensity score matching, survival outcomes were compared within different risk groupings with 200 mg/m2 CCD. Post-IC gross primary tumor (GTVp) and lymph node (GTVnd) volumes were calculated from planning computed tomography. The role of risk groupings and post-IC tumor volume to CCD was explored. Results Compared with the low-risk group, the high-risk group showed poor survival outcomes in terms of 5-year progression-free survival (PFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS). CCD ≥ 200 mg/m2 improved survival in terms of 5-year PFS, OS and DMFS in the high-risk group but not in the low-risk group. High-risk patients with unfavorable response to IC benefited from CCD ≥ 200 mg/m2 with respect to PFS and DMFS; while those in low-risk group or with favorable response to IC didn’t. Conclusions Risk groupings was effective for risk stratification. Combining risk groupings and post-IC tumor volume is a simple and useful method to guide individualized CCD treatment of CCRT for patients with LA-NPC receiving IC and CCRT. CCD ≥ 200 mg/m2 may be indicated for high-risk patients with unfavorable response to IC.

IntroductionSpinal cord injury (SCI) alters the integrity of the spinal cord, which leads to loss of multiple organs’ function including locomotor function. The present study evaluates the protective effect of tabersonine against SCI.Material and methodsSCI was induced by traumatic injury and animals were treated with tabersonine 20 and 40 mg/kg, intraperitoneally for the period of 10 days. Tabersonine’s effect was determined by estimating locomotor and neurological function in spinal cord injured rats. Moreover, mediators of inflammation were estimated using enzyme-linked immunosorbent assay (ELISA) and the effect of tabersonine on Notch/inflammasome signaling was estimated by reverse transcription polymerase chain reaction (RT-PCR), western blot assay and immunohistochemistry. Apoptosis of neuronal cells was estimated by staining with Nissl stain on spinal cord tissue in SCI rats.ResultsData of the study suggest that neurological and motor functions were improved in the tabersonine treated group compared to the spinal cord injured (SI) group. There was a decrease in the mediators of inflammation in the spinal cord tissue of the tabersonine treated group compared to the SI group. Treatment with tabersonine ameliorates the altered expression of NICD, Nestin and Hes-1 protein and mRNA expression of Notch-1 and Hes-1 in the SCI rats. It was also observed that the tabersonine treated group showed activation of CREB and inhibition of the NLRP-3 pathway in SCI rats. Moreover, apoptosis of neuronal cells was reduced in the tabersonine treated group compared to the SI group.ConclusionsData of the investigation suggest that tabersonine protects against spinal cord injury by activating CREB and reducing NLRP3/Notch signaling.

BACKGROUND The current study was performed to investigate whether circulating cell-free Epstein-Barr virus DNA (cfEBV DNA) would be useful for posttreatment surveillance in patients with nasopharyngeal carcinoma (NPC). METHODS The authors identified a total of 1984 nondisseminated NPC patients from an institutional big-data research platform. Blood samples were collected within 3 months of the completion of radiotherapy and every 3 to 12 months thereafter for cfEBV DNA analysis. Patients were followed until disease recurrence was detected or for a median of 60 months. Diagnostic performance was assessed by calculating the sensitivity, specificity, and accuracy based on the clinical detection of disease recurrence by conventional surveillance modalities (imaging scans and pathological examination). RESULTS During follow-up, a total of 767 patients (38.7%) had detectable cfEBV DNA. The recurrence rate among these patients was 63.8% (489 of 767 patients), which was significantly higher than that in patients with undetectable cfEBV DNA (8.6%; 105 of 1217 patients). cfEBV DNA sensitivity, specificity, and accuracy were 68.8%, 80.0%, and 78.2%, respectively, for local recurrence; 80.2%, 80.0%, and 85.9%, respectively, for regional recurrence; and 91.1%, 80.0%, and 92.8%, respectively, for distant metastasis. cfEBV DNA was found to have higher sensitivity for the detection of extrapulmonary metastases (94.9%-96.5%) compared with pulmonary metastases (78.4%). It is interesting to note that among the patients with disease recurrence with detectable cfEBV DNA, positive cfEBV DNA results preceded radiological and/or clinical evidence of disease recurrence by a median of 2.3 months (interquartile range, 0.1-9.5 months). In addition, of the 278 cfEBV DNA-positive patients who did not develop disease recurrence, 227 (81.7%) had transiently positive cfEBV DNA that fell to undetectable levels during long-term monitoring. CONCLUSIONS Plasma cfEBV DNA in patients with NPC appears to be an early sign of tumor recurrence, especially extrapulmonary metastases.

The value of post-neoadjuvant chemotherapy (NACT) tumor volume for prognostication in loco-regionally advanced nasopharyngeal carcinoma (LA-NPC) is unascertained. Here, we recruited 4109 histologically proven LA-NPC (stage III-IVA) that were treated with radical chemo-intensive-modulated radiotherapy (IMRT). Post-NACT gross primary tumor (GTVp) and lymph node (GTVnd) volumes of each patient were calculated from planning computed tomography (CT). We observed similar linear association between GTVp/GTVnd and overall survival (OS), thresholds of 52 cm3 for GTVp and 12 cm3 for GTVnd were consistent for risk discretization for OS, disease-free survival (DFS), distant metastasis-free survival (DMFS), and local relapse-free survival (LRFS). Recursive partitioning analysis (RPA) modelling incorporating T-/N-categories and GTVp/GTVnd yielded four T-N-volume (TNV) risk groupings with disparate OS (p &lt, 0.001). TNV risk stratification outperformed GTVp/GTVnd and eighth edition TNM for predicting OS (AUC 0.643 vs. 0.541&ndash, 0.591, p &lt, 0.001), DFS (0.629 vs. 0.545&ndash, 0.580, 0.001), and DMFS (0.652 vs. 0.522&ndash, 0.621, 0.001). NACT + concurrent chemoradiotherapy (CCRT) over NACT + IMRT was not superior for low- and low&ndash, intermediate-risk groupings (p &gt, 0.05 for both), but superior for intermediate- and high-risk groupings in terms of OS (HR 0.68 (95% CI 0.47&ndash, 0.99) for intermediate risk, 0.73 (0.55&ndash, 0.97) for high risk, both p &lt, 0.05). Overall, GTVp/GTVnd represent effective indicators for prognostication and decision-making in LA-NPC after NACT.

Ke-fu Sun,1–3 Wan-wen Feng,2,3 Yue-peng Liu,4 Yan-bin Dong,4 Li Gao,2,3 Hui-lin Yang1 1Department of Orthopedic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; 2Department of Orthopedics, Lianyungang Oriental Hospital, Lianyungang, Jiangsu, China; 3Department of Orthopedics, Affiliated Lianyungang Oriental Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, China; 4Center for Clinical Research and Translation Medicine, Lianyungang Oriental Hospital, Lianyungang, Jiangsu, China Objective: The analgesic effect on chronic pain of peripheral nerve stimulation (PNS) has been proven, but its underlying mechanism remains unknown. Therefore, this study aimed to assess the analgesic effect of PNS on bone cancer pain in a rat model and to explore the underlying mechanism.Materials and methods: PNS on sciatic nerves with bipolar electrode was performed in both naïve and bone cancer pain model rats. Then, the protein levels of activity-regulated cytoskeleton-associated protein (Arc), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type glutamate receptor 1 (GluA1), and phosphate N-methyl-d-aspartic acid-type glutamate receptor subunit 2B (pGluNR2B) in spinal cord were evaluated by immunohistochemistry and Western blotting. Thermal paw withdraw latency and mechanical paw withdraw threshold were used to estimate the analgesic effect of PNS on bone cancer pain. Intrathecal administration of Arc shRNA was used to inhibit Arc expression in the spinal cord. Results: PNS at 60 and 120 Hz for 20 min overtly induced Arc expression in the spinal cord, increased thermal pain thresholds in naïve rats, and relieved bone cancer pain; meanwhile, 10 Hz PNS did not achieve those results. In addition, PNS at 60 and 120 Hz also reduced the expression of GluA1, but not pGluNR2B, in the spinal cord. Finally, the anti-nociceptive effect and GluA1 downregulation induced by PNS were inhibited by intrathecal administration of Arc shRNA.Conclusion: PNS (60 Hz, 0.3 mA) can relieve bone-cancer-induced allodynia and hyperalgesia by upregulating Arc protein expression and then by decreasing GluA1 transcription in the spinal cord dorsal horn. Keywords: peripheral nerve stimulation, Arc, GluA1, bone cancer pain

(1) Purpose: This study aims to explore risk-adapted treatment for elderly patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) according to their pretreatment risk stratification and the degree of comorbidity. (2) Methods: A total of 583 elderly LA-NPC patients diagnosed from January 2011 to January 2018 are retrospectively studied. A nomogram for disease-free survival (DFS) is constructed based on multivariate Cox regression analysis. The performance of the model is evaluated by using the area under the curve (AUC) of the receiver operating characteristic curve and Harrell concordance index (C-index). Then, the entire cohort is divided into different risk groups according to the nomogram cutoff value determined by X-tile analysis. The degree of comorbidities is assessed by the Charlson Comorbidity Index (CCI). Finally, survival rates are estimated and compared by the Kaplan–Meier method and the log-rank test. (3) Results: A nomogram for DFS is constructed with T/N classification, Epstein-Barr virus DNA and albumin. The nomogram shows well prognostic performance and significantly outperformed the tumor-node-metastasis staging system for estimating DFS (AUC, 0.710 vs. 0.607, C-index, 0.668 vs. 0.585, both p &lt, 0.001). The high-risk group generated by nomogram has significantly poorer survival compared with the low-risk group (3-year DFS, 76.7% vs. 44.6%, p &lt, 0.001). For high-risk patients with fewer comorbidities (CCI = 2), chemotherapy combined with radiotherapy is associated with significantly better survival (p &lt, 0.05) than radiotherapy alone. (4) Conclusion: A prognostic nomogram for DFS is constructed with generating two risk groups. Combining risk stratification and the degree of comorbidities can guide risk-adapted treatment for elderly LA-NPC patients.

Assessment of upper limb function poststroke is critical for clinical management and determining the efficacy of interventions. We designed a unilateral upper limb task to simulate activities of daily living to examine how chronic stroke survivors manage reaching, grasping and handling skills simultaneously to perform the functional task using kinematic analysis. The aim of the study was to compare the motor strategies for performing a functional task between paretic and nonparetic arms. Sixteen chronic stroke survivors were instructed to control an ergonomic spoon to transfer liquid from a large bowl to a small bowl using paretic or nonparetic arm. Kinematic data were recorded using a Vicon motion capture system. Outcome measures included movement duration, relative timing, path length, joint excursions, and trial-to-trial variability. Results showed that movement duration, spoon path length, and trunk path length increased significantly when participants used paretic arm to perform the task. Participants tended to reduce shoulder and elbow excursions, and increase trunk excursions to perform the task with paretic arm and altered the relative timing of the task. Although participants used different motor strategies to perform the task with their paretic arms, we did not find the significant differences in trial-to trial variability of joint excursions between paretic and nonparetic arms. The results revealed differences in temporal and spatial aspects of motor strategies between paretic and nonparetic arms. Clinicians should explore the underlying causes of pathological movement patterns and facilitate preferred movement patterns of paretic arm.

This study sought to investigate the clinical characteristics and outcomes of propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in patients with Graves' disease.Sixteen patients diagnosed with PTU-induced ANCA-associated vasculitis at the authors' hospital from January 2010 to June 2017 were analyzed retrospectively.All 16 patients with PTU-induced ANCA-associated vasculitis were female. The mean age ± standard deviation of the patients was 39.4 ± 15.3 years (range 19-69 years), and the median time of onset was 36 months (range 1-193 months) post-PTU initiation. The median dose at the onset of PTU-induced ANCA-associated vasculitis was 150 mg/day (range 50-300 mg/day). All patients had a positive serum perinuclear staining pattern (p-ANCA) and antibodies directed against myeloperoxidase (anti-MPO). Six patients tested positive for both anti-MPO antibodies and antibodies directed against proteinase-3. Seven (43.8%) patients presented with involvement of a single organ. The kidney was the organ most commonly affected, as 12 (75%) patients were found to have disease involving this organ. PTU was stopped in all patients, corticosteroids were administered to two patients, and immunosuppressive agents and corticosteroids were administered to five patients. Three patients were lost to follow-up. However, the remaining patients achieved remission after a median follow-up period of 38 months (range 6-76 months). Patients who were positive for pANCA and displayed cytoplasmic staining showed negative findings at rates of approximately 53.8% (7/13) and 100% (6/6), respectively, following treatment.PTU-induced ANCA-positive vasculitis occurs at varying times and after exposure to various doses of PTU. The condition has a milder course and has a better prognosis after PTU cessation.

The aim of this study is to investigate whether use of cyclooxygenase-2 (COX-2) inhibitors as auxiliary drug in colorectal cancer (CRC) patients will lead to better survival outcome. This population-based retrospective cohort study was conducted using the Taiwan National Health Insurance Research Database. The cohort consisted of newly diagnosed CRC adult patients during 2003–2010 with at least one prescription of nonsteroidal anti-inflammation drugs. Analysis groups were defined as users or nonusers of COX-2 inhibitors based on their usage prior to or 1 year after diagnosis of CRC. The outcome measurement was overall survival. The application of propensity scores through the inverse probability of treatment weighting (IPTW) was applied to the study groups. Subgroup analyses included stratification of different cancer site, treatment modalities, and first chemotherapy regimens. Kaplan–Meier estimates and Cox regressions were used to compare survival outcome. We identified 14,688 patients with newly diagnosed CRC. The adjusted hazard ratio (HR) with IPTW was 0.91 [95% confidence interval (CI), 0.86–0.96] in patients using COX-2 inhibitors in before and after diagnosis groups, and statistical significance was not reached for usages at only prior to or only after diagnosis. In subgroup analyses, patients with rectal cancer (adjusted HR with IPTW=0.86; 95% CI, 0.79–0.94) who received surgery followed by chemoradiation (adjusted HR with IPTW=0.57; 95% CI, 0.47–0.77) and with adjuvant chemotherapy of FOLFOX regimen (adjusted HR with IPTW=0.81; 95% CI, 0.67–0.99) had survival benefits in using COX-2 inhibitors both prior to and after diagnosis. Use of COX-2 inhibitors was found to be associated with reduction in mortality for CRC patients when taken both prior to and after cancer diagnosis.

Background Persistent hyperparathyroidism after kidney transplantation has been associated with adverse outcomes. Parathyroidectomy is the definitive treatment approach, but the success of parathyroidectomy relies on the accurate preoperative localization of the culprit parathyroid lesions. Simultaneous intrathyroidal parathyroid adenomas and multifocal papillary thyroid carcinoma present important diagnostic challenges. Here, we describe a patient with kidney transplantation who underwent successful surgery after being evaluated with functional and structural imaging. Case presentation A 53-year-old man presented with potentially malignant multifocal thyroid nodules by ultrasonography 2 years after kidney transplantation. The patient had hypercalcaemia and persistent hyperparathyroidism. Thyroid papillary carcinoma was confirmed in the left thyroid nodules by fine-needle aspiration biopsy. The right superior thyroid hypoechoic nodule was 1.2 cm in size and showed marked uptake of the tracer 99mTcO4-sestamibi during single-photon emission computed tomography/computed tomography (SPECT/CT); additionally, a cystic parathyroid lesion without tracer uptake was present behind the left superior pole of the thyroid. The histological examination demonstrated the coexistence of right intrathyroidal parathyroid adenomas, left cystic parathyroid nodular hyperplasia and multifocal papillary thyroid carcinoma. At the 6-month follow-up, the serum calcium levels were within the normal range, and the patient’s kidney function remained stable. Conclusions Simultaneous intrathyroidal parathyroid adenomas and multifocal papillary thyroid carcinoma in a patient with kidney transplantation is a rare clinical scenario. Physicians must be aware that the combination of functional (SPECT/CT) and structural (ultrasonography) imaging is highly successful in diagnosing patients with coexistent intrathyroidal parathyroid adenomas and papillary thyroid carcinoma.

Objective To identify the predictors of minimal clinically important changes in actual and perceived functional arm use of the affected upper limb after rehabilitative therapy. Design Retrospective, observational cohort study. Setting Outpatient rehabilitation settings. Participants A cohort of 94 patients with chronic stroke. Interventions Patients received robot-assisted therapy, mirror therapy, or combined therapy for 4 weeks. Main Outcome Measures The primary outcome measures, assessed pre- and post intervention, included actual functional arm use measured by an accelerometer and perceived functional arm use measured by the Motor Activity Log (MAL). Candidate predictors included age, sex, time after stroke, side of stroke, and scores on the Fugl-Meyer Assessment, Modified Ashworth Scale, Medical Research Council scale, Wolf Motor Function Test, MAL (quality of movement), and Nottingham Extended Activities of Daily Living. Results Being male (odds ratio [OR], 3.17; 95% CI, 1.13-8.87) and having a higher than median Medical Research Council score (OR, 2.68; 95% CI, 1.12-6.41) significantly predicted minimal clinically important changes assessed by an accelerometer. Fugl-Meyer Assessment scores (odds ratio, 1.06; 95% CI, 1.02-1.11) were a significant predictor of achieving clinically important changes in MAL amount of use. Wolf Motor Function Test (quality) scores (OR, 3.05; 95% CI, 1.38-6.77) could predict clinically important improvements in MAL quality of movement. Conclusions Predictors of clinically important changes in the use of the affected upper limb after robot-assisted therapy, mirror therapy, or combined therapy in patients with chronic stroke for 4 weeks differ for actual vs perceived use. Further studies are recommended to validate these findings in a larger sample.

Background In China, the most populous developing country in the world, dementia represents a serious challenge. We performed a large-scale systematic review and meta-regression analysis to elucidate the prevalence of dementia and its subtypes and to identify potential factors underlying the differences between articles. Methods A comprehensive literature search was conducted in the following databases to identify studies published up to December 2015: Cochrane Library, CBMDISK, Chongqing VIP, CNKI, PubMed and EMBASE. All statistical analyses (including subtype and meta-regression analyses) were performed with R version 3.3.3. Results In total, 51 surveys were selected. The pooled prevalence rates of dementia and its main subtypes, namely, Alzheimer’s disease (AD) and vascular dementia (VAD), for the population aged 55 years and older were 4.03, 2.44 and 1.09%, respectively. The outcomes showed that the meta-regression analysis was affected by the publication year, sample size, region and diagnostic criteria. Conclusions Our analysis provided reliable estimates of the prevalence of dementia/ AD/ VD over the past 30 years, which may be affected by education level, and diagnostic criteria. The prevalence of AD/VAD was higher in northern than in southern China, which warrants further study. Electronic supplementary material The online version of this article (10.1186/s12889-019-6840-z) contains supplementary material, which is available to authorized users.

Mutations within the Shank3 gene, which encodes a key postsynaptic density (PSD) protein at glutamatergic synapses, contribute to the genetic etiology of defined autism spectrum disorders (ASDs), including Phelan-McDermid syndrome (PMS) and intellectual disabilities (ID). Although there are a series of genetic mouse models to study Shank3 gene in ASDs, there are few rat models with species-specific advantages. In this study, we established and characterized a novel rat model with a deletion spanning exons 11–21 of Shank3, leading to a complete loss of the major SHANK3 isoforms. Synaptic function and plasticity of Shank3-deficient rats were impaired detected by biochemical and electrophysiological analyses. Shank3-depleted rats showed impaired social memory but not impaired social interaction behaviors. In addition, impaired learning and memory, increased anxiety-like behavior, increased mechanical pain threshold and decreased thermal sensation were observed in Shank3-deficient rats. It is worth to note that Shank3-deficient rats had nearly normal levels of the endogenous social neurohormones oxytocin (OXT) and arginine-vasopressin (AVP). This new rat model will help to further investigate the etiology and assess potential therapeutic target and strategy for Shank3-related neurodevelopmental disorders.

Previous research demonstrated that the progressive accumulation of iron in the substantia nigra pars compacta (SNpc) may contribute to dopaminergic (DA) neurons selective degeneration in Parkinson's disease (PD). However, the etiology and mechanism underlying iron-induced neurotoxicity processes are as yet unresolved. It has been reported that L-type calcium channels (LTCCs) may mediate iron influx into neuronal cells and can compete with calcium for common routes to enter primary neurons. The present study, we found that isradipine can alleviate iron-induced toxicity caused by raising intracellular calcium in MES23.5 cells. Analysis of experimental results revealed that an increase in extracellular free CaCl2 (500 µmol/L) is sufficient to promote FeSO4 (100 µmol/L) entry by activating L-type Ca2+ channels (LTCCs) significantly. The enhancement of calcium and/or iron influx was accompanied by a corresponding decrease of cell viability and higher susceptibility of toxicity, such as decrease of mitochondrial membrane potential (ΔΨm) and increase of nucleus pyknosis ratio and cleaved caspase-3 protein expression in MPP+ (5 µmol/L) treatment MES23.5 cells. Pre-treatment with isradipine (10 µmol/L), a LTCCs blocker, for 15 min, can antagonize calcium and/or iron-induced neurotoxicity. These results suggest that application of isradipine may be a potential method for the treatment of the neurodegenerative disease induced by calcium and/or iron dysmetabolism.Read Complete Article at ijSciences: V72018121893 AND DOI: http://dx.doi.org/10.18483/ijSci.1893

Human glioma-associated mesenchymal stem cells (gbMSCs) are the stromal cell components that contribute to the tumourigenesis of malignant gliomas. Recent studies have shown that gbMSCs consist of two distinct subpopulations (CD90+ and CD90− gbMSCs). However, the different roles in glioma progression have not been expounded. In this study, we found that the different roles of gbMSCs in glioma progression were associated with CD90 expression. CD90high gbMSCs significantly drove glioma progression mainly by increasing proliferation, migration and adhesion, where as CD90low gbMSCs contributed to glioma progression chiefly through the transition to pericytes and stimulation of vascular formation via vascular endothelial cells. Furthermore, discrepancies in long non-coding RNAs and mRNAs expression were verified in these two gbMSC subpopulations, and the potential underlying molecular mechanism was discussed. Our data confirm for the first time that CD90high and CD90low gbMSCs play different roles in human glioma progression. These results provide new insights into the possible future use of strategies targeting gbMSC subpopulations in glioma patients.

Rationale: Meckel's diverticulum (MD) is common congenital abnormality of gastrointestinal tract, only about 6.4% of patients become symptomatic. A smaller minority develop potential fatal complications such as hemorrhage, perforation, abscess, and bowel obstruction. Patient concerns: A 15-year-old boy with history of appendicitis was admitted due to worsening abdominal pain and nausea for 1 day. The physical examination showed the abdomen was soft, with the diffuse tenderness to palpation and voluntary guarding. Diagnosis: Abdominal computed tomography showed a probable MD in the distal ileum. Single photon emission computed tomography/computed tomography (SPECT/CT) fusion imaging revealed the focal concentration at the right lower quadrant of abdomen region. Intervention: After the initial management including antibiotic administration and intravenous fluid resuscitation, MD with perforation and localized suppurative peritonitis was confirmed in surgery. The patient underwent a diverticulectomy. Histological examination was confirmed as MD with focal heterotopic gastric tissue. Outcomes: After surgery, the patient had uneventful recovery during 3 months follow-up. Lessons: Spontaneous perforation and intraabdominal abscess due to MD is very rare. Accurate diagnosis of MD remains challenging as clinical symptoms from these complications occur nonspecifically. SPECT/CT fusion imaging is critical for prompt recognition and accurate diagnosis in the successful management of this rarely life-threating complication.

Regulator of G protein signaling 11 (RGS11), a member of the R7 subfamily of RGS proteins, is a well-characterized GTPase-accelerating protein that is involved in the heterotrimeric G protein regulation of the amplitude and kinetics of receptor-promoted signaling in retinal bipolar and nerve cells. However, the role of RGS11 in cancer is completely unclear. Using subtractive hybridization analysis, we found that RGS11 was highly expressed in the lymph-node metastatic tissues and bone-metastatic tumors obtained from patients with lung adenocarcinoma. Characterization of the clinicopathological features of 91 patients showed that around 57.1% of the tumor samples displayed RGS11 overexpression that was associated with primary tumor status, nodal metastasis and increased disease stages. Its high expression was an independent predictive factor for poor prognosis of these patients. Cotransfection of guanine nucleotide-binding protein beta-5 (GNB5) markedly increased RGS11 expression. Enhancement or attenuation of RGS11 expression pinpointed its specific role in cell migration, but not in cell invasion and proliferation. Signaling events initiated by the RGS11–GNB5 coexpression activated the c-Raf/ERK/FAK-mediated pathway through upregulation of the Rac1 activity. Consistently, increasing the cell invasiveness of the transfectants by additional cotransfection of the exogenous urokinase–plasminogen activator gene caused a significant promotion in cell invasion in vitro and in vivo, confirming that RGS11 functions in cell migration, but requires additional proteolytic activity for cell and tissue invasion. Collectively, overexpression of RGS11 promotes cell migration, participates in tumor metastasis, and correlates the clinicopathological conditions of patients with lung adenocarcinoma.

Glioma, which accounts for more than 30% of primary central nervous system tumours, is characterised by symptoms such as headaches, epilepsy, and blurred vision. Glioblastoma multiforme is the most aggressive, malignant, and lethal brain tumour in adults. Even with progressive combination treatment with surgery, radiotherapy, and chemotherapy, the prognosis for glioma patients is still extremely poor. Compared with the poor outcome and slowly developing technologies for surgery and radiotherapy, the application of targeted chemotherapy with a new mechanism has become a research focus in this field. Moreover, targeted therapy is promising for most solid tumours. The tumour-tropic ability of stem cells, including neural stem cells and mesenchymal stem cells, provides an alternative therapeutic approach. Thus, mesenchymal stem cell-based therapy is based on a tumour-selective capacity and has been thought to be an effective anti-tumour option over the past decades. An increasing number of basic studies on mesenchymal stem cell-based therapy for gliomas has yielded complex outcomes. In this review, we summarise the biological characteristics of human mesenchymal stem cells, and the current status and potential challenges of mesenchymal stem cell-based therapy in patients with malignant gliomas.

Aim: The purpose of the current study was to conduct a systematic review of the published literature to evaluate the diagnostic accuracy of FDG-PET, PTE/CT, MRI and scintigraphy for multiple myeloma related bone disease. Methods: Through a search of PubMed, EMBASE, and the Cochrane Library, two reviewers independently assessed the methodological quality of each study. We estimated pooled sensitivity, specificity, positive and negative likelihood ratios (PLR and NLR), and two sample Z-tests were conducted to evaluate for differences in sensitivity, specificity, area under the curve (AUC), and the Q* index between any two diagnostic modalities. Results: A total of 17 studies were reviewed. The MRI had a pooled sensitivity of 0.88, specificity of 0.68, AUC of 0.897, and Q*index of 0.828, whereas for MIBI, the corresponding values were 0.98, 0.90, 0.991, and 0.962, respectively, and for bone scan, they were 066, 0.83, 0.805, and 0.740, respectively. The corresponding values of MIBI were 0.98, 0.90, 0.991, and 0.962, respectively. For PET and PET/CT, the values were 0.91, 0.69, 0.927 and 0.861, respectively. Statistically significant differences were not found in the sensitivity, specificity, AUC, and Q* index between MRI, scintigraphy, FDG-PET and PET/CT. Conclusions: On the condition that X ray is taken as a reference in our study, we suggested that FDG-PET, PTE/CT, MRI and scintigraphy are all associated with high detection rate of bone disease in patients with MM. Thus, in clinical practice, it is recommended that we could choose these tests according to the condition of the patient.

A 14-year-old intact male Chinchilla cat was presented to Veterinary Teaching Hospital, Chung Hsing University due to a sudden weakness of the hind limbs. Coldness was found on both hind limbs. Pulseless on the right hind limb and a weak-pulsed on the left hind limb were revealed by physical examination. Thrombus was detected in aortic bifurcation by ultrasonography. After treating the patient with supportive care, antithrombotics (including Dalteparin sodium, clopidgrel) and thrombolytics (Streptokinase), the thrombus lysed on the next day. Being able to use the affected limbs in the following days, the cat was discharged on the 6th day, although Ischemia-reperfusion injury was still presented. It indicated that thrombolytics may be a choice that is beneficial to some cats with distal aortic thromboembolism.

Objective The aim of this study was to evaluate the diagnostic performance of fluorine-18 fluorodeoxyglucose-PET (F-FDG-PET), leukocyte scintigraphy (LS), and monoclonal antigranulocyte antibody scintigraphy (MAAS) in patients with inflammatory bowel disease (IBD) and perform pairwise comparisons of the diagnostic accuracy between these different imaging modalities. Methods Through a search of PubMed, EMBASE, and the Cochrane Library (January 1993-May 2013), we performed a random effects meta-analysis and constructed summary receiver operating characteristic curves on per-bowel-segment or per-patient basis. Two-sample Z-tests were performed to evaluate differences in sensitivity, specificity, area under the curve (AUC), and the Q* index between any two diagnostic modalities on per-bowel-segment basis. Results Twenty prospective studies were reviewed. On per-bowel-segment basis, the F-FDG-PET had a pooled sensitivity of 0.84, specificity of 0.86, AUC of 0.913, and Q* index of 0.845, whereas for LS, the corresponding values were 0.79, 0.86, 0.877, and 0.808, respectively, and for MAAS they were 0.45, 0.94, 0.524, and 0.518, respectively. On per-patient basis, the corresponding values of LS were 0.91, 0.85, 0.937, and 0.874, respectively. Statistically significant differences were not found in the sensitivity, specificity, AUC, and Q* index between F-FDG-PET and LS on per-bowel-segment basis. Conclusion F-FDG-PET has a high degree of diagnostic performance compared with LS and MAAS on per-bowel-segment basis in patients with IBD. LS may be used with satisfactory diagnostic accuracy in detecting active IBD when PET systems are unavailable. A larger prospective validation of these findings would be valuable.

Purpose: To evaluate the effectiveness of the Taipei Osteoarthritis Program (TOAP) for community elderly persons who suffer from knee OA. Methods: A quasi-experimental study was conducted between January 2008 and December 2008. Two hundred and five community-dwelling individuals aged 67 ± 10 years with knee OA were recruited from four districts in Taipei City and randomized. By a clustered randomization according to the districts, 114 participants were in the intervention group (IG) with a 4-week TOAP program and 91 participants were in the control group (CG) with routine care. The main outcome measures included health-related quality of life (HRQOL) and disability level, which were assessed by the Short Form-36 Taiwan Version (T-SF36) and the Western Ontario McMaster Universities Arthritis Index Taiwan Version (T-WOMAC), respectively, and were repeatedly measured at the baseline, post invention (4 weeks after baseline), and follow-up (8 weeks after baseline). Results: Subjects in the IG increased their changes of GH scores from baseline to post-intervention and follow-up, which were significantly more than those of subjects in the CG (p = 0.011 and 0.005, respectively). Significant difference of changes was also found at follow-up for the mental component scale between the groups (p = 0.013). There was no change in disability level. Conclusions: The arthritis self-management program improved the psychological outcomes among the participants, but it had no significant effect on a self-reported disability level.

Background Glycolic acid (GA) has been widely used in cosmetic agents and superficial chemical peeling in recent years. It has long been concerned that UV irradiation would enhance the photosensitivity of GA on human skin. Therefore, it is mandatory to explore the biologic effects of concomitant exposure of GA and UV irradiation in human keratinocytes. Objective The aim of the study is to explore the effects of concomitant exposure of GA and UVB in a human keratinocyte cell line (HaCaT). Methods We used HaCaT to investigate the effects of GA (5mM), UVB (50mJ/cm 2 ), and co-treatment with GA and UVB (GA+UVB) in human keratinocytes. We used a phase contrast microscope to observe morphological changes of the cells, and employed flow cytometry to detect cell viability, cell cycle, and mitochondrial membrane potential (MMP), and intracellular reactive oxygen species (ROS) levels. Cell damage was detected by DAPI stain, and Western blot was used to detect the activities of apoptosis- related and cycle checkpoint-related proteins such as Bax, Bcl-2, caspases-3, -4, -9, Endo G, AIF, and p21, p27, p53, cdk2, cyclin E, cyclin A. Results We found that either GA or UVB alone had inhibitory effect on cell proliferation, and co-treatment with GA and UVB had synergistic anti-proliferative effect. GA alone did not affect the cell cycle, and UVB induced HaCaT cells accumulated at S phase, and co-treatment with GA and UVB arrested cells at S phase more prominently. Moreover, all the treatment with GA, UVB, and GA+UVB in HaCaT cells induced apoptosis. We further demonstrated that GA had synergistic apoptotic effect in human keratinocytes. GA and UVB both had effects on the decline of MMP and increase of ROS release, and GA had synergistic increase in the level of ROS in UVB-treated HaCaT cells. Besides, co-treatment with GA and UVB had synergistic effect on apoptosis through the over-expressions of Bax, p21, p53, caspases-3, -4, -9, Endo G and AIF, and confocal microscopy disclosed translocation of AIF and Endo G from cytoplasm to the nucleus. Therefore, apoptosis induced by co-treatment by GA+UVB was initiated and executed by multiple pathways including mitochondria- and ER-dependent, and caspase-dependent and caspase-independent pathways. Conclusion We demonstrated that GA, UVB, GA+UVB inhibited proliferation and induced apoptosis in HaCaT cells. The mechanisms of apoptosis induced by co-treatment of GA and UVB involve multiple pathways. The synergistic photo-toxicity may be related to cell cycle arrest and apoptosis in UVB-treated HaCaT cells. These results highlight the potential adverse effects of GA-containing cosmetic agents on human skin.

wu s.-f.v., kao m.-j., wu m.-p., tsai m.-w. & chang w.-w. (2011) Effects of an osteoarthritis self-management programme. Journal of Advanced Nursing67(7), 1491–1501. Abstract Aim. The aim of this study was to assess the effectiveness of a self-management programme among osteoarthritis knee sufferers. Background. Osteoarthritis of the knee is a major cause of loss of function and is common in the older people. A self-management programme is an effective way to increase arthritis self-efficacy, and helps with mastering self-management practices. Method. This study was carried out from January 2008 to December 2008 and included 205 participants, with 114 in the intervention group and 91 in the control group. The 4-week trial was followed by an 8-week follow-up assessment. The outcome measures included assessments of arthritis self-efficacy, pain beliefs, unplanned medical consultations, pain days and disability days using the Mann–Whitney U-test and Friedman test. Findings. At post-intervention, significant differences were found in pain beliefs (P

Purpose: To investigate the effectiveness and feasibility of Kinect-based upper extremity rehabilitation on functional performance in chronic stroke survivors. Methods: This was a single cohort pre-post test study. Participants (N = 10; mean age = 62.5 ± 9.06) engaged in Kinect-based training three times a week for four to five weeks in a university laboratory. To simulate a clinic to home transfer condition, individualized guidance was given to participants at the initial three sessions followed by independent usage. Outcomes included Fugl-Meyer assessment of upper extremity, Wolf Motor Function Test, Stroke Impact Scale, Confidence of Arm and Hand Movement and Active Range of Motion. Participant experience was assessed using a structured questionnaire and a semi-structured interview. Results. Improvement was found in Fugl-Meyer assessment scores (p = 0.001), Wolf Motor Function Test, (p = 0.008), Active Range of Motion (p

Supplemental Digital Content is available in the text, Background: Low-iodine intake has historically been an issue in China, causing widespread iodine deficiency diseases (IDD). China started to introduce universal salt iodization in 1995, but reports of increased thyroid disease are a concern and appropriate levels of iodine intake must be considered. Objective: To assess the prevalence of thyroid disease with different urinary iodine concentrations (UICs) in the general population of those residing in mainland China. Furthermore, we aimed to analyze the relationship between thyroid disease and UIC, to provide guidance in establishing effective health policies regarding iodine intake. Methods: PubMed, Cochrane, Embase, CNKI, Wan fang, and CQVIP databases were searched for random community-based relevant studies with UIC published before January 2016 in mainland China. Two independent reviewers extracted data from eligible citations, and obtained prevalence of thyroid disease for different UICs, as well as the intergroup interaction P values. Results: Forty-three articles were included. The prevalence of thyroid nodules was 22.3% (95% confidence interval [CI]: 20.6%–24.1%) for the low-iodine group, 25.4% (95% CI: 20.8%–28.8%) for the medium-iodine group, and 6.8% (95% CI: 2.8%–11.5%) for the high-iodine group. In the high-iodine group, the prevalence of thyroid nodules was lower than the other groups. The prevalence of 8.3% (95% CI: 3.8%–17.3%) for subclinical hypothyroidism in the high-iodine group was significantly higher than the low- and medium-iodine groups (P

Papillary thyroid cancer (PTC) frequently metastasizes to the cervical lymph region and less often to the lung and bone. Metastasis to the skeletal muscles from PTC is extremely rare, especially concurrent lung and skeletal muscle metastases. The present study reports the case of a 31-year-old man with synchronous metastasis to the skeletal muscle and lung from PTC, six years following total thyroidectomy and consecutive 131Iodine treatments. Magnetic resonance imaging (MRI) revealed a 1.7×1.2×1.5 cm mass in the left gastrocnemius muscle, indicating a neurogenic tumor. The mass was subsequently resected and confirmed via histopathology to be metastatic PTC. We propose that, in the follow-up of patients with PTC, the measurable serum thyroglobulin level, whole body scan and other imaging modalities including MRI or positron emission tomography/computed tomography, must be closely monitored for potential distant metastases, particularly in cases of PTC with aggressive pathological behavior.

Objective: To compare the outcome of robot-assisted therapy with dose-matched active control therapy by using accelerometers to study functional recovery in chronic stroke patients. Design: Prospective, randomized, controlled trial. Setting: Stroke units in three medical centres. Subjects: Twenty patients post stroke for a mean of 22 months. Intervention: Robot-assisted therapy ( n = 10) or dose-matched active control therapy ( n = 10). All patients received either of these two therapies for 90–105 minutes each day, 5 days per week, for four weeks. Main measures: Outcome measures included arm activity ratio (the ratio of mean activity between the impaired and unimpaired arm) and scores on the Fugl-Meyer Assessment Scale, Functional Independence Measure, Motor Activity Log and ABILHAND questionnaire. Results: The robot-assisted therapy group significantly increased motor function, hemiplegic arm activity and bilateral arm coordination (Fugl-Meyer Assessment Scale: 51.20 ± 8.82, P = 0.002; mean arm activity ratio: 0.76 ± 0.10, P = 0.026; ABILHAND questionnaire: 1.24 ± 0.28, P = 0.043) compared with the dose-matched active control group (Fugl-Meyer Assessment Scale: 40.90 ± 13.14; mean arm movement ratio: 0.69 ± 0.11; ABILHAND questionnaire: 0.95 ± 0.43). Conclusions: Symmetrical and bilateral robotic practice, combined with functional task training, can significantly improve motor function, arm activity, and self-perceived bilateral arm ability in patients late after stroke.

Ethnopharmacological relevance Danshensu is an active water-soluble component from Salvia Miltiorrhiza , which has been demonstrated holding multiple mechanisms for the regulation of cardiovascular system. However, the relative contribution of danshensu to its multiple cardiovascular activities remains largely unknown. Aim of the study To develop an artificial neural network (NN) model simultaneously characterizing danshensu pharmacokinetics and multiple cardiovascular activities in acute myocardial infarction (AMI) rats. The relationship between danshensu pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated using contribution values. Materials and methods Danshensu was intraperitoneally injected at a single dose of 20 mg/kg to AMI rats induced by coronary artery ligation. Plasma levels of danshensu, cardiac troponin T (cTnT), total homocysteine (Hcy) and reduced glutathione (GSH) were quantified. A back-propagation NN model was developed to characterize the PK and PD profiles of danshensu, in which the input variables contained time, area under plasma concentration–time curve (AUC) of danshensu and rat weights (covariate). Relative contribution of input variable to the output neurons was evaluated using neuron connection weights according to Garson's algorithm. The kinetics of contribution values was also compared and was validated using bootstrap resampling method. Results Danshensu exerted significant cTnT-lowering, Hcy- and GSH-elevating effect, and these marker profiles were well captured by the trained NN model. The calculation of relative contributions revealed that the effect of danshensu on the PD marker could be ranked as cTnT > GSH > Hcy, while the effect of AMI disease on the PD marker could be ranked in the following order: cTnT > Hcy > GSH. The activity of transsulfuration pathway was quite obvious under the AMI state. Conclusion NN is a powerful tool linking PK and PD profiles of danshensu with multiple cardioprotective mechanisms, it provides a simple method for identifying and ranking relative contribution to the multiple therapeutic effects of the drug.

Background and Objectives. Robot-assisted therapy (RT) is a current promising intervention in stroke rehabilitation, but more research is warranted for examining its efficacy and the dose–benefit relation. The authors investigated the effects of higher intensity versus lower intensity RT on movements of forearm pronation–supination and wrist flexion–extension relative to conventional rehabilitation (CR) in patients poststroke for a mean of 21 months. Methods. In this pilot study, 18 patients with initial mean Fugl-Meyer Assessment (FMA) of 37 to 44 for the upper extremity were randomized to higher intensity RT, lower intensity RT, or CR intervention for 4 weeks. The dose of the higher intensity RT was twice the number of repetitions in the lower intensity RT. Outcome measures at pretreatment and posttreatment were administered to patients to evaluate beneficial and adverse effects of interventions. Primary outcomes were the FMA and Medical Research Council scale. Results. There were significant differences in motor function ( P = .04) and daily performance ( P = .03) among the 3 groups. The higher intensity RT group showed better improvement in motor function, muscle strength, performance of daily activities, and bimanual ability than the other 2 groups. The intensive RT intervention did not induce higher levels of an oxidative DNA biomarker. Conclusions. Higher intensity of RT that assists forearm and wrist movements may lead to greater improvement in motor ability and functional performance in stroke patients. A sample size of only 20 to 25 in each arm of a larger randomized controlled trial is needed to confirm the findings for similar subjects.

Staphylococcus aureus may cause foodborne disease outbreaks and staphylococcal infections and is one of the major causes of mastitis. Rapid and reliable methods for detection of this microorganism in milk and other foods are needed. In this study, we designed a primer set from the sequence of the heat shock protein gene htrA, a gene coding for high-temperature-requirement A (HtrA) protein, and used it for real-time PCR detection of S. aureus isolates: 16 reference strains and 40 strains isolated from food-poisoning cases. All strains tested generated positive results. Bacterial strains other than S. aureus, including strains of other Staphylococcus species, did not produce positive results. When this primer set was used for the real-time PCR detection of S. aureus in milk and meat samples without the preenrichment step, samples with target cell numbers greater than 10(3) CFU/ml or CFU/g could be detected, indicating the potential quantitative ability of this real-time PCR assay. With a 10-h preenrichment step, however, a detection limit of 1 CFU/ml or CFU/g could be obtained.

The Peutz-Jeghers syndrome is a hereditary disease that requires frequent endoscopic and surgical intervention, leading to secondary complications such as short bowel syndrome. CASE REPORT: This paper reports on a 15-year-old male patient with a family history of the disease, who underwent surgery for treatment of an intestinal occlusion due to a small intestine intussusception. DISCUSSION: An intra-operative fiberscopic procedure was included for the detection and treatment of numerous polyps distributed along the small intestine. Enterotomy was performed to treat only the larger polyps, therefore limiting the intestinal resection to smaller segments. The postoperative follow-up was uneventful. CONCLUSION: We point out the importance of conservative treatment for patients with this syndrome, especially those who will undergo repeated surgical interventions because of clinical manifestation while they are still young. A síndrome de Peutz-Jeghers é uma doença de caráter hereditário que freqüentemente requer intervenções endoscópicas e cirúrgicas repetidas, levando a complicações secundárias como, por exemplo, a síndrome do intestino curto. RELATO DE CASO: Relatamos neste artigo o caso de paciente de 15 anos, masculino, com história familiar para a doença, que foi submetido ao procedimento cirúrgico para tratar oclusão devido a intussucepção de intestino delgado. DISCUSSÃO: Associou-se método fibroscópico intra-operatório com a finalidade de detecção e ressecção de numerosos pólipos distribuídos em todo o intestino delgado. Realizaram-se enterotomias para a retirada dos pólipos maiores, restringindo-se, portanto, a ressecção intestinal a segmentos menores. A evolução clínica foi boa. CONCLUSÃO: Ressalta-se a importância do manejo de forma conservadora dos pacientes portadores desta síndrome, principalmente naqueles cujas manifestações clínicas de importância cirúrgica aparecem precocemente.

The development of the hybridoma technique [8] has provided a powerful new tool for studies of tumor-associated antigens. Since 1978 Koprowski [9] and other investigators have prepared monoclonal antibodies (McAbs) to human melanoma, leukemia, lymphoma, colon cancer, breast cancer, lung cancer, and others. And some new tumor-associated antigens have been identified [4, 11]. However, there are only a few studies on antigens of gastric cancer. The mortality rate of gastric cancer is the highest one in China. Therefore, it is very interesting and necessary to investigate the antigens of gastric cancer in order to develop new approaches to the diagnosis and therapy of gastric cancer.