Structural insights into vesicular monoamine storage and drug interactions.

Biogenic monoamines-vital transmitters orchestrating neurological, endocrinal and immunological functions1-5-are stored in secretory vesicles by vesicular monoamine transporters (VMATs) for controlled quantal release6,7. Harnessing proton antiport, VMATs enrich monoamines around 10,000-fold and sequester neurotoxicants to protect neurons8-10. VMATs are targeted by an arsenal of therapeutic drugs and imaging agents to treat and monitor neurodegenerative disorders, hypertension and drug addiction1,8,11-16. However, the structural mechanisms underlying these actions remain unclear. Here we report eight cryo-electron microscopy structures of human VMAT1 in unbound form and in complex with four monoamines (dopamine, noradrenaline, serotonin and histamine), the Parkinsonism-inducing MPP+, the psychostimulant amphetamine and the antihypertensive drug reserpine. Reserpine binding captures a cytoplasmic-open conformation, whereas the other structures show a lumenal-open conformation stabilized by extensive gating interactions. The favoured transition to this lumenal-open state contributes to monoamine accumulation, while protonation facilitates the cytoplasmic-open transition and concurrently prevents monoamine binding to avoid unintended depletion. Monoamines and neurotoxicants share a binding pocket that possesses polar sites for specificity and a wrist-and-fist shape for versatility. Variations in this pocket explain substrate preferences across the SLC18 family. Overall, these structural insights and supporting functional studies elucidate the mechanism of vesicular monoamine transport and provide the basis to develop therapeutics for neurodegenerative diseases and substance abuse.

Genes associated with N6-methyladenosine regulators provide insight into the prognosis and immune response to renal clear cell carcinoma.

As one of the most common messenger ribonucleic acid modifications in eukaryotic organisms, N6-methyladenosine (m6A) is involved in a wide variety of biological functions. The imbalance of m6A RNA modification may be linked to cancer and other disorders, according to a growing body of studies. Its effects on clear cell renal cell carcinoma (KIRC) have not been well discussed, though. Here, we acquired the expression patterns of 23 important regulators of m6A RNA modification and assess how they might fare in KIRC. We observed that 17 major m6A RNA modification regulatory factors had a substantial predictive influence on KIRC. Using the "ConsensusCluster" program, we defined two groupings (Cluster 1 and Cluster 2) depending on the expression of the aforementioned 17 key m6A RNA methylation regulators. The Cluster 2 has a less favorable outcome and is strongly related with a lesser immune microenvironment, according to the findings. We also developed a strong risk profile for three m6A RNA modifiers (METTL14, YTHDF1, and LRPPRC) using multivariate Cox regression analysis. According to further research, the aforementioned risk profile could serve as an independent predicting factor for KIRC, and the chemotherapy response sensitivity was analyzed between two risk groups. Moreover, to effectively forecast the future outlook of KIRC clients, we established a novel prognostic approach according to gender, age, histopathological level, clinical stage, and risk score. Finally, the function of hub gene METTL14 was validated by cell proliferation and subcutaneous graft tumor in mice. In conclusion, we discovered that m6A RNA modifiers play an important role in controlling KIRC and created a viable risk profile as a marker of prediction for KIRC clients.

A Conway-Maxwell-Poisson-Binomial AR(1) Model for Bounded Time Series Data.

Binomial autoregressive models are frequently used for modeling bounded time series counts. However, they are not well developed for more complex bounded time series counts of the occurrence of n exchangeable and dependent units, which are becoming increasingly common in practice. To fill this gap, this paper first constructs an exchangeable Conway-Maxwell-Poisson-binomial (CMPB) thinning operator and then establishes the Conway-Maxwell-Poisson-binomial AR (CMPBAR) model. We establish its stationarity and ergodicity, discuss the conditional maximum likelihood (CML) estimate of the model's parameters, and establish the asymptotic normality of the CML estimator. In a simulation study, the boxplots illustrate that the CML estimator is consistent and the qqplots show the asymptotic normality of the CML estimator. In the real data example, our model takes a smaller AIC and BIC than its main competitors.

Association of Growth Differentiation Factor-15 Polymorphisms and Growth Differentiation Factor-15 Serum Levels with Susceptibility to Multiple Myeloma in a Chinese Population.

BACKGROUND: The aim of our study was to evaluate the relationship between growth differentiation factor-15 (GDF15) rs1058587, rs4808793, and rs1059369 polymorphisms, serum concentrations of GDF15, and International Staging System (ISS) staging or Durie-Salmon staging system (DS) staging in multiple myeloma patients and whether its polymorphism affects the expression of serum GDF15 in Chinese population. METHODS: A total of 120 patients with multiple myeloma and 119 healthy controls were included in the study. The SNaPshot technique was used to detect the GDF15 gene polymorphisms. Serum GDF15 levels were measured using an Enzyme-Linked ImmunoSorbent Assay (ELISA) kit. RESULTS: There was no significant difference in genotype distribution or allele frequency of three loci between multiple myeloma patients and healthy controls. However, the genotype distribution and allele frequencies of rs1059369 in ISS stage I were significantly different from those in ISS stage II (p = 0.008), and the distribution of rs1058587 genotype was different between ISS stage II and ISS stage III (p = 0.014). The overall serum concentration of GDF15 and the same genotype at the same locus (rs1058587: GC, GG; rs4808793: CC, GC; rs1059369: AA, AT, and TT) in patients with multiple myeloma was significantly higher than in the healthy control group (all p < 0.05). CONCLUSIONS: Our results showed the genotype distribution and allele frequencies of rs1059369 and rs1058587 of GDF15 gene have some association with ISS and DS stage. But the polymorphism of GDF15 did not affect the expression of serum GDF15 in patients with multiple myeloma.

Correlation between Pretreatment Hematologic Parameters and Cervical Cancer Patients Undergoing Hysterectomy: a Retrospective Study.

BACKGROUND: The objective of this study is to investigate the correlation of mean platelet volume (MPV), MPV/ platelet count, and monocyte to lymphocyte ratio (MLR) between cervical cancer patients and healthy people and to evaluate the value of those parameters in early diagnosis of cervical cancer. METHODS: The study population included 137 cervical cancer patients undergoing hysterectomy and 113 healthy controls. The clinical features (age, pathology type, tumor staging, and tumor size) were collected from the hospital information system. The hematology parameters (white blood cell, red blood cell, hemoglobin, platelet count, neutrophil, lymphocyte, monocyte, mean platelet volume, platelet distribution width) are obtained in the laboratory information system. RESULTS: We found that the monocyte count and MLR value are higher in the cervical cancer group. The MPV and MPV/platelet are lower in the cervical cancer group. The receiver operating characteristic (ROC) analysis shows that MPV+MLR can generate a moderate specificity with 71.68%, sensitivity with 65.69%, and AUC with 0.718 to distinguish cervical cancer and healthy people. CONCLUSIONS: MPV/platelet and MLR may be helpful for the early diagnosis of cervical cancer. A larger clinical data analysis is necessary to evaluate the diagnostic value of hematologic parameters in cervical cancer.

Single and Combined Use of Preoperative Inflammatory Biomarkers and CA199 in Diagnosing Pancreatic Cancer.

BACKGROUND: To determine the diagnostic value of preoperative inflammatory biomarkers and CA199, alone or in combination, in diagnosing pancreatic cancer (PCC). METHODS: This retrospective study was comprised of 75 PCC patients and 83 healthy controls (HC). The participant's medical data was mined from the electronic records of the First Affiliated Hospital of Guangxi Medical University. The data included the preoperative circulating albumin/fibrinogen ratio (AFR), the platelet/lymphocyte ratio (PLR), the lymphocyte/monocyte ratio (LMR), the neutrophil/lymphocyte ratio (NLR), and the derived NLR (dNLR). The receiver operating characteristic (ROC) curve and the area under the ROC curve (AUROC) were used to evaluate the diagnostic efficacy of these candidate biomarkers for PCC. RESULTS: A single AFR significantly distinguished PCC from the healthy controls (AUROC: 0.903, 95% CI: 0.846 - 0.945) and had a significantly higher sensitivity and larger AUROC than CA199 (AUROC: 0.814, 95% CI: 0.774 - 0.871). The combinations of AFR with CA199 (AUROC: 0.932, 95% CI: 0.881 - 0.966), RDW with CA199 (AUROC: 0.905, 95% CI: 0.849 - 0.946), Alb with CA199 (AUROC: 0.869, 95% CI: 0.806 - 0.917), and Fib with CA199 (AUROC: 0.921, 95% CI: 0.868 - 0.958) also yielded higher sensitivities and larger AUROCs than CA199 alone. CONCLUSIONS: Circulating AFR was an effective biomarker in diagnosing PCC. Combining AFR, RDW, Alb, and Fib with CA199 could improve the diagnostic efficacy for PCC.

Diagnostic value of platelet-lymphocyte ratio and hemoglobin-platelet ratio in patients with rectal cancer.

BACKGROUND: This study aimed to investigate the diagnostic value of platelet-lymphocyte ratio (PLR) and hemoglobin-platelet ratio (HPR) combined or not with carcinoembryonic antigen (CEA) in rectal cancer. METHODS: We recruited 235 patients pathologically diagnosed with rectal cancer, 113 patients with benign rectal diseases, and 229 healthy control patients in this retrospective analysis. Then, the correlation between PLR, HPR, and clinicopathological findings was analyzed. Receiver operating characteristic (ROC) curve was used to assess the diagnostic value of PLR and HPR combined or not with CEA in rectal cancer patients. RESULTS: The levels of PLR, HPR, and CEA were higher in rectal cancer patients than those in the subjects with benign rectal diseases (P < .001) and the healthy controls (P < .001). Platelet-lymphocyte ratio and HPR were associated with lymph node metastasis and tumor stage, rather than serosa invasion, distant metastasis, or tumor size. PLR or HPR combined with CEA produced larger area under curve (AUC) (AUCPLR+CEA  = 0.75, 95% CI = 0.70-0.79, AUCHPR+CEA  = 0.76, 95% CI = 0.71-0.80) than PLR (P < .0001), HPR (P < .0001), or CEA (P = .024) alone. CONCLUSION: Our results suggest that PLR or HPR combined with CEA can increase diagnostic efficacy and may be a useful diagnostic marker for patients with rectal cancer.

Radiolabeled 6-(2, 3-Dichlorophenyl)-N4-methylpyrimidine-2, 4-diamine (TH287): A Potential Radiotracer for Measuring and Imaging MTH1.

MTH1 (MutT homolog 1) or NUDT1 (Nudix Hydrolase 1), also known as oxidized purine nucleoside triphosphatase, has potential as a biomarker for monitoring cancer progression and quantifying target engagement for relevant therapies. In this study, we validate one MTH1 inhibitor TH287 as a PET MTH1 radiotracer. TH287 was radiolabeled with tritium and the binding of [3H]TH287 to MTH1 was evaluated in live glioblastoma cells (U251MG) through saturation and competitive binding assays, together with in vitro enzymatic assays. Furthermore, TH287 was radiolabeled with carbon-11 for in vivo microPET studies. Saturation binding assays show that [3H]TH287 has a dissociation constant (Kd) of 1.97 ± 0.18 nM, Bmax of 2676 ± 122 fmol/mg protein for U251MG cells, and nH of 0.98 ± 0.02. Competitive binding assays show that TH287 (Ki: 3.04 ± 0.14 nM) has a higher affinity for MTH1 in U251MG cells compared to another well studied MTH1 inhibitor: (S)-crizotinib (Ki: 153.90 ± 20.48 nM). In vitro enzymatic assays show that TH287 has an IC50 of 2.2 nM in inhibiting MTH1 hydrolase activity and a Ki of 1.3 nM from kinetics assays, these results are consistent with our radioligand binding assays. Furthermore, MicroPET imaging shows that [11C]TH287 gets into the brain with rapid clearance from the brain, kidney, and heart. The results presented here indicate that radiolabeled TH287 has favorable properties to be a useful tool for measuring MTH1 in vitro and for further evaluation for in vivo PET imaging MTH1 of brain tumors and other central nervous system disorders.

Transcranial Direct Current Stimulation Improves Cognitive Function in Mild to Moderate Alzheimer Disease: A Meta-Analysis.

OBJECTIVE: The purpose of this meta-analysis was to evaluate the therapeutic effect of transcranial direct current stimulation (tDCS) on mild to moderate Alzheimer disease (AD) patients. MATERIALS AND METHODS: PubMed, Embase, Web of Science, and Cochrane Library were searched until April 2018. The primary cognitive outcomes were extracted from included articles. A crude standardized mean difference with 95% CI was calculated by using fixed or random effect models. RESULTS: Seven studies with 146 patients were included in this meta-analysis. The pooled result showed that tDCS significantly improved cognitive function of AD patients (standardized mean difference=0.37; 95% CI, 0.09-0.65; P=0.01). Subgroup analyses showed that: a single session of tDCS was significantly effective (P<0.05) whereas repeated sessions of tDCS was not lower current density (0.06 mA/cm) (P>0.05) but not higher current density (0.08 mA/cm) significantly improved cognitive performance; stimulating the temporal cortex (P<0.05) but not the left dorsal lateral prefrontal cortex significantly improved cognitive function of AD patients; and improved cognitive function occurred in the group with higher education (P<0.05) but not in the group with lower education. CONCLUSIONS: Current evidence suggests that tDCS has a beneficial effect in mild to moderate AD patients. We must be cautious about the results of subgroup analysis given small sample sizes, and further well-designed studies with larger sample size are required to verify these results.

The Relationship of Neutrophil-to-Lymphocyte Ratio or Platelet-to-Lymphocyte Ratio and Pancreatic Cancer in Patients with Type 2 Diabetes.

BACKGROUND: The objective of the current study is to determine the importance of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in combination with cancer antigen 199 (CA199) in the diagnosis of pancreatic cancer (PC) in patients with type 2 diabetes. METHODS: The study population comprised 45 PC patients with type 2 diabetes, 50 patients with type 2 diabetes alone, and 60 control subjects. All data was mined from the electronic records of the First Affiliated Hospital of Guangxi Medical University in Nanning, Guangxi, China. RESULTS: We found that the NLRs and PLR of PC patients with type 2 diabetes were higher compared to patients with type 2 diabetes alone and healthy subjects. A receiver operating characteristic (ROC) curve analysis for the diagnosis of PC in type 2 diabetic patients revealed that the combination of NLR and CA199 had higher specificity than either NLR or CA199 alone, while the combination of PLR and CA199 had higher sensitivity than either PLR or CA199 alone. The area under the ROC curve (AUROC) for PLR combined with CA199 was significantly larger than CA199 alone, and the AUROC for NLR combined with CA199 was also larger than CA199 alone, al-though this difference was not significant. CONCLUSIONS: Combining PLR and CA199 values could allow earlier diagnosis of PC in type 2 diabetic patients.

Endothelial Cell Inflammation and Barriers Are Regulated by the Rab26-Mediated Balance between ß2-AR and TLR4 in Pulmonary Microvessel Endothelial Cells.

Rab26 GTPase modulates the trafficking of cell surface receptors, such as G protein-coupled receptors including α2-adrenergic receptors in some cell types. However, the effect of Rab26 on ß2-adrenergic receptor (ß2-AR) trafficking or/and Toll-like receptor 4 (TLR4) expression in human pulmonary microvascular endothelial cells (HPMECs) is still unclear. Here, we investigated the role of Rab26 in regulating the expression of ß2-ARs and TLR4 in HPMECs and the effect of these receptors' imbalance on endothelial cell barrier function. The results showed that there was unbalance expression in these receptors, where ß2-AR expression was remarkably reduced, and TLR4 was increased on the cell membrane after lipopolysaccharide (LPS) treatment. Furthermore, we found that Rab26 overexpression not only upregulated ß2-ARs but also downregulated TLR4 expression on the cell membrane. Subsequently, the TLR4-related inflammatory response was greatly attenuated, and the hyperpermeability of HPMECs also was partially relived. Taken together, these data suggest that basal Rab26 maintains the balance between ß2-ARs and TLR4 on the cell surface, and it might be a potential therapeutic target for diseases involving endothelial barrier dysfunction.

Correlation between hematological parameters and ancylostomiasis: A retrospective study.

OBJECTIVE: Our aim intended to determine the relationship between hematological parameters (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], and eosinophil-to-lymphocyte ratio [ELR]) and ancylostomiasis. METHODS: There were 140 patients with ancylostomiasis and 159 healthy controls enrolled in this study. All data were collected from electronic medical records of the First Affiliated Hospital of Guangxi Medical University. RESULTS: The levels of NLR, PLR, and ELR in ancylostomiasis patients were significantly higher than those in the healthy controls (all P = 0.000). A receiver operating characteristic curve was generated to assess the diagnostic efficacy of these three hematological parameters. ELR (AUC = 0.850; sensitivity = 75.00%; specificity = 86.80%) showed the superior AUC than those of NLR (AUC = 0.718; sensitivity = 53.57%; specificity = 88.68%) and PLR (AUC = 0.806; sensitivity = 68.57%; specificity = 86.79%), respectively. A multivariate regression model using the two selected indices (RBC and ELR) was established with the model's sensitivity and specificity reached 82.86% and 96.23%, respectively. In the ancylostomiasis patient group, NLR (r = -0.452, P = 0.000) and PLR (r = -0.357, P = 0.000) were reversely associated with eosinophils. CONCLUSION: The pretreatment levels of the three hematological parameters (NLR, PLR, and ELR) may serve as valuable indicators for distinguishing patients with ancylostomiasis from healthy controls. NLR and PLR are negatively associated with the previous indicator, eosinophils.

Value of Red Cell Distribution Width in Assessing the Severity of Hepatitis B Virus-Related Decompensated Cirrhosis.

BACKGROUND: Hepatitis B virus infection is the main reason for liver cirrhosis in China. Thus, evaluating the disease severity of hepatitis B-related decompensated cirrhosis (HBV-DeCi) is very important. The red cell distribution width (RDW) is thought to be correlated with the severity of various diseases. The purpose of this investigation is to verify whether RDW can estimate the disease severity of HBV-DeCi. METHODS: This retrospective study included 172 subjects who had been diagnosed with HBV-DeCi. They were categorized into three groups on the basis of their RDW values. Receiver operating curve (ROC) was used to estimate the severity predictive performances and binary logistic regression was used to assess the independent variable predicting the severity of liver disease. RESULTS: The RDW values were evidently increased in the HBV-DeCi patients in comparison with the healthy controls (18.00% ± 0.04 vs. 13.19% ± 0.74, p < 0.001). There was also a significant difference in the model for endstage liver disease score of the three different RDW groups of A, B and C (13.2 ± 4.6, 16.0 ± 9.0, and 18.8 ± 6.5, p = 0.002). The RDW was an independent risk factor of the severity of HBV-DeCi. The cutoff level for RDW was > 14.0%, where the sensitivity and specificity were 90.7%, 100.0%, respectively, and the area under the curve (AUC) of ROC was 0.969. For a combination of RDW and MELD score, the AUC was 0.997, and the sensitivity and specificity were 98.3% and 99.1%, respectively. CONCLUSIONS: The RDW is a simple biomarker that may play an important role in predicting the severity of HBVDeCi.

Short- and Long-term Effects of Repetitive Transcranial Magnetic Stimulation on Upper Limb Motor Function after Stroke: a Systematic Review and Meta-Analysis.

OBJECTIVE: The aim of this study was to evaluate the short- and long-term effects as well as other parameters of repetitive transcranial magnetic stimulation (rTMS) on upper limb motor functional recovery after stroke. DATA SOURCES: The databases of PubMed, Medline, Science Direct, Cochrane, and Embase were searched for randomized controlled studies reporting effects of rTMS on upper limb motor recovery published before October 30, 2016. REVIEW METHODS: The short- and long-term mean effect sizes as well as the effect size of rTMS frequency of pulse, post-stroke onset, and theta burst stimulation patterns were summarized by calculating the standardized mean difference (SMD) and the 95% confidence interval using fixed/random effect models as appropriate. RESULTS: Thirty-four studies with 904 participants were included in this systematic review. Pooled estimates show that rTMS significantly improved short-term (SMD, 0.43; P < 0.001) and long-term (SMD, 0.49; P < 0.001) manual dexterity. More pronounced effects were found for rTMS administered in the acute phase of stroke (SMD, 0.69), subcortical stroke (SMD, 0.66), 5-session rTMS treatment (SMD, 0.67) and intermittent theta burst stimulation (SMD, 0.60). Only three studies reported mild adverse events such as headache and increased anxiety . CONCLUSIONS: Five-session rTMS treatment could best improve stroke-induced upper limb dyskinesia acutely and in a long-lasting manner. Intermittent theta burst stimulation is more beneficial than continuous theta burst stimulation. rTMS applied in the acute phase of stroke is more effective than rTMS applied in the chronic phase. Subcortical lesion benefit more from rTMS than other lesion site.

Repetitive transcranial magnetic stimulation as an alternative therapy for dysphagia after stroke: a systematic review and meta-analysis.

OBJECTIVES: A meta-analysis and systematic review was conducted to investigate the potential effects of repetitive transcranial magnetic stimulation on dysphagia in patients with stroke, including different parameters of frequency and stimulation site. METHODS: PubMed, Embase, MEDLINE databases and the Cochrane Library, were searched for randomized controlled studies of repetitive transcranial magnetic stimulation treatment of dysphagia published before March 2016. RESULTS: Six clinical randomized controlled studies of a total of 163 stroke patients were included in this meta-analysis. A significant effect size of 1.24 was found for dysphagic outcome (mean effect size, 1.24; 95% confidence interval (CI), 0.67-1.81). A subgroup analysis based on frequency showed that the clinical scores were significantly improved in dysphagic patients with low frequency repetitive transcranial magnetic stimulation treatment ( P < 0.05) as well as high frequency repetitive transcranial magnetic stimulation treatment ( P < 0.05). A stimulation site stratified subgroup analysis implied significant changes in stroke patients with dysphagia for the unaffected hemisphere ( P < 0.05) and the bilateral hemisphere stimulation ( P < 0.05), but not for the affected hemisphere ( P > 0.05). The analysis of the follow-up data shows that patients in the repetitive transcranial magnetic stimulation groups still maintained the therapeutic benefit of repetitive transcranial magnetic stimulation four weeks after the last session of repetitive transcranial magnetic stimulation therapy ( P < 0.05). CONCLUSION: This meta-analysis indicates that repetitive transcranial magnetic stimulation has a positive effect on dysphagia after stroke. Compared with low-frequency repetitive transcranial magnetic stimulation, high-frequency repetitive transcranial magnetic stimulation may be more beneficial to the patients. This meta-analysis also supports that repetitive transcranial magnetic stimulation on an unaffected - or bilateral - hemisphere has a significant therapeutic effect on dysphagia.

Low-Frequency Repetitive Transcranial Magnetic Stimulation for Stroke-Induced Upper Limb Motor Deficit: A Meta-Analysis.

Background and Purpose: This meta-analysis aimed to evaluate the therapeutic potential of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) over the contralesional hemisphere on upper limb motor recovery and cortex plasticity after stroke. Methods: Databases of PubMed, Medline, ScienceDirect, Cochrane, and Embase were searched for randomized controlled trials published before Jun 31, 2017. The effect size was evaluated by using the standardized mean difference (SMD) and a 95% confidence interval (CI). Resting motor threshold (rMT) and motor-evoked potential (MEP) were also examined. Results: Twenty-two studies of 1 Hz LF-rTMS over the contralesional hemisphere were included. Significant efficacy was found on finger flexibility (SMD = 0.75), hand strength (SMD = 0.49), and activity dexterity (SMD = 0.32), but not on body function (SMD = 0.29). The positive changes of rMT (SMD = 0.38 for the affected hemisphere and SMD = -0.83 for the unaffected hemisphere) and MEP (SMD = -1.00 for the affected hemisphere and SMD = 0.57 for the unaffected hemisphere) were also significant. Conclusions: LF-rTMS as an add-on therapy significantly improved upper limb functional recovery especially the hand after stroke, probably through rebalanced cortical excitability of both hemispheres. Future studies should determine if LF-rTMS alone or in conjunction with practice/training would be more effective. Clinical Trial Registration Information: This trial is registered with unique identifier CRD42016042181.

Ipsilesional High Frequency Repetitive Transcranial Magnetic Stimulation Add-On Therapy Improved Diffusion Parameters of Stroke Patients with Motor Dysfunction: A Preliminary DTI Study.

Purpose. The aim of this study was to evaluate the effects of high frequency repetitive transcranial magnetic stimulation (HF-rTMS) on stroke patients with motor dysfunction and to investigate the underlying neural mechanism. Methods. Fifteen stroke patients were assigned to the rTMS treatment (RT) group and conventional treatment (CT) group. Patients in the RT received 10 Hz rTMS stimulation on the ipsilesional primary motor cortex for 10 days plus conventional treatment of CT, which consisted of acupuncture and antiplatelet aggregation medication. Difference in fractional anisotropy (FA) between pretreatment and posttreatment and between two groups was determined. Correlations between FA values and neurological assessments were also calculated. Results. Both groups significantly improved the neurological function after treatment. rTMS-treated patients showed better improvement in Fugl-Meyer Assessment (FMA) score and increased FA value in motor-related white matter and gray matter cortices compared with CT-treated patients and pretreatment status. Besides, the increased FA value in the ipsilesional posterior limb of the internal capsule in RT group was significantly correlated with the improved FMA score. Significance. HF-rTMS could be a supplement therapy to CT in improving motor recovery in patients with stroke. And this benefit effect may be achieved through modulating the ipsilesional corticospinal tracts and motor-related gray matter cortices.

Noninvasive imaging of experimental lung fibrosis.

Small animal models of lung fibrosis are essential for unraveling the molecular mechanisms underlying human fibrotic lung diseases; additionally, they are useful for preclinical testing of candidate antifibrotic agents. The current end-point measures of experimental lung fibrosis involve labor-intensive histological and biochemical analyses. These measures fail to account for dynamic changes in the disease process in individual animals and are limited by the need for large numbers of animals for longitudinal studies. The emergence of noninvasive imaging technologies provides exciting opportunities to image lung fibrosis in live animals as often as needed and to longitudinally track the efficacy of novel antifibrotic compounds. Data obtained by noninvasive imaging provide complementary information to histological and biochemical measurements. In addition, the use of noninvasive imaging in animal studies reduces animal usage, thus satisfying animal welfare concerns. In this article, we review these new imaging modalities with the potential for evaluation of lung fibrosis in small animal models. Such techniques include micro-computed tomography (micro-CT), magnetic resonance imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), and multimodal imaging systems including PET/CT and SPECT/CT. It is anticipated that noninvasive imaging will be increasingly used in animal models of fibrosis to gain insights into disease pathogenesis and as preclinical tools to assess drug efficacy.

A systematic review for the antidepressant effects of sleep deprivation with repetitive transcranial magnetic stimulation.

BACKGROUND: Sleep deprivation (SD) and repetitive transcranial magnetic stimulation (rTMS) have been commonly used to treat depression. Recent studies suggest that co-therapy with rTMS and SD may produce better therapeutic effects than either therapy alone. Therefore, this study was to review the current findings to determine if rTMS can augment the therapeutic effects of SD on depression. METHODS: Embase, JSTOR, Medline, PubMed, ScienceDirect, and the Cochrane Central Register of Controlled Trials were searched for clinical studies published between January 1985 and March 2015 using the search term "rTMS/repetitive transcranial magnetic stimulation AND sleep deprivation AND depress*". Only randomized and sham-controlled trials (RCTs) involving the combined use of rTMS and SD in depression patients were included in this systematic review. The scores of the Hamilton Rating Scale for Depression were extracted as primary outcome measures. RESULTS: Three RCTs with 72 patients that met the inclusion criteria were included for the systematic review. One of the trials reported skewed data and was described alone. The other two studies, which involved 30 patients in the experimental group (SD + active rTMS) and 22 patients in the control group (SD + sham rTMS), reported normally distributed data. The primary outcome measures showed different results among the three publications: two of which showed great difference between the experimental and the control subjects, and the other one showed non-significant antidepressant effect of rTMS on SD. In addition, two of the included studies reported secondary outcome measures with Clinical Global Impression Rating Scale and a self-reported well-being scale which presented good improvement for the depressive patients in the experiment group when compared with the control. The follow-up assessments in two studies indicated maintained results with the immediate measurements. CONCLUSIONS: From this study, an overview of the publications concerning the combined use of rTMS and SD is presented, which provides a direction for future research of therapies for depression. More studies are needed to confirm whether there is an augmentative antidepressant effect of rTMS on SD.

Epigallocatechin gallate and sulforaphane combination treatment induce apoptosis in paclitaxel-resistant ovarian cancer cells through hTERT and Bcl-2 down-regulation.

The cellular development of resistance to chemotherapy contributes to the high mortality noted in patients affected by ovarian cancer. Novel compounds that specifically target cellular drug resistance in ovarian cancer are therefore highly desired. Previous epidemiological studies indicate that consumption of green tea and cruciferous vegetables is inversely associated with occurrence of ovarian cancer. Therefore revealing the effects and mechanisms of major components of green tea (epigallocatechin gallate, EGCG) and cruciferous vegetables (sulforaphane, SFN) on ovarian cancer cells will provide necessary knowledge for developing potential novel treatments for the disease. In this study, EGCG or SFN was used to treat both paclitaxel-sensitive (SKOV3-ip1) and -resistant (SKOV3TR-ip2) ovarian cancer cell lines alone or in combination. We found that SFN inhibits cell viability of both ovarian cancer cell lines time- and dose-dependently and that EGCG potentiates the inhibiting effect of SFN on ovarian cancer cells. Cell cycle analysis indicates SFN can arrest ovarian cancer cells in G2/M phase, while EGCG and SFN co-treatment can arrest cells in both G2/M and S phase. Combined EGCG and SFN treatment increases apoptosis significantly in paclitaxel-resistant SKOV3TR-ip2 cells after 6 days of treatment, while reducing the expression of hTERT, the main regulatory subunit of telomerase. Western blotting also indicates that SFN can down-regulate Bcl-2 (a gene involved in anti-apoptosis) protein levels in both cell types. Cleaved poly(ADP-ribose) polymerase (PARP) becomes up-regulated by 6 days of treatment with SFN and this is more pronounced for combination treatment indicating induction of apoptosis. Furthermore, phosphorylated H2AX is up-regulated after 6 days of treatment with SFN alone, and EGCG can potentiate this effect, suggesting that DNA damage is a potential cellular mechanism contributing to the inhibiting effect of EGCG and SFN combination treatment. Taken together, these results indicate that EGCG and SFN combination treatment can induce apoptosis by down-regulating of hTERT and Bcl-2 and promote DNA damage response specifically in paclitaxel-resistant ovarian cancer cell lines and suggest the use of these compounds for overcoming paclitaxel resistance in ovarian cancer treatment.