GPR56, an Adhesion GPCR with Multiple Roles in Human Diseases, Current Status and Future Perspective.

Human G protein-coupled receptor 56 (GPR56) belongs to a member of the adhesion G-protein coupled receptor (aGPCR) family and widely exists in the central nervous system and various types of tumor tissues. Recent studies have shown that abnormal expression or dysfunction of GPR56 is closely associated with many physiological and pathological processes, including brain development, neuropsychiatric disorders, cardiovascular diseases and cancer progression. In addition, GPR56 has been proven to enhance the susceptibility of some antipsychotics and anticarcinogens in response to the treatment of neuropsychological diseases and cancer. Although there have been some reports about the functions of GPR56, the underlying mechanisms implicated in these diseases have not been clarified thoroughly, especially in depression and epilepsy. Therefore, in this review, we described the molecular structure and signal transduction pathway of GPR56 and carried out a comprehensive summary of GPR56's function in the development of psychiatric disorders and cancer. Our review showed that GPR56 deficiency led to depressive-like behaviors and an increase in resistance to antipsychotic treatment. In contrast, the upregulation of GPR56 contributed to tumor cell proliferation and metastasis in malignant diseases such as glioblastoma, colorectal cancer, and ovarian cancer. Moreover, we elucidated specific signaling pathways downstream of GPR56 related to the pathogenesis of these diseases. In summary, our review provides compelling arguments for an attractive therapeutic target of GPR56 in improving the therapeutic efficiency for patients suffering from psychiatric disorders and cancer.

Effectiveness and safety of Moluodan in the treatment of precancerous lesions of gastric cancer: A randomized clinical trial.

OBJECTIVE: To investigate the clinical potential and safety of Moluodan to reverse gastric precancerous lesions. METHODS: Patients aged 18-70 years diagnosed with moderate-to-severe atrophy and/or moderate-to-severe intestinal metaplasia, with or without low-grade dysplasia, and negative for Helicobacter pylori were recruited in this randomized, double-blind, parallel-controlled trial. The primary outcome was the improvement of global histological diagnosis at 1-year follow-up endoscopy using the operative link for gastritis assessment, the operative link for gastric intestinal metaplasia assessment, and the disappearance rate of dysplasia. RESULTS: Between November 3, 2017 and January 27, 2021, 166 subjects were randomly assigned to the Moluodan group, 168 to the folic acid group, 84 to the combination group, and 84 to the high-dose Moluodan group. The improvement in global histological diagnosis was achieved in 60 (39.5%) subjects receiving Moluodan, 59 (37.8%) receiving folic acid, 26 (32.1%) receiving the combined drugs, and 36 (47.4%) receiving high-dose Moluodan. Moluodan was non-inferior to folic acid (95% confidence interval: -9.2 to 12.5; P = 0.02). High-dose Moluodan had a trend for better protective efficacy, though there was no statistical significance. The disappearance rate of dysplasia was 82.8% in the Moluodan group, which was superior to folic acid (53.9%; P = 0.006). No drug-related serious adverse events were observed. CONCLUSIONS: One pack of Moluodan three times daily for 1 year was safe and effective in reversing gastric precancerous lesions, especially dysplasia. Doubling its dose showed a better efficacy trend.

Accuracy of different registration areas using active and passive dynamic navigation systems in dental implant surgery: An in vitro study.

OBJECTIVES: To gauge the relative accuracy of the use of passive and active dynamic navigation systems when placing dental implants, and to determine how registration areas affect the performance of these systems. MATERIALS AND METHODS: Eighty implants were assigned to be placed into 40 total resin mandible models missing either the left or right first molars using either passive or active dynamic navigation system approaches. U-shaped tube registration devices were fixed in the edentulous site for 20 models each on the left or right side. Planned and actual implant positions were superimposed to assess procedural accuracy, and parameters including 3D entry deviation, angular deviation, and 3D apex deviation were evaluated with Mann-Whitney U tests and Wilcoxon signed-rank tests. RESULTS: Respective angular, entry, and apex deviation values of 1.563 ± 0.977°, 0.725 ± 0.268 mm, and 0.808 ± 0.284 mm were calculated for all included implants, with corresponding values of 1.388 ± 1.090°, 0.789 ± 0.285 mm, and 0.846 ± 0.301 mm in the active group and 1.739 ± 0.826°, 0.661 ± 0.236 mm, and 0.769 ± 0.264 mm in the passive group. Only angular deviation differed significantly among groups, and the registration area was not associated with any significant differences among groups. CONCLUSIONS: Passive and active dynamic navigation approaches can achieve comparable in vitro accuracy. Registration on one side of the missing single posterior tooth area in the mandible can complete single-tooth implantation on both sides of the posterior teeth, highlighting the promise of further clinical research focused on this topic.

Intermittent theta-burst stimulation combined with physical therapy as an optimal rehabilitation in Parkinson's disease: study protocol for a randomised, double-blind, controlled trial.

BACKGROUND: First-line rehabilitative strategies to improve motor deficits are based on functional training (physical or occupational therapy), which has been demonstrated to facilitate neural reorganisation. Accumulating evidence suggests that non-invasive brain stimulation techniques, such as repetitive TMS (rTMS), may enhance neuroplasticity, thereby facilitating neural reorganisation and recovery from Parkinson's disease. Evidence also shows that intermittent theta-burst stimulation (iTBS) can improve motor function and quality of life in patients by promoting the excitability and neural remodelling of cerebral cortex. We aimed to combine iTBS stimulation with physiotherapy to improve the rehabilitation effect compared to physiotherapy alone in patients with Parkinson's disease. METHODS: This randomised, double-blind clinical trial will enrol 50 Parkinson's disease patients aged 45-70 years with Hoehn and Yahr scale scores of 1-3. Patients are randomly assigned to either the iTBS + physiotherapy or sham-iTBS + physiotherapy group. The trial consists of a 2-week double-blind treatment period and a 24-week follow-up period. iTBS and sham-iTBS will be administered twice daily for 10 days based on physiotherapy. The primary outcome will be the third part of Movement Disorders-Unified Parkinson's Disease Rating Scale (MDS-UPDRS III) from the baseline to the first 2 days following completion hospitalised intervention. The secondary outcome will be 39-item Parkinson's Disease Questionnaire (PDQ-39) at 4 weeks, 12 weeks and 24 weeks after intervention. Tertiary outcomes are clinical evaluations and mechanism study outcomes such as NMSS, 6MWD, 10MT, TUG, BBS, MRI, and EEG, the length of time between the drug needs to be adjusted when symptoms fluctuate. DISCUSSION: The aim of this study is to demonstrate that iTBS can promote overall function and quality of life in Parkinson's disease patients using physiotherapy and that this efficacy may be associated with altered neuroplasticity in exercise-related brain regions. The iTBS combined with physiotherapy training model will be evaluated during a 6-month follow-up period. With significant improvement in quality of life and motor function, iTBS combined with physiotherapy can be considered as a first-line rehabilitation option for Parkinson's disease. The potential of iTBS to enhance neuroplasticity in the brain should have a more positive impact in increasing the generality and efficiency of physiotherapy, improving the quality of life and overall functional status of patients with Parkinson's disease. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200056581. Registered on 8 February 2022.

Mechanism of Learning and Memory Impairment in Rats Exposed to Arsenic and/or Fluoride Based on Microbiome and Metabolome.

Objective: Arsenic (As) and fluoride (F) are two of the most common elements contaminating groundwater resources. A growing number of studies have found that As and F can cause neurotoxicity in infants and children, leading to cognitive, learning, and memory impairments. However, early biomarkers of learning and memory impairment induced by As and/or F remain unclear. In the present study, the mechanisms by which As and/or F cause learning memory impairment are explored at the multi-omics level (microbiome and metabolome). Methods: We stablished an SD rats model exposed to arsenic and/or fluoride from intrauterine to adult period. Results: Arsenic and/fluoride exposed groups showed reduced neurobehavioral performance and lesions in the hippocampal CA1 region. 16S rRNA gene sequencing revealed that As and/or F exposure significantly altered the composition and diversity of the gut microbiome，featuring the Lachnospiraceae_NK4A136_group, Ruminococcus_1, Prevotellaceae_NK3B31_group, [Eubacterium]_xylanophilum_group. Metabolome analysis showed that As and/or F-induced learning and memory impairment may be related to tryptophan, lipoic acid, glutamate, gamma-aminobutyric acidergic (GABAergic) synapse, and arachidonic acid (AA) metabolism. The gut microbiota, metabolites, and learning memory indicators were significantly correlated. Conclusion: Learning memory impairment triggered by As and/or F exposure may be mediated by different gut microbes and their associated metabolites.

Oral arsenic and retinoic acid for high-risk acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) has become curable over 95% patients under a complete chemo-free treatment with all-trans retinoic acid (ATRA) and arsenic trioxide in low-risk patients. Minimizing chemotherapy has proven feasible in high-risk patients. We evaluated oral arsenic and ATRA without chemotherapy as an outpatient consolidation therapy and no maintenance for high-risk APL. We conducted a multicenter, single-arm, phase 2 study with consolidation phases. The consolidation therapy included Realgar-Indigo naturalis formula (60 mg/kg daily in an oral divided dose) in a 4-week-on and 4-week-off regimen for 4 cycles and ATRA (25 mg/m2 daily in an oral divided dose) in a 2-week-on and 2-week-off regimen for 7 cycles. The primary end point was the disease-free survival (DFS). Secondary end points included measurable resident disease, overall survival (OS), and safety. A total of 54 participants were enrolled at seven centers from May 2019. The median age was 40 years. At the median follow-up of 13.8 months (through April 2022), estimated 2-year DFS and OS were 94% and 100% in an intention-to-treat analysis. All the patients achieved complete molecular remission at the end of consolidation phase. Two patients relapsed after consolidation with a cumulative incidence of relapse of 6.2%. The majority of adverse events were grade 1-2, and only three grade 3 adverse events were observed. Oral arsenic plus ATRA without chemotherapy was active as a first-line consolidation therapy for high-risk APL.Trial registration: chictr.org.cn number, ChiCTR1900023309.

Mechanism of subchronic vinyl chloride exposure combined with a high-fat diet on hepatic steatosis.

Vinyl chloride (VC) is a common industrial organic chlorine and environmental pollutant. In recent years, the dietary structure of residents especially Chinese has gradually shifted to western dietary patterns. VC aggravates dietary fatty acid-induced hepatic steatosis, but its mechanism is still unclear. And if the risk factors for steatosis persist, more severe diseases such as fibrosis and cirrhosis will occur. Therefore, we studied the effects and mechanisms of VC (160 and 800 mg/m3 ) and its metabolite (chloroacetaldehyde, 2.25, 4.5, and 9 µM) on hepatic steatosis of high-fat diet (HFD)-fed mice and palmitic acid (PA, 100 µM) treated HepG2 cells. Liver and serum biochemical indicators and pathological staining of the liver showed that the hepatic steatosis of VC combined with HFD groups was more severe than that of single-exposure groups (HFD group, low-dose VC group, and high-dose VC group). Moreover, VC enhanced HFD-induced oxidative stress (OS) and endoplasmic reticulum stress (ERS) and further upregulated the expression of sterol regulatory element-binding protein 1 (SREBP-1) and FAS. Besides, antioxidants and ERS inhibitors reduced the steatosis of HepG2 cells induced by VC metabolites and PA. These results suggest that VC exposure can enhance the degree of hepatic steatosis in HFD-fed mice. VC combined with HFD led to OS and ERS and upregulated the expression of de novo lipogenesis-related proteins, which may be related to the occurrence of hepatic steatosis. And the increased expression of CYP2E1 induced by VC combined with HFD may be the cause of OS.

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We examined the effects of phosphorus (P) levels on photosynthetic and P/Fe traits of soybean under the stress of low Fe and their genotypic differences, to provide a theoretical basis for rational application of P and Fe fertilizer. Six P-efficient and six P-inefficient soybean varieties screened in the early stage were used as experimental materials. Four treatments of P:Fe ratio were set, including 0:30, 30:30, 150:30 and 300:30 (µmol·L-1). We measured chlorophyll fluorescence traits and P-Fe utilization efficiency in soybean. A stepwise regression equation was established with seed weight per plant. Pathway analysis was performed, with the response of P-efficient and P-inefficient soybean genotypes to different P:Fe treatments being comprehensively evaluated by factor scores. The results showed significant main and interactive effects of genotype and P:Fe on the relative electron transfer rate of photosystem Ⅱ (ETR) at beginning of flowering stage (R1), the proportion of the energy absorbed by photosystem Ⅱ dissipated into heat (NPQ) at R1 stage, and proportion of energy absorbed by photosystem Ⅱ devoted to the photochemical reaction (qL) at R1 stage. Results of canonical correlation analysis showed a negative correlation between P utilization efficiency of seed at full maturity stage (R8) and photosynthetic rate at R1 stage of P-efficient genotypes. Seed Fe utilization efficiency of P-inefficient genotypes at R8 stage was positively correlated with NPQ at R1 stage, but negatively correlated with qL at R1 stage. The actual photochemical efficiency of PSⅡ (ΦPSⅡ) at R1 stage was negatively correlated with P-efficient genotypes, but positively correlated with P-inefficient genotypes, which indicated that ΦPSⅡ at R1 stage was an important indicator for identifying soybean genotypes with different P efficiency under stress of low Fe. The comprehensive performance of P-efficient soybean genotypes decreased first and then increased with P level, while P-inefficient soybean genotypes increased first and then decreased. The inflection point of both genotypes appeared in P:Fe of 30:30. Thus, P:Fe ratio of 30:30 could be used as a threshold to identify soybean genotypes with different P efficiency under stress of low Fe. In conclusion, P fertilizer application should be equal to or greater than 1:1 (P:Fe) when planting P-efficient soybean genotypes in low Fe area, while P fertilizer application should not exceed 1:1 (P:Fe) when planting P-inefficient soybean genotypes.

C-Gait for Detecting Freezing of Gait in the Early to Middle Stages of Parkinson's Disease: A Model Prediction Study.

OBJECTIVE: Efficient methods for assessing walking adaptability in individuals with Parkinson's disease (PD) are urgently needed. Therefore, this study aimed to assess C-Gait for detecting freezing of gait (FOG) in patients with early- to middle-stage PD. METHOD: People with PD (PWP) diagnosis (Hoehn and Yahr stages 1-3) were recruited from April 2019 to November 2019 in Beijing Rehabilitation Hospital. The participants performed six items of walking adaptability on an instrumented treadmill augmented with visual targets and obstacles (C-Mill). The patient's walking adaptability was evaluated by C-Gait assessment and traditional walking tests, and FOG-related indexes were collected as outcome measures. Two discriminant models were established by stepwise discriminant analysis; area under the receiver operating characteristic (ROC) curve (AUC) was used to validate the models. RESULT: In total, 53 patients were included in this study. Most C-Gait assessment items had no or low correlations with traditional walking tests. The obstacle avoidance (r = -0.639, P = 0.003) and speed of adaptation (r = -0.486, P = 0.035) items could lead to FOG with high sensitivity. In addition, the C-Gait assessment model (AUC = 0.755) had slightly better discrimination of freezers from non-freezers compared with traditional walking test models (AUC = 0.672); specifically, obstacle avoidance and speed of adaptation have uniquely discriminant potential. CONCLUSION: C-gait assessment could provide additional value to the traditional walking tests for PD. Gait adaptability assessment, as measured by C-Gait, may be able to help identify freezers in a PD population.

Methodological quality evaluation of systematic reviews or meta-analysis of trastuzumab-based therapy for breast cancer: A systematic review.

BACKGROUND: To evaluate the methodological quality of systematic reviews (SRs) or meta-analysis of trastuzumab-based therapy for breast cancer. METHODS: We searched the PubMed, EMBASE, Web of science, Cochrane library, international prospective register of systematic reviews, Chinese BioMedical Literature Database, Wan Fang, China National Knowledge Infrastructure and VIP database for SRs or meta-analysis. The methodological quality of included literatures was appraised by risk of bias in systematic review (ROBIS) tool. RESULTS: Twenty three eligible systematic reviews or meta-analysis were included. Only 2 systematic reviews provided protocol. The most frequently searched databases were PubMed, MEDLINE, EMBASE, and the Cochrane. The two-reviewers model described in the screening for eligible original articles, data extraction, and methodological quality evaluation had 30%, 61%, and 26%, respectively. In methodological quality assessment, 52% SRs or meta-analysis used the Jadad scoring or Cochrane reviewer' handbook. Research question were well matched to all SRs or meta-analysis in phase 1 and 35% of them evaluated "high" risk bias in study eligibility criteria. The "high" risk of bias in all non-Cochrane SRs or meta-analyses, which involve methods used to identify and/or select studies. And more than half SRs or meta-analysis had a high risk of bias in data collection and study appraisal. More than two-third of SRs or meta-analysis were accomplished with high risk of bias in the synthesis and findings. CONCLUSIONS: The study indicated poor methodological and reporting quality of SRs/meta-analysis assessing trastuzumab-based therapy for breast cancer. Registration or publishing the protocol and the reporting followed the PRISMA checklist are recommended in future research.

Efficacy of short-term multidisciplinary intensive rehabilitation in patients with different Parkinson's disease motor subtypes: a prospective pilot study with 3-month follow-up.

Parkinson's disease (PD) can be classified into three motor-based subtypes: postural instability/gait difficulty (PIGD), tremor dominant (TD), and indeterminate. The neuropathophysiological mechanisms of the three motor subtypes are different, which may lead to different responses to therapy. Sixty-nine patients with idiopathic Parkinson's disease (Hoehn-Yahr stage ≤ 3) were screened from 436 patients with Parkinsonism recruited through outpatient services and the internet. According to the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) TD/PIGD ratio, the patients were divided into PIGD (TD/PIGD ≤ 0.09; n = 36), TD (TD/PIGD ≥1.15; n = 19), and indeterminate (TD/PIGD = 0.90-1.15; n = 14) groups. All patients received 2 weeks of multidisciplinary intensive rehabilitation treatment (MIRT) during hospitalization, as well as a remote home rehabilitation health education class. Compared with the scores at admission, all patients showed significant improvements in their MDS-UPDRS III score, walking ability, balance, and posture control at discharge. Moreover, the MDS-UPDRS III score improvement was greater in the PIGD group than in the TD group. The follow-up data, collected for 3 months after discharge, showed that overall symptom improvement in each group was maintained for 1-3 months. Furthermore, there were no significant differences in the duration or grade effects of symptom improvement among the three groups. These findings suggest that 2 weeks of MIRT is effective for improving motor performance in all three motor subtypes. Patients in the PIGD group had a better response after hospitalization than those in the TD group. This study was approved by the Institutional Ethics Committee of Beijing Rehabilitation Hospital of Capital Medical University of China (approval No. 2018bkky022) on May 7, 2018 and registered with the Chinese Clinical Trial Registry (registration No. ChiCTR1900020771) on January 19, 2019.

Modeling the Long-term Antibody Response and Duration of Immune Protection Induced by an Inactivated, Preservative-free Hepatitis A Vaccine (Healive) in Children.

OBJECTIVE: Long-term seroprotection via the hepatitis A vaccine is essential for the prevention of disease from the hepatitis A virus (HAV). Due to documented difficulties during decade-long follow-ups after receiving vaccines, statistical-modeling approaches have been applied to predict the duration of immune protection. METHODS: Based on five-year follow-up data from a randomized positive-controlled trial among Chinese children (1-8 years old) following a 0, 6 months vaccination schedule, a power-law model accounting for the kinetics of B-cell turnover, as well as a modified power-law model considering a memory-B-cell subpopulation, were fitted to predict the long-term immune responses induced by HAV vaccination (Healive or Havrix). Anti-HAV levels of each individual and seroconversion rates up to 30 years after vaccination were predicted. RESULTS: A total of 375 participants who completed the two-dose vaccination were included in the analysis. Both models predicted that, over a life-long period, participants vaccinated with Healive would have close but slightly higher antibody titers than those of participants vaccinated with Havrix. Additionally, consistent with previous studies, more than 90% of participants were predicted to maintain seroconversion for at least 30 years. Moreover, the modified power-law model predicted that the antibody titers would reach a plateau level after nearly 15 years post-vaccination. CONCLUSIONS: Based on the results of our modeling, Healive may adequately induce long-term immune responses following a 0, 6 months vaccination schedule in children via induction of memory B cells to provide stable and durable immune protection.

Somatosensory changes in Chinese patients after coronectomy vs. total extraction of mandibular third molar: a prospective study.

OBJECTIVES: This study aimed to quantitatively compare the somatosensory function changes of inferior alveolar nerve (IAN) after mandibular third molar extraction with a surgery protocol of coronectomy, as opposed to the conventional method. MATERIALS AND METHODS: Patients with a lower third molar directly contacting IAN were recruited and assigned either to a test group (coronectomy group) or a control group (conventional extraction). A standardized quantitative sensory testing (QST) battery was performed for four times: one week before surgery and the second, seventh, and 28th days after surgery. Z-scores and the loss/gain coding system were applied for each participant. RESULTS: A total of 140 molars (test group: n = 91, control group: n = 49) were enrolled. The sensitivity of the mechanical detection threshold (MDT) and pressure pain threshold (PPT) significantly increased after surgery more than before surgery in both groups (P ≤ 0.001). After the surgery, the sensitivities of the cold detection threshold (CDT), cold pain threshold (CPT), and heat pain threshold (HPT) were significantly higher in the test group than in the control group (P ≤ 0.027). The risk of IANI was significantly larger (P = 0.041) in the test group than in the control group. CONCLUSIONS: QST was a sensitive way to detect somatosensory abnormalities even with no subjective complaint caused by surgery. Coronectomy had less influence on IAN function than conventional total extraction. CLINICAL RELEVANCE: The somatosensory function changes after mandibular third molar extraction were quantitatively studied, and coronectomy was proved a reliable alternation to reduce IAN injury rate.

Identification and profiling of microRNAs expressed in oral buccal mucosa squamous cell carcinoma of Chinese hamster.

MicroRNAs are known to play essential role in the gene expression regulation in cancer. In our research, next-generation sequencing technology was applied to explore the abnormal miRNA expression of oral squamous cell carcinoma (OSCC) in Chinese hamster. A total of 3 novel miRNAs (Novel-117, Novel-118, and Novel-135) and 11 known miRNAs (crg-miR-130b-3p, crg-miR-142-5p, crg-miR-21-3p, crg-miR-21-5p, crg-miR-542-3p, crg-miR-486-3p, crg-miR-499-5p, crg-miR-504, crg-miR-34c-5p, crg-miR-34b-5p and crg-miR-34c-3p) were identified. We conducted functional analysis, finding that 340 biological processes, 47 cell components, 46 molecular functions were associated with OSCC. Meanwhile the gene expression of Caspase-9, Caspase-3, Bax, and Bcl-2 were determined by qRT-PCR and the protein expression of PTEN and p-AKT by immunohistochemistry. Our research proposed further insights to the profiles of these miRNAs and provided a basis for investigating the regulatory mechanisms involved in oral cancer research.

Power Analysis and Sample Size Determination for Crossover Trials with Application to Bioequivalence Assessment of Topical Ophthalmic Drugs Using Serial Sampling Pharmacokinetic Data.

OBJECTIVE: To develop methods for determining a suitable sample size for bioequivalence assessment of generic topical ophthalmic drugs using crossover design with serial sampling schemes. METHODS: The power functions of the Fieller-type confidence interval and the asymptotic confidence interval in crossover designs with serial-sampling data are here derived. Simulation studies were conducted to evaluate the derived power functions. RESULTS: Simulation studies show that two power functions can provide precise power estimates when normality assumptions are satisfied and yield conservative estimates of power in cases when data are log-normally distributed. The intra-correlation showed a positive correlation with the power of the bioequivalence test. When the expected ratio of the AUCs was less than or equal to 1, the power of the Fieller-type confidence interval was larger than the asymptotic confidence interval. If the expected ratio of the AUCs was larger than 1, the asymptotic confidence interval had greater power. Sample size can be calculated through numerical iteration with the derived power functions. CONCLUSION: The Fieller-type power function and the asymptotic power function can be used to determine sample sizes of crossover trials for bioequivalence assessment of topical ophthalmic drugs.

Association between methylation of DNA damage response-related genes and DNA damage in hepatocytes of rats following subchronic exposure to vinyl chloride.

In the present study, we investigated the association between methylation of DNA damage response-related genes such as cyclin-dependent kinase inhibitor (CDKN)2A, Ras association (RalGDS/AF-6) domain family member (RASSF)1A, O6-methylguanine DNA methyltransferase (MGMT), Kirsten rat sarcoma viral oncogene homolog (KRAS), and spleen-associated tyrosine kinase (SYK) and DNA damage in hepatocytes of rats following subchronic exposure to vinyl chloride (VC). Sixty-four healthy rats were randomly divided into three VC exposure groups (5, 25, and 125 mg/kg) and an untreated negative control group (n = 16 each). VC was administered by intraperitoneal injection every other day for a total of three times a week. Eight randomly selected rats from each group were sacrificed at the end of 6 and 12 weeks, and liver tissue was harvested for the comet assay and for assessment of DNA methylation level and mRNA expression of related genes by PCR. Overall methylation levels in the genome of hepatocytes in VC-exposed rats were higher than those in the control group at 6 and 12 weeks (P < 0.05), although no differences were observed with regarding to dose (P > 0.05). After 12 weeks of exposure, differences in the methylation of RASSF1A and MGMT promoter regions were observed between the high-dose group and other groups (P < 0.05), whereas no differences were observed for the KRAS, SYK, and CDKN2A promoters (P > 0.05). These results suggest that DNA damage and increased genome-wide methylation are biomarkers for VC exposure and that RASSF1A and MGMT promoter methylation is related to the carcinogenic mechanism of VC.

Effect of Endostar combined with chemotherapy in advanced well-differentiated pancreatic neuroendocrine tumors.

The aim of the present study was to assess the effect of Endostar and temozolomide or dacarbazine plus 5-fluorouracil (5-FU) in patients with advanced pancreatic neuroendocrine tumors (pNETs).Phase II study of 14 patients with locally advanced or metastatic well-differentiated pNETs treated between April 2013 and September 2016. Patients received temozolomide or dacarbazine plus 5-FU, and Endostar. The primary outcome was the radiographic response rate.All 14 patients had nonfunctional pNETs. Six patients received temozolomide and 8 received dacarbazine + 5-FU, combined with Endostar. Thirteen patients were assessable for treatment response: 1(7%) with complete response, 5 (39%) with partial response, 5 (39%) with stable disease, and 2 (15%) with progression. The median progression-free survival was 12 months. The most common grade 1/2 toxicities were neutropenia (43%) and leucopenia (21%).Endostar combined with temozolomide or dacarbazine + 5-FU was effective in the treatment of advanced pNETs. The combinations were well tolerated.

Oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute promyelocytic leukaemia: a non-inferiority, randomised phase 3 trial.

BACKGROUND: Intravenous arsenic trioxide plus all-trans retinoic acid (ATRA) without chemotherapy is the standard of care for non-high-risk acute promyelocytic leukaemia (white blood cell count ≤10 × 109 per L), resulting in cure in more than 95% of cases. However, a pilot study of treatment with oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA without chemotherapy, which has a more convenient route of administration than the standard intravenous regimen, showed high efficacy. In this study, we compare an oral RIF plus ATRA treatment regimen with the standard intravenous arsenic trioxide plus ATRA treatment regimen in patients with non-high-risk acute promyelocytic leukaemia. METHODS: We did a multicentre, non-inferiority, open-label, randomised, controlled phase 3 trial at 14 centres in China. Patients aged 18-70 years with newly diagnosed (within 7 days) non-high-risk acute promyelocytic leukaemia, and a WHO performance status of 2 or less were eligible. Patients were randomly assigned (2:1) to receive treatment with RIF-ATRA or arsenic trioxide-ATRA as the induction and consolidation therapy. Randomisation was done centrally with permuted blocks and stratification according to trial centre and was implemented through an interactive web response system. RIF (60 mg/kg bodyweight daily in an oral divided dose) or arsenic trioxide (0·15 mg/kg daily in an intravenous dose) and ATRA (25 mg/m2 daily in an oral divided dose) were used until complete remission was achieved. The home-based consolidation therapy was RIF (60 mg/kg daily in an oral divided dose) or intravenous arsenic trioxide (0·15 mg/kg daily in an intravenous dose) in a 4-week on 4-week off regimen for four cycles and ATRA (25 mg/m2 daily in an oral divided dose) in a 2-week on 2-week off regimen for seven cycles. Patients and treating physicians were not masked to treatment allocation. The primary outcome was event-free survival at 2 years. A non-inferiority margin of -10% was used to assess non-inferiority. Primary analyses were done in a modified intention-to-treat population of all patients who received at least one dose of their assigned treatment and the per-protocol population. This study was registered with the Chinese Clinical Trial Registry (ChiCTR-TRC-13004054), and the trial is complete. FINDINGS: Between Feb 13, 2014, and Aug 31, 2015, 109 patients were enrolled and assigned to RIF-ATRA (n=72) or arsenic trioxide-ATRA (n=37). Three patients in the RIF-ATRA and one in the arsenic trioxide-ATRA did not receive their assigned treatment. After a median follow-up of 32 months (IQR 27-36), 67 (97%) of 69 patients in the RIF-ATRA group and 34 (94%) of 36 in the arsenic trioxide-ATRA group had achieved 2-year event-free survival in the modified intention-to-treat population. The percentage difference in event-free survival was 2·7% (95% CI, -5·8 to 11·1). The lower limit of the 95% CI for the difference in event-free survival was greater than the -10% non-inferiority margin, confirming non-inferiority (p=0·0017). Non-inferiority was also confirmed in the per-protocol population. During induction therapy, grade 3-4 hepatic toxic effects (ie, increased liver aspartate aminotransferase or alanine transaminase concentrations) were reported in six (9%) of 69 patients in the RIF-ATRA group versus five (14%) of 36 patients in the arsenic trioxide-ATRA group; grade 3-4 infection was reported in 15 (23%) of 64 versus 15 (42%) of 36 patients. Two patients in the arsenic trioxide-ATRA group died during induction therapy (one from haemorrhage and one from thrombocytopenia). INTERPRETATION: Oral RIF plus ATRA is not inferior to intravenous arsenic trioxide plus ATRA for the treatment of patients with non-high-risk acute promyelocytic leukaemia. This study suggests that a completely oral, chemotherapy-free model might be an alternative to the standard intravenous treatment for patients with non-high-risk acute promyelocytic leukaemia. FUNDING: Foundation for innovative research group of the National Natural Science Foundation of China, the Beijing Municipal Science and Technology Commission, the National Key R&D Program of China, and the National Natural Science Foundation of China.

Recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) versus alteplase (rt-PA) as fibrinolytic therapy for acute ST-segment elevation myocardial infarction (China TNK STEMI): protocol for a randomised, controlled, non-inferiority trial.

AIM: To evaluate the efficacy and safety of recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) in lowering major adverse cardiovascular and cerebrovascular events (MACCEs) in Chinese acute ST-segment elevation myocardial infarction (STEMI) patients. METHODS AND ANALYSIS: The study is designed as a multicentre, randomised, controlled non-inferiority phase IV trial with balanced randomisation (1:1) in patients with STEMI. The planned sample size is 6200 participants (or 3100 per arm). Participants with STEMI will be randomised to receive either rhTNK-tPA or alteplase (rt-PA), with stratification by research centre, age and the time from symptom onset to randomisation. All patients will receive concomitant antiplatelet and anticoagulant therapy before fibrinolytic therapy. The participants assigned to the intervention group will receive an intravenous bolus of 16 mg rhTNK-tPA, while those assigned to the control group will receive an intravenous bolus of 8 mg rt-PA followed by 42 mg infusion over 90 mins. Other medications can also be administered at the discretion of the cardiologists in charge. All participants will be followed up for the primary study endpoint, the occurrence of MACCEs within 30 days after fibrinolytic therapy, which is defined as all-cause mortality, non-fatal re-infarction, non-fatal stroke, percutaneous coronary intervention (PCI) due to thrombolysis failure, and PCI due to reocclusion. Both intention-to-treat and per-protocol analyses will be done for the primary analyses. ETHICS AND DISSEMINATION: The study procedures and informed consent form were approved by all participating hospitals. The results will be disseminated in peer review journals and academic conferences. This multicentre randomised controlled trial will provide high-quality data about the efficacy and safety of rhTNK-tPA and, once approved, its easier use should help improve the application of reperfusion therapy and hence the treatment outcomes of STEMI patients. TRIAL REGISTRATION NUMBER: NCT02835534.