Search

The mortalities of hepatobiliary malignancies are high. With the failure of conventional chemotherapy and unsatisfactory outcome of molecular targeted drugs, immune-based therapy has become a new focus of research in hepatobiliary cancers treatment.We performed a PubMed search with relevant articles published up to May 2022 and the following keywords: cellular immunotherapy, hepatobiliary cancer, antigen receptor T cell therapy, and receptor-engineered T cell. Information of clinical trials was obtained from https://clinicaltrials.gov/.Cell therapies for hepatobiliary malignancies are at early stage of development. The current review showed that cellular therapies are safe and feasible in patients. These findings provide an important platform for future lager scale clinical trials on immunotherapy in patients with hepatobiliary malignancies.With the continuous advances of cellular immunotherapy, the combination of cellular immunotherapy with surgery, chemotherapy and radiotherapy will be new therapeutic strategies for patients with hepatobiliary cancer.

Changes in thyroid hormone levels are commonly recognized characters among the elderly, which were reported to potentially influence incident frailty. Therefore, we examined the cross-sectional associations of thyroid hormones (THs) with frailty as well as the five components characterizing frailty (fatigue, resistance, ambulation, number of illnesses, and loss of weight) among the oldest-old.Four hundred and eighty-seven community-dwelling oldest-old from a local community in Haidian District, Beijing, participated in our recruitment campaign between April 2019 and May 2020. The primary outcomes were a definitive diagnosis of frailty according to the FRAIL scale (Fatigue, Resistance, Ambulation, Illnesses, Loss of weight) and a positive score for each frailty subdomain. Demographic information (age, sex, marital status, and educational status), comorbidities, and details on the participants' lifestyles were recorded. Serum THs including free triiodothyronin (fT3), triiodothyronine (T3), free thyroxine (fT4), and thyroxine (T4) and thyroid stimulating hormone (TSH) levels were also measured at the beginning of our study. Logistic regressions were conducted to screen for potential risk factors for frailty and its subdomains.Among the total 487 subjects at enrollment, 60 (12.23%) of them were diagnosed with subclinical hypothyroidism and 110 (22.59%) of the total population scored positive for frailty. Logistic regression analyses adjusted for all potential confounders, showed that frailty was significantly associated with the serum TSH concentration (odds ratio [OR]: 1.06), fT3 concentration (OR: 0.54), and subclinical hypothyroidism score (OR: 2.18). The association between fT4 and frailty was absent in our observational study. The fT3/fT4 ratio characterizing peripheral hormone conversion was also tested to be correlated with frailty.Subclinical hypothyroidism, higher TSH level, lower fT3 level, and decreased fT3/fT4 ratio were all associated with frailty assessed by the FRAIL scale among the community-dwelling oldest-old, suggesting a relevant role of thyroid function in aging. Future longitudinal studies are warranted to determine the casual relationship between thyroid dysfunction and frailty in the oldest-old.

The gut microbiota (GM) has been proven to play a role in the regulation of host lipid metabolism, which provides a new theory about the pathogenesis of dyslipidemia. However, the associations of GM with dyslipidemia based on sex differences remain unclear and warrant elucidation.To investigate the associations of GM features with serum lipid profiles based on sex differences in a Chinese population.This study ultimately recruited 142 participants (73 females and 69 males) at Honghui Hospital, Xi'an Jiaotong University. The anthropometric and blood metabolic parameters of all participants were measured. According to their serum lipid levels, female and male participants were classified into a high triglyceride (H_TG) group, a high total cholesterol (H_CHO) group, a low high-density lipoprotein cholesterol (L_HDL-C) group, and a control (CON) group with normal serum lipid levels. Fresh fecal samples were collected for 16S rRNA gene sequencing. UPARSE software, QIIME software, the RDP classifier and the FAPROTAX database were used for sequencing analyses.The GM composition at the phylum level included Firmicutes and Bacteroidetes as the core GM. Different GM features were identified between females and males, and the associations between GM and serum lipid profiles were different in females and males. The GM features in different dyslipidemia subgroups changed in both female patients and male patients. Proteobacteria, Lactobacillaceae,This study indicates associations of GM with serum lipid profiles, supporting the notion that GM dysbiosis may participate in the pathogenesis of dyslipidemia, and sex differences should be considered.

This study aimed to evaluate the efficacy and safety of entecavir(ETV) versus ETV maleate in Chinese patients with chronic hepatitis B(CHB). This was a randomized, double-blind, double-dummy, controlled, multicentre study. Patients were randomly assigned to receive 48 weeks of treatment with 0.5 mg/day ETV (group A) or 0.5 mg/day ETV maleate (group B), then, all patients received treatment with 0.5 mg/day ETV maleate from week 49 onwards. Patients were regularly followed up. Serum hepatitis B virus (HBV) markers were detected. Adverse events (AE) were recorded. The primary endpoint was the decline in HBV DNA in each group at the end of treatment. Secondary endpoints included the rate of HBV DNA below the lower limit of detection (LLOD) (20 I U/ml) at the end of treatment, the rate of hepatitis B e antigen (HBeAg) loss, the rate of HBeAg seroconversion and serum alanine aminotransferase (ALT) normalization. One hundred and thirty-seven (71 in group A) patients with HBeAg-positive CHB and 46 (21 in group A) patients with HBeAg-negative CHB completed the 240-week treatment and follow-up. Baseline characteristics were well balanced between the two groups. For the HBeAg-positive CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.67 log

Aim: This retrospective, observational study evaluated the long-term (>12 months) safety and effectiveness of bisphosphonate. Methods: Data collected for 359 patients included quantity and proportion of adverse events (AEs) and skeletal-related events (SREs), and times to first AE and first SRE. Results: Patients in the ≤24-month group experienced significantly fewer AEs compared with the >24-month treatment group (p = 0.008), and treatment for >24 months was a potential risk factor for AEs (p = 0.05). Neither the proportion nor the risk of SRE was significantly associated with therapy duration (p = 0.525 and 0.084, respectively). Conclusion: Bisphosphonate treatment beyond 2 years may increase the risk of AEs, but may prolong SRE-free survival early after 24 months, compared with medication administered for ≤24 months.

With the wide application of nanometer materials in daily life, people pay more attention to the potential toxicity of nanoparticles to human fetal development once the nanoparticles are absorbed into the human body during pregnancy. However, there was no directly solid evidence for ZnO NPs-caused congenital heart defects. Hence, we investigated the effect of ZnO NPs exposure on early cardiogenesis using the chicken/mouse embryo models. First, we showed ZnO NPs reduced H9c2 cell viability in a dose- and time-dependent manner, while cell autophagy was significantly activated too on the same pattern. During early cardiogenesis, ZnO NPs exposure increased the chance of heart tube malformation, while precardiac cell apoptosis rises in the phenotype of closure defect and Bifida. The hypertrophy was also observed in late-stage chicken/mouse survival embryos exposed to ZnO NPs. Apart from cell apoptosis, high-dose ZnO NPs exposure led to massive programmed necrosis, and further experiments verified that ferroptosis remained primarily in ZnO NPs-induced programmed necrosis. We also revealed that the toxicology of low-dose ZnO NPs was mainly featured in the changes of expressions of key genes instead of causing precardiac cell death. MYL2 and CSRP3 could work as the downstream molecules of the above key genes in the context of ZnO NPs exposure to early cardiogenesis based on RNA sequencing. Taken together, this study for the first time revealed the potential risk of heart tube malformation induced by ZnO NPs exposure through different cellular mechanisms, which depended on low- or high-dose ZnO NPs.

To investigate the prevalence of depression and anxiety in patients undergoing maintenance hemodialysis (MHD) in Hohhot, a large city on the northern border of China, and to identify independent risk factors for depression and anxiety in these patients.Patients receiving MHD for3 months were enrolled in the four largest hemodialysis centers between September 2020 and December 2020. Depression and anxiety were assessed using the Zung self-rated depression scale (SDS) and Zung self-rated anxiety scale (SAS), respectively, with demographic and other data collected for logistic regression analyses.Among 305 MHD patients included in this study, the prevalence of depression was 55.1%, including 27.5%, 21.0%, and 6.6% with mild, moderate and severe cases, respectively. The prevalence of anxiety was 25.9%, with 20.0%, 4.6%, and 1.3% having mild, moderate, and severe cases, respectively. An independent protective factor for depression was family income of ≥1415 US dollars/month relative to157 US dollars/month (odds ratio [OR] 0.209, 95% confidence interval [CI] 0.065-0.673), and predictors of depression included ≥3 comorbidities (OR 18.527, 95% CI 1.674-205.028) and severe pruritus (OR 15.971, 95% CI 5.173-49.315). Independent predictors of anxiety included infrequent exercise (OR 3.289, 95% CI 1.411-7.664) and severe pruritus (OR 5.912, 95% CI 1.733-20.168). The correlation between depression and anxiety in these patients was significant (MHD patients in Northern China had high prevalence rates of depression (55.1%) and anxiety (25.9%). Lower family income, more comorbidities, and a higher degree of pruritus were predictors of depression, while infrequent exercise and severe pruritus were predictors of anxiety. Depression correlated significantly with anxiety. Attention should be given to family income, comorbidity, exercise, and pruritus severity for improved management of depression and anxiety among MHD patients.

A biomechanical study, in which imaging modalities are used to strictly include patients with concurrent lateral ankle instability (LAI) and osteochondral lesions of the talus (OLT), is needed to demonstrate the static and dynamic ankle range of motion (ROM) restriction in these patients, and determine whether ankle ROM restriction can be corrected postoperatively.Eight patients with concurrent LAI and OLT treated with the arthroscopic modified Broström procedure and microfracture were recruited from June 2019 to January 2020. Patients were assessed using outcome scales, static ankle ROM, and a stair descent gait analysis for dynamic ankle ROM, a day prior to surgery and one year postoperatively. Eight healthy subjects were assessed using the same modalities upon recruitment. Operative outcomes and variables during stair descent were documented and compared among the preoperative, postoperative, and healthy groups. A curve analysis, one-dimensional statistical parametric mapping, was performed to compare the dynamic ankle kinematics and muscle activation curves over the entire normalised time series.The functional outcomes of patients with concurrent LAI and OLT were significantly worse than those of healthy subjects preoperatively, but were partially improved postoperatively. Patients had decreased static and dynamic ROM preoperatively, and static ROM did not significantly increase postoperatively (preoperative, 39.6 ± 11.3; postoperative, 44.9 ± 7.1; healthy, 52.0 ± 4.6; p = 0.021). Patients showed increased dynamic ankle flexion ROM (preoperative, 41.2 ± 11.6; postoperative, 53.6 ± 9.0; healthy, 53.9 ± 3.4; p = 0.012) postoperatively, as well as increased peroneus longus activation (preoperative, 35.8 ± 12.0; postoperative, 55.4 ± 25.1; healthy, 71.9 ± 13.4; p = 0.002) and muscle co-contraction of the tibialis anterior and peroneus longus (preoperative, 69.4 ± 23.4; postoperative, 88.4 ± 9.3; healthy, 66.2 ± 18.1; p = 0.045).Patients with concurrent LAI and OLT had decreased static and dynamic sagittal ankle ROM and altered neuromuscular activation patterns. The arthroscopic modified Broström procedure and microfracture did not significantly increase the static sagittal ankle ROM. However, the dynamic sagittal ankle ROM, peroneus longus activation and muscle co-contraction of the tibialis anterior and peroneus longus increased postoperatively.IV.

The American College of Radiology (ACR), the American Brachytherapy Society (ABS), and the American Society for Radiation Oncology (ASTRO) have jointly developed the following practice parameter for the performance of low-dose-rate (LDR) brachytherapy. LDR brachytherapy is the application of radioactive sources in or on tumors in a clinical setting with therapeutic intent. The advantages of LDR brachytherapy include improving therapeutic ratios with lower doses to nontarget organs-at-risk and higher doses to a specific target.This practice parameter was developed according to the process described under the heading. The Process for Developing ACR Practice Parameters and Technical Standards on the ACR website (https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters-Radiation Oncology of the Commission on Radiation Oncology, in collaboration with ABS and ASTRO.This practice parameter was developed to serve as a tool in the appropriate application of this evolving technology in the care of cancer patients or other patients with conditions where radiation therapy is indicated. It addresses clinical implementation of LDR brachytherapy including personnel qualifications, quality assurance standards, indications, and suggested documentation. This includes a contemporary literature search.This practice parameter is a tool to guide the use of LDR brachytherapy and does not assess relative clinical indication for LDR brachytherapy when compared with other forms of brachytherapy or external beam therapy, but to focus on the best practices required to deliver LDR brachytherapy safely and effectively, when clinically indicated. Comparative costs of versus other modalities therapy may also need to be considered.

The lung is the most common extra-abdominal metastasis site of colorectal cancer (CRC). This study aimed to investigate the genetic variation of pulmonary metastases (PM) and primary tumors in resectable CRC. The clinical data of 410 patients with PM after CRC surgery and 33 paraffin-embedded tissue samples from January 2012 to July 2019 in our hospital were collected retrospectively. Next, 450-panel gene detection technologies based on next-generation sequencing (NGS) were used to analyze the changes in the gene map and the overall variation in cancer-related genes in PM and primary tumors. After quality control, 19 samples were included in the final gene analysis. The results showed that APC (89.5%), TP53 (89.5%), and KRAS (53%) were the most common mutations in PM and primary tumors, but the gene amplification variation was enriched in primary tumors (4.6% vs. 11.4%). KRAS G12D was the most common site variation of the KRAS gene in both PM and primary tumors of CRC. There was no hotspot mutation in the TP53 locus in CRC, and the TP53 mutation in the PM was consistent with that in the primary lesion. The microsatellite instability (MSI) levels of 10 patients were MSS. The mean tumor mutation burden (TMB) of the primary tumor (5.3 muts·Mb−1) was slightly higher than that of metastasis (5.0 muts·Mb−1). In our institution, the genetic characteristics of resectable PM from CRC may be highly consistent with those of the primary tumor.

Plenty of epidemiological approaches have been explored to detect the effects of environmental and socioeconomic factors on acute myocardial infarction (AMI) mortality. Whereas, identifying the influence of potential affecting factors on AMI mortality based on a spatial epidemiological perspective was strongly desired. Moreover, the interaction effects of two potential factors on the diseases were always neglected previously. Here, the Geodetector and geographicallytemporally weighted regression model (GTWR) combined with multi-source spatiotemporal datasets were introduced to quantitatively determine the relationship between AMI mortality and potential influencing factors across Xi'an during 2014-2016. Besides, Moran's I was adopted to diagnose the spatial autocorrelation of AMI mortality. Some findings were achieved. The number of AMI mortality cases increased from 5075 in 2014 to 6774 in 2016. Air pollutants, meteorological factors, economic status, and topography factors exhibited a significant effect on AMI mortality. The AMI mortality demonstrated an obvious spatial autocorrelation feature during 2014-2016. POP and PE represented the most obvious impact on AMI mortality, respectively. Moreover, the interaction of any two factors was larger than that of the single factor on AMI mortality, and the factors with the strongest interaction vary according to lag groups and ages. The effects of factors on AMI mortality were POP (- 628.925) PE (140.102) RD (79.145) O

Response inhibition, a crucial component of executive function, is closely related to personal impulse control, social adaption, and mental health. Previous studies have found response inhibition deficit in patients with major depressive disorder, but whether it also exists in individuals with subclinical depression (SD) remains unclear. This study aimed to identify the ability of response inhibition to emotional face stimuli both under explicit and implicit conditions in individuals with SD. Thirty-six subclinical depressed college students and 39 healthy individuals were recruited and administered the non-emotional, explicit, and implicit emotional stop-signal tasks (SSTs). Mixed-model analyses of variance were used to analyze the differences between and within groups. In implicit emotional SST, the results showed a significant longer stop-signal response time, a shorter stop-signal delay time, a shorter go reaction time, and a similar proportion of stop success in the SD group compared to healthy controls. However, the above indices showed no significant difference between the two groups in the non-emotional SST and explicit emotional SST. These findings suggest a possible defect of response inhibition in implicit emotional processing in individuals with SD, which may potentially serve as a marker of susceptibility to depression and thus be applied to early screening and intervention for major depressive disorder.

Prenatal exposure to ambient air pollution has been associated with adverse perinatal outcomes in previous studies. However, few studies have examined the interaction between air pollution and the season of conception on term low birth weight (TLBW) or macrosomia. Birth registry data of singleton live births in Wenzhou, China, between January 2015 and December 2016 were accessed from the Wenzhou Maternal and Child Health Information Management platform, and data on the ambient air pollutants in Wenzhou were obtained from the Chinese Air Quality Online Monitoring and Analysis Platform. Single-/two-pollutant binary logistic regression models were used to assess the associations between ambient air pollutants (PM

Although poor parental supervision has been associated with an increased adolescents' propensity for risk-taking behavior, few researchers have investigated nuanced mechanisms of how and for whom from the perspective of "family × school." Inspired by ecological system theory and self-control theory, this study aimed to investigate the mediating role of self-control and the moderating role of school climate between the link between poor parental supervision and risk-taking behavior.Four hundred and ninety-one Chinese adolescents (231 females, MAfter controlling for W1 risk-taking behavior, our moderated mediation model indicated that W1 poor parental supervision was positively related to W3 risk-taking behavior by restraining the development of W2 self-control. Additionally, a high level of school climate as a protective factor buffered the negative impact of poor parental supervision on adolescents' self-control, further reducing risk-taking behavior.Our findings shed light on the processing mechanisms between poor parental supervision and risk-taking behavior among Chinese adolescents and underscore the importance of effective preventions and interventions to facilitate adolescents' healthy development.

This study assessed the effects of tislelizumab, a programmed cell death protein 1 inhibitor, in combination with chemotherapy versus chemotherapy alone as first-line treatment on health-related quality of life (HRQoL) in patients with advanced nonsquamous non-small cell lung cancer (nSQ-NSCLC).Patients in this randomized, open-label, multicenter phase III study RATIONALE 304 (NCT03663205) with histologically confirmed stage IIIB/IV nSQ-NSCLC were randomized 2:1 to tislelizumab plus platinum-pemetrexed (arm T + PP) or platinum-pemetrexed alone (arm PP). Health-related QoL was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer. Key patient-reported outcome endpoints include mean score change from baseline at weeks 12 (during chemotherapy) and 18 (following chemotherapy) in the 30-item Quality of Life Questionnaire Core's global health status/quality of life (GHS/QoL) and time to deterioration in GHS/QoL.Three hundred thirty-two patients received at least 1 dose of study drug and completed at least 1 HRQoL assessment. Global health status/QoL score improved in arm T + PP at week 18 (between-group least square mean difference, 5.7; 95% confidence interval [CI], 1.0-10.5; P = 0.018). Patients in arm T + PP experienced greater reduction in coughing (-5.9; 95% CI, -11.6 to -0.1; P = 0.044), dyspnea (-3.8; 95% CI, -7.8 to 0.1; P = 0.059), chest pain (-6.2; 95% CI, -10.8 to -1.6; P = 0.008), and peripheral neuropathy (-2.6; 95% CI, -5.5 to 0.2; P = 0.066). Median time to deterioration in GHS/QoL was not achieved for either arm.The addition of tislelizumab to platinum-based chemotherapy was associated with improvements in nSQ-NSCLC patients' HRQoL as well as the important disease-specific symptoms of coughing, chest pain, and dyspnea.ClinicalTrials.gov Identifier: NCT03663205.

The objective of this study was to investigate the clinical manifestations and pathologic appearances of the submandibular gland (SMG) in Stevens-Johnson syndrome (SJS).Patients with autologous transplantation of SMG for treatment of severe dry eye between March 1998 and May 2018 were divided into the SJS group (70 cases) and non-SJS group (50 cases) according to the history of SJS. The SMG weight and computed tomography volume and salivary flow rate were measured. The concentration index and secretion index were estimated using scintigraphy with technetium-99m-pertechnetate. Histopathology studies of SMG tissues were conducted, and the acini parameters were measured using a digital image analyzer.A decreased computed tomography volume and weight was observed in 48.57% the SJS group and 2% in the non-SJS group (P.01). The rest whole, acid-stimulated whole, and SMG rest salivary flow rates decreased in the SJS group (P.05). The normal SMG concentration index (37.5% vs 96.67%, P.001) and secretion index (35% vs 96.67%, P.001) rates were lower in the SJS group than in the non-SJS group. The glandular parenchyma was reduced, the acinar space was widened, and the fat content was increased in the SJS group.SMG atrophic and degenerative changes occurred in the SJS group, with a decrease in salivary secretion function in more than half of the patients.

PD-1 inhibitor plus chemotherapy had been shown to be an effective first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC). However, there was no robust evidence showing a PD-L1 inhibitor combined with chemotherapy benefited patients with squamous and non-squamous NSCLC. GEMSTONE-302 aimed to evaluate the efficacy and safety of a PD-L1 inhibitor, sugemalimab, plus chemotherapy for patients with metastatic squamous or non-squamous NSCLC.This randomised, double-blind, phase 3 trial was done in 35 hospitals and academic research centres in China. Eligible patients were aged 18-75 years, had histologically or cytologically confirmed stage IV squamous or non-squamous NSCLC without known EGFR sensitising mutations, ALK, ROS1, or RET fusions, no previous systemic treatment for metastatic disease, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned (2:1) to receive sugemalimab (1200 mg, intravenously, every 3 weeks) plus platinum-based chemotherapy (carboplatin [area under the curve (AUC) 5 mg/mL per min, intravenously] and paclitaxel [175 mg/mBetween Dec 13, 2018, and May 15, 2020, 846 patients were assessed for eligibility; 367 were ineligible, and the remaining 479 patients were randomly assigned to the sugemalimab group (n=320) or placebo group (n=159). At the preplanned interim analysis (data cutoff June 8, 2020; median follow-up 8·6 months [IQR 6·1-11·4]), GEMSTONE-302 met its primary endpoint, with significantly longer progression-free survival in the sugemalimab group compared with the placebo group (median 7·8 months [95% CI 6·9-9·0] vs 4·9 months [4·7-5·0]; stratified hazard ratio [HR] 0·50 [95% CI 0·39-0·64], p0·0001]). At the final analysis (March 15, 2021) with a median follow-up of 17·8 months (IQR 15·1-20·9), the improvement in progression-free survival was maintained (median 9·0 months [95% CI 7·4-10·8] vs 4·9 months [4·8-5·1]; stratified HR 0·48 [95% CI 0·39-0·60], p0·0001). The most common grade 3 or 4 any treatment-related adverse events were neutrophil count decreased (104 [33%] of 320 with sugemalimab vs 52 [33%] of 159 with placebo), white blood cell count decreased (45 [14%] vs 27 [17%]), anaemia (43 [13%] vs 18 [11%]), platelet count decreased (33 [10%] vs 15 [9%]), and neutropenia (12 [4%] vs seven [4%]). Any treatment-related serious adverse events occurred in 73 (23%) patients in the sugemalimab group and 31 (20%) patients in the placebo group. Any treatment-related deaths were reported in ten (3%) patients in the sugemalimab group (pneumonia with respiratory failure in one patient; myelosuppression with septic shock in one patient; pneumonia in two patients; respiratory failure, abdominal pain, cardiac failure, and immune-mediated pneumonitis in one patient each; the other two deaths had an unspecified cause) and in two (1%) patients in the placebo group (pneumonia and multiple organ dysfunction syndrome).Sugemalimab plus chemotherapy showed a statistically significant and clinically meaningful progression-free survival improvement compared with placebo plus chemotherapy, in patients with previously untreated squamous and non-squamous metastatic NSCLC, regardless of PD-L1 expression, and could be a newfirst-line treatment option for both squamous and non-squamous metastatic NSCLC.CStone Pharmaceuticals.For the Chinese translation of the abstract see Supplementary Materials section.

WX-0593 (Iruplinalkib) is a novel, highly selective oral ALK and ROS1 tyrosine kinase inhibitor (TKI). In this study, the safety, antitumor activity, and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell lung cancer (NSCLC) patients with ALK or ROS1 rearrangement. In the dose-escalation phase and dose-expansion phase, patients were treated with WX-0593 until disease progression, unacceptable toxicity, or subject withdrawal. In the dose-escalation phase, the primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety assessed by investigators. In the dose-expansion phase, the primary endpoint was objective response rate (ORR) assessed by investigators. Between September 25, 2017 and October 15, 2018, a total of 153 patients received WX-0593 treatment. Two dose-limiting toxicities (DLTs) including one grade 3 QT interval prolonged and one grade 2 chronic heart failure were reported at the dose of 300 mg in one patient. MTD was not reached. Overall, 140 of the 152 (92%) patients experienced treatment-related adverse events (TRAEs) and 35 of the 152 (23%) patients had TRAEs ≥grade 3. The overall ORR was 59.3% (32 of 54) for the dose-escalation phase and 56.6% (56 of 99) for the dose-expansion phase. For patients who were ALK-rearranged and ALK TKI naive, the ORR were 81.0% (17 of 21) in the dose-escalation phase and 76.3% (29 of 38) in the dose-expansion phase, and for patients who previously received crizotinib as the only ALK TKI, the ORR were 38.1% (8 of 21) and 45.7% (21 of 46) for the two phases, respectively. For patients who were ROS1-rearranged, the ORR were 30.0% (3 of 10) in the dose-escalation phase and 44.4% (4 of 9) in the dose-expansion phase. WX-0593 showed favorable safety and promising antitumor activity in advanced NSCLC patients with ALK or ROS1 rearrangement.

RNA-binding motif protein 10 (RBM10), one of the members of the RNA-binding protein (RBP) family, has a tumor suppressor role in multiple cancers. However, the functional role of RBM10 in lung adenocarcinoma (LUAD) and the underlying molecular mechanism remains unclear. In this study, we observed that RBM10 is significantly downregulated in LUAD tissues compared with normal tissues. Low RBM10 expression is significantly associated with poor outcome of LUAD patients. In vitro and in vivo experiments show that RBM10 inhibits cell proliferation, metastasis and EMT progression in LUAD. Mechanistically, we demonstrate that RBM10 interacts with β-catenin interacting protein 1 (CTNNBIP1) and positively regulates its expression, disrupting the binding of β-catenin to the transcription factor TCF/LEF, thereby inactivating the Wnt/β-catenin pathway. In conclusion, this is the first study reporting the role of RBM10 in suppressing LUAD progression at least via partly inactivating the Wnt/β-catenin pathway, which provides new insights into the tumorigenesis and metastasis of LUAD. Thus, RBM10 may be a promising new therapeutic target or clinical biomarker for LUAD therapy in the future.

Discerning between indolent and aggressive types is a big challenge of prostate cancer clinically to guide the adequate therapeutic regimen. We aimed to examine the relationship between miR-1255b-p expression and prostate cancer and elucidate the function of miR-1255b-5p in prostate cancer. miR-1255b-5p were measured using Quantitative Real-Time PCR from the blood 103 benign prostate hyperplasia (BPH) and 153 prostate cancer patients (117 indolent cases and 36 upgrading cases). Using receiver operating characteristic (ROC) curve analysis, the discriminating ability of miR-1255b-5p was accessed between BPH and prostate cancer participants, or indolent and aggressive type. Using CCK-8 and Transwell assays, the function of miR-1255b-5p on prostate cancer cells was investigated. The levels of miR-1255b-5p were significantly raised in prostate cancer patients when compared with BPH participants. MiR-1255b-5p level can distinguish prostate cancer patients from BPH or indolent type from aggressive type. Downregulation of miR-1255b-5p can suppress the proliferative, invasive, and migratory capacity, but this effect can be eradicated by EPB41L1 inhibition. The measurement of miR-1255b-5p in blood may provide a new noninvasive approach for the diagnosis of prostate cancer. miR-1255b-5p may become a potential therapeutic target for prostate cancer.

Met tyrosine kinase, a receptor for a hepatocyte growth factor (HGF), plays a critical role in tumor growth, metastasis, and drug resistance. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network. Dysregulated mitochondrial dynamics are responsible for the progression and metastasis of many cancers. Here, using structured illumination microscopy (SIM) and high spatial and temporal resolution live cell imaging, we identified mitochondrial trafficking of receptor tyrosine kinase Met. The contacts between activated Met kinase and mitochondria formed dramatically, and an intact HGF/Met axis was necessary for dysregulated mitochondrial fission and cancer cell movements. Mechanically, we found that Met directly phosphorylated outer mitochondrial membrane protein Fis1 at Tyr38 (Fis1 pY38). Fis1 pY38 promoted mitochondrial fission by recruiting the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) to mitochondria. Fragmented mitochondria fueled actin filament remodeling and lamellipodia or invadopodia formation to facilitate cell metastasis in hepatocellular carcinoma (HCC) cells both in vitro and in vivo. These findings reveal a novel and noncanonical pathway of Met receptor tyrosine kinase in the regulation of mitochondrial activities, which may provide a therapeutic target for metastatic HCC.

Background For lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) sensitive mutation and synchronous brain metastasis (syn‐BM), when and how to apply radiotherapy (RT) during first‐line tyrosine kinase inhibitor (TKI) treatment remains debatable. Methods From a real‐world multicenter database, EGFR‐mutant patients with syn‐BM diagnosed between 2010–2020 and treated with first‐line TKIs were enrolled and divided into upfront TKI + RT and upfront TKI groups. Median intracranial progression‐free survival (mIC‐PFS), median overall survival (mOS), and their risk factors were estimated. Results There were 60 and 186 patients in the upfront TKI + RT group and upfront TKI group, respectively. Their mIC‐PFS were 28.9 months (m) and 17.5 m (p = 0.023), and mOS were 42.7 m and 40.1 m (p = 0.51). Upfront brain RT improved mIC‐PFS in patients ≤60‐year‐old (p = 0.035), with symptomatic BM (p = 0.002), and treated with first‐generation TKIs (p = 0.012). There was no significant difference in mOS in any subgroup. Upfront brain stereotactic radiosurgery (SRS) showed a trend of better mIC‐PFS and mOS. mIC‐PFS was independently correlated with symptomatic BM (HR = 1.54, p = 0.030), EGFR L858R mutation (HR = 1.57, p = 0.019), and upfront brain RT (HR = 0.47, p = 0.001). mOS was independently correlated with being female (HR = 0.54, p = 0.007), ECOG 3–4 (HR = 10.47, p 3 (HR = 2.19, p = 0.002), and third‐generation TKI (HR = 0.54, p = 0.044) or antiangiogenic drugs (HR = 0.11, p = 0.005) as first/second‐line therapy. Conclusions Upfront brain RT based on first‐line EGFR‐TKI might improve IC‐PFS but not OS in EGFR‐mutant lung adenocarcinoma patients, indicating potential survival benefit from brain SRS and early application of drugs with higher intracranial activity., To our best knowledge, this is the most extensive multicenter real‐world study (Fig.1) on epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma with synchronous brain metastasis (BM) and treated with first‐line EGFR targeting tyrosine kinase inhibitor (TKI). On the basis of first‐line EGFR‐TKI therapy, additional upfront brain radiation therapy (RT) could improve intracranial progression free survival (PFS) (Fig.2a), particularly for patients with BM symptom and 1st‐generation EGFR‐TKI (Fig.4a). With no OS improvement (Fig.2d, Fig.3b, Fig.4b), upfront whole‐brain irradiation could be deferred during the first‐line EGFR‐TKI treatment; however, upfront brain stereotactic radio‐surgery (SRS) might have potential OS benefit (Fig.3d).

Background: Anticoagulation-free continuous renal replacement therapy (CRRT) was recommended by the current clinical guideline for patients with increased bleeding risk and contraindications of citrate. Nevertheless, anticoagulation-free CRRT yielded heterogeneous filter lifespan. Furthermore, the specific cutoff values for traditional coagulation parameters to predict sufficient filter lifespan of anticoagulation-free CRRT have not yet been determined. The purpose of our present study was to develop and validate a model for predicting sufficient filter lifespan in anticoagulation-free CRRT patients. Methods: Patients who underwent anticoagulation-free CRRT in our center between June 2013 and June 2019 were retrospectively included. The primary outcome was sufficient filter lifespan (≥24 h). Thirty-seven predictors were included for modeling based on their clinical significance and previous reports. The final model was developed by using multivariable logistic regression analysis and was validated in a separate external cohort. Results: The development cohort included 170 patients. Sufficient filter lifespan was observed in 80 patients. Thirteen variables were independent predictors for sufficient filter lifespan by logistic regression: body temperature, mean arterial pressure, activated partial thromboplastin time, direct bilirubin, alkaline phosphatase, blood urea nitrogen, vasopressor use, body mass index, white blood cell, platelet count, D-dimer, uric acid, and pH. The area under the curve (AUC) of the stepwise model and internal validation model was 0.82 (95% confidence interval [CI] [0.76–0.88]) and 0.8 (95% CI [0.74–0.87]), respectively. The positive predictive value and the negative predictive value of the stepwise model were 0.77 and 0.79, respectively. The validation cohort included 44 eligible patients and the AUC of the external validation model was 0.82 (95% CI [0.69–0.96]). Conclusions: The use of a prediction model instead of an assessment based only on coagulation parameters could facilitate the identification of the patients with filter lifespan of ≥24 h when they accepted anticoagulation-free CRRT.

Background Facial expression muscles atrophy is one kind of sequelae after peripheral facial paralysis. It causes critical problems in facial appearance of patient as well as social and psychological problems. This study aims to evaluate the efficacy and safety of Thread-embedding acupuncture (TEA) for the management of facial expression muscles atrophy after peripheral facial paralysis. Methods This is a patient-assessor blinded, randomized, sham-controlled trial. A total of fifty-six eligible patients will be randomly divided into TEA (n=28) and sham TEA (STEA) (n=28) groups. Both groups will receive TEA or STEA treatment at the frontal muscle and the depressor anguli oris muscle, at one predefined points once a week for eight weeks. Additionally, both groups will receive traditional acupuncture treatment at ten acupoints (GB20, LI4, LR3, GB12, ST7, SI18, LI20, BL2, SJ23, ST4) twice a week for eight weeks as a concurrent treatment. B-mode ultrasonography will be used to assess the changes in facial expression muscle thickness ratio of the affected/healthy side at baseline and at 10 weeks after screening, as the primary outcome. House-Brackmann Grade and lip mobility score will be measured and analyzed at baseline and 4, 8, 10, and 12 weeks after screening, as secondary outcomes. Discussion The study will compare TEA with sham TEA to explore the feasibility for TEA in improving facial expression muscles atrophy after peripheral facial paralysis. Trial registration Chinese Clinical Trial Registry, ChiCTR1900027170. Registered on 3 November 2019, http://www.chictr.org.cn/edit.aspx?pid=45173&htm=4

Background Diet, as a modifiable factor, plays an important role in cognitive function. However, the association between adherence to the 2015–2020 Dietary Guidelines for Americans (DGA), measured by Healthy Eating Index (HEI)-2015, and cognitive function remains unclear. This study aims to explore whether HEI-2015 is associated with various cognitive domains and whether such association is modified by age, gender, or ethnicity in the US adults aged 60 years or older using data from the National Health and Nutrition Examination Survey (NHANES) 2011–2014. Methods HEI-2015 scores were calculated from 24-h dietary recall interviews. Cognitive function was evaluated by Digit Symbol Substitution Test (DSST, a measure of processing speed), Animal Fluency Test (AFT, a measure of executive function), a subtest from Consortium to Establish a Registry for Alzheimer’s disease (CERAD, a measure of memory), and a composite-z score calculated by summing z scores of individual tests. The associations between HEI-2015 scores and cognitive performance were explored using multiple linear regression models. Results A total of 2450 participants aged 60 years or older were included. Participants with higher HEI-2015 scores were more likely to have higher DSST, AFT as well as composite-z scores (PPinteractionP Conclusion Higher adherence to DGA is associated with better cognitive performance, especially regarding processing speed and executive function among the US adults aged 60 years or older.

Background Ensuring high accuracy in multimodal image fusion for oral and maxillofacial tumors is crucial before further application. The aim of this study was to explore the factors influencing the accuracy of multimodal image fusion for oral and maxillofacial tumors. Methods Pairs of single-modality images were obtained from oral and maxillofacial tumor patients, and were fused using a proprietary navigation system by using three algorithms (automatic fusion, manual fusion, and registration point-based fusion). Fusion accuracy was evaluated including two aspects—overall fusion accuracy and tumor volume fusion accuracy—and were indicated by mean deviation and fusion index, respectively. Image modality, fusion algorithm, and other characteristics of multimodal images that may have potential influence on fusion accuracy were recorded. Univariate and multivariate analysis were used to identify relevant affecting factors. Results Ninety-three multimodal images were generated by fusing 31 pairs of single-modality images. The interaction effect of image modality and fusion algorithm (P = 0.02, P = 0.003) and thinner slice thickness (P = 0.006) were shown to significantly influence the overall fusion accuracy. The tumor volume (P P = 0.007), and image modality (P = 0.01) were significant influencing factors for tumor volume fusion accuracy. Conclusions To ensure high overall fusion accuracy, manual fusion was not preferred in CT/MRI image fusion, and neither was automatic fusion in image fusion containing PET modality. Using image sets with thinner slice thickness could increase overall fusion accuracy. CT/MRI fusion yielded higher tumor volume fusion accuracy than fusion containing PET modality. The tumor volume fusion accuracy should be taken into consideration during image fusion when the tumor volume is small and the tumor is located in the mandible.

Continuous renal replacement therapy (CRRT) is commonly employed for rhabdomyolysis (RM) patients. However, the optimal initiation timing of CRRT and prognostic factors were not well evaluated for patients with RM. We aimed to investigate the efficacy of CRRT timing on mortality and the risk factors for death in RM patients who received CRRT.RM patients who received CRRT between 1 May 2010 and 31 May 2021 in our center were retrospectively included. Univariate and multivariate logistic analyses were performed to identify the risk factors for primary outcome (90-day mortality).A total of 134 patients were included in our study. The 90-day mortality rate was 38.06%. The median time from CRRT initiation to peak CK occurrence was 4.8 h (IQR -16, 14), 67 patients received CRRT before 4.8 h after peak CK occurrence (early CRRT), and 67 patients received CRRT beyond 4.8 h after peak CK occurrence (late CRRT). Multivariate logistic regression analysis showed that the time from CRRT initiation to the peak CK (per 1 h, OR 1.026, 95% CI 1.004-1.049,Earlier CRRT initiation before 4.8 h after peak CK occurrence was associated with lower 90-day patient mortality.

Background Previous studies have demonstrated the preclinical pharmacological and toxicological consistency, and clinical pharmacokinetic equivalence of bevacizumab biosimilar LY01008 with reference bevacizumab (Avastin). This randomized controlled trial aimed to compare the efficacy and safety of LY01008 with Avastin in first‐line treatment of Chinese patients with advanced or recurrent non‐squamous non‐small cell lung cancer (NSCLC). Methods Stage IIIB‐IV NSCLC patients with evaluable lesions, good physical status, and adequate organ functions from 67 centers across China were randomized in a ratio of 1:1 to receive LY01008 or Avastin 15 mg/kg intravenously in combination with paclitaxel/carboplatin (combined treatment) for 4‐6 cycles, followed by maintenance monotherapy with LY01008 until disease progression, intolerable toxicity, or death. The primary endpoint was objective response rate (ORR) in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed by independent radiological review committees (IRRC). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression‐free survival (PFS), overall survival (OS), and safety. This study was registered in ClinicalTrials.gov (NCT03533127). Results Between December 15th, 2017, and May 15th, 2019, a total of 649 patients were randomized to the LY01008 (n = 324) or Avastin (n = 325) group. As of September 25th, 2019 for primary endpoint analysis, 589 patients received ORR evaluation, with a median number of combined treatment cycles of 5 (range 1‐6) and median duration of treatment of 3.0 (range 0.0‐5.1) months. ORR of response‐evaluable patients in the LY01008 and Avastin groups were 48.5% and 53.0%, respectively. The stratified ORR ratio was 0.91 (90% CI 0.80‐1.04, within the prespecified equivalence margin of 0.75‐1.33). Up to May 15th, 2020, with a median follow‐up of 13.6 (range 0.8‐28.4) months, no notable differences in DCR, median DoR, median PFS, median OS, and 1‐year OS rate were observed between the LY01008 and Avastin groups. There were no clinically meaningful differences in safety and immunogenicity across treatment groups. Conclusions LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non‐squamous NSCLC. LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable, metastatic, or recurrent non‐squamous NSCLC patients in the first‐line setting., This study demonstrated similarity between LY01008 and reference bevacizumab (Avastin) in terms of efficacy, safety, and immunogenicity in combination with paclitaxel and carboplatin as first‐line treatment in Chinese patients with advanced non‐squamous NSCLC.

Introduction Tislelizumab, an anti–programmed cell death protein-1 antibody, was specifically engineered to minimize FcɣR macrophage binding to abrogate antibody-dependent phagocytosis. Compared with chemotherapy alone, tislelizumab plus chemotherapy may improve clinical outcomes in patients with advanced nonsquamous NSCLC (nsq-NSCLC). Methods In this open-label phase 3 trial (RATIONALE 304; NCT03663205), patients with histologically confirmed stage IIIB or IV nsq-NSCLC were randomized (2:1) to receive either arm A: tislelizumab plus platinum (carboplatin or cisplatin) and pemetrexed every 3 weeks (Q3Ws) or arm B: platinum and pemetrexed alone Q3W during induction treatment, followed by intravenous maintenance pemetrexed Q3W. The primary end point was progression-free survival (PFS) assessed by an independent review committee; clinical response and safety and tolerability were secondary end points. Results Overall, 332 patients (n = 222 [A]; n = 110 [B]) received treatment. With a median study follow-up of 9.8 months, PFS was significantly longer with tislelizumab plus chemotherapy compared with chemotherapy alone (median PFS: 9.7 versus 7.6 mo; hazard ratio = 0.645 [95% confidence interval: 0.462–0.902], p = 0.0044). In addition, response rates were higher and response duration was longer with combination therapy versus chemotherapy alone. Hematologic adverse events (AEs) were common in both treatment arms; the most reported AEs were grades 1 to 2 in severity. The most common grade greater than or equal to 3 AEs were associated with chemotherapy and included neutropenia (44.6% [A]; 35.5% [B]) and leukopenia (21.6% [A]; 14.5% [B]). Conclusions Addition of tislelizumab to chemotherapy resulted in significantly prolonged PFS, higher response rates, and longer response duration compared with chemotherapy alone, identifying a new potential option for first-line treatment of advanced nsq-NSCLC irrespective of disease stage.

Controversy remains about the choice of reduction or arthrodesis in situ for surgical management of adolescent spondylolisthesis, while no systematic review and meta-analysis were performed to determine which one is the optimal surgical choice. The study aims to compare outcomes of the two surgical strategies for adolescent spondylolisthesis.A comprehensive search was performed through PubMed, Web of Science, Cochrane Library, Embase, OVID/MEDLINE, CBM, CNKI, and Wanfang with a cutoff date of May 21st, 2021. Search terms included "spondylolisthesis", "in situ" and "reduction". Included studies had following characteristics: (I) participants: adolescents with spondylolisthesis. (II) Intervention: reduction following arthrodesis. (III) Control: arthrodesis in situ. (IV) Outcomes: postoperative clinical and/or radiographic results. (V) Study design: randomized controlled trial (RCT), cohort or case-control study. Data were analyzed with Review Manager 5.4, and risk of bias assessment of studies was assessed via Newcastle-Ottawa quality assessment scale (NOS).Six cohort studies were included, with NOS scores of all ≥6. There were no significant differences regarding operative time [mean difference (MD) =152.62; 95% [confidence interval (CI)]: -54.02 to 359.26; I2=96%; P=0.15], blood loss (MD =786.61; 95% CI: -646.82 to 2,220.04; I2=90%; P=0.28), patient satisfaction (MD =1.98; 95% CI: 0.72 to 5.43; I2=0%; P=0.18), neurological complications (MD =1.02; 95% CI: 0.25 to 4.18; I2=0%; P=0.98), or total complications (MD =0.59; 95% CI: 0.29 to 1.19; I2=0%; P=0.14). However, patients undergoing reduction achieved better radiographic results: fusion rate (MD =3.09; 95% CI: 1.22 to 7.84; I2=40%; P=0.02), postoperative pseudarthrosis (MD =0.35; 95% CI: 0.15 to 0.79; I2=24%; P=0.01), percentage of slippage (MD =-20.58; 95% CI: -26.32 to -14.84; I2=0%; P0.00001), and slipping angle (MD =-10.05; 95% CI: -14.55 to -5.54; I2=0%; P0.0001). And no overt publication bias was found in the studies.Both reduction and arthrodesis in situ in adolescent spondylolisthesis are safe and demonstrate good clinical outcomes. However, reduction showed better radiographic results and was associated with less pseudarthrosis, better relief of disability, and improvements in self-image. In conclusion, reduction may be the optimal choice compared with arthrodesis in situ, but further verification of these findings is recommended using RCTs.

Cutaneous leukocytoclastic vasculitis (CLV) is a vasculitis that involves mainly small blood vessels in the skin. CLV has different causes (drugs, infections, or neoplastic or systemic inflammatory diseases). Sporotrichosis has rarely been associated with CLV. We report a case of disseminated cutaneous sporotrichosis caused by microorganisms in the Sporothrix clade in a Chinese woman with a tuberculous peritonitis history. Her lesions included many ulcers with crusts on the limbs. A skin biopsy yielded a histologic diagnosis of leukocytoclastic vasculitis. Periodic acid-Schiff and Grocott methenamine silver stains revealed numerous round-to-oval, thick-walled yeast cells in the necrotic tissue of the dermis. Mycological cultures grew pure dark brown wrinkled and villous fungus colonies morphologically and microscopic characteristics suggestive of the pathogenic Sporothrix clade which was followed confirmed as Sporothrix globosa (S. globosa) by the PCR method and sequencing based on calmodulin gene. Although infrequently, Sporothrix clade may cause CLV and should be considered in its differential diagnosis.

The present study investigated the pharmacodynamic material basis of Laportea bulbifera in the treatment of rheumatoid arthritis. Firstly, human rheumatoid arthritis fibroblast-like synoviocyte line MH7A was cultured in vitro and treated with tumor necrosis factor alpha(TNF-α, 50 ng·mL~(-1)). The proliferation and the levels of inflammatory cytokines such as prostaglandin E2(PGE2), interleukin-1β(IL-1β), and interleukin-6(IL-6) of the MH7A cells exposed to the serum containing L. bulbifera were determined to evaluate the anti-rheumatoid arthritis effects of the serum. Furthermore, the ultra-performance liquid chromatography tandem mass spectrometry fingerprints of the L. bulbifera crude extract, the drug-containing serum, and the drug-free serum were compared to identify the compounds newly generated in the serum after oral administration of the extract. According to the peak areas of common peaks and the results of anti-rheumatoid arthritis effect test, the active components were identified. The serum containing L. bulbifera significantly inhibited the proliferation of the MH7A cells activated by TNF-α and the expression of PGE2, IL-6, and IL-1β. Thirty newly generated compounds were detected in the drug-containing serum. Among them, neochlorogenic acid, cryptochlorogenic acid, chlorogenic acid, rutin, isoquercitrin, luteoloside, kaempferol-3-O-rutinoside, and quercitrin were also present in the crude extract. Twelve characteristic peaks(3, 7, 8, 14, 18, 19, 21, 23, 24, m6, m7, and m15) were significantly correlated with the pharmaceutical effect. According to the correlations, neochlorogenic acid, cryptochlorogenic acid, and chlorogenic acid had great contributions to the anti-rheumatoid arthritis activity. This study preliminarily clarified the potential pharmacodynamic substances of L. bulbifera in the treatment of rheumatoid arthritis, which laid a theoretical and experimental foundation for further development and application of the medicinal plant.

Radioactive iodine (RAI) plays an important role in the diagnosis and treatment of papillary thyroid cancer (PTC). The curative effects of RAI therapy are not only related to radiosensitivity but also closely related to the accumulation of radionuclides in the lesion in PTC. Sinomenine hydrochloride (SH) can suppress tumor growth and increase radiosensitivity in several tumor cells, including PTC. The aim of this research was to investigate the therapeutic potential of SH on PTC cell redifferentiation. In this study, we treated BCPAP and TPC-1 cells with SH and tested the expression of thyroid differentiation-related genes. RAI uptake caused by SH-pretreatment was also evaluated. The results indicate that 4 mM SH significantly inhibited proliferation and increased the expression of the thyroid iodine-handling gene compared with the control group (p < 0.005), including the sodium/iodide symporter (NIS). Furthermore, SH also upregulated the membrane localization of NIS and RAI uptake. We further verified that upregulation of NIS was associated with the activation of the thyroid-stimulating hormone receptor (TSHR)/cyclic adenosine monophosphate (cAMP) signaling pathway. In conclusion, SH can inhibit proliferation, induce apoptosis, promote redifferentiation, and then increase the efficacy of RAI therapy in PTC cells. Thus, our results suggest that SH could be useful as an adjuvant therapy in combination with RAI therapy in PTC.

To compare the pharmacokinetic (PK) characteristics, investigate relative bioavailability, and provide data for potential additional bioequivalence trials between generic fidaxomicin (test (T) formulation) and the original brand (reference (R) formulation) in healthy Chinese subjects.An open, randomized, single-dose, cross-over study was conducted in 18 healthy Chinese subjects. The subjects randomly received T or R formulations and the alternative formulations were received after a 14-day wash-out period. Blood and fecal samples were collected and tested by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PK parameters were calculated using a non-compartmental model. Relative bioavailability considering commonly established bioequivalence criteria was assessed.CDespite the differences in exposure, PK characteristics and fecal recovery of the two formulations were similar, suggesting that an effective concentration of the generic fidaxomicin could be achieved locally in the gastrointestinal tract. Fidaxomicin was a highly viable drug, thus providing reference for future clinical study design.

Osteonecrosis of the femoral head (ONFH), also known as vascular necrosis of the femoral head, is combined with lipid metabolism disorders in most patients. This study aims to explore the lipid metabolism profiles in different subtypes of ONFH.The subjects were divided into an alcohol-induced osteonecrosis of the femoral head (AONFH) group, a steroid-induced osteonecrosis of the femoral head (SONFH) group, and a normal control (NC) group (In this study, 1 358 lipid metabolites were detected in each plasma sample. Compared with the NC group, there were significant difference in the expression patterns of lipid metabolism profiles in the AONFH group and the SONFH group. A total of 62 and 64 differential lipid metabolites were screened in the AONFH and SONFH patients (FC2,This study analyzes the characteristics of the plasma lipid metabolism profile in the AONFH and SONFH patients, and which identifies the differential lipid metabolites related to disease diagnosis and evaluation. These results provide evidence for exploring lipid metabolism alterations and the mining of novel lipid biomarkers for the ONFH.

Research articles on the mechanisms of acupuncture in the treatment of dysmenorrhea model in rats were retrieved from PubMed and China National Knowledge Infrastructure (CNKI). As revealed by the analysis, the underlying mechanisms were mainly related to the regulation of endocrine system and neurotransmitters, the modulation of immunoinflammatory responses, the improvement of uterine microcirculation, and reduction of oxidative stress. In the future, research should be carried out to explore the mechanism of acupuncture in relieving dysmenorrhea via acupoints and the specific mechanism of classical acupoints, so as to enrich the multi-pathway mechanisms of acupuncture in treating dysmenorrhea and provide more scientific basis for optimizing clinical modalities for primary dysmenorrhea treatment by acupuncture.通过检索中国期刊全文数据库及PubMed数据库, 对筛选出的针刺治疗模拟原发性痛经(PD)大鼠机制研究文献进行分析, 发现针刺治疗PD的机制包括调控内分泌与镇痛物质、调节免疫炎性反应、改善子宫血流、减轻氧化应激等方面。不同针刺干预方式对经穴缓解PD的效应差异机制、经典效穴的特异性机制值得进一步研究, 以完善针刺治疗PD的多途径机制研究, 为临床优化针刺治疗PD方案提供科学依据。.

Clinical reports of multiple primary malignant tumors (MPMTs) in the digestive system are increasing. In China, although the survival rate of patients with MPMTs is increasing, the quality of life is very low. Many patients have reached the advanced stage when the second primary tumor is found, resulting in no early intervention and treatment. This is due to the misunderstanding of MPMTs by clinicians, who treat such tumors as metastases. Therefore, before a patient has a second primary tumor, doctors should understand some common combinations of digestive system MPMTs to provide clinical guidance to the patient.To explore the high incidence combination of digestive system MPMTs under heterochronism and synchronization.A total of 1902 patients with MPMTs at Peking Union Medical College Hospital were analyzed retrospectively. They were divided into metachronous MPMT and synchronous MPMT groups, and then the high incidence combinations of the first primary cancer and the second primary cancer in metachronous cancer and synchronous cancer were sorted. Sex and age differences between metachronous and synchronous tumors were tested by the chi square test andAmong the 1902 patients with MPMTs confirmed by pathology, 1811 (95.2%) cases were secondary primary cancers, 89 (4.7%) cases were tertiary primary cancers, and 2 (0.1%) cases were quaternary primary cancers. Most (88.2%) of the secondary primary cancers were identified as metachronous multiple primary cancers six months after diagnosis of the first primary cancer. The top ten most common MPMTs in the first primary cancer group ranged from high to low as follows: Breast cancer, thyroid cancer, nonuterine cancer, lung cancer, colon cancer, kidney cancer, uterine cancer, bladder cancer, rectal cancer, and gastric cancer. The highest incidence rate of the first primary cancer in male metachronous cancer was lung cancer (11.6%), the highest incidence rate of the second primary cancer was still lung cancer (24.9%), the highest incidence rate of the first primary cancer in female metachronous cancer was breast cancer (32.7%), and the highest incidence rate of the second primary cancer was lung cancer (20.8%). Among them, breast cancer, nonuterine cancer and uterine cancer were female-specific malignant tumor types, and thyroid cancer also accounted for 79.6% of female patients. The top five metachronous cancer combinations, independent of female-specific malignant tumor types and thyroid cancer, were colon cancer and lung cancer (26 cases), kidney cancer and lung cancer (25 cases), rectal cancer and lung cancer (20 cases), gastric cancer and lung cancer (17 cases), and bladder cancer and lung cancer (17 cases). The most common synchronous cancer combination was colon cancer and rectal cancer (15 cases).Screening for lung cancer should be performed six months after the detection of colon cancer while rectal cancer screening should be performed within six months.

To find the risk of time thresholds of PROM for infectious diseases of term neonates. A multi-center prospective cohort study including pregnancies with PROM at term with a single fetus were conducted. Time thresholds of the duration from PROM to delivery were examined in 2-h increments to assess the rates of infectious neonatal diseases. 7019 pregnancies were included in the study. Neonatal pneumonia and sepsis were most frequent infectious diseases in neonates born from mother with PROM at term. Rates of early-onset pneumonia varied significantly when comparing length of time of PROM greater than 16 h vs. less than 16 h (for EOP in 3 days of life, adjusted OR 1.864, 95% CI 1.159 ~ 2.997, p = 0.010; for EOP in 7 days of life, adjusted OR 1.704, 95% CI 1.104 ~ 2.628, p = 0.016). Neonates born from mother of whom the length of time from PROM to delivery ≥ 16 h were at a higher risk of acquiring EOP.

Previous studies have suggested that Helicobacter pylori (H. pylori) infection is associated with nonalcoholic fatty liver disease (NAFLD). The purpose of the present study was to investigate the effect of H. pylori eradication treatment on NAFLD patients. Two hundred NAFLD patients who tested positive for H. pylori infection were randomized into the H. pylori eradication treatment group or the control group. Metabolic and inflammatory parameters and FibroScan were measured in all subjects at baseline and 1 year after treatment. At 1 year after treatment, the decrease in metabolic indicators, such as fasting blood glucose, glycosylated haemoglobin, homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides, body mass index and controlled attenuation parameter values, were more obvious in the treatment group. Moreover, the inflammatory indicators white blood count and high-sensitivity C-reactive protein (hs-CRP) and the inflammatory factors interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) were also significantly decreased. H. pylori eradication can further reduce the metabolic indices of NAFLD and the degree of liver steatosis. H. pylori infection may participate in the occurrence and development of NAFLD through its influence on inflammatory factors. Thus, checking for the presence of H. pylori infection in patients at risk of NAFLD may be beneficial.

This paper reviews the application of "co-regulation of body and mind" of acupuncture for post-stroke spasticity. It is found that acupoints on the head and the back of the governor vessel, as well as Jiaji (Ex-B 2) points are mainly used for regulating the mind, and the local sites of spastic muscles and the points on the antagonistic muscles are for regulating the body specially. It is believed that regulating the mind should be integrated with regulating the body, while, the acupoint selection be associated with needling methods so as to fully achieve the "co-regulation of body and mind" and enhance the practical value of acupuncture for post-stroke spasticity. It is proposed that the classical anti-spastic needling techniques, such as论述“形神共调”在针刺治疗卒中后痉挛中的应用，发现头部穴、督脉背部穴、夹脊穴是调神的主要穴位，痉挛肌局部及其拮抗肌穴位则为调形的主要穴位，认为调神与调形相结合、穴位与刺法相结合，可凸显“形神共调”理念，提高针刺治疗卒中后痉挛的应用价值，提出针灸临床应多关注恢刺、关刺等经典抗痉挛刺法的应用。.

BACKGROUND AND OBJECTIVE Host immunity is crucial during periodontal inflammations. B cells are considered to have a function of immunoregulation, and TLRs are considered to be crucial in this process. The present study illustrates the potential roles and rules of CD25+ B cells during periodontitis, especially its effect on regulating host IL-35 level and Th1, Th17, and Treg differentiation. MATERIAL AND METHODS The proportion of local and systemic CD25+ B cell subpopulations from periodontitis models were identified by flow cytometry. To illustrate further mechanism, B cells were cultured with a different type of TLR activators. Expression of IL-10, IL-35, and TGF-β was detected by ELISA and real-time PCR. We also set adoptive transfer models by using CD25+ B cells. Alveolar bone erosion, proportion of Th1, Th17, and Tregs, and levels of IFN-γ, TNF-α, IL-1β, and IL-17 were identified. RESULT Periodontitis induces more CD25+ B cell subpopulations and promotes their IL-10, IL-35, and TGF-βproduction. TLR activators enhanced Breg proliferation and function. LPS+CpG obviously induced more CD25+ B cell differentiation and production of IL-10, IL-35, and TGF-β. Adoptive transfer of CD25+ B cells reduces alveolar bone destruction and local Tregs, proportion, especially the local level of IFN-γ and IL-17. In addition, adoptive transfer of CD25+ B cells remedies the pathological change in the proportion of IL-1β and Th1/Th17 in local lesions. We did not find any significant difference in peripheral blood, regardless of group and detected items. CONCLUSION Results of the present study clarify that CD25+ B cells enlarged and produced more IL-10, IL-35 and TGF-β during periodontitis, activation of TLR4 and TLR9 played crucial roles in this process. Also, CD25+ B cells alleviated periodontal inflammation and alveolar bone resorption. Our findings further expanded the potential of B cells during periodontitis.

Background The prevalence of neural tube defects (NTDs) in China declined during 2000–2017 with periconceptional folic acid (FA) supplementation, which is effective in reducing the risk of birth defects. We aimed to assess the knowledge and actual use of FA among Chinese pregnant women and to explore factors associated with FA use before pregnancy. Methods All data were collected in face-to-face interviews during health visits among pregnant women. We collected information about knowledge and use of FA supplements and demographic, socioeconomic, and health status. One maternity and childcare hospital was chosen in each of four cities: Beijing, Huaibei, Kunming, and Haikou. In total, 435 pregnant women were randomly recruited for interviews conducted from June to December 2016. Results A total of 428 pregnant women were included in this survey. Of these, 82.0% (351/428) knew that FA can prevent NTDs, and 75.9% (325/428) knew the correct time to take FA. Overall, 65.9% (282/428) of women knew both that FA can prevent NTDs and the recommended time to take FA before pregnancy. Approximately 95.1% (407/428) of women reported having ever taken FA, only 46.3% (198/428) had begun to take FA supplementation before conception, and 64.5% (109/169) of women from rural areas failed to take FA before pregnancy. Women living in northern China (odds ratio [OR] = 1.81, 95% confidence interval [CI], 1.18–2.77), those with unplanned pregnancy (OR = 1.99, 95% CI 1.30–3.04), and highly educated women (OR = 2.37, 95% CI 1.45–3.88) were more likely to know about FA. Women who were homemakers (OR = 1.94, 95% CI 1.21–3.11) and had unplanned pregnancy (OR = 6.18, 95% CI 4.01–9.53) were less likely to begin taking FA before pregnancy. Conclusions Our survey showed that most pregnant women knew about FA. Although preconception intake of FA can help to reduce NTDs, improving the rate of FA intake before pregnancy is needed in urban areas of China, especially among homemakers and women from rural areas or with unplanned pregnancy. Campaigns are needed to increase awareness about FA and FA use before pregnancy among rural women, homemakers, and those with unplanned pregnancy and lower education levels.

BACKGROUND AND AIMS Over-the-counter codeine products were up-scheduled to prescription only in Australia from February 2018. This trend study aimed to identify changes in codeine supply before and after the February 2018 implementation. DESIGN, SETTING AND CASES Time-series regression analysis of monthly medicine supplies in Australia from 2014 to 2018. The February 2018 up-scheduling was pre-specified as the intervention; outlier analysis was used to detect automatically sudden unexpected changes before February 2018. MEASUREMENTS Per-capita supplies based on national data for pharmaceutical wholesales and population exposure. Weight of supplies in milligrams for low-dose codeine (≤ 15 mg per tablet or ≤ 1.92 mg per ml, originally sold over the counter but up-scheduled after February 2018), high-dose combination codeine (30 mg per tablet, prescription only throughout the study period) and all codeine. FINDINGS Several level shifts in supply occurred during the 5 years, led by one of -4.4% [95% confidence interval (CI) = -6.6 to -2.1%] in high-dose codeine in 2015, followed by shifts in low-dose codeine of -40.0% (CI = -46.9 to -32.3%) and -82.2% (CI = -84.3 to -79.9%), respectively, before and after February 2018. High-dose codeine supply increased by 4.4% (CI = 1.8-7.1%) immediately after up-scheduling. Also detected were transient increases and decreases in 2016 and 2017. Compared with pre-2015 levels, the February 2018 up-scheduling was associated with reductions of 45.7% (CI = 43.2-48.0%) and 89.3% (CI = 87.9-90.6%), respectively, in all and low-dose codeine supply but no change in high-dose codeine supply. The level shifts and transient changes were located around various regulatory activities, including public announcements and expert advisory meetings on up-scheduling. CONCLUSION Up-scheduling of over-the-counter codeine products in Australia in 2018 appears to have been associated with a near halving of Australia's national codeine supply. The transition occurred in multiple forms and phases.

Macroautophagy/autophagy plays an important role during the development of human cancer. BECN1 (beclin 1), a core player in autophagy regulation, is downregulated in many kinds of malignancy. The underlying mechanism, however, has not been fully illuminated. Here, we found that CUL3 (cullin 3), an E3 ubiquitin ligase, could interact with BECN1 and promote the K48-linked ubiquitination and degradation of this protein; In addition, CUL3 led to a decrease in autophagic activity through downregulating BECN1. We also found that KLHL38 was a substrate adaptor of the CUL3 E3 ligase complex-mediated ubiquitination and degradation of BECN1. In breast and ovarian cancer, CUL3 could promote the proliferation of tumor cells, and the expression of CUL3 was related to poor prognosis in patients. Our study reveals the underlying mechanism of BECN1 ubiquitination and degradation that affects autophagic activity and subsequently leads to tumor progression, providing a novel therapeutic strategy that regulates autophagy to combat cancer. Abbreviations: ATG: autophagy-related BECN1: beclin 1 CHX: cycloheximide CoIP: co-immunoprecipitation CUL3: cullin 3 IP: immunoprecipitation MS: mass spectrometry PtdIns3K: phosphatidylinositol 3-kinase UPS: ubiquitin-proteasome system

Sema4D, a member of the immune semaphorin family, plays crucial roles in the immune regulation, bone resorption and nervous system. It is also involved in angiogenesis and tumour progression. However, systemic studies on the correlation between Sema4D expression and the immune infiltration or clinical outcomes in tumours are still limited. Here, we analysed the landscape of Sema4D expression and its prognostic value in the cancer genome atlas pan-cancer as well as the correlation between Sema4D and immune cell infiltration by Tumour Immune Estimation Resource and Gene Expression Profiling interactive analysis online tools. Results showed that a higher Sema4D expression was significantly correlated with a favourable overall survival in diverse solid tumours including bladder cancer (Hazards Ratio (HR)=0.68