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Background Changes in thyrotropin receptor antibody (TRAb) levels are associated with the clinical outcomes of Graves’ hyperthyroidism. However, the effects of the patterns of TRAb changes on patient prognosis according to the treatment duration of antithyroid drugs (ATDs) are not well established. Methods In this retrospective cohort study, 1,235 patients with Graves’ hyperthyroidism who were treated with ATDs for more than 12 months were included. Patients were divided into two groups according to treatment duration: group 1 (12–24 months) and group 2 (>24 months). Risk prediction models comprising age, sex, and either TRAb levels at ATD withdrawal (model A) or patterns of TRAb changes (model B) were compared. Results The median treatment duration in groups 1 (n=667, 54%) and 2 (n=568, 46%) was 17.3 and 37.1 months, respectively. The recurrence rate was significantly higher in group 2 (47.9%) than in group 1 (41.4%, P=0.025). Group 2 had significantly more goiter, thyroid eye disease, and fluctuating and smoldering type of TRAb pattern compared with group 1 (all P

Abstract Background Migraine is one of the most common diseases worldwide while current treatment options are not ideal. New therapeutic classes of migraine, the calcitonin gene-related peptide (CGRP) antagonists, have been developed and shown considerable effectiveness and safety. The present study aimed to systematically evaluate the efficacy and safety of atogepant, a CGRP antagonist, for migraine prophylaxis from the results of randomized controlled trials (RCTs). Methods The Cochrane Library, Embase, PubMed and https://www.clinicaltrials.gov/ were searched for RCTs that compared atogepant with placebo for migraine prophylaxis from inception of the databases to Feb 1, 2024. Outcome data involving efficacy and safety were combined and analyzed using Review Manager Software version 5.3 (RevMan 5.3). For each outcome, risk ratios (RRs) or standardized mean difference (SMD) were calculated. Results 4 RCTs with a total of 2813 subjects met our inclusion criteria. The overall effect estimate showed that atogepant was significantly superior to placebo in terms of the reduction of monthly migraine (SMD − 0.40, 95% CI -0.46 to -0.34) or headache (SMD − 0.39, 95% CI -0.46 to -0.33) days, the reduction of acute medication use days (SMD − 0.45, 95% CI -0.51 to -0.39) and 50% responder rate (RR 1.66, 95% CI 1.46 to 1.89), while no dose-related improvements were found between different dosage groups. For the safety, significant number of patients experienced treatment-emergent adverse events (TEAEs) with atogepant than with placebo (RR 1.10, 95% CI 1.02–1.21) while there was no obvious difference between the five dosage groups. Most TEAEs involved constipation (RR 2.55, 95% CI 1.91–3.41), nausea (RR 2.19, 95% CI 1.67–2.87) and urinary tract infection (RR 1.49, 95% CI 1.05–2.11). In addition, a high dosage of atogepant may also increase the risk of treatment-related TEAEs (RR 1.64, 95% CI 1.02–2.63) and fatigue (RR 3.07, 95% CI 1.13–8.35). Conclusions This meta-analysis suggests that atogepant is effective and tolerable for migraine prophylaxis including episodic or chronic migraine compared with placebo. It is critical to weigh the benefits of different doses against the risk of adverse events in clinical application of atogepant. Longer and multi-dose trials with larger sample sizes are required to verify the current findings.

As the body’s defense mechanism against damage and infection, the inflammatory response is a pathological process that involves a range of inflammatory cells and cytokines. A healthy inflammatory response helps the body repair by eliminating dangerous irritants. However, tissue fibrosis can result from an overly intense or protracted inflammatory response. The anti-aging gene Klotho suppresses oxidation, delays aging, and fosters development of various organs. Numerous investigations conducted in the last few years have discovered that Klotho expression is changed in a variety of clinical diseases and is strongly linked to the course and outcome of a disease. Klotho functions as a co-receptor for FGF and as a humoral factor that mediates intracellular signaling pathways such as transforming growth factor β (TGF-β), toll-like receptors (TLRs), nuclear factor-kappaB (NF-κB), renin -angiotensin system (RAS), and mitogen-activated protein kinase (MAPK). It also interferes with the phenotype and function of inflammatory cells, such as monocytes, macrophages, T cells, and B cells. Additionally, it regulates the production of inflammatory factors. This article aims to examine Klotho’s scientific advances in terms of tissue fibrosis and the inflammatory response in order to provide novel therapy concepts for fibrotic and inflammatory disorders.

ObjectiveTo establish variation trajectories and reference values of body mass index (BMI) for 0 – 6 year old children in Yanbian Korean Autonomous Prefecture (Yanbian) using the lambda-mu-sigma (LMS) method, and to analyze disparities between the BMI of local children and those of national references to evaluate the growth and development of children in the Yanbian region. MethodsUsing stratified random cluster sampling, we collected data from 6 650 children aged 0 – 6 years (1 557/1 860 and 1 356/1 859 Korean/Han boys and girls) who received a physical examination at five community health centers in five counties/prefectures in Yanbian region in September 2019. Simultaneous modeling of mean (mu), coefficient of variation (sigma), and skewness (lambda) of the children′s BMI was performed using the LMS method to calculate percentiles 3, 25, 50, 75, 97 of age-specific reference BMI values.ResultsVariations in BMI showed a similar trend with age among the boys and girls surveyed. There were significant gender differences in age-specific BMI values, with boys having higher mean BMIs than girls at 3 months (17.43 ± 1.53 vs. 16.77 ± 1.48), 6 months (17.89 ± 1.73 vs. 17.35 ± 1.62), 1 year (17.10 ± 1.44 vs. 16.72 ± 1.32), 1.5 years (16.53 ± 1.31 vs. 15.94 ± 1.26), 2 years (16.46 ± 1. 45 vs. 16.10 ± 1.50), 2.5 years (16.26 ± 1.32 vs. 15.73 ± 1.44), 3.5 years (16.11 ± 1.62 vs. 15.66 ± 1.69), 4.5 years (15.80 ± 1.74 vs. 15.51 ± 1. 70), 5 years (16.03 ± 2.10 vs. 15.54 ± 1.83), 5.5 years (16.44 ± 2.55 vs. 15.69 ± 1.86), and 6 years (16.77 ± 2.88 vs. 16.07 ± 2.76), respectively (all P < 0.05). The participants′ BMI growth trajectories derived from the LMS analysis showed that for the surveyed boys between one month and one year of age and girls between one month and 1.5 years of age, all percentile values of age-specific BMI were lower than those of the national reference values; but for the surveyed boys older than one year of age and girls older than 1.5 years of age, all the percentile values of age-specific BMI of were higher than those of the national reference values, except for the percentile 3 values, which were lower than those of the national reference values. ConclusionFor the children aged 0 – 6 years in Yanbian region, the BMI values of boys are generally higher than those of girls and the overall BMI values of the children have exceeded the national reference values.

Background Inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR), serve as valuable prognostic indicators in various cancers. This multicenter, retrospective cohort study assessed the treatment outcomes of lenvatinib in 71 patients with radioactive iodine (RAI)-refractory thyroid cancer, considering the baseline inflammatory biomarkers. Methods This study retrospectively included patients from five tertiary hospitals in Korea whose complete blood counts were available before lenvatinib treatment. Progression-free survival (PFS) and overall survival (OS) were evaluated based on the median value of inflammatory biomarkers. Results No significant differences in baseline characteristics were observed among patients grouped according to the inflammatory biomarkers, except for older patients with a higher-than-median NLR (≥2) compared to their counterparts with a lower NLR (P= 0.01). Patients with a higher-than-median NLR had significantly shorter PFS (P=0.02) and OS (P=0.017) than those with a lower NLR. In multivariate analysis, a higher-than-median NLR was significantly associated with poor OS (hazard ratio, 3.0; 95% confidence interval, 1.24 to 7.29; P=0.015). However, neither the LMR nor the PLR was associated with PFS. A higher-than-median LMR (≥3.9) was significantly associated with prolonged OS compared to a lower LMR (P=0.036). In contrast, a higher-than-median PLR (≥142.1) was associated with shorter OS compared to a lower PLR (P=0.039). Conclusion Baseline inflammatory biomarkers can serve as predictive indicators of PFS and OS in patients with RAI-refractory thyroid cancer treated with lenvatinib.

Abstract Objectives To investigate the factors associated with voluntary HIV counseling and testing (VCT) among young students engaging in casual sexual activity and to establish a scientific rationale for developing targeted intervention strategies for preventing HIV/AIDS in this population. Methods Stratified cluster sampling was used to conduct a survey using questionnaires to collect demographic and behavioral information for statistical analysis. Results Data from 611 young students, who reported engaging in casual sexual activity, were included in the statistical analysis. Among these, 68 (11.13%) students underwent the VCT. Among young students who engaged in casual sexual activity, those who were non-Zhejiang residents (adjusted odds ratio [aOR]: 2.11; 95% Confidence Interval [CI]: 1.17–3.80), those who had received AIDS-themed lectures or health education courses from the school in the past year (aOR = 3.96, 95% CI = 1.49–10.50), those who had received HIV risk self-assessment conducted by the school in the past year (aOR = 2.31, 95% CI = 1.17–4.59), and those who had engaged in commercial sex activity in the past year (aOR = 1.98, 95% CI = 1.07–3.66) were more inclined to have undergone VCT. Male students (aOR = 0.37, 95% CI = 0.18–0.77) and those who used condoms consistently during casual sexual activity (aOR = 0.45, 95% CI = 0.21–0.97) were less likely to undergo VCT. Conclusion Casual sexual activity was relatively prevalent among young students, posing a potential risk for HIV transmission. These findings will be instrumental in the development more effective HIV prevention and control strategies for young students. Additionally, it highlights the necessity of promoting and popularizing VCT among young students without Zhejiang province residency, who are involved in commercial sexual activity, and/or those who lacking HIV education. Moreover, additional research and implementation of refined HIV behavioral interventions specifically tailored to young students are necessary to enhance their awareness and knowledge of HIV prevention.

Objective To analyse the HIV-1 subtypes and molecular transmission characteristics of HIV-infected older individuals aged 50 and above in Huzhou City, and provide a scientific basis for prevention and treatment strategies for them.Design A cross-sectional study with clustered molecular transmission network cases was performed, and basic epidemiological information was retrieved from the Chinese Centres for Disease Prevention and Control (CDC) Information System.Setting and participants A molecular epidemiological study was conducted in 899 newly diagnosed HIV-infected individuals from January 2019 and March 2023 in Huzhou city, Zhejiang province, Eastern China. Out of these, HIV sequences were successfully obtained from 673 individuals, including 274 who were older individuals aged 50 and above.Primary and secondary outcomes Reverse transcription-polymerase chain reaction (PCR) and nested PCR were used to amplify the polymerase gene of HIV-1, and gene sequencing was performed. We used univariate and multivariate logistic regression to describe the association of clustered molecular transmission network cases.Results In total, 274 valid HIV sequences of older individuals were obtained, which revealed 14 subtypes. Circulating recombinant forms (CRF) 07_BC accounted for 55.8% and CRF01_AE accounted for 20.1% of the subtypes. Data of 150 older individuals were included in the molecular transmission network, and the proportion of elderly individuals in clustered cases is 52.26% (150/287). The results of multivariable logistic regression analysis showed that the older age group (60–82 years) and CRF07_BC subtype were associated with case clustering (transmission risk).Conclusions The key high-risk transmission network was mainly composed of the older age group (60–82 years) and CRF07_BC subtype. It is necessary to further strengthen AIDS health promotion and education for individuals aged 60 years and above, as well as for patients with the CRF07_BC subtype, to reduce HIV transmission and clustering risk.

Objective To evaluate the effectiveness of standardised antiretroviral therapy (ART) among different HIV subtypes in people living with HIV/AIDS (PLWHA), and to screen the best ART regimen for this patient population.Design A retrospective cohort study was performed, and PLWHA residing in Huzhou, China, between 2018 and 2020, were enrolled.Setting and participants Data from 625 patients, who were newly diagnosed with HIV/AIDS in the AIDS Prevention and Control Information System in Huzhou between 2018 and 2020, were reviewed.Analysis and outcome measures Data regarding demographic characteristics and laboratory investigation results were collected. Immune system recovery was used to assess the effectiveness of ART, and an increased percentage of CD4+ T lymphocyte counts >30% after receiving ART for >1 year was determined as immunopositive. A multiple logistic regression model was used to comprehensively quantify the association between PLWHA immunological response status and virus subtype. In addition, the joint association between different subtypes and treatment regimens on immunological response status was investigated.Results Among 326 enrolled PLWHA with circulating recombinant forms (CRFs) CRF01_AE, CRF07_BC and other HIV/AIDS subtypes, the percentages of immunopositivity were 74.0%, 65.6% and 69.6%, respectively. According to multivariate logistic regression models, there was no difference in the immunological response between patients with CRF01_AE, CRF07_BC and other subtypes of HIV/AIDS who underwent ART (CRF07_BC: adjusted OR (aOR) (95% CI) = 0.8 (0.4 to 1.4); other subtypes: aOR (95% CI) = 1.2 (0.6 to 2.3)). There was no evidence of an obvious joint association between HIV subtypes and ART regimens on immunological response.Conclusions Standardised ART was beneficial to all PLWHA, regardless of HIV subtypes, although it was more effective, to some extent, in PLWHA with CRF01_AE.

Most of vaccinees and COVID-19 convalescents can build effective anti-SARS-CoV-2 humoral immunity, which helps preventing infection and alleviating symptoms. However, breakthrough viral infections caused by emerging SARS-CoV-2 variants, especially Omicron subvariants, still pose a serious threat to global health. By monitoring the viral infections and the sera neutralization ability of a long-tracked cohort, we found out that the immune evasion of emerging Omicron subvariants and the decreasing neutralization led to the mini-wave of SARS-CoV-2 breakthrough infections. Meanwhile, no significant difference had been found in the infectivity of tested SARS-CoV-2 variants, even though the affinity between human angiotensin-converting enzyme 2 (hACE2) and receptor-binding domain (RBDs) of tested variants showed an increasing trend. Notably, the immune imprinting of inactivated COVID-19 vaccine can be relieved by infections of BA.5.2 and XBB.1.5 variants sequentially. Our data reveal the rising reinfection risk of immune evasion variants like Omicron JN.1 in China, suggesting the importance of booster with updated vaccines.

Abstract This study evaluated changes in the peripheral blood immune cell population in patients with advanced thyroid cancer receiving lenvatinib treatment to confirm the immune-modulatory effect of lenvatinib. After obtaining informed consent from patients, we prospectively collected 20 ml of whole blood at 2–3 months intervals 2–4 times from each patient; peripheral blood mononuclear cells (PBMCs) were separated, and the Maxpar Direct Immune Profiling Assay was performed. A total of 10 patients were enrolled, and 31 blood samples were obtained. The median age of patients was 65 years, and all patients showed durable responses to the lenvatinib treatment. When we compared the PBMC profiles between the pre-treatment, on-treatment, and off-treatment samples, the peripheral natural killer (NK) cell proportion differed significantly. The proportion of NK cells among total live cells significantly increased from 9.3 ± 4.5 (%) in the pre-treatment samples to 20.8 ± 7.9 (%) in the on-treatment samples (P = 0.009) and decreased to 13.3 ± 3.1 (%) in the off-treatment samples (P = 0.07). There was a significant increase in the peripheral NK cell population with lenvatinib treatment in advanced thyroid cancer patients. This finding confirms the immune-modulatory effect of lenvatinib.

Objective: This study evaluated the efficacy of antithyroid drugs (ATDs) and risk factors associated with the recurrence of Graves’ hyperthyroidism using a comprehensive retrospective cohort. Methods: We included 1829 patients newly diagnosed with Graves’ hyperthyroidism, with sufficient follow-up data. Clinical outcomes of the patients and risk factors associated with recurrence-free survival, including the changes in thyrotropin receptor antibody, were evaluated. Results: The median age of the patients was 44.5 years, and 69% were female. Among the patients, 1235 had a chance to withdraw ATD after a median of 23 (interquartile range (IQR) 17.0–35.5) months of treatment. The first remission rate was 55.6% during a median of 72.7 months of follow-up. After the first recurrence, 95% of patients underwent the second course of ATD treatment for a median of 21 .1 (IQR 14.8–31.7) months, and the remission rate was 54.1%. During a median of 67 months of follow-up, 7.7% of patients underwent surgery, and 10.5% underwent radioac tive iodine therapy. Approximately 30% were still on ATD therapy for recurrent disease or prolonged lowdose maintenance. Younger age (

The nucleolus is a liquid-liquid phase separation droplet that dynamically changes under stress. Here, the authors report PQBP5/NOL10 is a critical component of the nucleolus, maintaining its structure and position in the nucleus during osmotic stress.

Summary: Prion-like protein propagation is considered a common pathogenic mechanism in neurodegenerative diseases. Here we investigate the in vivo propagation pattern and aggregation state of mutant α-synuclein by injecting adeno-associated viral (AAV)-α-synuclein-A53T-EGFP into the mouse olfactory cortex. Comparison of aggregation states in various brain regions at multiple time points after injection using western blot analyses shows that the monomeric state of the mutant/misfolded protein propagates to remote brain regions by 2 weeks and that the propagated proteins aggregate in situ after being incorporated into neurons. Moreover, injection of Alexa 488-labeled α-synuclein-A53T confirms the monomeric propagation at 2 weeks. Super-resolution microscopy shows that both α-synuclein-A53T proteins propagate via the lymphatic system, penetrate perineuronal nets, and reach the surface of neurons. Electron microscopy shows that the propagated mutant/misfolded monomer forms fibrils characteristic of Parkinson’s disease after its incorporation into neurons. These findings suggest a mode of propagation different from that of aggregate-dependent propagation.

Metabolic reprogramming is a hallmark of human cancer. Cancer cells exhibit enhanced glycolysis, which allows glycolytic intermediates to be diverted into several other biosynthetic pathways, such as serine synthesis. Here, we explored the anti-cancer effects of the pyruvate kinase (PK) M2 inhibitor PKM2-IN-1 alone or in combination with the phosphoglycerate dehydrogenase (PHGDH) inhibitor NCT-503 in human NSCLC A549 cells in vitro and in vivo. PKM2-IN-1 inhibited proliferation and induced cell cycle arrest and apoptosis, with increased glycolytic intermediate 3-phosphoglycerate (3-PG) level and PHGDH expression. The combination of PKM2-IN-1 and NCT-503 further suppressed cancer cell proliferation and induced G2/M phase arrest, accompanied by the reduction of ATP, activation of AMPK and inhibition of its downstream mTOR and p70S6K, upregulation of p53 and p21, as well as downregulation of cyclin B1 and cdc2. In addition, combined treatment triggered ROS-dependent apoptosis by affecting the intrinsic Bcl-2/caspase-3/PARP pathway. Moreover, the combination suppressed glucose transporter type 1 (GLUT1) expression. In vivo, co-administration of PKM2-IN-1 and NCT-503 significantly inhibited A549 tumor growth. Taken together, PKM2-IN-1 in combination with NCT-503 exhibited remarkable anti-cancer effects through induction of G2/M cell cycle arrest and apoptosis, in which the metabolic stress induced ATP reduction and ROS augmented DNA damage might be involved. These results suggest that the combination of PKM2-IN-1 and NCT-503 might be a potential strategy for the therapy of lung cancer.

BackgroundThe estimated lifetime risk of stroke was the highest in East Asia worldwide, especially in China. Antihypertensive therapy can significantly reduce stroke mortality. However, blood pressure control is poor. Medication adherence is a barrier as patients’ out-of-pocket costs have risen. We aimed to take advantage of a free hypertension pharmacy intervention and quantified the impact on stroke mortality.MethodsA free pharmaceutical intervention program was implemented in Deqing, Zhejiang province in April 2018. Another non-pharmaceutical intervention, social distancing due to the pandemic of Coronavirus disease 2019 (COVID-19), was also key to affecting stroke mortality. We retrospectively collected the routine surveillance data of stroke deaths from Huzhou Municipal Center for Disease Prevention and Control in 2013–2020 and obtained within-city mobility data from Baidu Migration in 2019–2020, then we quantified the effects of both pharmaceutical intervention and social distancing using Serfling regression model.ResultsCompared to the predicted number, the actual number of stroke deaths was significantly lower by 10% (95% CI, 6–15%; p

Background Immunoglobulin G4 (IgG4)-related disease is an entity that can involve the thyroid gland. The spectrum of IgG4-related thyroid disease (IgG4-RTD) includes Hashimoto thyroiditis (HT) and its fibrotic variant, Riedel thyroiditis, as well as Graves’ disease. The early diagnosis of IgG4-RTD is important because it is a medically treatable disease, and a delay in the diagnosis might result in unnecessary surgery. We present a case series of IgG4-RTD with a review of the literature. Methods We retrospectively reviewed the clinical presentation and the radiological and pathological findings of patients diagnosed with IgG4-RTD between 2017 and 2021 at a tertiary medical center in Korea. We also conducted a literature review of IgG4-RTD. Results Five patients were diagnosed with IgG4-RTD during the study period. The patients’ age ranged from 31 to 76 years, and three patients were men. Most patients visited the clinic for a neck mass, and hypoechogenic nodular lesions were observed on neck ultrasonography. Three patients had IgG4 HT, and two patients had IgG4 Riedel thyroiditis. All patients developed hypothyroidism that necessitated L-thyroxine replacement. The diagnosis of IgG4-RTD was confirmed after a pathological examination of the surgical specimen in the first two cases. However, the early diagnosis was possible after a core needle biopsy in three clinically suspected patients. Conclusion The diagnosis of IgG4-RTD requires clinical suspicion combined with serology and histological analyses using IgG4 immunostaining. The early diagnosis of IgG4-RTD is difficult; thus, biopsy with IgG4 immunostaining and serum IgG4 measurements will help diagnose patients suspected of having IgG4-RTD.

Although previous studies have suggested that hemoglobin is related to the health status of people living with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) (PLWHA), the role of anemia in mortality remains unclear. This study aimed to comprehensively quantify the effect of anemia on the mortality risk of PLWHA. In this retrospective cohort study, we thoroughly estimated the effect of anemia on PLWHA mortality, using data collected from January 2005 to June 2022 in the Huzhou area, in 450 subjects extracted from the database of the China Disease Prevention and Control Information System and matched them using a propensity score matching approach to balance potential confounding bias. The potential exposure–response relationship between anemia, hemoglobin concentration, and the mortality of PLWHA was also carefully estimated. A series of subgroup analyses, including interaction analysis, was further conducted to validate the robustness of the effect of anemia on PLWHA death risk. Anemia was significantly associated with an elevated death risk in PLWHA, with an increase of 74% (adjusted hazard ratio [AHR]: 1.74; 95% confidence interval [CI]: 1.03–2.93; p = 0.038) in those with anemia after adjusting for potential confounders. PLWHA with moderate or severe anemia had a higher risk of death, with an 86% increase (AHR = 1.86; 95% CI: 1.01–3.42; p = 0.045). Meanwhile, the AHR tended to increase by 85% on average (AHR = 1.85, 95% CI: 1.37–2.50; p

Background The association between Graves’ disease (GD) and co-existing thyroid cancer is still controversial and most of the previously reported data have been based on surgically treated GD patients. This study investigated the clinicopathological findings and prognosis of concomitant thyroid cancer in GD patients in the era of widespread application of ultrasonography. Methods Data of GD patients who underwent thyroidectomy for thyroid cancer between 2010 and 2019 in three tertiary hospitals in South Korea (Asan Medical Center, Chonnam National University Hwasun Hospital, and Pusan National University Hospital) were collected and analyzed retrospectively. In the subgroup analysis, aggressiveness and clinical outcomes of thyroid cancer were compared nodular GD and non-nodular GD groups according to the presence or absence of the thyroid nodules other than thyroid cancer (index nodules). Results Of the 15,159 GD patients treated at the hospitals during the study period, 262 (1.7%) underwent thyroidectomy for coexisting thyroid cancer. Eleven patients (4.2%) were diagnosed with occult thyroid cancer and 182 patients (69.5%) had microcarcinomas. No differences in thyroid cancer aggressiveness, ultrasonographic findings, or prognosis were observed between the nodular GD and non-nodular GD groups except the cancer subtype. In the multivariate analysis, only lymph node (LN) metastasis was an independent prognostic factor for recurrent/persistent disease of thyroid cancer arising in GD (P=0.020). Conclusion The prevalence of concomitant thyroid cancer in GD patients was considerably lower than in previous reports. The clinical outcomes of thyroid cancer in GD patients were also excellent but, more cautious follow-up is necessary for patients with LN metastasis in the same way as for thyroid cancer in non-GD patients.

Salidroside (SAL) is a phenylpropanoid glycoside monomer extracted from Rhodiola at high altitudes. It has been proven to have protective effects on myocardial injury, liver cancer, renal fibrosis, and other organ diseases, as well as play neuroprotective roles in central nervous system (CNS) diseases. Specifically, SAL can inhibit a series of pathological reactions in CNS diseases and improve neurological dysfunction. This review elucidated the pharmacological effects of SAL on inflammation, oxidative stress, apoptosis, autophagy, and neuronal regeneration. Furthermore, how SAL affects various signaling pathways to regulate pathological processes in CNS diseases is also assessed. However, the relationship between various pathways and the mechanisms in different pathological stages remains unclear. Additionally, the appropriate dosage and side effects of SAL on the clinical outcomes of CNS diseases have not been fully determined due to the limited number of clinical studies on SAL. Therefore, the regulatory mechanisms and clinical applications of SAL still need to be further demonstrated. This review tracked and summarized studies from the past eight years reported in databases, including PubMed, ScienceDirect, and Google Scholar, filtered using the keywords ''salidroside'' and/or paired with ''diseases'' and ''CNS diseases''.

Brain inflammation generally accelerates neurodegeneration but the mechanisms of this are not fully characterised. Here the authors show that PQBP1 in microglia is important for sensing extrinsic Tau 3 R/4 R proteins and triggers an innate immune response through cGAS and STING resulting in cognitive impairment.

Tanaka et al use phosphoproteome analysis of post-mortem Alzheimer’s Disease (AD) brains and identified abnormal phosphorylation of Ku70, which leads to DNA damage and transcriptional repression-induced atypical cell death. In a mouse model of AD, the authors show that Ku70 phosporylation is regulated by extracellular high mobility group box 1 protein, thus shedding light on the mechanism of DNA damage in AD.

Background Hürthle cell carcinoma (HCC), a type of thyroid carcinoma, is rare in South Korea, and few studies have investigated its prognosis. Methods This long-term multicenter retrospective cohort study evaluated the clinicopathological features and clinical outcomes in patients with HCC who underwent thyroid surgery between 1996 and 2009. Results The mean age of the 97 patients included in the study was 50.3 years, and 26.8% were male. The mean size of the primary tumor was 3.2±1.8 cm, and three (3.1%) patients had distant metastasis at initial diagnosis. Ultrasonographic findings were available for 73 patients; the number of nodules with low-, intermediate-, and high suspicion was 28 (38.4%), 27 (37.0%), and 18 (24.7%), respectively, based on the Korean-Thyroid Imaging Reporting and Data System. Preoperatively, follicular neoplasm (FN) or suspicion for FN accounted for 65.2% of the cases according to the Bethesda category, and 13% had malignancy or suspicious for malignancy. During a median follow-up of 8.5 years, eight (8.2%) patients had persistent/recurrent disease, and none died of HCC. Older age, gross extrathyroidal extension (ETE), and widely invasive types of tumors were significantly associated with distant metastasis (all P

Jin et al use dynamic molecular network analysis to characterise the phosphoproteome in mouse models of neurodegenerative disease. Analyzing four models of frontotemporal lobar degeneration and four models of Alzheimer’s disease, they observe conserved signaling networks and confirm a therapeutic effect of human anti-HMGB1, demonstrating the utility of the approach.

Background: Catabolism of serine via serine hydroxymethyltransferase2 (SHMT2) through the mitochondrial one-carbon unit pathway is important in tumorigenesis. Therefore, SHMT2 may play a role in thyroid cancer. Methods: Thyroid tissue samples and The Cancer Genome Atlas (TCGA) database were used to evaluate SHMT2 expression in thyroid tissues and the association with clinical outcomes. Results: SHMT2 protein expression was evaluated in thyroid tissues consisting of 52 benign nodules, 129 papillary thyroid carcinomas (PTC) and matched normal samples, and 20 anaplastic thyroid carcinomas (ATC). ATCs presented the highest (95.0%) positivity of SMHT2 protein expression. PTCs showed the second highest (73.6%) positivity of SHMT2 expression, which was significantly higher than that of be nign nodules (19.2%, P = 0.016) and normal thyroid tissues (0%, P < 0.001). Analysis of TCGA data showed that SHMT2 messenger RNA (mRNA) expression was significantly higher in tumo rs than in normal tissues (P < 0.001). When we classified thyroid cancer into high and low gr oups according to SHMT2 mRNA expression levels, the thyroid differentiation score for t he high SHMT2 group was significantly lower than that of the low SH MT2 group (P < 0.001). There was also a significant correlation between SHMT2 mRNA expression and the stemness index (r = 0.41, P < 0.001). The high SHMT2 group had more advanced TNM stages and shorter progression-free survival rates than the low SHMT2 group (P < 0.01 and P = 0.007, respectively). Conclusion: SHMT2 expression is higher in thyroid cancers than normal or benign tissues and is associated with de-differentiation and poor clinical outc omes. Thus, SHMT2 might be useful as a diagnostic and prognostic marker for thyroid cancer.

Amlodipine is a Ca2+ channel blocker commonly used to cardiovascular diseases such as hypertension and angina; however, its anticancer effects in lung cancer A549 cells remain unknown. In the present study, we explored the antitumor effects and molecular mechanisms underlying the action of amlodipine in non-small cell lung cancer (NSCLC) A549 cells in vitro and in vivo. We observed that amlodipine suppressed the proliferation of A549 lung cancer cells by arresting the tumor cell cycle. Mechanistically, our results revealed that amlodipine could attenuate the phosphoinositide 3 kinase (PI3K)/Akt and Raf/MEK/extracellular signal-regulated kinase (ERK) pathways through epidermal growth factor receptor (EGFR) and modulated cell cycle-related proteins such as cyclin D1, p-Rb, p27, and p21. Subsequently, amlodipine combined with gefitinib could synergistically inhibit cell proliferation by arresting the cell cycle. Moreover, amlodipine combined with gefitinib effectively attenuated the growth of A549 lung cancer xenografts when compared with monotherapy, affording an excellent therapeutic effect. Collectively, our results indicate that amlodipine alone or combined with the novel anticancer drug gefitinib might be a potential therapeutic strategy for NSCLC patients with wild-type EGFR.

Abstract Cancer cells secrete abundant exosomes, and the secretion can be promoted by an increase of intracellular Ca2+. Stromal interaction molecule 1 (STIM1) plays a key role in shaping Ca2+ signals. MicroRNAs (miRNAs) have been reported to be potential therapeutic targets for many diseases, including breast cancer. Recently, we investigated the effect of exosomes from STIM1-knockout breast cancer MDA-MB-231 cells (Exo-STIM1-KO), and from SKF96365-treated MDA-MB-231 cells (Exo-SKF) on angiogenesis in human umbilical vein endothelial cells (HUVECs) and nude mice. The exosomes Exo-STIM1-KO and Exo-SKF inhibited tube formation by HUVECs remarkably. The miR-145 was increased in SKF96365 treated or STIM1-knockout MDA-MB-231 cells, Exo-SKF and Exo-STIM1-KO, and HUVECs treated with Exo-SKF or Exo-STIM1-KO. Moreover, the expressions of insulin receptor substrate 1 (IRS1), which is the target of miR-145, and the downstream proteins such as Akt/mammalian target of rapamycin (mTOR), Raf/extracellular signal regulated-protein kinase (ERK), and p38 were markedly inhibited in HUVECs treated with Exo-SKF or Exo-STIM1-KO. Matrigel plug assay in vivo showed that tumor angiogenesis was suppressed in Exo-STIM1-KO, but promoted when miR-145 antagomir was added. Taken together, our findings suggest that STIM1 promotes angiogenesis by reducing exosomal miR-145 in breast cancer MDA-MB-231 cells.

Background The clinical outcomes of delayed radioiodine remnant ablation (RRA) therapy in patients with low-risk papillary thyroid carcinoma (PTC) are unclear. We aimed to evaluate the clinical impact of the interval between total thyroidectomy (TT) and RRA therapy in patients with low-risk PTC. Methods We included 526 patients who underwent TT and RRA for low-risk PTC with a primary tumor size of >1 cm between 2000 and 2012. Patients were divided into the early (3 months after TT considering other prognostic factors.

Background The study aimed to compare the prognostic value of the 4th edition of World Health Organization classification (WHO-2017) with the previous WHO classification (WHO-2004) for follicular thyroid carcinoma (FTC). Methods This multicenter retrospective cohort study included 318 patients with FTC from five tertiary centers who underwent thyroid surgery between 1996 and 2009. We evaluated the prognosis of patients with minimally invasive (MI), encapsulated angioinvasive (EA), and widely invasive (WI) FTC according to WHO-2017. Further, we evaluated the proportion of variation explained (PVE) and Harrell’s C-index to compare the predictability of disease-free survival (DFS) and disease-specific survival (DSS). Results In total, 227, 58, and 33 patients had MI-, EA-, and WI-FTC, respectively. During a median follow-up of 10.6 years, 46 (14.5%) patients had disease recurrence and 20 (6.3%) patients died from FTC. The 10-year DFS rates of patients with MI-, EA-, and WI-FTC were 91.1%, 78.2%, and 54.9%, respectively (P

Background The optimal dose of radioactive iodine (RAI) therapy for N1b papillary thyroid carcinoma (PTC) is controversial. We evaluated the clinical outcome of N1b PTC patients treated with either 100 or 150 mCi of RAI. Methods We retrospectively analyzed N1b PTC patients who underwent total thyroidectomy and postoperative RAI therapy at a tertiary referral center between 2012 and 2017. As the baseline characteristics differed between treatment groups, we performed exact matching for various pathological factors according to RAI dose. We evaluated the response to therapy and recurrence-free survival (RFS) in the matched patients. Structural recurrent/persistent disease was defined as new structural disease detected after initial therapy, which was confirmed by cytology or pathology. Results Of the total 436 patients, 37 (8.5%) received 100 mCi of RAI and 399 (91.5%) received 150 mCi of RAI. After an exact 1:3 matching, 34 patients in the 100 mCi group and 100 patients in the 150 mCi group remained. There was no significant difference in response to therapy between the groups in the matched population (P=0.63). An excellent response was achieved in 70.6% (n=24) of patients in the 100 mCi group and 76.0% (n=76) in the 150 mCi group. Two (5.9%) patients in the 100 mCi group and four (4.0%) in the 150 mCi group had recurrence and there was no significant difference in RFS between the groups in the matched population (P=0.351). Conclusion There were no differences in response to therapy and RFS in N1b PTC patients according to RAI dose.

Background. Highly active antiretroviral therapy (HAART) can effectively reduce the risk of death and opportunistic infections in patients with HIV/AIDS. The aim of this study was to analyse the survival status and its influencing factors in HIV/AIDS after HAART. Methods. The data on patients’ sociodemographic characteristics, treatment information, and follow-up results from the Information Management System of the Chinese Center for Disease Control and Prevention were obtained. Bivariate and stepwise multivariate Cox proportional hazards regression model analyses were performed. Results. A total of 1812 participants were included in this study, of which 1716 were still alive (survival group) and 96 had died (death group). The results indicated that respondents who were elderly (HR = 1.053, 95% CI: 1.037–1.069, P

Background The coexistence of Graves’ disease with thyroid cancer is well-known and total thyroidectomy is recommended in such cases. However, Graves’ disease might be dormant at the time of surgery and diagnosed after lobectomy for thyroid cancer. Methods We assessed the incidence and clinicopathological characteristic of newly developed Graves’ disease after lobectomy for thyroid cancer between 2010 and 2019. Results In all, 11043 patients underwent lobectomy for thyroid cancer during the study period, and 26 (0.2%) were diagnosed with Graves’ disease during follow-up. The median age was 43.8 years, 88.5% were female, and all were euthyroid before surgery. The median time from lobectomy to the diagnosis of Graves’ disease was 3.3 years. Half of the patients were diagnosed based on thyroid function tests during routine follow-up, and others were diagnosed due to symptoms of thyrotoxicosis. Among patients who had checked preoperative thyroid autoantibodies, 61.1% showed positivity. Twenty-one (80.8%), and 2 (7.7%) patients received antithyroid drugs and radioactive iodine therapy, respectively, and 3 (11.5%) underwent completion thyroidectomy. Conclusion Although rare, Graves’ disease can occur in the remnant thyroid after lobectomy. Such patients are more likely to have autoantibodies. An appropriate workup is required when hyperthyroidism is found during the follow-up of patients after lobectomy.

Colon interposition is a surgical procedure used for maintenance of luminal conduit after esophagectomy. Although epithelial neoplasia, such as adenoma and adenocarcinoma, may develop in the interposed colon, there are only few case reports on the condition. Due to the rarity of this condition, there is no definite consensus on recommending screening endoscopy for the early detection of neoplasia in the interposed colons. Here, we report a case of intramucosal adenocarcinoma in an interposed colon. Initial endoscopic resection for this tumor failed to accomplish complete resection. A subsequent endoscopic resection was performed 1 month later and complete resection was achieved. Based on our experience and recommendation on screening endoscopy for gastric cancer in Korea, we suggest that regular screening esophagogastroduodenoscopies should be performed following esophagectomy to detect early neoplasia in the stomach and interposed colon and avoid adverse results induced by delayed detection.

The oncogene c-Jun is activated by Jun N-terminal kinase (JNK). Exosomes are nanometer-sized membrane vesicles released from a variety of cell types, and are essential for cell-to-cell communication. By using specific JNK inhibitor SP600125 or CRISPR/Cas9 to delete c-Jun, we found that exosomes from SP600125-treated A549 cancer cells (Exo-SP) or from c-Jun-KO-A549 cells (Exo-c-Jun-KO) dramatically inhibited tube formation of HUVECs. And the miR-494 levels in SP600125 treated or c-Jun-KO A549 cells, Exo-SP or Exo-c-Jun-KO, and HUVECs treated with Exo-SP or Exo-c-Jun-KO were significantly decreased. Meanwhile, Exo-SP and Exo-c-Jun-KO enhanced expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Addition of miR-494 agomir in Exo-c-Jun-KO treated HUVECs inhibited PTEN expression and promoted tube formation, suggesting the target of miR-494 might be PTEN in HUVECs. Moreover, A549 tumor xenograft model and Matrigel plug assay demonstrated that Exo-c-Jun-KO attenuated tumor growth and angiogenesis through reducing miR-494. Taken together, inhibition of c-Jun in A549 cancer cells exhibited antiangiogenic activity in vitro and in vivo through exosome/miRNA-494-3p/PTEN signal pathway.

Lansoprazole (Lpz) is an FDA-approved proton pump inhibitor (PPI) drug for the therapy of acid-related diseases. Aiming to explore the new application of old drugs, we recently investigated the antitumor effect of Lpz. We demonstrated that the PPI Lpz played a tumor suppressive role in non-small cell lung cancer (NSCLC) A549 cells. Mechanistically, Lpz induced apoptosis and G0/G1 cell cycle arrest by inhibiting the activation of signal transducer and activator of transcription (Stat) 3 and the phosphoinositide 3-kinase (PI3K)/Akt and Raf/ERK pathways. In addition, Lpz inhibited autophagy by blocking the fusion of autophagosomes with lysosomes. Furthermore, Lpz in combination with gefitinib (Gef) showed a synergistic antitumor effect on A549 cells, with enhanced G0/G1 cell cycle arrest and apoptosis. The combination inhibited Stat3 phosphorylation, PI3K/Akt and Raf/ERK signaling, affecting cell cycle-related proteins such as p-Rb, cyclin D1 and p27, as well as apoptotic proteins such as Bax, Bcl-2, caspase-3, and poly (ADP-ribose) polymerase (PARP). In vivo, coadministration with Lpz and Gef significantly attenuated the growth of A549 nude mouse xenograft models. These findings suggest that Lpz might be applied in combination with Gef for NSCLC therapy, but further evidence is required.

Objectives To develop a model of in-hospital mortality using medical record front page (MRFP) data and assess its validity in case-mix standardisation by comparison with a model developed using the complete medical record data.Design A nationally representative retrospective study.Setting Representative hospitals in China, covering 161 hospitals in modelling cohort and 156 hospitals in validation cohort.Participants Representative patients admitted for acute myocardial infarction. 8370 patients in modelling cohort and 9704 patients in validation cohort.Primary outcome measures In-hospital mortality, which was defined explicitly as death that occurred during hospitalisation, and the hospital-level risk standardised mortality rate (RSMR).Results A total of 14 variables were included in the model predicting in-hospital mortality based on MRFP data, with the area under receiver operating characteristic curve of 0.78 among modelling cohort and 0.79 among validation cohort. The median of absolute difference between the hospital RSMR predicted by hierarchical generalised linear models established based on MRFP data and complete medical record data, which was built as ‘reference model’, was 0.08% (10th and 90th percentiles: −1.8% and 1.6%). In the regression model comparing the RSMR between two models, the slope and intercept of the regression equation is 0.90 and 0.007 in modelling cohort, while 0.85 and 0.010 in validation cohort, which indicated that the evaluation capability from two models were very similar.Conclusions The models based on MRFP data showed good discrimination and calibration capability, as well as similar risk prediction effect in comparison with the model based on complete medical record data, which proved that MRFP data could be suitable for risk adjustment in hospital performance measurement.

ObjectiveThe purpose of this study was to explore the situations and factors influencing casual sexual behavior among male college students, in order to provide scientific evidences and measures of the prevention and control for HIV/AIDS.MethodUsing the stratified cluster sampling method, male college students who self-reported sexual behavior were selected as survey subjects in 13 colleges and universities in 11 cities of Zhejiang Province from October to November 2018. We used a custom online questionnaire to collect information on the demographic characteristics, sexual attitudes, sexual behaviors, and HIV interventions of the respondents. The χ2 test was performed on the composition ratios between different groups. With the occurrence of casual sexual behavior as the dependent variable, logistic regression was used to analyze the factors influencing casual male sexual behavior.ResultsA total of 2734 male college students were surveyed, aged 20.20±1.41 years, of which 595 had casual sex, accounting for 21.7%. The rate of HIV prevention awareness among the participants was 85.1%. Multivariate analysis showed that receiving a self-assessment of HIV risk conducted by the school (Ajusted OR = 1.45, 95% CI = 1.14-1.84), knowing that HIV self-test kits were available at school (Ajusted OR = 2.02, 95% CI = 1.56-2.62), accepting one-night stands (Ajusted OR = 2.82, 95% CI = 2.18-3.66), accepting commercial sex (Ajusted OR = 1.95, 95% CI = 1.53-2.48), being a man who has sex with men (Ajusted OR = 1.81, 95% CI = 1.37-2.39), being a senior (Ajusted OR = 0.46, 95% CI = 0.30-0.71), having knowledge of HIV/AIDS prevention and treatment (Ajusted OR = 0.66, 95% CI = 0.51-0.86), and knowing that the CDC provides HIV testing services (Ajusted OR = 0.56, 95% CI = 0.41-0.77) were factors influencing male college students' casual sexual behavior.ConclusionMale college students who have causal sexual behaviors have a high degree of openness in sexual attitudes, insufficient knowledge of AIDS prevention, and knowledge of HIV testing-related information but low testing rates. For male college students' HIV prevention education intervention, it is necessary to emphasize the establishment of correct sexual attitudes and concepts and promote safe sexual behaviors to prevent the spread of HIV.

The activation of metastatic reprogramming is vital for cancer metastasis, but little is known about its mechanism. This study investigated the potential role of death-associated protein kinase 1 (DAPK1) in thyroid cancer progression. We generated knockdown (KD) DAPK1 using siRNA or shRNA in 8505C and KTC-1 cell lines, which we transiently or stably overexpressed in MDA-T32 and BCPAP cell lines. DAPK1 KD in 8505C and KTC-1 cells significantly increased cell proliferation and colony formation compared with controls. We observed significant inhibition of cancer cell invasion in cells overexpressing DAPK1, but the opposite effect in KD cells. Tumorsphere formation significantly increased after inhibition of DAPK1 expression in 8505C cells and was significantly suppressed in DAPK1-overexpressing MDA-T32 and BCPAP cells. DAPK1 overexpression inhibited mRNA and protein levels of stem markers (OCT4, Sox2, KLF4, and Nanog). Furthermore, the expression of these markers increased after KD of DAPK1 in 8505C cells. Mechanistic studies suggest that DAPK1 may modulate the expression of stem cell markers through the inhibition of β-catenin pathways. These findings were consistent with the public data and our thyroid tissue analysis, which showed higher DAPK1 expression was associated with advanced-stage papillary thyroid cancer with a higher stemness index and lower disease-free survival.

Inspired by the antifouling properties of scaly fish, the conventional silicone coating with phenylmethylsilicone oil (PSO/PDMS) composite coating was fabricated and modified with single layer polystyrene (PS) microsphere (PSO/PDMS-PS) arrays. The fish scale like micro-nano structures were fabricated on the surface of bio-inspired coating, which can reduce the contact area with the secreted protein membrane of fouling organisms effectively and prevent further adhesion between fouling organisms and bio-inspired coating. Meanwhile, PSO exuded to the coating surface has the similar function with mucus secreted by fish epidermis, which make the coating surface slithery and will be polished with the fouling organisms in turbulent waters. Compared to PSO/PDMS coating without any structure and conventional silicone coating, PSO/PDMS-PS showed better antiadhesion activity against both marine bacteria and benthic diatom (Navicula sp.). Additionally, the existence of PS microspheres can reduce the release rate of PSO greatly, which will extend the service life of coating. Compared to PSO/PDMS coating, the sustained release efficiency of PSO/PDMS-PS coating can reach 23.2%. This facile method for fabricating the bio-inspired composite slow-release antifouling coating shows a widely fabricating path for the development of synergistic anti-fouling coating.

Novel therapeutic strategies are still urgently expected for leukemia despite undisputed success of various targeted therapeutics. The antileukemia activity of Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on human leukemia cells was investigated. Atorvastatin inhibited K562 and HL60 cell proliferation, induced G2/M cell cycle arrest in K562 cells by down-regulating cyclinB1 and cdc2, but G0/G1 arrest in HL60 cells by up-regulating p27 and down-regulating cyclinD1 and p-pRb. Atorvastatin also induced apoptosis in both cell lines, in which the reactive oxygen species (ROS)-related mitochondrial apoptotic signaling might be involved, with increase of ROS and Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (MMP), release of cytochrome C into cytosol, and activation of Bax/Caspase-9/Caspase-3/PARP pathway. Inhibition of YAP nuclear localization and activation by Atorvastatin was reversed by the addition of mevalonate, GGPP, or FPP. Further, the effects on cell cycle arrest- and apoptosis- related proteins by Atorvastatin were alleviated by addition of mevalonate, suggesting the antileukemia effect of Atorvastatin might be through mevalonate-YAP axis in K562 and HL60 cells. Our results suggest that Atorvastatin might be used for leukemia therapy while evidence of clinical efficacy is required.

Abstract Objective To identify factors associated with recent HIV infection among men who have sex with men (MSM) in Huzhou City, Eastern China, who seek sexual partners via the internet. Methods Adult members of Tencent QQ instant messaging software, who completed a face-to-face interview questionnaire and serological HIV testing at baseline, were enrolled into this prospective cohort study. Questionnaires and serological testing were also completed at 6 and 12 months. Cox proportional hazards was used for initial bivariate analyses of differences between participants with or without recent HIV infection, and for subsequent forward stepwise multiple regression of statistically significant variables. Results Out of 415 baseline participants, 283 completed the 12-month follow-up (25 with recent HIV infection and 258 without; recent HIV infection rate, 8.20 per 100 person-years). Recent HIV infection was shown to be significantly associated with ≤ high school education (versus college/university), registered residence outside Huzhou City (versus within Huzhou City), having ≥ two male sexual partners, and syphilis infection. Conclusions Improving education levels, treating syphilis promptly, and reducing the number of male sexual partners may reduce HIV transmission among MSM in Eastern China.

DT-13, a saponin monomer 13 from the dwarf lilyturf tuber, was reported to exhibit anti-inflammatory, hepatoprotective, cardioprotective as well as antitumor activities in a number of tumor cells. Prostate cancer is the second leading cause of cancer death in males, discovery of novel antitumor drug for therapy of prostate cancer is expected. Aiming to evaluate whether DT-13 could become a candidate to treat prostate cancer, we recently investigated the antitumor effect of DT-13 on human prostate cancer cells and the underlying mechanism. DT-13 was found to effectively inhibit proliferation and metastasis of prostate cancer PC3 and DU145 cell lines in a dose-dependent manner. Treatment by DT-13 resulted in a mitochondria-mediated apoptosis, which was accompanied by the chromatin condensation and nuclear shrinkage in the prostate cancer cells. Moreover, DT-13 caused remarkable upregulation of Bax, Bad, Cytochrome C, cleaved -caspase 3, -caspase 9 and -PARP, in contrast to the downregulation of Bcl-2. Nevertheless, no obvious change in intracellular ROS level was observed after DT-13 treatment. We further demonstrated that DT-13 could inhibit PC3 cell metastasis in which suppression of Integrinβ1 and MMP2/9 might be involved. Western blot analysis indicated DT-13 significantly decreased the phosphorylation of PDK1, Akt, mTOR as well as p70S6K, suggesting the pro-apoptotic and anti-metastatic effects of DT-13 on prostate cancer cells might be attributed to the blockade of PI3K/Akt pathway. Collectively, our findings suggest DT-13 is worthy of further investigation as a drug candidate for the treatment of prostate cancer.

We previously reported the anti-inflammatory and anti-asthmatic activities of the extract of the Inula japonica Thunb. Aiming for discovery of a novel anti-inflammatory compound, we isolated spinacetin from the extract and investigated its in vitro and in vivo anti-inflammatory effect and the related mechanism. Effect of spinacetin on the Syk signaling pathway was studied in bone marrow-derived mast cells (BMMCs), and that on the nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) was investigated in Rat basophilic leukemia (RBL)-2H3 cells and human mast cell line (HMC-1). The in vivo anti-inflammatory activity was assessed with passive cutaneous anaphylaxis (PCA) reaction assay. Spinacetin significantly inhibited the release of histamine, and production of inflammatory mediators such as leukotriene C4 (LTC4) and interlukin-6 (IL-6) in IgE/Ag stimulated BMMCs. Analysis of the signaling pathways demonstrated that spinacetin inhibited activation of Syk, linker of activated T cells (LAT), phospholipase Cγ (PLCγ), cytosolic phospholipase A2 (cPLA2), MAPKs, Akt/NF-κB, and intracellular Ca2+ mobilization but with no effect on Fyn and Lyn. On the other hand, spinacetin suppressed IgE/Ag-induced activation of RBL-2H3 cells with inhibition against phosphorylation of extracellular signal regulated-protein kinase (ERK), c-Jun-NH2-terminal kinase (JNK), p38 MAPKs, PLCγ, translocation of cPLA2, and Akt/IκBα/NF-κB signal. However, spinacetin had no effect on PMA and A23187-induced activation of HMC-1. Furthermore, oral administration of spinacetin dose-dependently attenuated IgE/Ag-mediated PCA reaction in mouse model. Taken together, spinacetin showed the activities in preventing inflammatory processes, which might be at least partially attributed to the abolishment of Syk-dependent activation of IgE/Ag-mediated mast cells.

Glioblastoma is the most malignant and invasive brain tumor with extremely poor prognosis. p53-inducible gene 3, a downstream molecule of the tumor suppressor p53, has been found involved in apoptosis and oxidative stress response. However, the functions of p53-inducible gene 3(PIG3) in cancer are far from clear including glioblastoma. In this study, we found that p53-inducible gene 3 expression was suppressed in glioblastoma tissues compared with normal tissues. And the expression of p53-inducible gene 3 was significantly associated with the World Health Organization grade. Patients with high p53-inducible gene 3 expression have a significantly longer median survival time (15 months) than those with low p53-inducible gene 3 expression (8 months). According to Cox regression analysis, p53-inducible gene 3 was an independent prognostic factor with multivariate hazard ratio of 0.578 (95% confidence interval, 0.352–0.947; p = 0.030) for overall survival. Additionally, gain and loss of function experiments showed that knockdown of p53-inducible gene 3 significantly increased the proliferation and invasion ability of glioblastoma cells while overexpression of p53-inducible gene 3 inhibited the proliferation and invasion ability. The results of in vivo glioblastoma models further confirmed that p53-inducible gene 3 suppression promoted glioblastoma progression. Altogether, our data suggest that high expression of p53-inducible gene 3 is significant for glioblastoma inhibition and p53-inducible gene 3 independently indicates good prognosis in patients, which might be a novel prognostic biomarker or potential therapeutic target in glioblastoma.

Stellettin B was isolated from marine sponge Jaspis stellifera. In vitro antitumor activities were investigated on 39 human cancer cell lines. Stellettin B exhibited highly potent inhibition against the growth of a human glioblastoma cell line SF295, with a GI50 of 0.01 μM. In contrast, stellettin B showed very weak inhibitory activity on normal cell lines including HMEC, RPTEC, NHBE and PrEC, with GI50s higher than 10 μM, suggesting its relatively selective cytotoxicity against human cancer cells compared to normal human cell lines. We then focused on the antitumor activity of this compound on SF295 cells. Flow cytometric analysis indicated that stellettin B induced apoptosis in SF295 cells in a concentration-dependent manner. Further study indicated that stellettin B increased the production of ROS, the activity of caspase 3/7, as well as the cleavage of PARP, each of which is known to be involved in apoptosis. To investigate the molecular mechanism for cell proliferation inhibition and apoptosis induction, effect on the phosphorylation of several signal proteins of PI3K/Akt and RAS/MAPK pathways was examined. Stellettin B inhibited the phosphorylation of Akt potently, with no activity on p-ERK and p-p38, suggesting that inhibition of PI3K/Akt pathway might be involved in the antiproliferative and apoptosis-inducing effect. However, homogenous time-resolved fluorescence (HTRF) assay indicated that stellettin B did not inhibit PI3K activity, suggesting that the direct target might be signal protein upstream of Akt pathway other than PI3K.

Alisol B 23-acetate (AB23A), a natural triterpenoid, has been reported to exert hepatoprotective and antitumor activities. Aiming to investigate the anti-inflammatory activity, this study examined the effect of AB23A on mast cells and allergic reaction. AB23A inhibited the degranulation of mast cells stimulated by immunoglobulin E/antigen (IgE/Ag), and also decreased the synthesis of leukotriene C4 (LTC4), production of interlukin-6 (IL-6), and expression of cyclooxygenase-2 (COX-2) in a concentration-dependent manner with no significant cytotoxicity in bone marrow-derived mast cells (BMMCs). AB23A inhibited spleen tyrosine kinase (Syk) and the downstream signaling molecules including phospholipase Cγ (PLCγ), serine-threonine protein kinase/inhibitor of nuclear factor kappa-B kinase/nuclear factor kappa-B (Akt/IKK/NF-κB), and mitogen-activated protein kinases/cytosolic phospholipase A2 (MAPK/cPLA2). Furthermore, AB23A blocked mobilization of Ca2+. Similar results were obtained in other mast cell lines Rat basophilic leukemia (RBL)-2H3 cells and a human mast cell line (HMC-1). In addition, AB23A attenuated allergic responses in an acute allergy animal model, passive cutaneous anaphylaxis (PCA). Taken together, this study suggests that AB23A inhibits the activation of mast cells and ameliorates allergic reaction, and may become a lead compound for the treatment of mast cell-mediated allergic diseases.

Tumor metastasis is the main cause of lethality of prostate cancer, because conventional therapies like surgery and hormone treatment rarely work at this stage. Tumor cell migration, invasion and adhesion are necessary processes for metastasis. By providing nutrition and an escape route from the primary site, angiogenesis is also required for tumor metastasis. Phosphatidylinositol 3-kinases (PI3Ks) are well known to play important roles in tumorigenesis as well as metastasis. ZSTK474 is a specific PI3K inhibitor developed for solid tumor therapy. In the present report, antimetastatic activities of ZSTK474 were investigated in vitro by determining the effects on the main metastatic processes. ZSTK474 exhibited inhibitory effects on migration, invasion and adhesive ability of prostate cancer PC3 cells. Furthermore, ZSTK474 inhibited phosphorylation of Akt substrate-Girdin, and the secretion of matrix metalloproteinase (MMP), both of which were reported to be closely involved in migration and invasion. On the other hand, ZSTK474 inhibited the expression of HIF-1α and the secretion of vascular endothelial growth factor (VEGF), suggesting its potential antiangiogenic activity on PC3 cells. Moreover, we demonstrated the antiangiogenesis by determining the effect of ZSTK474-reduced VEGF on tube formation of human umbilical vein endothelial cells (HUVECs). In conclusion, ZSTK474 was demonstrated to have potential in vitro antimetastatic effects on PC3 cells via dual mechanisms: inhibition of metastatic processes including cell migration, invasion and adhesion, and antiangiogenesis via blockade of VEGF secretion.

We previously demonstrated that type 5 adenylyl cyclase (AC5) functions in autonomic regulation in the heart. Based on that work, we hypothesized that pharmacological modulation of AC5 activity could regulate the autonomic control of the heart rate under micro- and hypergravity. To test this hypothesis, we selected the approach of activating AC5 activity in mice with a selective AC5 activator (NKH477) or inhibitor (vidarabine) and examining heart rate variability during parabolic flight. The standard deviation of normal R-R intervals, a marker of total autonomic variability, was significantly greater under micro- and hypergravity in the vidarabine group, while there were no significant changes in the NKH477 group, suggesting that autonomic regulation was unstable in the vidarabine group. The ratio of low frequency and high frequency (HF) in heart rate variability analysis, a marker of sympathetic activity, became significantly decreased under micro- and hypergravity in the NKH477 group, while there was no such decrease in the vidarabine group. Normalized HF, a marker of parasympathetic activity, became significantly greater under micro- and hypergravity in the NKH477 group. In contrast, there was no such increase in the vidarabine group. This study is the first to indicate that pharmacological modulation of AC5 activity under micro- and hypergravity could be useful to regulate the autonomic control of the heart rate. Keywords:: adenylyl cyclase isoform, autonomic nerve activity, parabolic flight, heart rate variability, microgravity

We previously isolated aaptamine, a benzonaphthyridine alkaloid, from marine sponge Aaptos suberitoids. In this study, we investigated the anti-proliferative effect of aaptamine on chronic myeloid leukemia (CML) K562 cells. Aaptamine inhibited growth of K562 with a GI50 as 10 μM, and arrested cell cycle at G2/M phase. Western blot analysis indicated that aaptamine induced p21 expression in K562 cells. Moreover, p21 promoter was activated by aaptamine treatment in p21 transfected K562 cells. Since K562 is p53 negative, aaptamine was demonstrated to be a p53-independent p21 inducer in CML cells.