Immunoadjuvant-Modified Rhodobacter sphaeroides Potentiate Cancer Photothermal Immunotherapy.

Photothermal immunotherapy has become a promising strategy for tumor treatment. However, the intrinsic drawbacks like light instability, poor immunoadjuvant effect, and poor accumulation of conventional inorganic or organic photothermal agents limit their further applications. Based on the superior carrying capacity and active tumor targeting property of living bacteria, an immunoadjuvant-intensified and engineered tumor-targeting bacterium was constructed to achieve effective photothermal immunotherapy. Specifically, immunoadjuvant imiquimod (R837)-loaded thermosensitive liposomes (R837@TSL) were covalently decorated onto Rhodobacter sphaeroides (R.S) to obtain nanoimmunoadjuvant-armed bacteria (R.S-R837@TSL). The intrinsic photothermal property of R.S combined R837@TSL to achieve in situ near-infrared (NIR) laser-controlled release of R837. Meanwhile, tumor immunogenic cell death (ICD) caused by photothermal effect of R.S-R837@TSL, synergizes with released immunoadjuvants to promote maturation of dendritic cells (DCs), which enhance cytotoxic T lymphocytes (CTLs) infiltration for further tumor eradication. The photosynthetic bacteria armed with immunoadjuvant-loaded liposomes provide a strategy for immunoadjuvant-enhanced cancer photothermal immunotherapy.

Pyrroloquinoline quinone ameliorates PM2.5-induced pulmonary fibrosis through targeting epithelial-mesenchymal transition.

Pulmonary fibrosis is a lung disorder affecting the lungs that involves the overexpressed extracellular matrix, scarring and stiffening of tissue. The repair of lung tissue after injury relies heavily on Type II alveolar epithelial cells (AEII), and repeated damage to these cells is a crucial factor in the development of pulmonary fibrosis. Studies have demonstrated that chronic exposure to PM2.5, a form of air pollution, leads to an increase in the incidence and severity of pulmonary fibrosis by stimulation of epithelial-mesenchymal transition (EMT) in lung epithelial cells. Pyrroloquinoline quinone (PQQ) is a bioactive compound found naturally that exhibits potent anti-inflammatory and anti-oxidative properties. The mechanism by which PQQ prevents pulmonary fibrosis caused by exposure to PM2.5 through EMT has not been thoroughly discussed until now. In the current study, we discovered that PQQ successfully prevented PM2.5-induced pulmonary fibrosis by targeting EMT. The results indicated that PQQ was able to inhibit the expression of type I collagen, a well-known fibrosis marker, in AEII cells subjected to long-term PM2.5 exposure. We also found the alterations of cellular structure and EMT marker expression in AEII cells with PM2.5 incubation, which were reduced by PQQ treatment. Furthermore, prolonged exposure to PM2.5 considerably reduced cell migratory ability, but PQQ treatment helped in reducing it. In vivo animal experiments indicated that PQQ could reduce EMT markers and enhance pulmonary function. Overall, these results imply that PQQ might be useful in clinical settings to prevent pulmonary fibrosis.

Isolation of novel simian adenoviruses from macaques for development of a vector for human gene therapy and vaccines.

IMPORTANCE: Adenoviruses are widely used in gene therapy and vaccine delivery. Due to the high prevalence of human adenoviruses (HAdVs), the pre-existing immunity against HAdVs in humans is common, which limits the wide and repetitive use of HAdV vectors. In contrast, the pre-existing immunity against simian adenoviruses (SAdVs) is low in humans. Therefore, we performed epidemiological investigations of SAdVs in simians and found that the SAdV prevalence was as high as 33.9%. The whole-genome sequencing and sequence analysis showed SAdV diversity and possible cross species transmission. One isolate with low level of pre-existing neutralizing antibodies in humans was used to construct replication-deficient SAdV vectors with E4orf6 substitution and E1/E3 deletion. Interestingly, we found that the E3 region plays a critical role in its replication in human cells, but the absence of this region could be compensated for by the E4orf6 from HAdV-5 and the E1 expression intrinsic to HEK293 cells.

First-line treatment of driver gene-negative metastatic lung adenocarcinoma with malignant pleural effusion: Should chemotherapy be combined with an immune checkpoint inhibitor or bevacizumab?

Patients with metastatic lung adenocarcinoma (MLA) and malignant pleural effusion (MPE) without driver gene mutations have a poor prognosis. None of the standard treatment strategies is recommended for such patients. We retrospectively analyzed the efficacy of the first-line treatment for this specific population: standard platinum-based doublet chemotherapy (CT), CT plus an immune checkpoint inhibitor (CT plus ICI), and CT plus bevacizumab (CT plus Bev). A total of 323 eligible patients were enrolled: CT alone (n = 166), CT plus Bev (n = 72), and CT plus ICI (n = 85). Treatment efficacy assessments were performed every two cycles according to the RECIST guidelines. The endpoints were overall survival (OS) and progression-free survival (PFS). Kaplan-Meier (K‒M) curves and the log-rank test were used to compare OS and PFS. p < 0.05 was the threshold of significance (statistical software: SPSS). The median follow-up was 11.4 months (range, 2.1-49.6 months). PFS and OS in the CT plus ICI/CT plus Bev cohort were significantly longer than those in the CT group (PFS: 7.8/6.4/3.9 months, p < 0.0001; OS: 16.4/15.6/9.6 months, p < 0.0001, respectively). CT plus Bev had better PFS and OS than CT plus ICI/CT in PD-L1 < 1% patients (PFS: 8.4/5.0/3.8 months, p < 0.0001; OS: 15.6/12.9/9.3 months, p < 0.0001). Among patients with PD-L1 1-49%, CT plus ICI led to a longer PFS and OS (PFS: 8.9/5.8/4.2 months, p = 0.009; OS: 24.2/18.8/11.5 months, p = 0.03). In the cohort with PD-L1 ≥ 50%, CT plus ICI was still the best first-line treatment (PFS: 19.7/13.8/9.6 months, p = 0.033; OS: 27.2/19.6/14.9 months, p = 0.047). In driver gene-negative MLA with MPE, CT plus Bev or ICI better controlled MPE and significantly prolonged survival compared to CT alone. PD-L1 expression (negative/positive) may be a key factor influencing the choice of CT plus Bev or ICI.

Melatonin prevents pulmonary fibrosis caused by PM2.5 exposure by targeting epithelial-mesenchymal transition.

Pulmonary fibrosis is a lung disorder characterized by the accumulation of abnormal extracellular matrix, scar tissue formation, and tissue stiffness. Type II alveolar epithelial cells (AEII) play a critical role in repairing lung tissue after injury, and repeated injury to these cells is a key factor in the development of pulmonary fibrosis. Chronic exposure to PM2.5, a type of air pollution, has been shown to increase the incidence and severity of pulmonary fibrosis by enhancing the activation of EMT in lung epithelial cells. Melatonin, a hormone with antioxidant properties, has been shown to prevent EMT and reduce fibrosis in previous studies. However, the mechanism through which melatonin targets EMT to prevent pulmonary fibrosis caused by PM2.5 exposure has not been extensively discussed before. In this current study, we found that melatonin effectively prevented pulmonary fibrosis caused by prolonged exposure to PM2.5 by targeting EMT. The study demonstrated changes in cellular morphology and expression of EMT markers. Furthermore, the cell migratory potential induced by prolonged exposure to PM2.5 was greatly reduced by melatonin treatment. Finally, in vivo animal studies showed reduced EMT markers and improved pulmonary function. These findings suggest that melatonin has potential clinical use for the prevention of pulmonary fibrosis.

Comprehensive analysis the prognostic and immune characteristics of mitochondrial transport-related gene SFXN1 in lung adenocarcinoma.

BACKGROUND: Mitochondria, which serve as the fundamental organelle for cellular energy and metabolism, are closely linked to the growth and survival of cancer cells. This study aims to identify and assess Sideroflexin1 (SFXN1), an unprecedented mitochondrial gene, as a potential prognostic biomarker for lung adenocarcinoma (LUAD). METHODS: The mRNA and protein levels of SFXN1 were investigated based on the Cancer Genome Atlas (TCGA) LUAD dataset, and then validated by real-time quantitative PCR, Western Blotting and immunohistochemistry from our clinical samples. The clinical correlation and prognostic value were evaluated by the TCGA cohort and verified via our clinical dataset (n = 90). The somatic mutation, drug sensitivity data, immune cell infiltration and single-cell RNA sequencing data of SFXN1 were analyzed through public databases. RESULTS: SFXN1 was markedly upregulated at both mRNA and protein levels in LUAD, and high expression of SFXN1 were correlated with larger tumor size, positive lymph node metastasis, and advanced clinical stage. Furthermore, SFXN1 upregulation was significantly associated with poor clinical prognosis. SFXN1 co-expressed genes were also analyzed, which were mainly involved in the cell cycle, central carbon metabolism, DNA repair, and the HIF-1α signaling pathway. Additionally, SFXN1 expression correlated with the expression of multiple immunomodulators, which act to regulate the tumor immune microenvironment. Results also demonstrated an association between SFXN1 expression and increased immune cell infiltration, such as activated CD8 + T cells, natural killer cells (NKs), activated dendritic cells (DCs), and macrophages. LUAD patients with high SFXN1 expression exhibited heightened sensitivity to multiple chemotherapies and targeted drugs and predicted a poor response to immunotherapy. SFXN1 represented an independent prognostic marker for LUAD patients with an improved prognostic value for overall survival when combined with clinical stage information. CONCLUSIONS: SFXN1 is frequently upregulated in LUAD and has a significant impact on the tumor immune environment. Our study uncovers the potential of SFXN1 as a prognostic biomarker and as a novel target for intervention in LUAD.

Quantification of preexisting lung ground glass opacities on CT for predicting checkpoint inhibitor pneumonitis in advanced non-small cell lung cancer patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can lead to life-threatening pneumonitis, and pre-existing interstitial lung abnormalities (ILAs) are a risk factor for checkpoint inhibitor pneumonitis (CIP). However, the subjective assessment of ILA and the lack of standardized methods restrict its clinical utility as a predictive factor. This study aims to identify non-small cell lung cancer (NSCLC) patients at high risk of CIP using quantitative imaging. METHODS: This cohort study involved 206 cases in the training set and 111 cases in the validation set. It included locally advanced or metastatic NSCLC patients who underwent ICI therapy. A deep learning algorithm labeled the interstitial lesions and computed their volume. Two predictive models were developed to predict the probability of grade ≥ 2 CIP or severe CIP (grade ≥ 3). Cox proportional hazard models were employed to analyze predictors of progression-free survival (PFS). RESULTS: In a training cohort of 206 patients, 21.4% experienced CIP. Two models were developed to predict the probability of CIP based on different predictors. Model 1 utilized age, histology, and preexisting ground glass opacity (GGO) percentage of the whole lung to predict grade ≥ 2 CIP, while Model 2 used histology and GGO percentage in the right lower lung to predict grade ≥ 3 CIP. These models were validated, and their accuracy was assessed. In another exploratory analysis, the presence of GGOs involving more than one lobe on pretreatment CT scans was identified as a risk factor for progression-free survival. CONCLUSIONS: The assessment of GGO volume and distribution on pre-treatment CT scans could assist in monitoring and manage the risk of CIP in NSCLC patients receiving ICI therapy. CLINICAL RELEVANCE STATEMENT: This study's quantitative imaging and computational analysis can help identify NSCLC patients at high risk of CIP, allowing for better risk management and potentially improved outcomes in those receivingICI treatment.

Recombinant Bacillus subtilis expressing functional peptide and its effect on blunt snout bream (Megalobrama amblycephala) in two state of stress.

This study was conducted to investigate the effects of recombinant Bacillus subtilis CM66-P4' (secreting P4, which related to previous research in this laboratory) on the antioxidant capacity and immune function of blunt snout bream (Megalobrama amblycephala) through in vitro and in vivo experiment. The culture experiment was divided into 3 groups, including control group (CG, with no additional bacteria), original bacteria group (OBG, with 2×109 CFU/kg Bacillus subtilis CM66) and recombinant bacteria group (RBG, with 2×109 CFU/kg Bacillus subtilis CM66-P4'). After 8 weeks of feeding, a part of the fish were subjected to fishing stress, and the rest were subjected to starvation stress test. Blood samples were collected for the determination of immune and stress-related indexes. The hepatocytes were divided into control group (CG) and experiment group with P4 peptide (LTG and HTG). The cells were collected after starvation treatment and the expression of related genes was detected. The results showed as follows: compared with the CG group, the gene expressions of hepatocytic hsp60 and hsp70 in the LTG and HTG groups were significantly suppressed after 24 h starvation stress (P < 0.05). The content of MDA, the activities of AKP and ALT in OBG group were significantly changed after 30 days starvation (P < 0.05), while the indexes in RBG group had no significant change. The changes of plasma cortisol, malondialdehyde (MDA) and Immunoglobulin M (IgM) in CG and OBG groups were significantly changed at 4 h after fishing stress (P < 0.05), while the indexes in RBG group was not. In conclusion, this study confirmed that Bacillus subtilis CM66-P4' has great potential in preventing adverse effects of stress on aquatic livestock.

[Intervention effect of Erchen Decoction on methionine and choline deficient diet-induced non-alcoholic steatohepatitis in mice].

This study investigated the effect of Erchen Decoction(ECD) on the prevention of non-alcoholic steatohepatitis(NASH) in mice and explored its possible mechanism, so as to provide scientific data for the clinical application of ECD in the prevention of NASH. C57BL/6 male mice were randomly divided into normal group(methionine and choline supplement, MCS), model group(methionine and choline deficient, MCD), low-dose ECD group(ECD＿L, 6 g·kg~(-1)), medium-dose ECD group(ECD＿M, 12 g·kg~(-1)), and high-dose ECD group(ECD＿H, 24 g·kg~(-1)), with eight mice in each group. The MCS group was fed with an MCS diet, and the other groups were fed with an MCD diet. The mice in each group were given corresponding diets, but the drug intervention group was given low-, medium-, and high-dose ECD(10 mL·kg~(-1)·d~(-1)) by intragastric administration for six weeks on the basis of MCD diet feeding, and the mice could eat and drink freely during the whole experiment. At the end of the experiment, mice were fasted overnight(12 h) and were anesthetized with 20% urethane. Thereafter, the blood and liver tissue were collected. The serum was used to detect the levels of alanine aminotransferase(ALT), aspartate aminotransaminase(AST), interleukin-1ß(IL-1ß), interleukin-6(IL-6), interleukin-10(IL-10), and tumor necrosis factor-α(TNF-α). Liver tissue was processed by hematoxylin-eosin(HE) staining and used for hepatic histological analysis and detection of the expression levels of genes and proteins related to nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4(Nrf2/GPX4) pathway by real-time quantitative reverse transcriptase-polymerase chain reaction(RT-qPCR) and Western blot analysis, respectively. The results showed that compared with the MCS group, the MCD group showed higher serum ALT and AST levels; the HE staining exhibited fat vacuoles and obvious inflammatory cell infiltration in liver tissue; serum IL-1ß, IL-6, and TNF-α levels were significantly increased, and the serum IL-10 level was significantly decreased. The mRNA expressions of fatty acid synthase(FASN), monocyte chemoattractant protein-1(MCP-1), and IL-1ß in liver tissue were significantly up-regulated, while those of GPX4, Nrf2, and NAD(P)H:quinine oxidoreductase(NQO1) were significantly down-regulated. Compared with the MCD group, the serum ALT and AST levels of ECD＿M and ECD＿H groups were significantly decreased, and the AST level in the ECD＿L group was significantly decreased. The number of fat vacuoles and the degree of inflammatory cell infiltration in liver tissue were improved; serum IL-1ß, IL-6, and TNF-α levels were significantly decreased, but the serum IL-10 level was significantly increased only in the ECD＿H group. The mRNA expressions of FASN, MCP-1, and IL-1ß in liver tissue were significantly down-regulated, and those of GPX4 and NQO1 were significantly up-regulated. The mRNA expressions of Nrf2 in ECD＿M and ECD＿H groups were significantly up-regulated. Western blot results showed that compared with the MCD group, the protein expression levels of Nrf2 and GPX4 in each group were significantly increased after ECD administration, and the protein expression level of FASN was significantly decreased; the protein expression of NQO1 was increased in ECD＿M and ECD＿H groups. In summary, ECD can reduce hepatic lipid accumulation, oxidative stress, liver inflammation, and liver injury in NASH mice, which may be related to the activation of the Nrf2/GPX4 pathway.

Sodium aescinate improve behavioral performance by inhibiting dorsal raphe nucleus NLRP3 inflammasome in Post-traumatic stress disorder Rat Model.

Growing evidence suggest that NLRP3 inflammasome activation in hippocampus and amygdala is involved in the pathophysiology of PTSD. Our previous studies have demonstrated that apoptosis of dorsal raphe nucleus (DRN) contributes to the pathological progression of PTSD. Recent studies by others have shown that in brain injury sodium aescinate (SA) has a protective effect on neurons by inhibiting inflammatory response pathways, thereby relieving symptoms. Here, we extend the therapeutic effects of SA to PTSD rats. We found that PTSD was associated with significant activation of the NLRP3 inflammasome in DRN, whereas administration of SA significantly inhibited DRN NLRP3 inflammasome activation and reduced DRN apoptosis level. SA also improved learning and memory ability and reduced anxiety and depression level in PTSD rats. In addition, NLRP3 inflammasome activation in DRN of PTSD rats impaired mitochondria function by inhibiting ATP synthesis and increasing ROS production, whereas SA can effectively reverse the pathological progression of mitochondria. We recommend SA as a new candidate for the pharmacological treatment of PTSD.

Impact of antibiotic use before definitive concurrent chemoradiation in patients with locally advanced non-small cell lung cancer.

PURPOSE: This study evaluated whether antibiotic treatment before chemoradiotherapy influenced outcomes in patients with locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: The records of LA-NSCLC patients treated with chemoradiotherapy between 2010 and 2017 at West China Hospital of Sichuan University were retrospectively examined together with their antibiotic use (antibiotic type, duration of treatment, and time between discontinuation and chemoradiotherapy). The influence of antibiotics on progression-free survival (PFS) and overall survival (OS) was evaluated with Kaplan-Meier curves and univariate and multivariate Cox regression. RESULTS: Of 522 patients, 176 had received intravenous broad-spectrum antibiotics in the month before chemoradiotherapy. Antibiotic use was linked to both reduced PFS (7.9 vs. 13.4 months, p < 0.001) and OS (20.4 vs. 25.3 months, p = 0.049). Multivariate regression demonstrated that antibiotic treatment was an unfavorable independent prognostic factor for LA-NSCLC patients who received chemoradiotherapy (HR 1.234; 95% CI 1.019-1.494; p = 0.031). Prognosis was also influenced by antibiotic type, length of treatment, and interval between discontinuation and chemoradiotherapy initiation. ß­lactamase inhibitors were found to be the most harmful (median OS for ß­lactamase inhibitors/fluoroquinolones/cephalosporins: 16.5/19.9/25.9 months, p = 0.045). Cutoff values for interval and duration calculated by the X­tile procedure showed that intervals of 7-16 days or durations ≤ 6 days did not significantly affect OS relative to untreated patients (intervals: p = 0.9; duration: p = 0.93). CONCLUSION: Antibiotic treatment for longer than 6 days, especially with ß­lactamase inhibitors, was associated with poor prognosis. Furthermore, delaying chemoradiotherapy for 7-16 days after antibiotic discontinuation may reduce these negative effects.

Perfect excitation and attenuation-free propagation of graphene surface polaritons under optical admittance matching.

Graphene supports both transverse magnetic and electric modes of surface polaritons due to the intraband and interband transition properties of electrical conductivity. Here, we reveal that perfect excitation and attenuation-free propagation of surface polaritons on graphene can be achieved under the condition of optical admittance matching. With both vanished forward and backward far-field radiation, incident photons are fully coupled to surface polaritons. This requires an exact match between the admittance difference of sandwiching media and the conductivity of graphene, resulting in no decay of propagating surface polaritons. The dispersion relation has a completely different line shape for structures that support compared to those that do not support admittance matching. This work promotes complete comprehension of the excitation and propagation behaviors of graphene surface polaritons and may further inspire ideas for research on surface waves on two-dimensional materials.

Survival of Patients With Inoperable Non-Small Cell Lung Cancer With Baseline Severe Pulmonary Dysfunction: Impacts of Thoracic Radiotherapy and Predictive Analysis for Acute Radiation Pneumonitis.

BACKGROUND AND PURPOSE: Currently, there is no standard treatment for patients with lung cancer with deteriorated pulmonary function. In this study, we aimed to assess the efficacy of thoracic radiotherapy for unresectable non-small cell lung cancer (NSCLC) with baseline severe pulmonary dysfunction and severe acute radiation pneumonitis (SARP). METHODS: Patients were categorized into a radiotherapy group and a nonradiotherapy group, followed by analysis of clinical variables. A Cox regression was used to evaluate the impact of various factors on overall survival (OS). Each SARP factor's predictive value was assessed using logistic regression, receiver operating characteristic curve, and Kaplan-Meier analyses. RESULTS: The median OS in the radiotherapy group was 21.6 months vs 8.9 months in the nonradiotherapy group. Cox analysis revealed that chemotherapy (HR, 0.221; 95% CI, 0.149-0.329; P < .001) and radiotherapy (HR, 0.589; 95% CI, 0.399-0.869; P = .008) are independent prognostic factors for the current cohort. The data suggested that the ipsilateral lung V10 (ilV10, the percentage of the lung volume that received more than 10 Gy) was an independent predictor of SARP. CONCLUSIONS: Our findings suggested that thoracic radiotherapy might be associated with clinical benefits to inoperable NSCLC in patients with severe pulmonary dysfunction and that ilV10 may be involved in the prediction of risk for SARP in these patients.

Altered circulating GDF-15 level predicts sex hormone imbalance in males with major depressive disorder.

BACKGROUND: It has been hypothesized that higher growth differentiation factor 15 (GDF15) level and lower testosterone/ estradiol (T/E) ratio are associated with major depressive disorder (MDD), yet the underlying effect of serum GDF15 on hinting the T/E ratio imbalance is not fully understood. We observed the correlation between serum T/E ratio and circulating GDF15 in male depressed cohort. METHODS: The sample consisted of participants (aged 18 ~ 65 years) from the Renmin Hospital of Wuhan University with MDD (n = 412) defined according to a Structured Clinical Interview for DSM-V (SCID), and male healthy controls (n = 137). Serum levels of testosterone, estradiol, and depression risk biomarkers (thyroid hormone, lipids, hs-CRP, Tenascin-C [TNC], GDF15, KLF4, Gas6, and sgp130) were measured. The associations among log-transformed T/E ratio and these biomarkers were analyzed using univariate correlation analysis, category analyses, and linear regression adjusting for standard risk factors. RESULTS: Of the sample, 36.89% had lower T/E ratio (< 10:1) and 10.20% had higher T/E ratio (> 20:1). After multivariable adjustment, T/E ratio was negatively associated with GDF15 (-0.095 [95% CI -0.170 ~ -0.023] standard deviation [SD] change per SD increase in lg[T/E], P = 0.015) and inversely related to TNC (-0.085 [95% CI -0.167 ~ 0.003] standard deviation [SD] change per SD increase in lg[T/E], P = 0.048). Serum T/E ratio was negatively associated with GDF15 level in both FT3, TSH and HDL strata, whereas this association was not observed in TNC. In T/E ratio strata analyses, there is a significant and negative correlation among T/E ratio and GDF15 in depressive patients with sex hormone imbalance, yet this relationship was not investigated in patients with sex hormone balance. CONCLUSION: In our community-based observation, circulating GDF-15 level was greatly and inversely associated with serum T/E ratio, indicating that higher GDF-15 alerts sex hormone imbalance in patients with MDD.

α-Mangostin Suppresses Melanoma Growth, Migration, and Invasion and Potentiates the Anti-tumor Effect of Chemotherapy.

Purpose: Melanoma is a highly malignant tumor, which metastasizes and has poor prognosis in late-stage cancer patients. α-Mangostin possesses pharmacological properties, including antioxidant, anti-infective, and anticarcinogenic activities. We investigated α-Mangostin effect on melanoma growth, migration, and invasion and its possible molecular mechanism. Methods: Melanoma cells growth inhibition was determined by the colorimetric 4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay. Morphological changes of α-Mangostin-treated melanoma cells were evaluated by transmission electron microscopy and JC-1 staining. Cell apoptosis and cell cycle arrest were assessed by flow cytometry. The effect of α-Mangostin on tumor cells migration and invasion was observed by migration and invasion in vitro assay. Furthermore, the nude and C57BL/6 mouse subcutaneous melanoma models were used to evaluate the in vivo anti-tumor effect of α-Mangostin. Western blot and real time-PCR were performed to analyze the influence of α-Mangostin on some of the common signaling pathways in melanoma cell lines. Signaling pathways were further verified in dissected tumor tissues. Results: α-Mangostin inhibited in vitro melanoma cells proliferation, migration, and invasion of melanoma cells, induced cell cycle arrest in G0/G1 phase, and caused mitochondrial swelling and membrane depolarization, whereas it effectively suppressed melanoma growth in xenografted mice. In addition, α-Mangostin potentiated the in vitro and in vivo anti-tumor effects of cisplatin both in vitro and in vivo. Mechanistically, α-Mangostin down-regulated expression of RAS protein and mRNA, as well as phosphorylation of PI3K in A375, B16F10, M14 and SK-MEL-2 cells. MITF protein and mRNA were inhibited only in M14 cells. Conclusion: α-Mangostin suppresses melanoma cells growth, migration and invasion, and synergistically enhances the anti-tumor effect of chemotherapy, whose mechanism may be mediated through inhibiting Ras, PI3K and MITF.

Timing of gestational diabetes diagnosis, gestational weight gains and offspring growth trajectory: a prospective birth cohort study.

BACKGROUND: The evidence on the associations of the timing of maternal gestational diabetes mellitus (GDM) with the comprehensive growth trajectory from perinatal to early childhood in offspring is limited. The potential mechanism remains elusive. Our aim is to estimate the associations of the timing of GDM diagnosis and gestational weight gains (GWG) with the growth trajectory of children from perinatal to early childhood. METHODS: A total of 7609 participants are included from the Maternal & Infants Health in Hefei cohort study. Primary predictors were the timing of maternal GDM diagnosis and GWG during pregnancy. The main outcomes included fetal ultrasonic measurements, birth size as well as BMI peak indicators during infancy within 48 months. RESULTS: GDM diagnosed before 26 weeks was associated with increased risks of overgrowth for fetal abdominal circumference (OR 1.19, 95% CI 1.04-1.36) and birth weight (OR 1.51, 95% CI 1.19-1.91) when compared with unexposed. GDM diagnosis < 26 weeks was related to the higher BMI peak (ß 0.16, 95%CI 0.03-0.28) within 48 months. The significantly additive impacts of maternal early GDM diagnosis and excessive gestational weight gains (EGWG) on offspring overgrowth were observed. Women in GDM < 26 weeks with early EGWG group had higher levels of hsCRP compared with GDM > 26 weeks (P < 0.001). CONCLUSIONS: Exposure to maternal GDM diagnosed before 26 weeks with early EGWG could lead to shifts and/or disruptions from the typical growth trajectory from perinatal to early childhood in offspring.

Social and ecological disparities in anaemia among adolescent girls 15-19 years old in Nepal.

OBJECTIVE: Adolescent girls are at risk of anaemia due to increased nutrient demands because of growth, menstrual blood loss and possible pregnancies. Sociocultural and household conditions influence their anaemia risk. We aimed to identify the sociocultural and economic factors associated with anaemia among adolescent girls in Nepal. DESIGN: The Nepal Demographic and Health Surveys (NDHS) conducted in 2006, 2011 and 2016 were pooled for secondary analysis. We used data on haemoglobin measurements for anaemia and conducted bivariate and multivariable logistic regression analyses to identify factors associated with anaemia. SETTING: Nationally representative NDHS households with adolescent girls 15-19 years of age. PARTICIPANTS: Non-pregnant adolescent girls 15-19 years, with a haemoglobin measurement (n = 3731). RESULTS: The overall prevalence of anaemia among adolescent girls was 39·6 %. Adolescents from socially disadvantaged caste/ethnicity groups were 1·42 times (95 % CI: 1·13, 1·78) more likely to have anaemia compared with those from Brahmin/Chhetri households. We found a counter-intuitive association between socio-economic status and anaemia where adolescents from the middle (adjusted OR (aOR) 1·37, 95 % CI: 1·01, 1·85) and highest (aOR 1·74, 95 % CI: 1·18, 2·56) quintiles were at increased odds of anaemia. Relative geographical inequality was observed where adolescents from the Terai region had 3·5 times (95 % CI: 2·32, 5·33) higher odds of anaemia. CONCLUSIONS: The disparities in the distribution of anaemia among adolescents by caste/ethnicity groups, wealth quintiles and geographical regions are evident. Reducing the anaemia burden will require addressing the social determinants of anaemia by allocating resources and expanding anaemia prevention programmes to target adolescents at higher risk.

Development of a real-world database for asthma and COPD: The SingHealth-Duke-NUS-GSK COPD and Asthma Real-World Evidence (SDG-CARE) collaboration.

PURPOSE: The SingHealth-Duke-GlaxoSmithKline COPD and Asthma Real-world Evidence (SDG-CARE) collaboration was formed to accelerate the use of Singaporean real-world evidence in research and clinical care. A centerpiece of the collaboration was to develop a near real-time database from clinical and operational data sources to inform healthcare decision making and research studies on asthma and chronic obstructive pulmonary disease (COPD). METHODS: Our multidisciplinary team, including clinicians, epidemiologists, data scientists, medical informaticians and IT engineers, adopted the hybrid waterfall-agile project management methodology to develop the SingHealth COPD and Asthma Data Mart (SCDM). The SCDM was developed within the organizational data warehouse. It pulls and maps data from various information systems using extract, transform and load (ETL) pipelines. Robust user testing and data verification was also performed to ensure that the business requirements were met and that the ETL pipelines were valid. RESULTS: The SCDM includes 199 data elements relevant to asthma and COPD. Data verification was performed and found the SCDM to be reliable. As of December 31, 2019, the SCDM contained 36,407 unique patients with asthma and COPD across the spectrum from primary to tertiary care in our healthcare system. The database updates weekly to add new data of existing patients and to include new patients who fulfil the inclusion criteria. CONCLUSIONS: The SCDM was systematically developed and tested to support the use RWD for clinical and health services research in asthma and COPD. This can serve as a platform to provide research and operational insights to improve the care delivered to our patients.

PM2.5 promotes pulmonary fibrosis by mitochondrial dysfunction.

Pulmonary fibrosis is known as an incurable lung disorder with irreversible progression of chronic injury, myofibroblast proliferation, extracellular matrix (ECM) accumulation, and tissue scarring. Atmospheric particulate matter 2.5 (PM2.5 ) is implicated as a risk factor of several diseases, especially lung diseases such as pulmonary fibrosis. The molecular mechanism which participates PM2.5 -induced pulmonary fibrosis in type II alveolar cells (AEII) has yet to be determined. Our results proved that short- and long-term exposure to PM2.5 significantly stimulated epithelial-mesenchymal transition (EMT) activity in AEII cells, according to, changes in gene signature analyzed by RNA-seq and cell morphology. Furthermore, Gene Ontology (GO) enrichment analysis also suggested that mitochondrial dysfunction was related to progression of pulmonary fibrosis in AEII after PM2.5 exposure. We observed a marked decline in mitochondria membrane potential (MMP), as well as fragmented mitochondria, in AEII cells exposed to PM2.5 , which suggests that energy metabolism is suppressed after PM2.5 exposure. We also confirmed that PM2.5 exposure could influence the expression levels of Mfn1, Mfn2, and Drp1 in AEII. Pretreatment of mitochondrial fusion promoter M1 was able to reverse mitochondrial dysfunction as well as EMT in AEII. These data suggested the key role of mitochondrial fragmentation in AEII, which was induced by PM2.5 exposure, and participated pathogenesis of pulmonary fibrosis. Finally, we investigated the response of lung tissue exposed to PM2.5 in vivo. The data indicated that the lung tissue exposed to PM2.5 obviously induced collagen accumulation. Moreover, IHC results revealed that PM2.5 enhanced Drp1 expression but suppressed Mfn1 and Mfn2 expression in lung tissue. The current study provides novel insight of pulmonary fibrosis caused by PM2.5 exposure.

Analysis of the influencing factors associated with dyssynchrony and cardiac dysfunction in children with ventricular pre-excitation.

OBJECTIVE: To investigate the correlation between ventricular pre-excitation-related dyssynchrony, on cardiac dysfunction, and recovery. METHODS AND RESULTS: This study included 76 children (39 boys and 37 girls) with a median age of 5.25 (2.67-10.75) years. The patients with pre-excitation-related cardiac dysfunction (cardiac dysfunction group, n = 34) had a longer standard deviation of the time-to-peak systolic strain of the left ventricle and larger difference between the maximum and minimum times-to-peak systolic strain than those with a normal cardiac function (normal function group, n = 42) (51.77 ± 24.70 ms versus 33.29 ± 9.48 ms, p < 0.05; 185.82 ± 92.51 ms versus 111.93 ± 34.27 ms, p < 0.05, respectively). The cardiac dysfunction group had a maximum time-to-peak systolic strain at the basal segments of the anterior and posterior septa and the normal function group at the basal segments of anterolateral and posterolateral walls. The prevalence of ventricular septal dyssynchrony in the cardiac dysfunction group was significantly higher than that in the normal function group (94.1% (32/34) versus 7.7% (3/42), p < 0.05). The patients with ventricular septal dyssynchrony (n = 35) had a significantly higher prevalence of intra-left ventricular systolic dyssynchrony than those with ventricular septal synchrony (n = 41) (57.1% (20/35) versus 14.6% (6/41), p < 0.05). During follow-up after pathway ablation, the patients who recovered from intra-left ventricular dyssynchrony (n = 29) had a shorter left ventricular ejection fraction recovery time than those who did not (n = 5) (χ2 = 5.94, p < 0.05). Among the patients who recovered, 93.1% (27/29) had a normalised standard deviation of the time-to-peak systolic strain and difference between the maximum and minimum times-to-peak systolic strain within 1 month after ablation. CONCLUSION: Ventricular pre-excitation may cause ventricular septal dyssynchrony; thus, attention must be paid to intra-left ventricular dyssynchrony and cardiac dysfunction. Whether intra-left ventricular systolic dyssynchrony can resolve within 1 month may be a new early predictor of patient prognosis.