GLUT4 mediates the protective function of gastrodin against pressure overload-induced cardiac hypertrophy.

Gastrodia elata exhibits extensive pharmacological activity; its extract gastrodin (GAS) has been used clinically to treat cardiovascular diseases. In the present study, we examined the effect of GAS in a mice model of pathological cardiac hypertrophy, which was induced using transverse aortic constriction (TAC). Male C57BL/6 J mice underwent either TAC or sham surgery. GAS was administered post-surgically for 6 weeks and significantly improved the deterioration of cardiac contractile function caused by pressure overload, cardiac hypertrophy, and fibrosis in mice. Treatment with GAS for 6 weeks upregulated myosin heavy chain α and down-regulated myosin heavy chain ß and atrial natriuretic peptide, while insulin increased the effects of GAS against cardiac hypertrophy. In vitro studies showed that GAS could also protect phenylephrine-induced cardiomyocyte hypertrophy, and these effects were attenuated by BAY-876, and increased by insulin. Taken together, our results suggest that the anti-hypertrophic effect of gastrodin depends on its entry into cardiomyocytes through GLUT4.

Halogen atoms determine the inhibitory potency of halogenated bisphenol A derivatives on human and rat placental 11ß-hydroxysteroid dehydrogenase 2.

Some halogenated bisphenol A (BPA) derivatives (tetrabromobisphenol A, TBBPA, and tetrachlorobisphenol A, TCBPA) are produced in a high volume and exist in PM2.5 after waste burning. 11ß-Hydroxysteroid dehydrogenase 2 (11ß-HSD2) is a critical enzyme for placental function. However, whether halogenated bisphenols inhibit 11ß-HSD2 and the mode of action remains unclear. The objective of this study was to investigate BPA derivatives on human and rat placental 11ß-HSD2. The inhibitory strength on human 11ß-HSD2 was TBBPA (IC50, 0.665 µM)>TCBPA (2.22 µM)>trichloro BPA (TrCBPA, 19.87 µM)>tetrabromobisphenol S (TBBPS, 36.76 µM)>monochloro BPA (MCBPA, 104.0 µM)>BPA (144.9 µM)>bisphenol S. All chemicals are mixed and competitive inhibitors. Rat 11ß-HSD2 was less sensitive to BPA derivatives, with TBBPA (IC50, 96.63 µM)>TCBPA (99.69 µM)>TrCBPA (104.1 µM)>BPA (117.1 µM)>others. Docking analysis showed that BPA derivatives bind steroid active sites. Structure-activity relationship revealed that halogen atoms and LogP were inversely correlated with inhibitory strength on human 11ß-HSD2, while LogS and polar desolvation energy were positively correlated with the inhibitory strength. In conclusion, halogenated BPA derivatives are mostly potent inhibitors on human 11ß-HSD2 and there is structure-dependent inhibition.

Highly efficient metal-free borocarbonitride catalysts for electrochemical reduction of N2 to NH3.

The electrocatalytic nitrogen reduction reaction (NRR) for ammonia (NH3) under ambient conditions is emerging as a potentially sustainable alternative to the traditional, energy-intensive Haber-Bosch process for ammonia production. Currently, metal-based electrocatalysts constitute the majority of reported NRR catalysts. However, they often suffer from the shortcomings of competitive reactions of nitrogen adsorption/activation and hydrogen generation. Therefore, there is an urgent need to develop more environmentally friendly, low energy consumption, and non-polluting high-performance metal-free electrocatalysts. In this study, borocarbonitride (BCN) materials derived from boron imidazolate framework (BIF-20) were used to boost efficient electrochemical nitrogen conversion to ammonia under ambient conditions. The BCN catalyst demonstrated excellent performance in 0.1 M KOH, with an ammonia yield of 21.62 µg h-1 mgcat-1 and a Faradaic efficiency of 9.88% at -0.3 V (Reversible Hydrogen Electrode, RHE). This performance is superior to most metal-free catalysts and even some metal catalysts for NRR. The 15N2/14N2 isotope labeling experiments and density functional theory (DFT) calculations showed that N2 can be adsorbed and converted to NH3 on the surface of BCN, and that the energy barrier can be significantly reduced by structural design for BCN. This work highlights the important role played by the presence of Lewis acid-base pairs in metal-free catalysts for enhancing electrochemical NRR performance.

Analytical high-dimensional operators in canonical polyadic finite basis representation (CP-FBR).

In the present work, we introduce a simple means of obtaining an analytical (i.e., grid-free) canonical polyadic (CP) representation of a multidimensional function that is expressed in terms of a set of discrete data. For this, we make use of an initial CP guess, even not fully converged, and a set of auxiliary basis functions [finite basis representation (FBR)]. The resulting CP-FBR expression constitutes the CP counterpart of our previous Tucker sum-of-products-FBR approach. However, as is well-known, CP expressions are much more compact. This has obvious advantages in high-dimensional quantum dynamics. The power of CP-FBR lies in the fact that it requires a grid much coarser than the one needed for the dynamics. In a subsequent step, the basis functions can be interpolated to any desired density of grid points. This is useful, for instance, when different initial conditions (e.g., energy content) of a system are to be considered. We show the application of the method to bound systems of increased dimensionality: H2 (3D), HONO (6D), and CH4 (9D).

Early Triage of Critically Ill Adult Patients With Mushroom Poisoning: Machine Learning Approach.

BACKGROUND: Early triage of patients with mushroom poisoning is essential for administering precise treatment and reducing mortality. To our knowledge, there has been no established method to triage patients with mushroom poisoning based on clinical data. OBJECTIVE: The purpose of this work was to construct a triage system to identify patients with mushroom poisoning based on clinical indicators using several machine learning approaches and to assess the prediction accuracy of these strategies. METHODS: In all, 567 patients were collected from 5 primary care hospitals and facilities in Enshi, Hubei Province, China, and divided into 2 groups; 322 patients from 2 hospitals were used as the training cohort, and 245 patients from 3 hospitals were used as the test cohort. Four machine learning algorithms were used to construct the triage model for patients with mushroom poisoning. Performance was assessed using the area under the receiver operating characteristic curve (AUC), decision curve, sensitivity, specificity, and other representative statistics. Feature contributions were evaluated using Shapley additive explanations. RESULTS: Among several machine learning algorithms, extreme gradient boosting (XGBoost) showed the best discriminative ability in 5-fold cross-validation (AUC=0.83, 95% CI 0.77-0.90) and the test set (AUC=0.90, 95% CI 0.83-0.96). In the test set, the XGBoost model had a sensitivity of 0.93 (95% CI 0.81-0.99) and a specificity of 0.79 (95% CI 0.73-0.85), whereas the physicians' assessment had a sensitivity of 0.86 (95% CI 0.72-0.95) and a specificity of 0.66 (95% CI 0.59-0.73). CONCLUSIONS: The 14-factor XGBoost model for the early triage of mushroom poisoning can rapidly and accurately identify critically ill patients and will possibly serve as an important basis for the selection of treatment options and referral of patients, potentially reducing patient mortality and improving clinical outcomes.

Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway.

Multiple chemotherapies are proposed to cause cell death in part by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs exactly how the resultant ROS function and are sensed is poorly understood. In particular, it's unclear which proteins the ROS modify and their roles in chemotherapy sensitivity/resistance. To answer these questions, we examined 11 chemotherapies with an integrated proteogenomic approach identifying many unique targets for these drugs but also shared ones including ribosomal components, suggesting one mechanism by which chemotherapies regulate translation. We focus on CHK1 which we find is a nuclear H 2 O 2 sensor that promotes an anti-ROS cellular program. CHK1 acts by phosphorylating the mitochondrial-DNA binding protein SSBP1, preventing its mitochondrial localization, which in turn decreases nuclear H 2 O 2 . Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway required to resolve nuclear H 2 O 2 accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.

G2GT: Retrosynthesis Prediction with Graph-to-Graph Attention Neural Network and Self-Training.

Retrosynthesis prediction, the task of identifying reactant molecules that can be used to synthesize product molecules, is a fundamental challenge in organic chemistry and related fields. To address this challenge, we propose a novel graph-to-graph transformation model, G2GT. The model is built on the standard transformer structure and utilizes graph encoders and decoders. Additionally, we demonstrate the effectiveness of self-training, a data augmentation technique that utilizes unlabeled molecular data, in improving the performance of the model. To further enhance diversity, we propose a weak ensemble method, inspired by reaction-type labels and ensemble learning. This method incorporates beam search, nucleus sampling, and top-k sampling to improve inference diversity. A simple ranking algorithm is employed to retrieve the final top-10 results. We achieved new state-of-the-art results on both the USPTO-50K data set, with a top-1 accuracy of 54%, and the larger more challenging USPTO-Full data set, with a top-1 accuracy of 49.3% and competitive top-10 results. Our model can also be generalized to all other graph-to-graph transformation tasks. Data and code are available at https://github.com/Anonnoname/G2GT_2.

Direct inhibition of bisphenols on human and rat 11ß-hydroxysteroid dehydrogenase 2: Structure-activity relationship and docking analysis.

Bisphenols (BPs) as endocrine-disrupting compounds have drawn attention to their health hazards. Whether a BP interferes with glucocorticoid metabolism remains unclear. 11ß-Hydroxysteroid dehydrogenase 2 (11ß-HSD2) is a key glucocorticoid-metabolizing enzyme that controls fetal glucocorticoid levels across the placental barrier and mineralocorticoid receptor specificity in the kidney. In this study, 11 BPs were tested to inhibit human placental and rat renal 11ß-HSD2 and were analyzed for inhibitory potency, mode action, and docking parameters. BPs had inhibitory potency against human 11ß-HSD2: BPFL>BPAP>BPZ>BPB>BPC>BPAF>BPA>TDP and the IC10 values were 0.21, 0.55, 1.04, 2.04, 2.43, 2.57, 14.43, and 22.18 µM, respectively. All BPs are mixed inhibitors except BPAP, which is a competitive inhibitor for human 11ß-HSD2. Some BPs also inhibited rat renal 11ß-HSD2, with BPB (IC50, 27.74 ± 0.95) > BPZ (42.14 ± 0.59) > BPAF (54.87 ± 1.73) > BPA (77.32 ± 1.20) > other BPs (about 100 µM). Docking analysis showed that all BPs bound to the steroid-binding site, interacting with the catalytic residue Tyr232 of both enzymes and the most potent human 11ß-HSD2 inhibitor BPFL acts possibly due to its large fluorene ring that has hydrophobic interaction with residues Glu172 and Val270 and π-stacking interaction with catalytic residue Tyr232. The increase in the size of substituted alkanes and halogenated groups in the methane moiety of the bridge of BPs increases its inhibitory potency. Regressions of the lowest binding energy with inhibition constant indicated that there was an inverse regression. These results indicated that BPs significantly inhibited human and rat 11ß-HSD2 activity and that there were species-dependent differences.

[Sequencing Analysis of miRNAs in Brain-Derived Exosomes of Adolescent Mice With Depression-Like Behaviors].

Objective: To explore the differential expression of microRNAs (miRNAs) in brain-derived exosomes (BDEs) of adolescent mice with depression-like behavior. Methods: The experimental group consisted of susceptible adolescent mice exposed to chronic social defeat stress (CSDS), and sucrose preference test (SPT) and open field test (OFT) were performed to evaluate their depression-like behaviors. BDEs were extracted by ultracentrifugation (UC). The morphology, particle size, and surface marker proteins of BDEs were examined by transmission electron microscopy, nano-flow cytometry and Western blot. The expression of miRNA in BDEs was evaluated by high-throughput RNA sequencing. GO enrichment analysis and KEGG pathway enrichment analysis were carried out based on bioinformatics. Results: The particle size of BDEs ranged between 50 to 100 nm and they displayed a typical disc-shaped vesicle structure. TSG101 and syntenin, the exosome-positive proteins, were detected. In the BDEs of mice with depression-like behaviors induced by CSDS, 13 miRNAs were significantly upregulated and 4 miRNAs were significantly downregulated. Go and KEGG analysis showed that differentially expressed miRNAs were significantly enriched in PI3K-Akt signaling pathway, axonal guidance, and hypoxic response. Conclusion: It was found in this study that exosomal miRNAs in brain tissue might be involved in such biological processes as insulin resistance, neuroplasticity, and hypoxic response, thereby regulating brain functions and causing depression-like behaviors.

Pretherapy investigations using highly robust visualized biomarkers from CT imaging by multiple machine-learning techniques toward its prognosis prediction for ALK-inhibitor therapy in NSCLC: a feasibility study.

PURPOSE: Molecularly targeted therapy has revolutionized the therapeutic landscape and is emerging as the first-line treatment option for ALK-rearranged non-small-cell lung cancer (NSCLC). In this study, the highly informative and robust biomarkers based on pre-treatment CT images and clinicopathologic features will be developed and validated to predict the prognosis for ALK-inhibitor therapy in NSCLC patients. METHODS: A total of 161 ALK-positive NSCLC patients treated with ALK inhibitors were retrospectively collected as training, validation and test sets from multi-center institutions. Cox proportional hazard regression (CPH) penalized by LASSO and random survival forest (RSF) coupled with recursive feature elimination (RFE) were used for radiomics and clinical features identification and model construction. An overlapping post-processing method was extra added to training process to investigate the stronger biomarker on the whole set. RESULTS: 123 of the collected cases progressed after a median follow-up of 15.5 months (IQR, 8.3-25.3). The T and M staging, pericardial effusion, age and ALK inhibitor-alectinib were determined as significant predictors in the survival analysis. Furthermore, we visualized the finally retained 4 radiomics feature. The RSF models built from overlapping-processed clinical and radiomics features respectively reached the maximum C-index of 0.68 and 0.75,but the combination of them,radioclinical signature, improved the score to 0.78. The model on the validation and external test datasets yielded the C-index of 0.73 and 0.79, with the iAUC of 0.76 and 0.83, the IBS of 0.119 and 0.112. CONCLUSION: With respect to a simple selection strategy of overlapping optimal radiomics and clinical features from different survival models may promote better progression-free survival(PFS) prediction than conventional survival analysis, which provides a potential method for guiding personalized pre-treatment options of NSCLC.

Clinical and genomic characterization of Chinese patients with functional high-risk multiple myeloma: A real-world validation study.

Objective: Precise risk stratification is increasingly essential in the management of multiple myeloma (MM) as some standard-risk (SR) patients still exhibit similar poor outcomes as genetically high-risk (GHR) patients in the era of novel agents. It has recently been demonstrated that functional high-risk (FHR) patients, those with suboptimal response to first-line induction therapy or early relapse within 12 months, have identifiable molecular characteristics from the SR group in the CoMMpass dataset. However, these findings lack practical validation in the real world. Methods: MM cells purified by CD138 microbeads from newly diagnosed MM (NDMM) patients received fluorescence in situ hybridization and sequencing with a 92-gene Panel. Cytogenetic abnormalities defined GHR patients with t(4;14) or t(14;16) or complete loss of functional P53 or 1q21 gain and International Staging System (ISS) stage 3. SR group was patients who did not fulfill any criteria for GHR or FHR. Results: There were 145 patients with NDMM, 78 in the SR group, 56 in the GHR group, and 11 in the FHR group. In the FHR group, eight patients were suboptimal responses to induction therapy, and three relapsed within 12 months. We found that male patients, patients with extra-medullary plasmacytoma (EMD), circulating clonal plasma cells (CPC) ≥0.05%, and P53 mono-allelic inactivation were significantly higher in the FHR group compared to the SR group. After a median follow-up of 21.0 months, the median progression-free survival (PFS) and overall survival (OS) were 5.0 months, 19.1 months and 36.6 months in the FHR, GHR, and SR groups, respectively. Compared to the SR group, FHR patients had a higher frequency of mutations in MKI67, ERN1, and EML4. GO analysis showed that mutations in FHR were enriched for oxidative stress, chromosomal segregation, and hypoxia tolerance. Conclusion: The FHR found in the SR NDMM patient group has unique clinical features, including being male, with EMD and CPC, and genetic characteristics of mutations affecting oxidative stress, chromosome segregation, and hypoxia tolerance. In contrast to previous reports, our data suggested that patients with P53 mono-allelic inactivation should be classified in the GHR group rather than the FHR group.

HOTAIR knockdown impairs metastasis of cervical cancer cells by down-regulating metastasis-related genes.

This study investigated the role of LncRNA HOTAIR knockdown in the biological impacts on cervical cancer cells. The HOTAIR gene in two human cervical cancer cell lines was silenced with small interfering (si) RNA siHOTAIR. Proliferation, apoptosis, migration and invasion of cells were assessed following the knockdown. The expressions of Notch1, EpCAM, E-cadherin, vimentin and STAT3 were assessed using qRT-PCR and Western blotting analysis. Compared with controls, HOTAIR levels were reduced significantly, the OD values of cells were significantly decreased in proliferation assays, cell apoptosis was significantly increased, cell migration and invasion were significantly reduced after HOTAIR knockdown. Molecular analysis showed that Notch1, EpCAM, vimentin and STAT3 expressions were decreased significantly, while the expression of E-cadherin was significantly increased after HOTAIR knockdown. Rescue experiments further confirmed that Notch1 and STAT3 were involved in siHOTAIR-mediated reduction of migration and invasion of cervical cancer cells.IMPACT STATEMENTWhat is already known on this subject? Long non-coding RNAs including HOTAIR, is implicated in occurrence and development of cancer and have been explored to develop new therapeutic options for cancer.What do the results of this study add? HOTAIR silencing significantly reduces the viability and migration ability of cells and induces cell apoptosis, adding experimental data supporting the potential use of HOTAIR specific-siRNA as a therapeutic avenue for the cancer.What are the implications of these findings for clinical practice and/or further research? The finding from this study would help develop clinically applicable therapeutic avenues for the cancer and identify new treatment targets in the relevant pathways leading to new drugs or treatments.

Effects of non-fasting molting on performance, oxidative stress, intestinal morphology, and liver health of laying hens.

Animal welfare concerns in laying-hen production facilities have necessitated research on alternative strategies for improving egg production and hen health. At present, most laying-hen facilities in China use the fasting method, but with international emphasis on animal welfare, scholars have begun to find ways to improve production efficiency while ensuring animal welfare standards are adhered to. Therefore, this study investigated the effects of non-fasting molting on production performance, oxidative stress, intestinal morphology, and liver health of laying hens. A total of 180 healthy 90-week-old Dawu Jinfeng laying hens with similar body weights and laying rates (76 ± 2%) were randomly divided into three groups, with five replicates per group and 12 hens per replicate. The hens in the experimental group (NF) were molted using the non-fasting method, the negative control group (C) was not treated with centralized molting, and the positive control group (F) was molted using the fasting method. The results showed that: (1) During the molting period, the laying rate in the NF group (10.58%) decreased and was significantly lower than that in the other two groups (P < 0.05). During the secondary laying peak period, the laying rate in the NF group was highest (89.71%); significantly higher than that in the C group (P < 0.05). (2) During the molting period, compared to the C group, the NF group showed a significant decrease and increase in the total antioxidant capacity (T-AOC) and superoxide dismutase (T-SOD) activity, respectively (P < 0.05). During the secondary laying peak period, the T-SOD activity of the NF group was significantly lower than that of the C group (P < 0.05). (3) During the molting period, the villus height (VH) and the ratios of VH to crypt depth (V/C) of the duodenum, jejunum, and ileum in the NF group were significantly lower than those in the C group (P < 0.05). At the secondary laying peak period, the jejunum V/C was significantly higher than that in the C group (P < 0.05), whereas in the duodenum and ileum it increased but not significantly (P > 0.05). (4) During the molting period, serum glutathione transaminase (AST) and glutathione alanine transaminase (ALT) activities were significantly higher (P < 0.05), and very low-density lipoprotein (VLDL) content and liver weight were significantly lower (P < 0.05) in the non-fasted and fasted groups. However, there was a low degree of liver injury (cell boundary still visible) in the NF group. At the secondary laying peak period, there was no significant difference (P > 0.05) in the indices among the three groups and the liver returned to normal. In summary, non-fasting molting can improve the production performance of laying hens in the later stages, ensure the welfare and health of animals, and provide a theoretical basis for the efficient production of laying hens.

Comparative Bioequivalence of Tablet and Capsule Formulations of Ulotaront and the Effect of Food on the Pharmacokinetics of the Tablet Form in Humans.

INTRODUCTION: Ulotaront (SEP-363856), a dual trace animeassociated receptor 1 (TAAR1) and 5-HT1A receptor agonist, is in phase 3 clinical development for the treatment of schizophrenia. This study evaluated the comparative bioequivalence (BE) between tablet and capsule formulations of ulotaront and the food effect (FE) on pharmacokinetics (PK) of tablet form in healthy adult human subjects. METHODS: The BE study applied an open-label two-period crossover design in 24 healthy volunteers. Subjects were randomly assigned (1:1) to dosing sequence AB or BA (A, 25 mg ulotaront tablet; B, 25 mg ulotaront capsule). The FE study also used an open-label randomized two-period crossover design in 20 healthy volunteers. Subjects were fasted overnight then randomly assigned (1:1) to dosing sequence AB or BA (A, fasted condition; B, fed condition). Dosing periods were separated by 1 week for both studies. Serial plasma samples from each period were collected and analyzed by LC-MS/MS. PK parameters were calculated using Phoenix WinNonlin® software. RESULTS: For the BE study, geometric mean ulotaront Cmax values were 93.28 and 86.98 ng/mL for tablet and capsule, respectively. Cmax ratio was 107.25% (90% CI 101.84-112.94%). Geometric mean ulotaront area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) values were 868.8 and 829.3 ng·h/mL for tablet and capsule, respectively. AUC0-∞ ratio was 104.76% (90% CI 100.68109.01%). For the FE study, geometric mean ulotaront Cmax was 157.89 and 157.95 ng/mL under fed and fasted conditions, respectively. Geometric mean ratio of Cmax was 99.96% (90% CI 94.48-105.77%). Geometric mean ulotaront AUC0-∞ was 1584.2 ng·h/mL fed and 1589.2 ng·h/mL fasted. Geometric mean ratio for AUC0-∞ was 99.69% (90% CI 95.02-104.58%). There was a delay in tmax (median difference 1.47 h) in the fed condition. CONCLUSIONS: The results showed geometric mean ratios and 90% CIs for both Cmax and AUC0-∞ for ulotaront were well within typical bioequivalence criteria of 80-125% for both the BE and FE studies, thereby confirming the bioequivalence of the two dosage forms and no significant food effect.

Activation of α7nAChR by PNU282987 improves cognitive impairment through inhibiting oxidative stress and neuroinflammation in D-galactose induced aging via regulating α7nAChR/Nrf2/HO-1 signaling pathway.

Aging is an important risk factor for neurodegenerative diseases. The activation of α7 nicotinic acetylcholine receptor (α7nAChR) is involved in inflammation and cognition, but the specific role it plays in aging remains unknown. This study aimed to investigate the anti-aging effect of the activation of α7nAChR on aging rats and BV2 cells induced by D-galactose, as well as its potential mechanism. D-galactose induced an increase in the SA-ß-Gal positive cells, expression of p16 and p21 in vivo and in vitro. α7nAChR selective agonist PNU282987 decreased levels of pro-inflammatory factors, MDA, and Aß, enhanced SOD activity and levels of anti-inflammatory factor (IL10) in vivo. PNU282987 enhanced the expression of Arg1, decreased the expression of iNOS, IL1ß and TNFα in vitro. PNU282987 upregulated the levels of α7nAChR, Nrf2 and HO-1 in vivo and in vitro. The results of Morris water maze and novel object recognition tests showed that PNU282987 improved cognitive impairment in aging rats. Furthermore, α7nAChR selective inhibitor methyllycaconitine (MLA) results were opposite with PNU282987. PNU282987 improves cognitive impairment through inhibiting oxidative stress and neuroinflammation in D-galactose induced aging via regulating the α7nAChR/Nrf2/HO-1 signaling pathway. Therefore, targeting the α7nAChR may be a viable therapeutic approach for anti-inflammaging and neurodegenerative diseases.

Disparity in Lung Cancer Screening Among Smokers and Nonsmokers in China: Prospective Cohort Study.

BACKGROUND: Low-dose computed tomography (LDCT) screening is effective in reducing lung cancer mortality in smokers; however, the evidence in nonsmokers is scarce. OBJECTIVE: This study aimed to evaluate the participant rate and effectiveness of one-off LDCT screening for lung cancer among smokers and nonsmokers. METHODS: A population-based prospective cohort study was performed to enroll participants aged between 40 and 74 years from 2013 to 2019 from 4 cities in Zhejiang Province, China. Participants who were evaluated as having a high risk of lung cancer from an established risk score model were recommended to undergo LDCT screening. Follow-up outcomes were retrieved on June 30, 2020. The uptake rate of LDCT screening for evaluated high-risk participants and the detection rate of early-stage lung cancer (stage 0-I) were calculated. The lung cancer incidence, lung cancer mortality, and all-cause mortality were compared between the screened and nonscreened groups. RESULTS: At baseline, 62.56% (18,818/30,079) of smokers and 6% (5483/91,455) of nonsmokers were identified as high risk (P<.001), of whom 41.9% (7885/18,818) and 66.31% (3636/5483) underwent LDCT screening (P<.001), respectively. After a median follow-up of 5.1 years, 1100 lung cancer cases and 456 all-cause death cases (116 lung cancer death cases) were traced. The proportion of early-stage lung cancer among smokers was 60.3% (173/287), which was lower than the proportion of 80.3% (476/593) among nonsmokers (P<.001). Among smokers, a higher proportion was found in the screened group (72/106, 67.9%) than the nonscreened group (56/114, 49.1%; P=.005), whereas no significance was found (42/44, 96% vs 10/12, 83%; P=.20) among nonsmokers. Compared with participants who were not screened, LDCT screening in smokers significantly increased lung cancer incidence (hazard ratio [HR] 1.39, 95% CI 1.09-1.76; P=.007) but reduced lung cancer mortality (HR 0.52, 95% CI 0.28-0.96; P=.04) and all-cause mortality (HR 0.47, 95% CI 0.32-0.69; P<.001). Among nonsmokers, no significant results were found for lung cancer incidence (P=.06), all-cause mortality (P=.89), and lung cancer mortality (P=.17). CONCLUSIONS: LDCT screening effectively reduces lung cancer and all-cause mortality among high-risk smokers. Further efforts to define high-risk populations and explore adequate lung cancer screening modalities for nonsmokers are needed.

An epidemiological study on skin tumors of the elderly in a community in Shanghai, China.

The morbidity of skin tumors (ST) in China is a great concern as the population ages. No epidemiological survey on ST in elderly communities in China has been reported. A questionnaire survey was conducted among the residents over 60 years old in a community in Shanghai, China from May 1, 2011 to November 30, 2011. The prevalence of cutaneous tumors and associated factors were analyzed. Among 2038 valid cases, a total of 78 (3.8%, 95% CI 3.0-4.7) skin cancers (SC) were confirmed. According to the final multivariate regression analysis, age, gender and previous occupation were the significantly influential factors for SC. Actinic keratosis (AK) accounted for the largest proportion (63, 3.1%) in SC. The head and neck was the physiological site with the highest incidence of SC (64, 82.1%), and AK was the most common (55, 87.3%) in head and neck SC. The common concomitant diseases of SC were hypertension (26, 33.3%) and diabetes mellitus (9, 11.5%). Seborrheic keratosis (SK) was the most common benign skin tumor with a prevalence of 100%. Men and women developed SK in significantly different parts of the body (P < 0.0001). The incidence of ST in the elderly population in Shanghai community increased with age. ST preferred to occur in the head and neck, which might be attributed to excessive ultraviolet (UV) exposure in these areas. Therefore, early diagnosis and sun-protection education are essential interventions for ST in the elderly.

Sediment-water distribution and potential sources of polyhalogenated carbazoles in a coastal river locating at a north metropolis, China.

The fate and transformation of PHCZs in the coastal river environment are not yet comprehensively understood. Paired river water and surface sediment were collected, and 12 PHCZs were analyzed to find out their potential sources and investigate the distribution of PHCZs between river water and sediment. The concentration of ∑PHCZs varied from 8.66 to 42.97 ng/g (mean 22.46 ng/g) in sediment and 17.91 to 81.82 ng/L (mean 39.07 ng/L) in river water. 18-B-36-CCZ was the dominant PHCZ congener in sediment, while 36-CCZ was in water. Meanwhile, the logKoc values for CZ and PHCZs were among the first calculated in the estuary and the mean logKoc varied from 4.12 for 1-B-36-CCZ to 5.63 for 3-CCZ. The logKoc values of CCZs were higher than those of BCZs, this may suggest that sediments have a higher capacity for accumulation and storage of CCZs than highly mobile environmental media.

SULT1A1-dependent sulfonation of alkylators is a lineage-dependent vulnerability of liver cancers.

Adult liver malignancies, including intrahepatic cholangiocarcinoma and hepatocellular carcinoma, are the second leading cause of cancer-related deaths worldwide. Most individuals are treated with either combination chemotherapy or immunotherapy, respectively, without specific biomarkers for selection. Here using high-throughput screens, proteomics and in vitro resistance models, we identify the small molecule YC-1 as selectively active against a defined subset of cell lines derived from both liver cancer types. We demonstrate that selectivity is determined by expression of the liver-resident cytosolic sulfotransferase enzyme SULT1A1, which sulfonates YC-1. Sulfonation stimulates covalent binding of YC-1 to lysine residues in protein targets, enriching for RNA-binding factors. Computational analysis defined a wider group of structurally related SULT1A1-activated small molecules with distinct target profiles, which together constitute an untapped small-molecule class. These studies provide a foundation for preclinical development of these agents and point to the broader potential of exploiting SULT1A1 activity for selective targeting strategies.