Immunotherapy and the ovarian cancer microenvironment: Exploring potential strategies for enhanced treatment efficacy.

Despite progress in cancer immunotherapy, ovarian cancer (OC) prognosis continues to be disappointing. Recent studies have shed light on how not just tumour cells, but also the complex tumour microenvironment, contribute to this unfavourable outcome of OC immunotherapy. The complexities of the immune microenvironment categorize OC as a 'cold tumour'. Nonetheless, understanding the precise mechanisms through which the microenvironment influences the effectiveness of OC immunotherapy remains an ongoing scientific endeavour. This review primarily aims to dissect the inherent characteristics and behaviours of diverse cells within the immune microenvironment, along with an exploration into its reprogramming and metabolic changes. It is expected that these insights will elucidate the operational dynamics of the immune microenvironment in OC and lay a theoretical groundwork for improving the efficacy of immunotherapy in OC management.

Targeting EFHD2 inhibits interferon-γ signaling and ameliorates non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The precise pathomechanisms underlying the development of non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. In this study, we investigated the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in the pathogenesis of NASH. METHODS: Hepatic EFHD2 expression was characterized in patients with NASH and two diet-induced NASH mouse models. Single-cell RNA sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma were assessed. Molecular mechanisms underlying EFHD2 function were investigated, while chemical and genetic investigations were performed to assess its potential as a therapeutic target. RESULTS: EFHD2 expression was significantly elevated in hepatic macrophages/monocytes in both patients with NASH and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related hepatocellular carcinoma. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane. This interaction mediates interferon-γ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a novel stapled α-helical peptide targeting EFHD2 was shown to be effective in protecting against NASH pathology in mice. CONCLUSION: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all patients with NAFLD progress to NASH. A key challenge is identifying the factors that trigger inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of interferon-γ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings support the potential of EFHD2 as a therapeutic target in NASH.

Synergistic Integration of Anammox and Endogenous Denitrification Processes for the Simultaneous Carbon, Nitrogen, and Phosphorus Removal.

The feasibility of a synergistic endogenous partial denitrification-phosphorus removal coupled anammox (SEPD-PR/A) system was investigated in a modified anaerobic baffled reactor (mABR) for synchronous carbon, nitrogen, and phosphorus removal. The mABR comprising four identical compartments (i.e., C1-C4) was inoculated with precultured denitrifying glycogen-accumulating organisms (DGAOs), denitrifying polyphosphate-accumulating organisms, and anammox bacteria. After 136 days of operation, the chemical oxygen demand (COD), total nitrogen, and phosphorus removal efficiencies reached 88.6 ± 1.0, 97.2 ± 1.5, and 89.1 ± 4.2%, respectively. Network-based analysis revealed that the biofilmed community demonstrated stable nutrient removal performance under oligotrophic conditions in C4. The metagenome-assembled genomes (MAGs) such as MAG106, MAG127, MAG52, and MAG37 annotated as denitrifying phosphorus-accumulating organisms (DPAOs) and MAG146 as a DGAO were dominated in C1 and C2 and contributed to 89.2% of COD consumption. MAG54 and MAG16 annotated as Candidatus_Brocadia (total relative abundance of 16.5% in C3 and 4.3% in C4) were responsible for 74.4% of the total nitrogen removal through the anammox-mediated pathway. Functional gene analysis based on metagenomic sequencing confirmed that different compartments of the mABR were capable of performing distinct functions with specific advantageous microbial groups, facilitating targeted nutrient removal. Additionally, under oligotrophic conditions, the activity of the anammox bacteria-related genes of hzs was higher compared to that of hdh. Thus, an innovative method for the treatment of low-strength municipal and nitrate-containing wastewaters without aeration was presented, mediated by an anammox process with less land area and excellent quality effluent.

Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes.

Histone acetyltransferases (HATs) and deacetylases (HDACs) function antagonistically to control histone acetylation. As acetylation is a histone mark for active transcription, HATs have been associated with active and HDACs with inactive genes. We describe here genome-wide mapping of HATs and HDACs binding on chromatin and find that both are found at active genes with acetylated histones. Our data provide evidence that HATs and HDACs are both targeted to transcribed regions of active genes by phosphorylated RNA Pol II. Furthermore, the majority of HDACs in the human genome function to reset chromatin by removing acetylation at active genes. Inactive genes that are primed by MLL-mediated histone H3K4 methylation are subject to a dynamic cycle of acetylation and deacetylation by transient HAT/HDAC binding, preventing Pol II from binding to these genes but poising them for future activation. Silent genes without any H3K4 methylation signal show no evidence of being bound by HDACs.

ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes.

Histone acetylation, including acetylated H3K14 (H3K14ac), is generally linked to gene activation. Monomethylated histone H3 lysine 4 (H3K4me1), together with other gene-activating marks, denotes active genes. In contrast to usual gene-activating functions of H3K14ac and H3K4me1, we here show that the dual histone modification mark H3K4me1-H3K14ac is recognized by ZMYND8 (also called RACK7) and can function to counteract gene expression. We identified ZMYND8 as a transcriptional corepressor of the H3K4 demethylase JARID1D. ZMYND8 antagonized the expression of metastasis-linked genes, and its knockdown increased the cellular invasiveness in vitro and in vivo. The plant homeodomain (PHD) and Bromodomain cassette in ZMYND8 mediated the combinatorial recognition of H3K4me1-H3K14ac and H3K4me0-H3K14ac by ZMYND8. These findings uncover an unexpected role for the signature H3K4me1-H3K14ac in attenuating gene expression and reveal a metastasis-suppressive epigenetic mechanism in which ZMYND8's PHD-Bromo cassette couples H3K4me1-H3K14ac with downregulation of metastasis-linked genes.

Pharmacokinetics of four tannin compounds from Sanguisorba officinalis L. before and after processing by ultra-high-performance liquid chromatography-tandem mass spectrometry.

Sanguisorba officinalis L. possesses detoxifying, analgesic, and hemostatic properties. After charred processing, S. officinalis exhibits significantly enhanced medicinal effects. Currently, most pharmacokinetic studies focus on the chemical constituents of unprocessed S. officinalis. There is limited research on the comparison of chemical constituents before and after processing. This study established a pharmacokinetic method using ultra-high-performance liquid chromatography-tandem mass spectroscopy (UHPLC-MS/MS) to simultaneously determine the levels of four tannin compounds in rat plasma. In negative ion mode, MS/MS detection was performed using an electrospray ionization source. Chromatographic separation was performed using WATERS ACQUITY HSS T3 column (2.1 × 100 mm, 1.8 µm) with a gradient elution of water and acetonitrile as the mobile phase. The pharmacokinetic results indicate that all four compounds reached peak concentrations within 2 h, demonstrating rapid absorption into the bloodstream within the gastrointestinal tract. Notably, the absorption was generally faster in the charred compound of S. officinalis after processing. These four compounds exhibited slower elimination in rat plasma, while in S. officinalis charcoal, the compounds were eliminated more rapidly. The pharmacokinetic results have revealed the pharmacokinetic characteristics of the four analytes in rat plasma which provides valuable reference information for further investigating the in vivo absorption process of S. officinalis after processing.

Circulating Concentrations of advanced Glycation end Products, Carboxymethyl Lysine and Methylglyoxal are Associated With Renal Function in Individuals With Diabetes.

OBJECTIVE: Diabetic kidney disease (DKD) is one of the most severe chronic complications of diabetes and is associated with higher level of advanced glycation end products (AGEs). The aim of this study was to investigate the diagnostic potential of combined detection of multiple serum AGEs in diagnosing DKD. METHODS: Serum AGEs, Nε-(carboxymethyl) lysine (CML), Nε-(carboxyethyl) lysine, and methylglyoxal (MGO) levels were measured by enzyme-linked immunosorbent assay in 176 individuals with type 2 diabetes. Participants were classified into normoalbuminuria, microalbuminuria, and macroalbuminuria group according to their urinary albumin to creatinine ratio (UACR). RESULTS: Higher serum AGEs levels were found to be positively correlated with U-Alb, UACR, and blood urea nitrogen in the study of 176 individuals with type 2 diabetes. CML and MGO levels were positively correlated with U-Alb, UACR, blood urea nitrogen, Scr, and uric acid, and negatively correlated with estimated glomerular filtration rate (P < .05). Multivariate logistic regression analysis showed that elevated levels of AGEs, CML, and MGO were independent risk factors for the progression of DKD (odds ratio = 1.861, 1.016, 7.607, P < .01). The sensitivity, specificity, and area under receiver operating characteristic curve of combined detection of AGEs, MGO, and CML were higher than those of three individual detections (area under the curve = 0.952, 0.772, 0.868, 0905, respectively, P < .05). CONCLUSION: The combined detection of AGEs, CML, and MGO may improve the reliability of early diagnosis of DKD.

Phytochemistry of Genus Buxus and Pharmacology of Cyclovirobuxine D.

BACKGROUND: Genus Buxus plants, commonly known as "boxwood", are widely distributed in China. The stems, branches, and leaves of the plant are traditionally used for rheumatism, toothache, chest pain, abdominal gas, and other diseases. However, an overview of the genus Buxus remains to be provided. PURPOSE: To provide a scientific basis for the appropriate use and further research the recent advancements in the traditional usage, phytochemistry, and, pharmacology of Buxus. STUDY DESIGN: Chemical composition and pharmacological correlation studies through a literature review. METHODS: Between 1970 and 2023, the available data concerning Buxus was compiled from online scientific sources, such as Sci-Finder, PubMed, CNKI, Google Scholar, and the Chinese Pharmacopoeia. Plant names were verified from "The Plant List" (http://www.theplantlist.org/). RESULTS: To date, 266 structurally diverse chemicals have been extracted and identified from the genus Buxus. Alkaloids constitute one of its primary bioactive phytochemicals. A summary of the channels of action of Cyclovirobuxine D on the cytotoxicity of a variety of cancers has been provided. CONCLUSION: Numerous findings from contemporary phytochemical and pharmacological studies support the traditional use, facilitating its application. Further research is necessary to address various shortcomings, including the identification of the active ingredients and quality control of the genus Buxus.

A breakthrough in phytochemical profiling: ultra-sensitive surface-enhanced Raman spectroscopy platform for detecting bioactive components in medicinal and edible plants.

A perennial challenge in harnessing the rich biological activity of medicinal and edible plants is the accurate identification and sensitive detection of their active compounds. In this study, an innovative, ultra-sensitive detection platform for plant chemical profiling is created using surface-enhanced Raman spectroscopy (SERS) technology. The platform uses silver nanoparticles as the enhancing substrate, excess sodium borohydride prevents substrate oxidation, and methanol enables the tested molecules to be better adsorbed onto the silver nanoparticles. Subsequently, nanoparticle aggregation to form stable "hot spots" is induced by Ca2+, and the Raman signal of the target molecule is strongly enhanced. At the same time, deuterated methanol was used as the internal standard for quantitative determination. The method has excellent reproducibility, RSD ≤ 1.79%, and the enhancement factor of this method for the detection of active ingredients in the medicinal plant Coptis chinensis was 1.24 × 109, with detection limits as low as 3 fM. The platform successfully compared the alkaloid distribution in different parts of Coptis chinensis: root > leaf > stem, and the difference in content between different batches of Coptis chinensis decoction was successfully evaluated. The analytical technology adopted by the platform can speed up the determination of Coptis chinensis and reduce the cost of analysis, not only making better use of these valuable resources but also promoting development and innovation in the food and pharmaceutical industries. This study provides a new method for the development, evaluation, and comprehensive utilization of both medicinal and edible plants. It is expected that this method will be extended to the modern rapid detection of other medicinal and edible plants and will provide technical support for the vigorous development of the medicinal and edible plants industry.

Clinical characterization of EFHD2 (swiprosin-1) in Glioma-associated macrophages and its role in regulation of immunosuppression.

Glioblastoma has been extensively studied due to its high mortality and short survival. The evolution mechanism of tumor-associated macrophages (TAMs) to Glioma-associated microglia and macrophages (GAMs) in the tumor microenvironment (TME) remains to be elucidated. The tumor cell-to-cell interaction patterns have not been well defined yet. The EF-Hand Domain Family Member D2 (EFHD2) has been reported to be differentially expressed as an immunomodulatory molecule in a variety of cancers. But large-scale clinical data from multiple ethnic communities have not been used to investigate the role of EFHD2 in glioma. RNA-seq data from 313 or 657 glioma patients from the Chinese Glioma Genome Atlas (CGGA) database and 603 glioma patients from the Cancer Genome Atlas (TCGA) database were analyzed retrospectively. Cell localization was performed using single-cell sequencing data from the CGGA database and the GSE131928 dataset. Mouse glioma cell lines and primary macrophages isolated from Efhd2 knockout mice were co-cultured to validate the immunomodulatory effects of EFHD2 on macrophages and the remodeling of TME of glioblastoma. EFHD2 is enriched in high-grade gliomas, isocitrate dehydrogenase wild-type, and 1p/19q non-co-deficient gliomas. It is a potential biomarker of glioma-proneuronal subtypes and an independent prognostic factor for overall survival in patients with malignant glioblastoma. EFHD2 regulates the monocyte-macrophage system function and positively correlates with immunosuppressive checkpoints. Further experimental data demonstrates that Efhd2 influences the polarization state of GAMs and inhibits the secretion of TGF-ß1. In vitro experiments have revealed that macrophages lacking Efhd2 suppress the vitality of two glioma cell lines and decelerate the growth of glioma xenografts. In conclusion, EFHD2 promises to be a key target for TME-related immunotherapy.

Recent Advances in Polysaccharides from Chaenomeles speciosa (Sweet) Nakai.: Extraction, Purification, Structural Characteristics, Health Benefits, and Applications.

This article systematically reviews the extraction and purification methods, structural characteristics, structure-activity relationship, and health benefits of C. speciosa polysaccharides, and their potential application in food, medicine, functional products, and feed, in order to provide a useful reference for future research. Chaenomeles speciosa (Sweet) Nakai. has attracted the attention of health consumers and medical researchers as a traditional Chinese medicine with edible, medicinal, and nutritional benefits. According to this study, C. speciosa polysaccharides have significant health benefits, such as anti-diaetic, anti-inflammatory and analgesic, anti-tumor, and immunomodulatory effects. Researchers determined the molecular weight, structural characteristics, and monosaccharide composition and ratio of C. speciosa polysaccharides by water extraction and alcohol precipitation. This study will lay a solid foundation for further optimization of the extraction process of C. speciosa polysaccharides and the development of their products. As an active ingredient with high value, C. speciosa polysaccharides are worthy of further study and full development. C. speciosa polysaccharides should be further explored in the future, to innovate their extraction methods, enrich their types and biological activities, and lay a solid foundation for further research and development of products containing polysaccharides that are beneficial to the human body.

Moslae Herba: Botany, Traditional Uses, Phytochemistry, and Pharmacology.

Moslae Herba (MH) can be used for both medicine and food and has a long history of medicine. MH has the effects of sweating and relieving the exterior, removing dampness and harmonizing, and is mainly used for colds caused by damp heat in summer. It is called "Xiayue Zhi Mahuang" in China. So far, 123 chemical compounds have been isolated and identified from MH, including flavonoids, terpenoids, phenolic acids, phenylpropanoids, and other chemical compounds. Its chemical components have a wide range of pharmacological activities, including antibacterial, antiviral, anti-inflammatory, antioxidant, analgesic sedation, antipyretic, immune regulation, insecticidal, and other effects. In addition, because of its aromatic odor and health care function, MH also has development and utilization value in food, chemical, and other fields. This paper reviewed the research progress of MH in botany, traditional uses, phytochemistry, and pharmacology and provided a possible direction for further research.

Isovaleryl Sucrose Esters from Atractylodes japonica and Their Cytotoxic Activity.

Cancer represents one of the most significant health challenges currently facing humanity, and plant-derived antitumour drugs represent a prominent class of anticancer medications in clinical practice. Isovaleryl sucrose esters, which are natural constituents, have been identified as having potential antitumour effects. However, the mechanism of action remains unclear. In this study, 12 isovaleryl sucrose ester components, including five new (1-5) and seven known compounds (6-12), were isolated from the roots of Atractylodes japonica. The structures of the compounds were elucidated using 1D and 2D-NMR spectroscopy, complemented by HR-ESI-MS mass spectrometry. The cytotoxic activities of all the compounds against human colon cancer cells (HCT-116) and human lung adenocarcinoma cells (A549) were also evaluated using the CCK8 assay. The results demonstrated that compounds 2, 4, and 6 were moderately inhibitory to HCT-116 cells, with IC50 values of 7.49 ± 0.48, 9.03 ± 0.21, and 13.49 ± 1.45 µM, respectively. Compounds 1 and 6 were moderately inhibitory to A549, with IC50 values of 8.36 ± 0.77 and 7.10 ± 0.52 µM, respectively. Molecular docking revealed that compounds 1-9 exhibited a stronger affinity for FGFR3 and BRAF, with binding energies below -7 kcal/mol. Compound 2 exhibited the lowest binding energy of -10.63 kcal/mol to FGFR3. We screened the compounds with lower binding energies, and the protein-ligand complexes already obtained after molecular docking were subjected to exhaustive molecular dynamics simulation experiments, which simulated the dynamic behaviour of the molecules in close proximity to the actual biological environment, thus providing a deeper understanding of their functions and interaction mechanisms. The present study provides a reference for the development and use of iso-valeryl sucrose esters in the antitumour field.

Aerosol liquid water in PM2.5 and its roles in secondary aerosol formation at a regional site of Yangtze River Delta.

Aerosol liquid water content (ALWC) plays an important role in secondary aerosol formation. In this study, a whole year field campaign was conducted at Shanxi in north Zhejiang Province during 2021. ALWC estimated by ISORROPIA-II was then investigated to explore its characteristics and relationship with secondary aerosols. ALWC exhibited a highest value in spring (66.38 µg/m3), followed by winter (45.08 µg/m3), summer (41.64 µg/m3), and autumn (35.01 µg/m3), respectively. It was supposed that the secondary inorganic aerosols (SIA) were facilitated under higher ALWC conditions (RH > 80%), while the secondary organic species tended to form under lower ALWC levels. Higher RH (> 80%) promoted the NO3- formation via gas-particle partitioning, while SO42- was generated at a relative lower RH (> 50%). The ALWC was more sensitive to NO3- (R = 0.94) than SO42- (R = 0.90). Thus, the self-amplifying processes between the ALWC and SIA enhanced the particle mass growth. The sensitivity of ALWC and OX (NO2 + O3) to secondary organic carbon (SOC) varied in different seasons at Shanxi, more sensitive to aqueous-phase reactions (daytime R = 0.84; nighttime R = 0.54) than photochemical oxidation (daytime R = 0.23; nighttime R = 0.41) in wintertime with a high level of OX (daytime: 130-140 µg/m3; nighttime: 100-140 µg/m3). The self-amplifying process of ALWC and SIA and the aqueous-phase formation of SOC will enhance aerosol formation, contributing to air pollution and reduction of visibility.

[Research on mechanism of hypolipidemic effect of Massa Medicata Fermentata based on metabolomics].

This paper aims to study the therapeutic effect of Massa Medicata Fermentata on hyperlipidemia model rats and investigate its mechanism of hypolipidemic effect with the help of non-targeted metabolomics. The mixed hyperlipidemia model rats were constructed by giving high-fat chow. After successful modeling, the rats were divided into the model group, pravastatin sodium group(4.4 mg·kg~(-1)), lipotropic group(0.1 g·kg~(-1)), high-dose group(2.4 g·kg~(-1)), medium-dose group(1.2 g·kg~(-1)), and low-dose group(0.6 g·kg~(-1)) of Massa Medicata Fermentata, and they were administered for four weeks once daily. An equal volume of ultrapure water was given to the blank group and model group. Serum lipid level and liver hematoxylin-eosin(HE) staining were used as indicators to estimate the intervention effect of Massa Medicata Fermentata on mixed hyperlipidemia, and the changes in metabolites in plasma of mixed hyperlipidemia model rats were analyzed by non-targeted metabolomics. The mechanism of the hypolipidemic effect of Massa Medicata Fermentata was analyzed through metabolite pathway enrichment. The results showed that compared with the model group, the Massa Medicata Fermentata administration group, especially the high-dose group, could significantly reduce the content of total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-c)(P<0.05 or P<0.01), and liver HE staining revealed that the number of adipocytes in the high-dose group was reduced to some extent. The potential biomarkers obtained by non-targeted metabolomics screening included glycerol 3-phosphate, sphingomyelin, sphingosine 1-phosphate, and deoxyuridine, which were mainly involved in the sphingolipid metabolism process, glycerophospholipid metabolism process, glycerol ester metabolism pathway, and pyrimidine metabolism pathway, totaling four possible metabolic pathways related to lipid metabolism. This study provides a reference for an in-depth investigation of the hypolipidemic mechanism of Massa Medicata Fermentata, which is of great significance for further promoting the clinical application of Massa Medicata Fermentata and increasing the indications.

The prognosis of patients with small cell carcinoma of the cervix: a retrospective study of the SEER database and a Chinese multicentre registry.

BACKGROUND: Small cell carcinoma of the cervix is a rare but poor prognosis pathological type of cervical cancer, for which advice in clinical guidelines is unspecific. We therefore aimed to investigate the factors and treatment methods that affect the prognosis of patients with small cell carcinoma of the cervix. METHODS: In this retrospective study, we collected data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries cohort and a Chinese multi-institutional registry. The SEER cohort included females diagnosed with small cell carcinoma of the cervix between Jan 1, 2000, and Dec 31, 2018, whereas the Chinese cohort included women diagnosed between Jun 1, 2006, and April 30, 2022. In both cohorts, eligibility was limited to female patients older than 20 years with a confirmed diagnosis of small cell carcinoma of the cervix. Participants who were lost to follow-up or those for whom small cell carcinoma of the cervix was not the primary malignant tumour were excluded from the multi-institutional registry, and those with an unknown surgery status (in addition to those for whom small cell carcinoma of the cervix was not the primary malignant tumour) were excluded from the SEER data. The primary outcome of this study was overall survival (length of time from the date of first diagnosis until the date of death from any cause, or the last follow-up). Kaplan-Meier analysis, propensity score matching, and Cox-regression analyses were used to assess treatment outcomes and risk factors. FINDINGS: 1288 participants were included in the study; 610 in the SEER cohort and 678 in the Chinese cohort. Both univariable and multivariable Cox regression analysis (SEER hazard ratio [HR] 0·65 [95% CI 0·48-0·88], p=0·0058; China HR 0·53 [0·37-0·76], p=0·0005) showed that surgery was associated with a better prognosis. In subgroup analyses, surgery remained a protective factor for patients with locally advanced disease in both cohorts (SEER HR 0·61 [95% CI 0·39-0·94], p=0·024; China HR 0·59 [0·37-0·95]; p=0·029). Furthermore, the protective effect of surgery was observed among patients with locally advanced disease after propensity score matching in the SEER cohort (HR 0·52 [95% CI 0·32-0·84]; p=0·0077). In the China registry, surgery was associated with better outcomes in patients with stage IB3-IIA2 cancer (HR 0·17 [95% CI 0·05-0·50]; p=0·0015). INTERPRETATION: This study provides evidence that surgery improves outcomes of patients with small cell carcinoma of the cervix. Although guidelines recommend non-surgical methods as first-line treatment, patients with locally advanced disease or stage IB3-IIA2 cancer might benefit from surgery. FUNDING: The National Key R&D Program of China and the National Natural Science Foundation of China.

Causal effects of COVID-19 on structural changes in specific brain regions: a Mendelian randomization study.

BACKGROUND: Previous studies have found a correlation between coronavirus disease 2019 (COVID-19) and changes in brain structure and cognitive function, but it remains unclear whether COVID-19 causes brain structural changes and which specific brain regions are affected. Herein, we conducted a Mendelian randomization (MR) study to investigate this causal relationship and to identify specific brain regions vulnerable to COVID-19. METHODS: Genome-wide association study (GWAS) data for COVID-19 phenotypes (28,900 COVID-19 cases and 3,251,161 controls) were selected as exposures, and GWAS data for brain structural traits (cortical thickness and surface area from 51,665 participants and volume of subcortical structures from 30,717 participants) were selected as outcomes. Inverse-variance weighted method was used as the main estimate method. The weighted median, MR-Egger, MR-PRESSO global test, and Cochran's Q statistic were used to detect heterogeneity and pleiotropy. RESULTS: The genetically predicted COVID-19 infection phenotype was nominally associated with reduced cortical thickness in the caudal middle frontal gyrus (ß = - 0.0044, p = 0.0412). The hospitalized COVID-19 phenotype was nominally associated with reduced cortical thickness in the lateral orbitofrontal gyrus (ß = - 0.0049, p = 0.0328) and rostral middle frontal gyrus (ß = - 0.0022, p = 0.0032) as well as with reduced cortical surface area of the middle temporal gyrus (ß = - 10.8855, p = 0.0266). These causal relationships were also identified in the severe COVID-19 phenotype. Additionally, the severe COVID-19 phenotype was nominally associated with reduced cortical thickness in the cuneus (ß = - 0.0024, p = 0.0168); reduced cortical surface area of the pericalcarine (ß = - 2.6628, p = 0.0492), superior parietal gyrus (ß = - 5.6310, p = 0.0408), and parahippocampal gyrus (ß = - 0.1473, p = 0.0297); and reduced volume in the hippocampus (ß = - 15.9130, p = 0.0024). CONCLUSIONS: Our study indicates a suggestively significant association between genetic predisposition to COVID-19 and atrophy in specific functional regions of the human brain. Patients with COVID-19 and cognitive impairment should be actively managed to alleviate neurocognitive symptoms and minimize long-term effects.

Triglyceride to high-density lipoprotein cholesterol ratio is associated with regression to normoglycemia from prediabetes in adults: a 5-year cohort study in China.

OBJECTIVE: The current body of evidence on the association between the ratio of triglycerides to high-density lipoprotein cholesterol (TG/HDL-c) and the reversal of prediabetes to normoglycemia remains limited. The aim of this study is to investigate the association between TG/HDL-c and the reversion to normoglycemia in patients with prediabetes. METHODS: This retrospective cohort study included 15,107 individuals with prediabetes from 32 Chinese districts and 11 cities who completed health checks from 2010 to 2016. The Cox proportional-hazards regression model examined baseline TG/HDL-c and reversion to normoglycemia from prediabetes. Cox proportional hazards regression with cubic spline functions and smooth curve fitting determined the non-linear connection between TG/HDL-c and reversion to normoglycemia. We also ran sensitivity and subgroup analysis. By characterizing progression to diabetes as a competing risk for the reversal of prediabetes to normoglycemic event, a multivariate Cox proportional hazards regression model with competing risks was created. RESULTS: Upon adjusting for covariates, the findings indicate a negative association between TG/HDL-c and the likelihood of returning to normoglycemia (HR = 0.869, 95%CI:0.842-0.897). Additionally, a non-linear relationship between TG/HDL-c and the probability of reversion to normoglycemia was observed, with an inflection point of 1.675. The HR on the left side of the inflection point was 0.748 (95%CI:0.699, 0.801). The robustness of our results was confirmed through competing risks multivariate Cox's regression and a series of sensitivity analyses. CONCLUSION: The present study reveals a negative and non-linear correlation between TG/HDL-c and the reversion to normoglycemia among Chinese individuals with prediabetes. The findings of this study are anticipated to serve as a valuable resource for clinicians in managing dyslipidemia in prediabetic patients. Interventions aimed at reducing the TG/HDL-c ratio through the reduction of TG or elevation of HDL-c levels may substantially enhance the likelihood of achieving normoglycemia in individuals with prediabetes.

Carrier-envelope-phase-dependent below-threshold harmonic generation in few-cycle mid-infrared laser fields.

We theoretically study the dependence of below-threshold harmonic generation (BTHG) of atoms on the carrier-envelope phase (CEP) driven by few-cycle mid-infrared laser pulses. The BTHG spectra can be accurately and efficiently calculated by solving the three-dimensional time-dependent Schrödinger equation using the time-dependent generalized pseudospectral method. We present the BTHG spectra as a function of the laser-field CEP. CEP-dependent enhancement or suppression occurred at low laser field intensities owing to the changes in the resonant effects associated with multiple quantum trajectories. However, the BTHG of atoms driven by high laser intensities is insensitive to the CEP. The synchrosqueezing time-frequency transform of the BTHG and extended semiclassical analysis are performed to elucidate the underlying physical mechanism.

Nomogram model and risk score to predict 5-year risk of progression from prediabetes to diabetes in Chinese adults: Development and validation of a novel model.

AIM: To develop a personalized nomogram and risk score to predict the 5-year risk of diabetes among Chinese adults with prediabetes. METHODS: There were 26 018 participants with prediabetes at baseline in this retrospective cohort study. We randomly stratified participants into two cohorts for training (n = 12 947) and validation (n = 13 071). The least absolute shrinkage and selection operator (LASSO) model was applied to select the most significant variables among candidate variables. And we further established a stepwise Cox proportional hazards model to screen out the risk factors based on the predictors chosen by the LASSO model. We presented the model with a nomogram. The model's discrimination, clinical use and calibration were assessed using the area under the receiver operating characteristic (ROC) curve, decision curve and calibration analysis. The associated risk factors were also categorized according to clinical cut-points or tertials to create the diabetes risk score model. Based on the total score, we divided it into four risk categories: low, middle, high and extremely high. We also evaluated our diabetes risk score model's performance. RESULTS: We developed a simple nomogram and risk score that predicts the risk of prediabetes by using the variables age, triglyceride, fasting blood glucose, body mass index, alanine aminotransferase, high-density lipoprotein cholesterol and family history of diabetes. The area under the ROC curve of the nomogram was 0.8146 (95% CI 0.8035-0.8258) and 0.8147 (95% CI 0.8035-0.8259) for the training and validation cohort, respectively. The calibration curve showed a perfect fit between predicted and observed diabetes risks at 5 years. Decision curve analysis presented the clinical use of the nomogram, and there was a wide range of alternative threshold probability spectrums. A total risk score of 0 to 2.5, 3 to 4.5, 5 to 7.5 and 8 to 13.5 is associated with low, middle, high and extremely high diabetes risk status, respectively. CONCLUSIONS: We developed and validated a personalized prediction nomogram and risk score for 5-year diabetes risk among Chinese adults with prediabetes, identifying individuals at a high risk of developing diabetes. Doctors and other healthcare professionals can easily and quickly use our diabetes score model to assess the diabetes risk status in patients with prediabetes. In addition, the nomogram model and risk score we developed need to be validated in a prospective cohort study.