Combining untargeted and targeted metabolomics to reveal the mechanisms of herb pair Anemarrhena asphodeloides Bunge and Phellodendron chinense C. K. Schneid on benign prostatic hyperplasia.

ETHNOPHARMACOLOGICAL RELEVANCE: Anemarrhena asphodeloides Bunge (Ane) and Phellodendron chinense C. K. Schneid (Phe) is classical herb pair in traditional Chinese medicine, commonly used to ameliorate the symptoms of Benign Prostatic Hyperplasia (BPH). However, the mechanisms underlying this effect are remained indistinct. AIM OF THE STUDY: This study aimed to clarify potential therapeutic mechanisms of herb pair on BPH from a metabolic perspective. MATERIALS AND METHODS: Testosterone propionate-induced BPH rat model was established, prostatic parameters, histopathology and the levels of serum dihydrotestosterone (DHT) and testosterone (T) were used to evaluate the pharmacological effect of the herb pair on BPH. Subsequently, untargeted metabolomics of prostate tissues samples was performed by UHPLC-Q-Exactive-Orbitrap-MS, followed by multivariate statistical analysis. Targeted metabolomics by UHPLC-QQQ-MS was further utilized to verify and supplement the results of lipids and amino acids found by untargeted metabolomics, clarifying the relationship between disease, herbal pair and metabolism pathway. RESULTS: The study found that Ane-Phe could relieve the progression of BPH and regulate metabolic imbalances. The levels of 13 metabolites decreased and 11 increased in prostatic tissues including glycerolphospholipid, arachidonic acid, citric acid and so on, these altered metabolites were primarily associated with TCA cycle, arachidonic acid metabolism, lipid metabolism and amino acid metabolism. Furthermore, targeted metabolomics was fulfilled to further analyze the lipid metabolism disorders, the levels of 5 lipids in serum and 21 in prostatic tissues were changed in the herb pair group compared to the model group, which closely related to glycerophospholipid, sphingolipid and glycerolipid metabolism. Besides, amino acid metabolism may be regulated by activating arginine metabolism pathway. CONCLUSIONS: In this study, the combination of untargeted metabolomics and targeted metabolomics was applied to explore therapeutic mechanisms of Ane-Phe on BPH. In summary, Ane-Phe could improve the levels of endogenous metabolites by regulating multiple metabolic pathways and plays a role in energy supply, anti-inflammation and oxidative stress in BPH treatment.

Prospective cohort studies underscore the association of abnormal glycemic measures with all-cause and cause-specific mortalities.

The role of fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), and triglyceride-glucose index (TyG index) in predicting all-cause and cause-specific mortalities remains elusive. This study included 384,420 adults from the Shanghai cohort and the UK Biobank (UKB) cohort. After multivariable adjustment in the Cox models, FPG ≥7.0 mmol/L or HbA1c ≥ 6.5% increased the risk of all-cause mortality, FPG ≥5.6 mmol/L or HbA1c ≥ 6.5% increased CVD-related mortality, and higher or lower TyG index increased all-cause and CVD-related mortalities in the Shanghai cohort; FPG ≥5.6 mmol/L, HbA1c ≥ 5.7%, TyG index <8.31 or ≥9.08 increased the risks of all-cause, CVD-related, and cancer-related mortalities in the UKB cohort. FPG or HbA1c increased the discrimination of the conventional risk model in predicting all-cause and CVD-related mortalities in both cohorts. Thus, increased levels of FPG and HbA1c and U-shaped TyG index increase the risks of all-cause especially CVD-related mortalities.

[Analysis and prediction of epidemiological characteristics of tuberculosis deaths among Chinese residents from 2006 to 2021].

Objective: The epidemiological characteristics of tuberculosis deaths among Chinese residents from 2006 to 2021 were analyzed, and the tuberculosis mortality rate from 2022 to 2027 was predicted to provide a reference for tuberculosis prevention and control in China. Methods: The data set of tuberculosis deaths from 2006 to 2021 was published regularly by the China CDC, and the crude mortality rate (CMR) and age-standardized mortality rates (ASMR) were calculated according to the population structure of China in 2000. The distribution characteristics of age, sex, region, and time of tuberculosis deaths were analyzed, the Joinpoint regression analysis model was used to analyze the changing trend, and the grey model was applied to predict CMR and ASMR from 2022 to 2027. Results: From 2006 to 2021, the CMR and ASMR of tuberculosis showed a downward trend among males and females, urban and rural areas, and all age groups, in a word, all the Chinese residents. Except for the age group ≥85 years old, the mortality trend was insignificant. In the eastern, central, or western regions. CMR and ASMR were significantly higher in males than in females.CMR and ASMR were significantly lower in urban areas than in rural areas. In general, active tuberculosis patients present a higher mortality rate. The CMR and ASMR in the western region were higher than those in the eastern and central regions and lower in the eastern region than in the central region, but the differences were less obvious. The ASMR of the eastern cities was lower than that of the central and western regions, and the ASMR of the central cities was higher than that of the western region from 2006 to 2009 and 2012 and lower than that of the western region in other years. The ASMR in the western countryside was higher than that in the eastern and central regions and lower in the eastern part than in the central region, but the difference was not obvious. The grey model prediction results show that the CMR (/100 000) of Chinese residents from 2022 to 2027 is 1.585, 1.471, 1.360, 1.250, 1.143, and 1.038, and the ASMR (/100 000) is 0.779, 0.653, 0.531, 0.411, 0.295 and 0.181, respectively. Conclusions: The CMR and ASMR of tuberculosis will continue to decline, and extraordinary achievements have been made in tuberculosis prevention and control in Chinese residents from 2006 to 2021 and, presumably, from 2022 to 2027. However, tuberculosis screening and treatment programs in the western region, men, the elderly population, and rural areas should be further strengthened, and targeted prevention and control measures should be formulated to reduce mortality.

Extracellular vesicle-mediated pre-metastatic niche formation via altering host microenvironments.

The disordered growth, invasion and metastasis of cancer are mainly attributed to bidirectional cell-cell interactions. Extracellular vesicles (EVs) secreted by cancer cells are involved in orchestrating the formation of pre-metastatic niches (PMNs). Tumor-derived EVs mediate bidirectional communication between tumor and stromal cells in local and distant microenvironments. EVs carrying mRNAs, small RNAs, microRNAs, DNA fragments, proteins and metabolites determine metastatic organotropism, enhance angiogenesis, modulate stroma cell phenotypes, restructure the extracellular matrix, induce immunosuppression and modify the metabolic environment of organs. Evidence indicates that EVs educate stromal cells in secondary sites to establish metastasis-supportive microenvironments for seeding tumor cells. In this review, we provide a comprehensive overview of PMN formation and the underlying mechanisms mediated by EVs. Potential approaches to inhibit cancer metastasis by inhibiting the formation of PMNs are also presented.

Salt Effect Engineering Single Fe-N2P2-Cl Sites on Interlinked Porous Carbon Nanosheets for Superior Oxygen Reduction Reaction and Zn-Air Batteries.

Developing efficient metal-nitrogen-carbon (M-N-C) single-atom catalysts for oxygen reduction reaction (ORR) is significant for the widespread implementation of Zn-air batteries, while the synergic design of the matrix microstructure and coordination environment of metal centers remains challenges. Herein, a novel salt effect-induced strategy is proposed to engineer N and P coordinated atomically dispersed Fe atoms with extra-axial Cl on interlinked porous carbon nanosheets, achieving a superior single-atom Fe catalyst (denoted as Fe-NP-Cl-C) for ORR and Zn-air batteries. The hierarchical porous nanosheet architecture can provide rapid mass/electron transfer channels and facilitate the exposure of active sites. Experiments and density functional theory (DFT) calculations reveal the distinctive Fe-N2P2-Cl active sites afford significantly reduced energy barriers and promoted reaction kinetics for ORR. Consequently, the Fe-NP-Cl-C catalyst exhibits distinguished ORR performance with a half-wave potential (E1/2) of 0.92 V and excellent stability. Remarkably, the assembled Zn-air battery based on Fe-NP-Cl-C delivers an extremely high peak power density of 260 mW cm-2 and a large specific capacity of 812 mA h g-1, outperforming the commercial Pt/C and most reported congeneric catalysts. This study offers a new perspective on structural optimization and coordination engineering of single-atom catalysts for efficient oxygen electrocatalysis and energy conversion devices.

The efficacy and safety of different systemic combination therapies on advanced hepatocellular carcinoma: a systematic review and meta-analysis.

Background and aims: Systemic combinations have recently brought significant therapeutic benefits for advanced hepatocellular carcinoma (aHCC). To design the most effective combination regimens, a systematic review (PROSPERO ID: CRD42022321949) was conducted to evaluate the efficacy and safety of systemic combinations on aHCC. Methods: We retrieved all the studies from PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and China National Knowledge Infrastructure (CNKI) using the Medical Subject Headings (MeSH) terms until December 21, 2022. The effect indicators (hazard ratio [HR], relative risk [RR], and median) were pooled by a fixed- or random-effects model. A subgroup analysis was conducted according to types and specific therapies. Results: In total, 88 eligible studies were selected from 7249 potential records. Each kind of combination treatment (chemotherapy plus chemotherapy, targeted plus immune checkpoint inhibitor (ICI) therapy, targeted plus chemotherapy, and targeted plus targeted therapy) had a better objective response rate (ORR) in patients with aHCC, compared to the monotherapy mostly with sorafenib (RR: 1.57 [1.44-1.71]; I 2 = 30%). Of those, targeted plus ICI therapy showed better therapeutic efficiency in overall survival (median: 15.02 [12.67-17.38]), progression-free survival (median: 7.08 [6.42-7.74]), and ORR (RR: 1.81 [1.55-2.13]), compared to the monotherapy. Specifically, Atezo plus Beva showed all those benefits. Our pooled result showed all the combinations had increased ≥3 Grade treatment-related adverse events (TrAEs), with an RR of 1.25 [95% CI: 1.15-1.36], compared to the monotherapy. Conclusion: The systemic combinations, especially targeted plus ICI therapy, including Atezo plus Beva, significantly improve clinical outcomes but increase side effects in patients with aHCC. Future trials should concentrate on improvement in therapeutic efficiency and reduction of toxicity of targeted plus ICI therapy. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022321949.

Smoke and Spike: Benzo[a]pyrene Enhances SARS-CoV-2 Infection by Boosting NR4A2-Induced ACE2 and TMPRSS2 Expression.

Cigarette smoke aggravates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the underlying mechanisms remain unclear. Here, they show that benzo[a]pyrene in cigarette smoke extract facilitates SARS-CoV-2 infection via upregulating angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). Benzo[a]pyrene trans-activates the promoters of ACE2 and TMPRSS2 by upregulating nuclear receptor subfamily 4 A number 2 (NR4A2) and promoting its binding of NR4A2 to their promoters, which is independent of functional genetic polymorphisms in ACE2 and TMPRSS2. Benzo[a]pyrene increases the susceptibility of lung epithelial cells to SARS-CoV-2 pseudoviruses and facilitates the infection of authentic Omicron BA.5 in primary human alveolar type II cells, lung organoids, and lung and testis of hamsters. Increased expression of Nr4a2, Ace2, and Tmprss2, as well as decreased methylation of CpG islands at the Nr4a2 promoter are observed in aged mice compared to their younger counterparts. NR4A2 knockdown or interferon-λ2/λ3 stimulation downregulates the expression of NR4A2, ACE2, and TMPRSS2, thereby inhibiting the infection. In conclusion, benzo[a]pyrene enhances SARS-CoV-2 infection by boosting NR4A2-induced ACE2 and TMPRSS2 expression. This study elucidates the mechanisms underlying the detrimental effects of cigarette smoking on SARS-CoV-2 infection and provides prophylactic options for coronavirus disease 2019, particularly for the elderly population.

Integrative transcriptome and proteome analyses of clear cell renal cell carcinoma develop a prognostic classifier associated with thrombus.

Clear cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) is associated with poor prognosis. Our integrative analyses of transcriptome and proteome reveal distinctive molecular features of ccRCC with VTT, and yield the development of a prognostic classifier to facilitate ccRCC molecular subtyping and treatment. The RNA sequencing and mass spectrometry were performed in normal-tumor-thrombus tissue triples of five ccRCC patients. Statistical analysis, GO and KEGG enrichment analysis, and protein-protein interaction network construction were used to interpret the transcriptomic and proteomic data. A six-gene-based classifier was developed to predict patients' survival using Cox regression, which was validated in an independent cohort. Transcriptomic analysis identified 1131 tumorigenesis-associated differentially expressed genes (DEGs) and 856 invasion-associated DEGs. Overexpression of transcription factor EGR2 in VTT indicated its important role in tumor invasion. Furthermore, proteomic analysis showed 597 tumorigenesis-associated differentially expressed proteins (DEPs) and 452 invasion-associated DEPs. The invasion-associated DEPs showed unique enrichment in DNA replication, lysine degradation, and PPAR signaling pathway. Integration of transcriptome and proteome reveals 142 tumorigenesis-associated proteins and 84 invasion-associated proteins displaying changes consistent with corresponding genes in transcriptomic profiling. Based on their different expression patterns among normal-tumor-thrombus triples, RAB25 and GGT5 were supposed to play a consistent role in both tumorigenesis and invasion processes, while SHMT2 and CADM4 might play the opposite roles in tumorigenesis and thrombus invasion. A prognostic classifier consisting of six DEGs (DEPTOR, DPEP1, NAT8, PLOD2, SLC7A5, SUSD2) performed satisfactorily in predicting survival of ccRCC patients (HR = 4.41, P < 0.001), which was further validated in an independent cohort of 40 cases (HR = 5.52, P = 0.026). Our study revealed the transcriptomic and proteomic profiles of ccRCC patients with VTT, and identified the distinctive molecular features associated with VTT. The six-gene-based prognostic classifier developed by integrative analyses may facilitate ccRCC molecular subtyping and treatment.

[Global incidence and mortality of renal cell carcinoma in 2020].

Objective: To analyze the global epidemiology of renal cell carcinoma (RCC) in 2020. Methods: The incidence and mortality data of RCC in the cooperative database GLOBOCAN 2020 of International Agency for Research on Cancer of WHO and the human development index (HDI) published by the United Nations Development Programme in 2020 were collated. The crude incidence rate (CIR), age-standardized incidence rate (ASIR), crude mortality rate (CMR), age-standardized mortality rate (ASMR) and mortality/incidence ratio (M/I) of RCC were calculated. Kruskale-Wallis test was used to analyze the differences in ASIR or ASMR among HDI countries. Results: In 2020, the global ASIR of RCC was 4.6/100 000, of which 6.1/100 000 for males and 3.2/100 000 for females and ASIR was higher in very high and high HDI countries than that in medium and low HDI countries. With the rapid increase of age after the age of 20, the growth rate of ASIR in males was faster than that in females, and slowed down at the age of 70 to 75. The truncation incidence rate of 35-64 years old was 7.5/100 000 and the cumulative incidence risk of 0-74 years old was 0.52%. The global ASMR of RCC was 1.8/100 000, 2.5/100 000 for males and 1.2/100 000 for females. The ASMR of males in very high and high HDI countries (2.4/100 000-3.7/100 000) was about twice that of males (1.1/100 000-1.4/100 000) in medium and low HDI countries, while the ASMR of female (0.6/100 000-1.5/100 000) did not show significant difference. ASMR continued to increase rapidly with age after the age of 40, and the growth rate of males was faster than that of females. The truncation mortality rate of 35-64 years old was 2.1/100 000, and the cumulative mortality risk of 0-74 years old was 0.20%. M/I decreases with the increase of HDI, with M/I as 0.58 in China, which was higher than the global average of 0.39 and the United States' 0.17. Conclusion: The ASIR and ASMR of RCC presented significant regional and gender disparities globally, and the heaviest burden was in very high HDI countries.

The efficacy of bone marrow mesenchymal stem cells on rat intestinal immune-function injured by ischemia/reperfusion.

Background: Transplantation of bone marrow mesenchymal stem cells (BMSCs) has a promising therapeutic efficiency for varieties of disorders caused by ischemia or reperfusion impairment. It has been shown that BMSCs can mitigate intestinal ischemia/reperfusion (I/R) injuries, but the underlying mechanism is still unclear. This study aimed at investigating the efficacy of BMSCs on the immune function of intestinal mucosal microenvironment after I/R injuries. Methods: Twenty adult Sprague-Dawley rats were randomly assigned to a treatment or a control group. All the rats underwent superior mesenteric artery clamping and unclamping. In the treatment group, BMSCs were implanted into the intestine of ten rats by direct submucosal injection whereas the other ten rats in the control group were injected with the same volume of saline. On the fourth and seventh day after BMSCs transplantation, intestinal samples were examined for the CD4 (CD4-positive T-lymphocytes)/CD8 (CD8-positive T-lymphocytes) ratio of the bowel mucosa via flow cytometry, and for the level of Interleukin-2 (IL-2), Interleukin-4 (IL-4) and Interleukin-6 (IL-6) via ELISA. Paneth cell counts and Secretory Immunoglobulin A (SIgA) level were examined via immunohistochemical (IHC) analysis. Real time PCR (RT-PCR) was used to detect the expression levels of tumor necrosis factor-α (TNF-α) and trypsinogen (Serine 2) (PRSS2) genes. White blood cell (WBC) count was measured by manual counting under the microscope. Results: The CD4/CD8 ratio in the treatment group was significantly lower compared with that in the control group. The concentration of IL-2 and IL-6 was lower in the treatment group compared with the control group, while the level of IL-4 is the reverse between the two groups. The number of Paneth cells in intestinal mucosa increased significantly, while the level of SIgA in intestinal mucosa decreased significantly, after BMSCs transplantation. The gene expression levels of TNF-α and PRSS2 in intestinal mucosa of treatment group were significantly lower than those of control group. The WBC count in the treatment group was significantly lower than that in the control group. Conclusion: We identified immune-relevant molecular changes that may explain the mechanism of BMSCs transplantation efficacy in alleviating rat intestinal immune-barrier after I/R.

Integrative analysis of transcriptomic landscape and urinary signature reveals prognostic biomarkers for clear cell renal cell carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) patients with venous tumor thrombus (VTT) have poor prognosis. We aimed to reveal features of ccRCC with VTT and develop a urine-based prognostic classifier to predict ccRCC prognosis through integrative analyses of transcriptomic landscape and urinary signature. Methods: RNA sequencing was performed in five patients with ccRCC thrombus-tumor-normal tissue triples, while mass spectrometry was performed for urine samples from 12 ccRCC and 11 healthy controls. A urine-based classifier consisting of three proteins was developed to predict patients' survival and validated in an independent cohort. Results: Transcriptomic analysis identified 856 invasion-associated differentially expressed genes (DEGs). Furthermore, proteomic analysis showed 133 differentially expressed proteins (DEPs). Integration of transcriptomic landscape and urinary signature reveals 6 urinary detectable proteins (VSIG4, C3, GAL3ST1, TGFBI, AKR1C3, P4HB) displaying abundance changes consistent with corresponding genes in transcriptomic profiling. According to TCGA database, VSIG4, TGFBI, and P4HB were significantly overexpressed in patients with shorter survival and might be independent prognostic factors for ccRCC (all p<0.05). A prognostic classifier consisting of the three DEPs highly associated with survival performed satisfactorily in predicting overall survival (HR=2.0, p<0.01) and disease-free survival (HR=1.6, p<0.001) of ccRCC patients. The ELISA analysis of urine samples from an independent cohort confirmed the satisfied predictive power of the classifier for pathological grade (AUC=0.795, p<0.001) and stage (AUC=0.894, p<0.001). Conclusion: Based on integrative analyses of transcriptomic landscape and urinary signature, the urine-based prognostic classifier consisting of VSIG4, TGFBI, and P4HB has satisfied predictive power of ccRCC prognosis and may facilitate ccRCC molecular subtyping and treatment.

A Novel Tumor Hypoxia Imaging Agent: [99mTc]Tc(CO)3-CPA-2-NIM.

INTRODUCTION: Hypoxia imaging agents can selectively remain in hypoxic tissue, which can directly reflect the location and degree of hypoxia. METHODS: Synthesized a novel tumor hypoxia imaging probe [99mTc]Tc(CO)3-CPA-2-NIM and evaluated its biological behavior with the purpose to assess its possibility of becoming a qualified tumor hypoxia imaging agent. RESULTS: Radiochemcial purity of [99mTc]Tc(CO)3-CPA-2-NIM was greater than 95% after HPLC purification. Lipophilicity coefficient of this complex was -1.74 ± 0.10 (n = 5, number of experiments), indicating it was a hydrophilic complex. In vitro cell experiments demonstrated that this complex has selectivity for hypoxia at oxygen concentrations < 10 ppm (parts per million). Biodistribution experiment in S180 tumor bearing mice showed that tumor uptake reached its highest at 2 h post-injection with mice tumor-to-muscle ratio. CONCLUSIONS: Complex [99mTc]Tc(CO)3-CPA-2-NIM has the possibility of becoming a tumor hypoxia imaging agent.

Potential Role of the Fragile Histidine Triad in Cancer Evo-Dev.

Cancer development follows an evolutionary pattern of "mutation-selection-adaptation" detailed by Cancer Evolution and Development (Cancer Evo-Dev), a theory that represents a process of accumulating somatic mutations due to the imbalance between the mutation-promoting force and the mutation-repairing force and retro-differentiation of the mutant cells to cancer initiation cells in a chronic inflammatory microenvironment. The fragile histidine triad (FHIT) gene is a tumor suppressor gene whose expression is often reduced or inactivated in precancerous lesions during chronic inflammation or virus-induced replicative stress. Here, we summarize evidence regarding the mechanisms by which the FHIT is inactivated in cancer, including the loss of heterozygosity and the promoter methylation, and characterizes the role of the FHIT in bridging macroevolution and microevolution and in facilitating retro-differentiation during cancer evolution and development. It is suggested that decreased FHIT expression is involved in several critical steps of Cancer Evo-Dev. Future research needs to focus on the role and mechanisms of the FHIT in promoting the transformation of pre-cancerous lesions into cancer.

Exosomes of Adipose Tissue-Derived Stem Cells Promote Wound Healing by Sponging miR-17-5p and Inducing Autophagy Protein Ulk1.

BACKGROUND: Wound healing undergoes intricate phases: hemostasis, inflammation, proliferation, and remodeling. Stem cell therapy based on adipose tissue-derived stem cell exosomes (ADSCs-exo) is considered a potential effective treatment for accelerating wound healing. However, the molecular mechanisms of wound healing using ADSCs-exo remain largely unknown. METHODS: Circular wounds, 1 × 1 cm, were generated on C57BL/6 mice, followed by OriCell C57BL/6 mouse adipose-derived mesenchymal stem cell suspension treatment, and wound area was measured and recorded at days 0, 7, and 21, respectively. A comprehensive transcriptome profiling of skin wounds was conducted in the mouse model. Importantly, the authors also examined autophagy and cell migration in mouse keratinocytes treated with ADSCs-exo. Further competing endogenous RNA networks were also used to reveal the relationship between Neat1 and Ulk1 . RESULTS: Mouse keratinocytes treated with ADSCs-exo showed significant up-regulation of pathways related to wound healing, including response to virus, bacterium, immune system, and wounding. Activated autophagy was detected, which significantly promoted the wound repair of mice. Competing endogenous RNA networks uncovered that Neat1 induces the expression of Ulk1 and thus up-regulates autophagic activity to promote wound repair through sponging miR-17-5p. CONCLUSIONS: Collectively, these results reveal a novel molecular mechanism that the autophagy pathway enhanced by the Neat1 /miR-17-5p/ Ulk1 axis can promote the wound healing and suggest that long noncoding RNA Neat1 loaded by ADSCs-exo might be a potential therapeutic target for skin nonhealing wounds. CLINICAL RELEVANCE STATEMENT: This study may provide new clues for the applications of ADSCs-exo in skin wounds and promote the development of ADSCs-exo therapy in clinical treatment of skin wounds.

Engineering adjacent N, P and S active sites on hierarchical porous carbon nanoshells for superior oxygen reduction reaction and rechargeable Zn-air batteries.

Heteroatom-doped carbon materials have been regarded as sustainable alternatives to the noble-metal catalysts for oxygen reduction reaction (ORR), while the catalytic performances still remain unsatisfactory. Herein, we develop a metal-free adjacent N, P and S-codoped hierarchical porous carbon nanoshells (NPS-HPCNs) through a novel layer-by-layer template coating method. The NPS-HPCNs is rationally fabricated by crosslinking of polyethyenemine (PEI) and phytic acid (PA) on nano-SiO2 template surface and subsequently coating of viscous sulfur-bearing petroleum pitch, followed by pyrolysis and alkaline etching. Soft X-ray absorption near-edge spectroscopy (XANES) analysis and density functional theory (DFT) calculations prove the engineering of adjacent N, P and S atoms to generate synergistic and reinforced active sites for oxygen electrocatalysis. The NPS-HPCNs manifests excellent ORR activity with a half-wave potential (E1/2) of 0.86 V, as well as promoted durability and methanol tolerance in alkaline medium. Remarkably, the NPS-HPCNs-based Zn-air battery delivers an open-circuit voltage of 1.479 V, a considerable peak power density of 206 mW cm-2 and robust cycling stability (over 200 h), even exceeding the commercial Pt/C catalyst. This study offers fundamental insights into the construction and synergistic mechanism of adjacent heteroatoms on carbon substrate, providing advanced metal-free electrocatalysts for Zn-air batteries and other energy conversion and storage devices.

The mortalities of female-specific cancers in China and other countries with distinct socioeconomic statuses: A longitudinal study.

INTRODUCTION: Female-specific cancers seriously affect physical and psychological health of women worldwide. OBJECTIVES: We aimed to elucidate trends in the age-standardized mortality rates (ASMRs) of breast cancer, cervical cancer, uterine cancer, and ovarian cancer in female populations with different socioeconomic statuses in China and in countries with different Human Development Index (HDI). METHODS: A longitudinal study was performed using the data of cancer death in China and other 39 countries. The mortality rates were standardized with the Segi's world population. Trends in the mortalities were exhibited by estimated annual percentage change (EAPC). Pearson correlation was used to assess the association between EAPC and HDI. RESULTS: In mainland China, female breast cancer, cervical cancer, uterine cancer, and ovarian cancer accounted for 6.60 %, 4.21 %, 2.50 %, and 2.02 % of cancer death (n = 1,314,040) in women with 1,220,251,032 person-years, respectively. The ASMRs of cervical cancer (EAPC = 3.87 %, P < 0.001) and ovarian cancer (EAPC = 1.81 %, P < 0.001) increased, that of female breast cancer unchanged, whereas that of uterine cancer was extremely higher and rapidly decreased (EAPC =  - 7.65 %, P < 0.001), during 2004-2019. The ASMRs of female breast and ovarian cancers were higher in urban and developed regions than in rural and undeveloped regions, in contrast to cervical and uterine cancers. The ASMRs of female breast and ovarian cancers were lower in China than in other countries, in contrast to uterine cancer. The ASMR of cervical cancer decreased, that of uterine cancer increased, in other countries during 2004-2017. EAPCs for the ASMRs of breast and ovarian cancers were inversely correlated to HDI. CONCLUSION: The ASMRs of cervical and ovarian cancers increased, in contrast to uterine cancer, in China during socioeconomic transition. Trends in the ASMRs of breast and ovarian cancers were inversely associated with HDI. These data help control female-specific cancers.

The recovery of intestinal barrier function and changes in oral microbiota after radiation therapy injury.

Introduction: Colorectal cancer (CRC) is the third most common malignant tumor, and neoadjuvant chemo-radiotherapy is usually recommended for advanced stage colorectal cancer. Radiotherapy can cause damage to intestinal mucosal barrier, which may be related to perioperative complications. Intestinal microbiota is one of the constituents of the intestinal mucosal biological barrier, and literature reports that patients with CRC have changes in corresponding oral microbiota. This study aims to analyze the levels of immunoglobulin SIgA, inflammatory factors, lymphocyte subsets quantity, and proportion in surgical specimens of intestinal mucosa at different time intervals after radiotherapy, in order to seek investigation for the optimal surgical time after radiotherapy and to provide evidence for finding probiotics or immunomodulators through high-throughput sequencing of bacterial 16s rRNA in patients' saliva microbiota. Ultimately, this may provide new ideas for reducing perioperative complications caused by radiotherapy-induced intestinal damage. Methods: We selected intestinal mucosal tissue and saliva samples from over 40 patients in our center who did not undergo radiotherapy and underwent surgery at different time intervals after radiotherapy. Detection of SIgA was performed using ELISA assay. Western Blotting was used to detect IL-1ß, IL-6, and IL-17 in the intestinal mucosal tissue. Flow cytometry was used to detect CD4 and CD8. And the microbial community changes in saliva samples were detected through 16s rRNA sequencing. Results: After radiotherapy, changes in SIgA, various cytokines, CD4CD8 lymphocyte subsets, and oral microbiota in the intestinal mucosal tissue of rectal cancer patients may occur. Over time, this change may gradually recover. Discussion: In colorectal cancer, oncological aspects often receive more attention, while studies focusing on the intestinal mucosal barrier are less common. This study aims to understand the repair mechanisms of the intestinal mucosal barrier and reduce complications arising from radiotherapy-induced damage. The relationship between oral microbiota and systemic diseases has gained interest in recent years. However, the literature on the oral microbiota after radiotherapy for rectal cancer remains scarce. This study addresses this gap by analysing changes in the salivary microbiota of rectal cancer patients before and after radiotherapy, shedding light on microbiota changes. It aims to lay the groundwork for identifying suitable probiotics or immunomodulators to alleviate perioperative complications and improve the prognosis of CRC.

Heterogeneity, inherent and acquired drug resistance in patient-derived organoid models of primary liver cancer.

PURPOSE: We aimed to elucidate the applicability of tumor organoids for inherent drug resistance of primary liver cancer (PLC) and mechanisms of acquired drug resistance. METHODS: PLC tissues were used to establish organoids, organoid-derived xenograft (ODX) and patient-derived xenograft (PDX) models. Acquired drug resistance was induced in hepatocellular carcinoma (HCC) organoids. Gene expression profiling was performed by RNA-sequencing. RESULTS: Fifty-two organoids were established from 153 PLC patients. Compared with establishing PDX models, establishing organoids of HCC showed a trend toward a higher success rate (29.0% vs. 23.7%) and took less time (13.0 ± 4.7 vs. 25.1 ± 5.4 days, p = 2.28 × 10-13). Larger tumors, vascular invasion, higher serum AFP levels, advanced stages and upregulation of stemness- and proliferation-related genes were significantly associated with the successful establishment of HCC organoids and PDX. Organoids and ODX recapitulated PLC histopathological features, but were enriched in more aggressive cell types. PLC organoids were mostly resistant to lenvatinib in vitro but sensitive to lenvatinib in ODX models. Stemness- and epithelial-mesenchymal transition (EMT)-related gene sets were found to be upregulated, whereas liver development- and liver specific molecule-related gene sets were downregulated in acquired sorafenib-resistant organoids. Targeting the mTOR signaling pathway was effective in treating acquired sorafenib-resistant HCC organoids, possibly via inducing phosphorylated S6 kinase. Genes upregulated in acquired sorafenib-resistant HCC organoids were associated with an unfavorable prognosis. CONCLUSIONS: HCC organoids perform better than PDX for drug screening. Acquired sorafenib resistance in organoids promotes HCC aggressiveness via facilitating stemness, retro-differentiation and EMT. Phosphorylated S6 kinase may be predictive for drug resistance in HCC.

The effects of hypertension on the prognosis of coronavirus disease 2019: a systematic review and meta-analysis on the interactions with age and antihypertensive treatment.

BACKGROUND: Hypertension and angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) have been reported to be associated with the prognosis of COVID-19, but the findings remain controversial. Here, we conducted a systematic review to summarize the current evidence. METHODS: We retrieved all the studies by MEDLINE via PubMed, CENTRAL, and Embase using the MeSH terms until 30 April 2021. A fixed or random effect model was applied to calculate pooled adjusted odds ratio (AOR) with 95% confidence interval (CI). Interactive analysis was performed to identify the interaction effect of hypertension and age on in-hospital mortality. RESULTS: In total, 86 articles with 18 775 387 COVID-19 patients from 18 countries were included in this study. The pooled analysis showed that the COVID-19 patients with hypertension had increased risks of in-hospital mortality and other adverse outcomes, compared with those without hypertension, with an AOR (95% CI) of 1.36 (1.28-1.45) and 1.32 (1.24-1.41), respectively. The results were mostly repeated in countries with more than three independent studies. Furthermore, the effect of hypertension on in-hospital mortality is more evident in younger and older COVID-19 patients than in 60-69-year-old patients. ACEI/ARBs did not significantly affect the mortality and adverse outcomes of COVID-19 patients, compared with those receiving other antihypertensive treatments. CONCLUSION: Hypertension is significantly associated with an increased risk of in-hospital mortality and adverse outcomes in COVID-19. The effect of hypertension on in-hospital mortality among consecutive age groups followed a U-shaped curve. ACEI/ARB treatments do not increase in-hospital mortality and other poor outcomes of COVID-19 patients with hypertension.