(Pro)renin receptor promotes colorectal cancer progression through inhibiting the NEDD4L-mediated Wnt3 ubiquitination and modulating gut microbiota.

BACKGROUND: We previously found that (pro)renin receptor ((P)RR) augments Wnt3 protein without affecting Wnt3 gene transcription in colorectal cancer (CRC) cells, thus contributes to CRC initiation. The present study aims to investigate whether (P)RR further promotes CRC progression following oncogenesis and the related mechanisms. Notably, we deeply elaborate how (P)RR affects Wnt3 protein level and the key enzyme that mediates this process. METHODS: Immunohistochemistry, western blotting and immunofluorescence were performed to detect protein expression status. A kind of gastrointestinal epithelium-specific ATP6AP2 ((P)RR encoding gene) knock-in mice were generated using Crispr/Cas9 system. RESULTS: We found that increased (P)RR expression in primary CRC lesions is positively associated with higher Wnt3 protein level and disease progression. Progressive CRC presents less colocalization of Wnt3 and an E3 ubiquitin ligase NEDD4L in primary lesions than non-progressive CRC. In colon cancer cells, (P)RR dramatically inhibits the NEDD4L-mediated Wnt3 protein ubiquitination. ATP6AP2 knock-in mice show more diminished Wnt3-NEDD4L colocalization in their gut epithelium in comparison to wildtype mice. They also have abnormal gut bacterial flora distribution. Especially, Lachnospiraceae_NK4A136 and Bacteroides genus, which are generally protective against CRC, are suppressed in guts of ATP6AP2 knock-in mice. CONCLUSIONS: Collectively, (P)RR promotes CRC progression through inhibiting the NEDD4L-mediated Wnt3 ubiquitination and modulating gut microbiota. Video Abstract.

Horseradish peroxidase (HRP) and glucose oxidase (GOX) based dual-enzyme system: Sustainable release of H2O2 and its effect on the desirable ping pong bibi degradation mechanism.

In this study, an adaptable HRP/GOX-Glu system was established due to the trait, efficient degradation of pollutants in the catalytic process of HRP named the ping-pong bibi mechanism and a sustained release of H2O2 in-situ under the catalysis of glucose oxidase (GOX). Compared with the traditional HRP/H2O2 system, the HRP was more stable in the HRP/GOX-Glu system based on the feature of persistent releasing H2O2 in-situ. Simultaneously, the high valent iron was found out to give a greater contribution to Alizarin Green (AG) removal through ping-pong mechanism, whereas the hydroxyl radical and superoxide free radical generated by Bio-Fenton were also the main active substances for AG degradation. Furthermore, on the basis of effect evaluation of the co-existence of two different degradation mechanisms in the HRP/GOX-Glu system, the degradation pathways of AG were proposed. Moreover, the optimum reaction conditions preferentially triggering ping-pong bibi mechanism instead of Bio-Fenton were determined by single factor analysis and degradation mechanism elaboration. This study would provide a reference for how to give full play to the advantages of ping-pong bibi mechanism in the dual-enzyme system based on HRP to degrade pollutants with high efficiency.

Genetic and pharmacological targeting of GSDMD ameliorates systemic inflammation in macrophage activation syndrome.

Macrophage activation syndrome (MAS), a potentially life-threatening complication of autoimmune/autoinflammatory diseases, is characterized by the excessive expansion and activation of macrophages and cytotoxic T lymphocytes in multiple organs. Most commonly, MAS occurs in patients with systemic juvenile idiopathic arthritis and in its adult equivalent, adult-onset Still's disease (AOSD). Gasdermin D (GSDMD) is a critical pore-forming effector protein that mediates pro-inflammatory cytokine secretion via releasing its N terminal fragments to form transmembrane pores. GSDMD has been implicated in various inflammatory diseases, however, its role in MAS remains elusive. Here, we unveiled that the serum levels of GSDMD-N were elevated in patients with AOSD compared to heathy controls. In addition, the emergence of MAS features in AOSD patients resulted in further elevation. The serum levels of GSDMD were positively correlated with ferritin and interleukin-18 (IL-18). Repeated toll-like receptor 9 stimulation with unmethylated cytosine-phosphate-guanine (CpG) induced MAS symptoms in wild-type mice, including body weight loss, pancytopenia and hepatosplenomegaly. Genetic deletion and pharmacological inhibition of GSDMD ameliorated MAS symptoms in mice with the concomitant reduction of splenic and hepatic macrophage infiltration and IL-18 production. Consistent with these in vivo results, bone marrow-derived macrophages obtained from GSDMD-/- mice or treated with GSDMD inhibitor disulfiram exhibited attenuated IL-18 expression after CpG stimulation. Collectively, our findings identified GSDMD as a novel marker for MAS complication and a promising target for MAS treatment.

Four new fatty acid derivatives from Diaporthe sp. T24, an endophytic fungus isolated from Ligularia fischer.

The endophytic fungus Diaporthe sp. is known to contain many secondary metabolites, but fatty acid derivatives have rarely been found. In this study, four new fatty acid derivatives (1-4), together with four known compounds (5-8), were isolated from Diaporthe sp., which was obtained from the stem of Ligularia fischeri. The absolute configurations of the new compounds 1-4 were deduced based on spectroscopic technique and J-based coupling constant analysis. Moreover, compound 1 exhibited cytotoxic activities against HCT-8 and MCF-7 cancer cells, and compounds 3 and 4 showed modest selectivity for HCT-8 cells by MTT assay.

Risk of macrophage activation syndrome in patients with adult-onset Still's disease with skin involvement: A retrospective cohort study.

BACKGROUND: Small case series and case reports indicated that atypical persistent pruritic eruptions (PPEs), another type of skin lesions seen in adult-onset Still's disease (AOSD), imply a worse prognosis than typical evanescent rashes. OBJECTIVE: To investigate clinical characteristics and macrophage activation syndrome (MAS) occurrence in AOSD with PPEs. METHODS: A retrospective cohort study analyzed 150 patients with AOSD with rashes at the First Affiliated Hospital of Zhejiang University from January 2013 to December 2019. RESULTS: Patients with AOSD with PPEs had higher lactate dehydrogenase (492.00 U/L vs 382.00 U/L; P < .001) and ferritin (6944.10 ng/ml vs 4286.60 ng/ml; P = .033), and lower fibrinogen (5.05 g/L vs 5.77 g/L; P = .014) than those with evanescent rashes. Patients with AOSD with PPEs had a higher incidence (17.4% vs 3.1%, P = .006) and cumulative event rate for MAS (P = .008) and tended to receive high-dose glucocorticoid (36% vs 20.3%; P = .036). Multivariate analysis indicated that PPEs (hazard ratio [HR], 5.519; 95% confidence interval [CI], 1.138-26.767; P = .034), aspartate aminotransferase of greater than 120 U/L (HR, 8.084; 95% CI, 1.728-37.826; P = .008), and splenomegaly (HR, 21.152; 95% CI, 2.263-197.711; P = .007) were independent risk factors for MAS. LIMITATIONS: Single-center, retrospective nature, small sample size. CONCLUSION: PPEs indicated increased severity and MAS occurrence versus evanescent rashes. PPEs, aspartate aminotransferase of greater than 120 U/L, and splenomegaly were risk factors for MAS in AOSD with skin involvement.

Systematic review and sequential network meta-analysis on the efficacy of periodontal regenerative therapies.

AIMS: We aimed to update a previous network meta-analysis comparing the efficacy of periodontal regenerative therapies on the treatment of infrabony lesions. MATERIALS AND METHODS: Seven clinical trials were added after literature research for studies published between January 2011 and September 2019. We conducted network meta-analysis (NMA) to compare the effects of guided tissue regeneration (GTR), enamel matrix derivatives (EMD) and their combination therapies on probing pocket depth (PPD) reduction and clinical attachment level (CAL) gain. Sequential network meta-analysis (SNMA) was also used to control the type-I error rate due to multiple testing. RESULTS: A total of 60 studies were included. For both PPD reduction and CAL gain, the flap operation (FO) was the least effective treatment. Although the differences between periodontal regenerative therapies were small, GTR attained the greatest reduction in PPD, and EMD with bone graft the greatest CAL gain compared to other therapies. SNMA used stricter efficacy criteria, yielding slightly different results from NMA. CONCLUSIONS: EMD, GTR, and their combined therapies were more effective than flap operation, although the differences between regenerative therapies remain small in this updated study. SNMA reduces the risk of false-positive findings, thereby providing more robust evidence on the superiority of treatments.

[Intensive care unit survey of cognition status of donation after brain death].

OBJECTIVE: To explore the development approach of donation after brain death through analyzing the cognition status of donation after brain death among medical staff and potential donor (PD) family members of intensive care unit (ICU). METHODS: Analysis was conducted for the cognition of donation after brain death among 149 ICU professionals and 879 PD family members at 89 hospitals from July 2011 to April 2013. RESULTS: Medical staff: 100% (149/149) recognized the significance of donation after brain death, 96.6% (144/149) approved of donation after brain death, 85.9% (128/149) knew about brain death criteria, 94.0% (140/149) accepted the equivalence of brain death as death. Awareness of standard of potential donor: 13.4% (20/149) were aware of donation age, 40.9% (61/149) familiar with the donation criteria of liver and kidney function and 44.3% (66/149) knew the hepatitis B donation criteria. Necessity of brain death legislation: 79.2% (118/149) considered it necessary, 14.8% (22/149) unimportant and 6.0% (9/149) not necessary. How to manage donation after brain death: 43.6% (65/149) did not know how, 79.2% (118/149) were afraid and 30.9% (46/149) never considered. Family members: 0/879 knew about brain death, 98.6% (867/879) accepted the equivalence of brain death as death, 99.5% (875/879) approved the significance of donation after brain death and 47.0% (413/879) agreed with donation after brain death. The reasons for approving the significance of donation after brain death but not agreeing with donation: 80.5% (372/462) required a full corpse after death and 19.5% (90/462) for other reasons. Reasons for agreeing with donation but refuse: 50.1% (207/413) were opposed by other family members, 11.4% (47/413) beware of neighbors' chat about their organ trading, 9.2% (38/413) hoped to be paid and 8.0% (33/413) for the others. CONCLUSIONS: The cognitive deficits of donation after brain death for medical staff and family members, medical staff's worries about brain death legislation and traditional thoughts of family members are the main reasons for a low conversion rate of PD. A professional transplant coordinating team should be built for national organ donation knowledge education.

KEYNOTE-811: Potential to revise first-line therapy for metastatic human epidermal growth factor receptor 2-positive gastric cancer.

The first-line therapy pattern transition of metastatic HER2-positive gastric cancer is shifting. The KEYNOTE-811 study demonstrated that the addition of immunotherapy to the standard treatment of HER2-targeted therapy and chemotherapy showed good results in terms of PFS, especially in subgroup patients with PD-L1 CPS≥1. In the future, the first-line therapy pattern of metastatic HER2-positive gastric cancer will be radically changed based on ongoing randomized controlled clinical trials.

The death burden of colorectal cancer attributable to modifiable risk factors, trend analysis from 1990 to 2019 and future predictions.

BACKGROUND: The death burden attributable to modifiable risk factors is key to colorectal cancer (CRC) prevention. This study aimed to assess the prevalence and regional distribution of attributable CRC death burden worldwide from 1990 to 2019. METHODS: We extracted data from the Global Burden of Disease Study in 2019 and assessed the mortality, age-standardized death rate (ASDR), population attributable fractions, and time trend in CRC attributable to risk factors by geography, socio-demographic index (SDI) quintile, age, and sex. RESULTS: Over the past 30 years, from high to low SDI region, the number of deaths increased by 46.56%, 103.55%, 249.64%, 231.89%, 163.11%, and the average annual percentage change (AAPC) for ASDR were -1.06%, -0.01%, 1.32%, 1.19%, and 0.65%, respectively. ASDR in males was 1.88 times than in females in 2019; ASDR in males showed an increasing trend (AAPC 0.07%), whereas ASDR in females showed a decreasing trend (AAPC -0.69%) compared to figures in 1990. In 2019, from high to low SDI region, the 15-49 age group accounted for 3%, 6%, 10%, 11%, and 15% of the total population; dietary and metabolic factors contributed 43.4% and 20.8% to CRC-attributable death worldwide. From high to low SDI region, ASDRs caused by dietary and metabolic factors increased by -23.4%, -5.5%, 25.8%, 29.1%, 13.5%, and 1.4%, 33.3%, 100.8%, 128.4%, 77.7% respectively, compared to 1990. CONCLUSIONS: The attributable CRC death burden gradually shifted from higher SDI to lower SDI regions. The limitation in males was more significant, and the gap is expected to be further expanded. In lower SDI regions, the death burden tended to affect younger people. The leading cause of CRC-attributable deaths was the inadequate control of dietary and metabolic risk factors.

Distinct time trends in colorectal cancer incidence in countries with SDI levels from 1990 to 2019: an age-period-cohort analysis for the Global Burden of Disease 2019 study.

Introduction: The burden of colorectal cancer (CRC) plays a pivotal role in the global cancer epidemic. Our study reported the incidence trends in CRC and the associated effects of age, period, and birth cohort in 204 countries and territories over the past 30 years. Methods: The incidence data of CRC were extracted from the Global Burden of Disease Study (GBD) 2019. We performed the age-period-cohort (APC) model to estimate the overall annual percentage change (net drift) in the incidence rate, the annual percentage change by age group (local drift), and the relative risk (period and cohort effects) of the period and cohort in CRC during 1990-2019. This approach allows examining and distinguishing age, period, and cohort effects in incidence and potentially distinguishing colorectal cancer gaps in prevention and screening. Results: In 2019, the incidence of CRC was 2.17 (95% UI 2.00-2.34) million, of which China, the United States of America, and Japan had the highest incidence population, accounting for 45.9% of the global population. The age-standardized incidence rate (ASIR) was 26.7 (95% UI 28.9-24.6) per 100,000 people, of which 30 countries had an incidence rate greater than 40.0 per 100,000 people. From 1990 to 2019, the middle SDI region had the largest increase in incidence rate, with a net drift of 2.33% (95% CI 2.2-2.46%, p < 0.001). Globally, the incidence population was concentrated in the age group of 50-69 years, and the age group of 30-34 years had the largest increase in incidence rate (local drift 1.19% (95% CI 1.01-1.37%)). At the same time, the sex and age distributions of CRC incidence had significant heterogeneity across regions and countries. In the past 30 years, the incidence rate in 31 countries has been well controlled (net drift <0), and most of them were concentrated in high-and high-middle-SDI regions, such as Australia, Czechia, and Belgium, and the relative risk of incidence generally improved over time and consecutive young birth cohorts. CRC incidence showed an unfavorable trend (net drift ≥1%) in 89 countries, of which 27 countries were more significant (net drift >2%), mostly concentrated in the middle SDI region, such as China, Mexico, and Brazil, and the risk of period and birth cohort was unfavorable. Conclusion: Globally, the incidence of CRC has shown an overall upward trend over the past 30 years, with the exception of some countries with higher SDI values. Significant age-period-cohort differences were observed in the risk of incidence in CRC worldwide. Effective prevention and control policies need to take into account the age-period-cohort effect characteristics of different regions.

Application of Dural Suturing in Reconstruction of Sellar Floor for Cerebrospinal Fluid Leakage During Neuroendoscopic Intranasal Approach Surgery: A meta-analysis.

AIM: This study aimed to assess the safety and efficacy of utilizing dural suturing as an adjunctive procedure for saddle floor reconstruction in patients undergoing endoscopic surgery in the sellar region. MATERIAL AND METHODS: According to the PRISMA guidelines, we searched the literature on sellar floor reconstruction in endoscopic sellar surgery. Fixed- or random-effects meta-analysis was used to pool the rate of return to postoperative cerebrospinal fluid (poCSF) leakage, repair operations, postoperative hospitalization, complete resection, infection, lumbar drainage (LD), and operative duration. RESULTS: A total of six studies involving 723 participants were included in the current meta-analysis. The pooled results demonstrated that patients in the dural suturing group had a lower incidence of poCSF leakage [odds ratio (OR), 0.18; 95% confidence interval (CI), 0.07 - 0.44; p = 0.0002] and repair operation [OR, 0.24; 95% CI, 0.07 - 0.78; p = 0.02], as well as a shorter hospitalization period [standardized mean difference (SMD), -0.45; 95% CI, -0.62 - -0.28; p 0.00001]. There was no significant difference between the two groups in terms of the complete resection [OR, 1.06; 95% CI, 0.62 - 1.80; po = 0.84], po infection [OR, 0.49; 95% CI, 0.21 - 1.15; p = 0.10] and lumbar drainage (LD) [OR, 0.28; 95% CI, 0.06 - 1.23; p = 0.09]. Additionally, the dural suturing group may require a longer operative duration [SMD, 0.29; 95% CI, 0.02 - 0.56; p = 0.03]. CONCLUSIONS: The results suggest that dural suturing can be advantageous in reducing postoperative complications and shortening postoperative hospitalization following neuroendoscopic surgery in the sellar region without increasing the risk of infection.

Berberine stimulates lysosomal AMPK independent of PEN2 and maintains cellular AMPK activity through inhibiting the dephosphorylation regulator UHRF1.

Aim: AMPK is the key regulatory kinase mediating the effect of berberine (BBR) and metformin on metabolic improvement. The present study investigated the mechanism of BBR on AMPK activation at low doses, which was different from that of metformin. Methods: Lysosomes were isolated, and AMPK activity assay was performed. PEN2, AXIN1 and UHRF1 were investigated through gain/loss of function approaches, including overexpression, RNA interfering and CRISPR/Cas9-mediated gene knockout. Immunoprecipitation was utilized for detecting the interaction of UHRF1 and AMPKα1 after BBR treatment. Results: BBR activated lysosomal AMPK, but weaker than metformin. AXIN1 mediated BBR's effect on lysosomal AMPK activation, while PEN2 did not. BBR, but not metformin, decreased UHRF1 expression by promoting its degradation. BBR reduced the interaction between UHRF1 and AMPKα1. And overexpression of UHRF1 abolished the effect of BBR on AMPK activation. Conclusion: BBR activated lysosomal AMPK as dependent on AXIN1, but not PEN2. BBR maintained cellular AMPK activity by reducing UHRF1 expression and its interaction with AMPKα1. The mode of action of BBR was different from that of metformin on AMPK activation.

Emerging patterns and trends in global cancer burden attributable to metabolic factors, based on the Global Burden of Disease Study 2019.

Background: The exponential growth of the cancer burden attributable to metabolic factors deserves global attention. We investigated the trends of cancer mortality attributable to metabolic factors in 204 countries and regions between 1990 and 2019. Methods: We extracted data from the Global Burden of Disease Study (GBD) 2019 and assessed the mortality, age-standardized death rate (ASDR), and population attributable fractions (PAFs) of cancers attributable to metabolic factors. Average annual percentage changes (AAPCs) were calculated to assess the changes in the ASDR. The cancer mortality burden was evaluated according to geographic location, SDI quintiles, age, sex, and changes over time. Results: Cancer attributable to metabolic factors contributed 865,440 (95% UI, 447,970-140,590) deaths in 2019, a 167.45% increase over 1990. In the past 30 years, the increase in the number of deaths and ASDR in lower SDI regions have been significantly higher than in higher SDI regions (from high to low SDIs: the changes in death numbers were 108.72%, 135.7%, 288.26%, 375.34%, and 288.26%, and the AAPCs were 0.42%, 0.58%, 1.51%, 2.36%, and 1.96%). Equatorial Guinea (AAPC= 5.71%), Cabo Verde (AAPC=4.54%), and Lesotho (AAPC=4.42%) had the largest increase in ASDR. Large differences were observed in the ASDRs by sex across different SDIs, and the male-to-female ratios of ASDR were 1.42, 1.50, 1.32, 0.93, and 0.86 in 2019. The core population of death in higher SDI regions is the age group of 70 years and above, and the lower SDI regions are concentrated in the age group of 50-69 years. The proportion of premature deaths in lower SDI regions is significantly higher than that in higher SDI regions (from high to low SDIs: 2%, 4%, 7%, 7%, and 9%). Gastrointestinal cancers were the core burden, accounting for 50.11% of cancer deaths attributable to metabolic factors, among which the top three cancers were tracheal, bronchus, and lung cancer, followed by colon and rectum cancer and breast cancer. Conclusions: The cancer mortality burden attributable to metabolic factors is shifting from higher SDI regions to lower SDI regions. Sex differences show regional heterogeneity, with men having a significantly higher burden than women in higher SDI regions but the opposite is observed in lower SDI regions. Lower SDI regions have a heavier premature death burden. Gastrointestinal cancers are the core of the burden of cancer attributable to metabolic factors.

Multiple inflammatory pseudotumor formation after craniopharyngioma resection via an extended nasal endoscopic approach: A case report.

BACKGROUND: This report describes a case of intracranial multiple inflammatory pseudotumors (IP) after endoscopic resection of a craniopharyngioma, which is relatively rarely reported in the literature, and neurosurgeons should be aware of its existence. CASE SUMMARY: Herein, we report the case of a 56-year-old man who developed decreased visual acuity and blurred vision without obvious cause or inducement on April 27, 2020. To seek further treatment, he went to the Department of Neurosurgery, Clinical Medical College, Yangzhou University. After falling ill, there was no nausea, vomiting, limb convulsions, obvious disturbance of consciousness, speech disorders, cough, or persistent fever. The neurological examination findings were normal, and pituitary magnetic resonance imaging (MRI) revealed multiple nodules with abnormal signals in the sellar region. The diagnosis was craniopharyngioma. We performed total resection of the tumor via transnasal endoscopy, and the postoperative pathology suggested that the type of tumor was craniopharyngioma. Six months after the operation, the patient experienced sudden hearing loss in the right ear, tinnitus in both ears, and numbness on the right side of the face and head. Meanwhile, cranial MRI showed multiple IP. After steroid hormone and anti-inflammatory therapy, the above symptoms did not significantly improve. Finally, the patient's symptoms were well improved by surgery, and the postoperative pathological diagnosis was multiple IP. CONCLUSION: Intracranial inflammatory pseudotumor is a benign disease with slow progression, but the clinical symptoms and imaging findings are not typical, there are no pathological findings, and the diagnosis is relatively difficult. Most of the cases are treated by surgical resection, and the prognosis is good after surgery.

Immunotherapy combined with local therapy in the late-line treatment of repair-proficient (pMMR)/microsatellite stable (MSS) metastatic colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies, and at the initial visit, most patients are diagnosed with metastatic CRC (mCRC). However, immunotherapy is only and highly effective in a very small proportion of patients with mCRC having mismatch repair defect (dMMR)/high microsatellite instability, and the majority of the patients with mCRC having mismatch repair proficient (pMMR)/microsatellite stability (MSS) cannot benefit from it. At present, many clinical studies of immunotherapy combined with tyrosine kinase inhibitors (TKIs) are trying to regulate the immune microenvironment of pMMR/MSS mCRC, transforming a "cold tumor" into a "hot tumor," which has not only surprising effects but also certain limitations, i.e., the response could not be specific to metastasis. Therefore, regarding the bottleneck encountered by immunotherapy in patients with patients pMMR/MSS mCRC, this study summarized current research and possible mechanisms of immunotherapy combined with local therapy for metastasis, including radiotherapy, ablation, and transcatheter arterial chemoembolization.

Development and validation of the AF score for diagnosis of adult-onset Still's disease in fever of unknown origin.

Objective: To develop and validate a diagnostic score to identify adult-onset Still's disease (AOSD) in fever of unknown origin (FUO). Methods: A single center, retrospective case-control study of inpatients with FUO from January 2018 to December 2021. Using clinical and laboratory data from 178 cases with AOSD and 486 cases with FUO, we developed an AOSD/FUO (AF) score with a Bayesian Model Averaging approach. AF score and Yamaguchi's criteria were evaluated by sensitivity, specificity, accuracy, and positive/negative predictive value for diagnosis of AOSD in developmental and validation samples. Results: Persistent pruritic eruptions (PPEs) in patients with rashes was higher in AOSD group than FUO group (52.3% vs 7.4%; P < 0.01). PPEs yielded a specificity of 97.5% and a sensitivity of 44.9%. AF score = PPEs × 3.795+Evanescent rash × 2.774+Serum ferritin × 1.678+Myalgia × 0.958+Neutrophil count × 0.185+Platelet count × 0.004. A cut-off value ≥ 5.245 revealed the maximizing sensitivity of 88.7% and specificity of 95.8% in discriminating AOSD from FUO in the validation group. And AF score improved the accuracy from 82.6% to 93.3% compared with Yamaguchi's criteria. Conclusions: We developed and validated a new score which can identify AOSD in FUO with higher classification accuracy than Yamaguchi's criteria. Future multi-centric prospective studies need to be designed to confirm the diagnosis value of AF score.

Global burden of tracheal, bronchus, and lung cancer attributable to occupational carcinogens in 204 countries and territories, from 1990 to 2019: results from the global burden of disease study 2019.

BACKGROUND: Occupational-related cancers are a substantial global health issue. The largest proportion of occupational-related cancers is tracheal, bronchus, and lung (TBL) cancer. This study aimed to explore the geographical and temporal trends in occupational carcinogens related to TBL cancer. METHODS: Data on TBL cancer attributable to occupational carcinogens were collected from the Global Burden of Disease Study 2019. Numbers and age-standardized rates (ASRs) of deaths, disability-adjusted life years (DALYs), and corresponding average annual percentage change (AAPC) were evaluated and stratified by geographic location, socio-demographic index (SDI) quintiles, age, and sex. RESULTS: Globally, ASRs of deaths and DALYs in TBL cancer attributable to occupational carcinogens showed a downward trend (AAPC = - 0.69%, - 1.01%) while increases were observed in the low, low-middle, and middle SDI quintiles. Although males accounted for 82.4% and 81.5% of deaths and DALYs in 2019, respectively, it showed an upward trend of ASRs in females (AAPC = 0.33%, 0.02%). Occupational exposure to asbestos, silica and diesel engine exhaust were the top three causes of age-standardized TBL cancer deaths and DALYs. Over the past three decades, the percentage of age-standardized TBL cancer deaths and DALYs attributable to occupational asbestos and silica exposure decreased by 18.24, 6.71 and 20.52%, 4.00% globally, but increased significantly in lower SDI regions, while the burden attributable to occupational diesel engine exhaust exposure increased by 32.76, 37.23% worldwide. CONCLUSIONS: Occupational exposure remains an important risk factor for TBL cancer. The burden of TBL cancer attributable to occupational carcinogens showed obvious heterogeneity which decreased in higher SDI but increased in lower SDI regions. The burden of males was significantly higher than females, but the females showed an increasing trend. Occupational exposure to asbestos was the main causes of the burden. Therefore, effective prevention and control measures tailored to local conditions are necessary.

Three undescribed compounds from Diaporthe biguttusis T-24, an endophytic fungus isolated from Ligularia fischeri.

Diaporthpyran A (1), diaporthester E (2) and diaporthester F (3), three new compounds along with four known compounds (4-7) were isolated from the crude extract of Diaporthe biguttusis T-24, an endophytic fungus isolated from Ligularia fischeri. The planar structures of compounds 1-3 including the relative and absolute configurations were elucidated on the basis of HRMS, NMR, J-based coupling constant analysis, CD, and calculated ECD analysis. In addition, compounds 1 and 3 were evaluated for their cytotoxic activities against four human cancer cell lines.