Effects of comprehensive nursing intervention on quality of life, Self-efficacy, gastrointestinal reaction and immune function of patients with breast cancer undergoing chemotherapy.

Objective: To assess the effects of comprehensive nursing intervention on quality of life, self-efficacy, gastrointestinal reaction and immune function of patients with breast cancer undergoing chemotherapy. Methods: This was a retrospective study. One hundred and twenty patients receiving chemotherapy after breast cancer surgery were randomly divided into the experimental group and the control group(n=60) from January 2021 to January 2023. Patients in the perioperative period, the experimental group were given comprehensive nursing intervention, while those in the control group were given conventional specialist nursing intervention. The differences in quality of life, self-efficacy, gastrointestinal reaction, immune function and patient satisfaction between the two groups were compared and analyzed. Results: After the intervention, the SF-36 scores in the experimental group were significantly higher than those in the control group (P=0.00), the efficacy indicators were significantly improved compared to the control group(P=0.00); the scores of gastrointestinal symptoms in the experimental group were significantly lower than those in the control group after the intervention(P<0.05). The indexes of CD3+, CD4+ and CD4+/CD8+ in the experimental group after the intervention were significantly higher than those in the control group(P=0.00); The patient satisfaction in the experimental group was 100%, which was significantly higher than 92% in the control group, with statistically significant differences(P=0.02). Conclusion: Comprehensive nursing intervention leads to a variety of benefits in the treatment of patients with breast cancer during postoperative chemotherapy, such as relieving patients' gastrointestinal reactions, improving their immune function and quality of life, besides effectively improving their self-efficacy, which is worthy of clinical application.

Flavonoids and Gastric Cancer Therapy: From Signaling Pathway to Therapeutic Significance.

Gastric cancer (GC) is a prevalent gastrointestinal tumor characterized by high mortality and recurrence rates. Current treatments often have limitations, prompting researchers to explore novel anti-tumor substances and develop new drugs. Flavonoids, natural compounds with diverse biological activities, are gaining increasing attention in this regard. We searched from PubMed, Web of Science, SpringerLink and other databases to find the relevant literature in the last two decades. Using "gastric cancer", "stomach cancers", "flavonoid", "bioflavonoid", "2-Phenyl-Chromene" as keywords, were searched, then analyzed and summarized the mechanism of flavonoids in the treatment of GC. It was revealed that the anti-tumor mechanism of flavonoids involves inhibiting tumor growth, proliferation, invasion, and metastasis, as well as inducing cell death through various processes such as apoptosis, autophagy, ferroptosis, and pyroptosis. Additionally, combining flavonoids with other chemotherapeutic agents like 5-FU and platinum compounds can potentially reduce chemoresistance. Flavonoids have also demonstrated enhanced biological activity when used in combination with other natural products. Consequently, this review proposes innovative perspectives for the development of flavonoids as new anti-GC agents.

Analytical validation of a novel comprehensive genomic profiling informed circulating tumor DNA monitoring assay for solid tumors.

Emerging technologies focused on the detection and quantification of circulating tumor DNA (ctDNA) in blood show extensive potential for managing patient treatment decisions, informing risk of recurrence, and predicting response to therapy. Currently available tissue-informed approaches are often limited by the need for additional sequencing of normal tissue or peripheral mononuclear cells to identify non-tumor-derived alterations while tissue-naïve approaches are often limited in sensitivity. Here we present the analytical validation for a novel ctDNA monitoring assay, FoundationOne®Tracker. The assay utilizes somatic alterations from comprehensive genomic profiling (CGP) of tumor tissue. A novel algorithm identifies monitorable alterations with a high probability of being somatic and computationally filters non-tumor-derived alterations such as germline or clonal hematopoiesis variants without the need for sequencing of additional samples. Monitorable alterations identified from tissue CGP are then quantified in blood using a multiplex polymerase chain reaction assay based on the validated SignateraTM assay. The analytical specificity of the plasma workflow is shown to be 99.6% at the sample level. Analytical sensitivity is shown to be >97.3% at ≥5 mean tumor molecules per mL of plasma (MTM/mL) when tested with the most conservative configuration using only two monitorable alterations. The assay also demonstrates high analytical accuracy when compared to liquid biopsy-based CGP as well as high qualitative (measured 100% PPA) and quantitative precision (<11.2% coefficient of variation).

Animal-derived natural products for hepatocellular carcinoma therapy: current evidence and future perspectives.

Hepatocellular carcinoma (HCC) has a high morbidity and mortality rate, and the survival rate of HCC patients remains low. Animal medicines have been used as potential therapeutic tools throughout the long history due to their different structures of biologically active substances with high affinity to the human body. Here, we focus on the effects and the mechanism of action of animal-derived natural products against HCC, which were searched in databases encompassing Web of Science, PubMed, Embase, Science Direct, Springer Link, and EBSCO. A total of 24 natural products from 12 animals were summarized. Our study found that these natural products have potent anti-hepatocellular carcinoma effects. The mechanism of action involving apoptosis induction, autophagy induction, anti-proliferation, anti-migration, and anti-drug resistance via phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), Ras/extracellular signal regulated kinases (ERK)/mitogen-activated protein kinase (MAPK), Wnt/ß-catenin, and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways. Huachansu injection and sodium cantharidate have been used in clinical applications with good efficacy. We review the potential of animal-derived natural products and their derivatives in the treatment of HCC to date and summarize their application prospect and toxic side effects, hoping to provide a reference for drug development for HCC.

Targeting oxidative stress with natural products: A novel strategy for esophageal cancer therapy.

Esophageal cancer (ESC) is a malignant tumor that originates from the mucosal epithelium of the esophagus and is part of the digestive tract. Although the exact pathogenesis of ESC has not been fully elucidated, excessive oxidative stress is an important characteristic that leads to the development of many cancers. Abnormal expression of several proteins and transcription factors contributes to oxidative stress in ESCs, which alters the growth and proliferation of ESCs and promotes their metastasis. Natural compounds, including alkaloids, terpenes, polyphenols, and xanthine compounds, can inhibit reactive oxygen species production in ESCs. These compounds reduce oxidative stress levels and subsequently inhibit the occurrence and progression of ESC through the regulation of targets and pathways such as the cytokine interleukins 6 and 10, superoxide dismutase, the NF-+ACY-kappa+ADs-B/MAPK pathway, and the mammalian Nrf2/ARE target pathway. Thus, targeting tumor oxidative stress has become a key focus in anti-ESC therapy. This review discusses the potential of Natural products (NPs) for treating ESCs and summarizes the application prospects of oxidative stress as a new target for ESC treatment. The findings of this review provide a reference for drug development targeting ESCs. Nonetheless, further high-quality studies will be necessary to determine the clinical efficacy of these various NPs.

Natural products for gastric carcinoma prevention and treatment: Focus on their antioxidant stress actions in the Correa's cascade.

BACKGROUND: Correa's cascade is a pathological process beginning from gastritis to gastric precancerous lesions, and finally to gastric carcinoma (GC). While the pathogenesis of GC remains unclear, oxidative stress plays a prominent role throughout the entire Correa's cascade process. Studies have shown that some natural products (NPs) could halt and even reverse the development of the Correa's cascade by targeting oxidative stress. METHODS: To review the effects and mechanism by which NPs inhibit the Correa's cascade through targeting oxidative stress, data were collected from PubMed, Embase, Web of Science, ScienceDirect, and China National Knowledge Infrastructure databases from initial establishment to April 2023. NPs were classified and summarized by their mechanisms of action. RESULTS: NPs, such as terpenoid, polyphenols and alkaloids, exert multistep antioxidant stress effects on the Correa's cascade. These effects include preventing gastric mucosal inflammation (stage 1), reversing gastric precancerous lesions (stage 2), and inhibiting gastric carcinoma (stage 3). NPs can directly impact the conversion of gastritis to GC by targeting oxidative stress and modulating signaling pathways involving IL-8, Nrf2, TNF-α, NF-κB, and ROS/MAPK. Among which polyphenols have been studied more and are of high research value. CONCLUSIONS: NPs display a beneficial multi-step action on the Correa's cascade, and have potential value for clinical application in the prevention and treatment of gastric cancer by regulating the level of oxidative stress.

Aberrant follicular regulatory T cells associate with immunoglobulin hyperproduction in nasal polyps with ectopic lymphoid tissues.

BACKGROUND: Ectopic lymphoid tissues (eLTs) and associated follicular helper T (TFH) cells contribute to local immunoglobulin hyperproduction in nasal polyps (NPs). Follicular regulatory T (TFR) cells in secondary lymphoid organs counteract TFH cells and suppress immunoglobulin production; however, the presence and function of TFR cells in eLTs in peripheral diseased tissues remain poorly understood. OBJECTIVE: We sought to investigate the presence, phenotype, and function of TFR cells in NPs. METHODS: The presence, abundance, and phenotype of TFR cells in NPs were examined using single-cell RNA sequencing, immunofluorescence staining, and flow cytometry. Sorted polyp and circulating T-cell subsets were cocultured with autologous circulating naïve B cells, and cytokine and immunoglobulin production were measured by ELISA. RESULTS: TFR cells were primarily localized within eLTs in NPs. TFR cell frequency and TFR cell/TFH cell ratio were decreased in NPs with eLTs compared with NPs without eLTs and control inferior turbinate tissues. TFR cells displayed an overlapping phenotype with TFH cells and FOXP3+ regulatory T cells in NPs. Polyp TFR cells had reduced CTLA-4 expression and decreased capacity to inhibit TFH cell-induced immunoglobulin production compared with their counterpart in blood and tonsils. Blocking CTLA-4 abolished the suppressive effect of TFR cells. Lower vitamin D receptor expression was observed on polyp TFR cells compared with TFR cells in blood and tonsils. Vitamin D treatment upregulated CTLA-4 expression on polyp TFR cells and restored their suppressive function in vitro. CONCLUSIONS: Polyp TFR cells in eLTs have decreased CLTA-4 and vitamin D receptor expression and impaired capacity to suppress TFH cell-induced immunoglobulin production, which can be reversed by vitamin D treatment in vitro.

Type 2 Biomarkers for the Indication and Response to Biologics in CRSwNP.

PURPOSE OF REVIEW: Three biologics targeting type 2 inflammation have been approved for the treatment of severe and uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP). Nevertheless, around 40-60% of patients do not respond well to these biological treatments. Selecting appropriate patients is crucial to improve treatment outcome of biologics. This review summarizes the literature data on type 2 biomarkers, with a specific focus on the indication to biologics for severe CRSwNP. RECENT FINDINGS: No consensus has been reached on how to define mucosal type 2 inflammation in CRSwNP. Clinical markers (e.g., 22-item Sino-nasal Outcome Test (SNOT-22) score, Lund-Mackay CT score (LMS), ethmoid/maxillary sinus CT score, and CT-radiomics), nasal secretion biomarkers (e.g., eosinophil cationic protein and interleukin-5), blood and nasal cytology eosinophil counts, and nasal swab eosinophil peroxidase activity have been reported to be associated with type 2 inflammation in CRSwNP. The time duration since the last surgery, SNOT-22 score at 1 week of treatment, and baseline serum osteoprotegerin levels might indicate the response to dupilumab. LMS and asthma control test scores were found to have moderate predictive value for acceptable improvement after 24-week treatment of omalizumab. High blood eosinophil levels at baseline were associated with treatment response to mepolizumab and benralizumab. Although several clinical and biological markers might be associated with type 2 inflammation and response to biologics in patients with CRSwNP, their validity requires further investigation. Identifying clinically applicable biomarkers for biologic treatment holds significant promise for advancing personalized approaches to biologics and optimizing treatment outcomes for patients with CRSwNP.

Berberine: An inspiring resource for the treatment of colorectal diseases.

Colorectal cancer is a prevalent malignant tumor with a complex and diverse pathogenesis. In recent years, natural products have shown promising application prospects as sources of anticancer drugs. BBR, a class of benzoquinoline alkaloids extracted from various plants, is widely used in disease treatments owing to its pharmacological activities, including antibacterial, anti-inflammatory, antioxidant, anticancer, and anti-angiogenesis properties. Research has demonstrated that BBR exerts an anti-Salmonella and -Escherichia coli infection effect, attenuating inflammatory reactions by inhibiting harmful bacteria. During the stage of colorectal precancerous lesions, BBR inhibits the activity of cell cyclin by regulating the PI3K/AKT, MAPK, and Wnt signaling pathways, thereby decelerating the cell cycle progression of polyp or adenoma cells. Moreover, the inhibitory effect of BBR on colorectal cancer primarily occurs through the regulation of the cancer cell cycle, anti-angiogenesis, gut microbiota, and antioxidant pathways. The specific involved pathways include the MPK/ERK, NF-kB, and EGFR signaling pathways, encompassing the regulation of Bcl-2 family proteins, vascular endothelial growth factor, and superoxide dismutase. This study reviews and summarizes, for the first time, the specific mechanisms of action of BBR in the carcinogenesis process of colorectal cancer, providing novel insights for its clinical application in intestinal diseases.

A 71-year-old male with a life-threatening recurrence of hemolytic anemia, thrombocytopenia, and acute kidney injury after pembrolizumab therapy: a case report.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, their use has been restricted in patients with preexisting autoimmune diseases due to concerns about increased risk of immune-related adverse events (irAEs). CASE PRESENTATION: We present a case of a patient with stage IV lung adenocarcinoma and a history of complement-mediated autoimmune hemolytic anemia in remission. After receiving a single dose of pembrolizumab, the patient experienced life-threatening recurrent hemolytic anemia, de novo thrombocytopenia, diarrhea, myocarditis, and acute kidney injury. Laboratory tests confirmed the diagnosis of Evan's syndrome, with positive PAIgG and direct antiglobulin test. Treatment with intravenous methylprednisolone at a dose of 2 mg/kg resulted in a favorable response, with resolution of symptoms and rapid recovery of kidney function. The probable cause of pre-renal hypoperfusion (evidenced by a BUN-to-creatinine ratio of 48.1) leading to acute tubular injury was attributed to pembrolizumab-induced diarrhea. CONCLUSIONS: This case illustrates a life-threatening recurrence of complement-mediated autoimmune hemolytic anemia induced by ICIs. Clinicians should carefully consider the expected efficacy and potential toxicity before initiating ICIs therapy in patients with preexisting autoimmune diseases. Additionally, the occurrence of acute kidney injury during ICIs therapy adds complexity and requires careful differential diagnosis.

Identification of Inflammatory Endotypes by Clinical Characteristics and Nasal Secretion Biomarkers in Chronic Rhinosinusitis with Nasal Polyps.

INTRODUCTION: The emergency of biologics and surgical techniques targeting the specific inflammatory endotype in chronic rhinosinusitis with nasal polyps (CRSwNP) asks for efficient identification of patients with different endotypes. Although mucosal IL-4, IL-5, IL-13, and IgE have been used to define type 2 (T2) inflammation, the optimal one remains unclear. In this study, we aimed to determine the optimal anchor for T2 inflammation and identify clinical characteristics and nasal secretion biomarkers predicting different endotypes in CRSwNP. METHODS: Six mediators in sinonasal tissue and 36 mediators in nasal secretion samples were detected by the Bio-Plex suspension array system. Mucosal IFN-γ and IL-17A levels were used to define the T1 and T3 endotype, respectively. The efficacy of mucosal IL-4, IL-5, IL-13, and IgE to define the T2 endotype was compared. The power of clinical characteristics and nasal secretion biomarkers to predict the T1, T2, and T3 endotype was analyzed. RESULTS: Among mucosal IL-4, IL-5, IL-13, and IgE, IL-13 was the best one to coincide with the expression of other T2 biomarkers. A combination of atopy, facial pain symptom score, ethmoid/maxillary computed tomography score ratio, and blood eosinophil percentage had a moderate predictive performance for T2 endotype (area under the receiver operating curve [AUC] = 0.815), comparable to that of nasal secretion IL-5 (AUC = 0.819). For the T3 endotype, nasal secretion IL-1Rα identified it with an AUC value of 0.756. No efficient marker for the T1 endotype was found. CONCLUSION: IL-13 is a primary anchor for the T2 endotype in CRSwNP. Clinical characteristics and nasal secretion biomarkers are helpful for identifying the T2 and T3 endotype of CRSwNP.

MEX3B inhibits collagen production in eosinophilic nasal polyps by downregulating epithelial cell TGFBR3 mRNA stability.

Although the expression of Mex3 RNA-binding family member B (MEX3B) is upregulated in human nasal epithelial cells (HNECs) predominately in the eosinophilic chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) subtype, its functions as an RNA binding protein in airway epithelial cells remain unknown. Here, we revealed the role of MEX3B based on different subtypes of CRS and demonstrated that MEX3B decreased the TGF-ß receptor III (TGFBR3) mRNA level by binding to its 3' UTR and reducing its stability in HNECs. TGF-ßR3 was found to be a TGF-ß2-specific coreceptor in HNECs. Knocking down or overexpressing MEX3B promoted or inhibited TGF-ß2-induced phosphorylation of SMAD2 in HNECs, respectively. TGF-ßR3 and phosphorylated SMAD2 levels were downregulated in CRSwNP compared with controls and CRS without nasal polyps with a more prominent downregulation in the eosinophilic CRSwNP. TGF-ß2 promoted collagen production in HNECs. Collagen abundance decreased and edema scores increased in CRSwNP compared with control, again more prominently in the eosinophilic type. Collagen expression in eosinophilic CRSwNP was negatively correlated with MEX3B but positively correlated with TGF-ßR3. These results suggest that MEX3B inhibits tissue fibrosis in eosinophilic CRSwNP by downregulating epithelial cell TGFBR3 expression; consequently, MEX3B might be a valuable therapeutic target against eosinophilic CRSwNP.

Targeting lipid metabolism with natural products: A novel strategy for gastrointestinal cancer therapy.

Gastrointestinal cancer (GIC), including gastric cancer and colorectal cancer, is a common malignant tumor originating from gastrointestinal epithelial cells. Although the pathogenesis of GIC remains unclear, aberrant lipid metabolism has emerged as a hallmark of cancer. Several enzymes, proteins, and transcription factors are involved in lipid metabolism reprogramming in GIC, and their abnormal expression can promote lipid synthesis and accumulation of lipid droplets through numerous mechanisms, thereby affecting the growth, proliferation, and metastasis of GIC cells. Studies show that some natural compounds, including flavonoids, alkaloids, and saponins, can inhibit the de novo synthesis of lipids in GIC, reduce the level of lipid accumulation, and subsequently, inhibit the occurrence and development of GIC by regulating Sterol regulatory element-binding protein 1 (SREBP-1), adenosine monophosphate-activated protein kinase (AMPK), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), phosphatidylinositol-3-kinase/Akt and the mammalian target of rapamycin PI3K/Akt/mTOR, amongst other targets and pathways. Therefore, targeting tumor lipid metabolism is the focus of anti-gastrointestinal tumor therapy. Although most natural products require further high-quality studies to firmly establish their clinical efficacy, we review the potential of natural products in the treatment of GIC and summarize the application prospect of lipid metabolism as a new target for the treatment of GIC, hoping to provide a reference for drug development for gastrointestinal tumors.

Differential regulation of H3K9/H3K14 acetylation by small molecules drives neuron-fate-induction of glioma cell.

Differentiation therapy using small molecules is a promising strategy for improving the prognosis of glioblastoma (GBM). Histone acetylation plays an important role in cell fate determination. Nevertheless, whether histone acetylation in specific sites determines GBM cells fate remains to be explored. Through screening from a 349 small molecule-library, we identified that histone deacetylase inhibitor (HDACi) MS-275 synergized with 8-CPT-cAMP was able to transdifferentiate U87MG GBM cells into neuron-like cells, which were characterized by cell cycle arrest, rich neuron biomarkers, and typical neuron electrophysiology. Intriguingly, acetylation tags of histone 3 at lysine 9 (H3K9ac) were decreased in the promoter of multiple oncogenes and cell cycle genes, while ones of H3K9ac and histone 3 at lysine 14 (H3K14ac) were increased in the promoter of neuron-specific genes. We then compiled a list of genes controlled by H3K9ac and H3K14ac, and proved that it is a good predictive power for pathologic grading and survival prediction. Moreover, cAMP agonist combined with HDACi also induced glioma stem cells (GSCs) to differentiate into neuron-like cells through the regulation of H3K9ac/K14ac, indicating that combined induction has the potential for recurrence-preventive application. Furthermore, the combination of cAMP activator plus HDACi significantly repressed the tumor growth in a subcutaneous GSC-derived tumor model, and temozolomide cooperated with the differentiation-inducing combination to prolong the survival in an orthotopic GSC-derived tumor model. These findings highlight epigenetic reprogramming through H3K9ac and H3K14ac as a novel approach for driving neuron-fate-induction of GBM cells.

Chronic exposure to ambient PM2.5/NO2 and respiratory health in school children: A prospective cohort study in Hong Kong.

Despite increasing concerns about the detrimental effects of air pollution on respiratory health, limited evidence is available on these effects in the Hong Kong population, especially in children. In this prospective cohort study between 2012 and 2017, we aimed to investigate the associations between exposure to air pollution (concentrations of fine particulate matter [PM2.5] and nitrogen dioxide [NO2]) and respiratory health (lung function parameters and respiratory diseases and symptoms) in schoolchildren. We recruited 5612 schoolchildren aged 6-16 years in Hong Kong. We estimated the annual average concentrations of ambient PM2.5 and NO2 at each participant's address using spatiotemporal models. We conducted spirometry tests on all participants to measure their lung function parameters and used a self-administered questionnaire to collect information on their respiratory diseases and symptoms and a wide range of covariates. Linear mixed models were used to investigate the associations between exposure to air pollution and lung function. Mixed-effects logistic regression models with random effects were used to investigate the associations of exposure to air pollution with respiratory diseases and symptoms. In all of the participants, every 5-µg/m3 increase in the ambient PM2.5 concentration was associated with changes of - 13.90 ml (95 % confidence interval [CI]: -23.65 ml, -4.10 ml), - 4.20 ml (-15.60 ml, 7.15 ml), 27.20 ml/s (-3.95 ml/s, 58.35 ml/s), and - 19.80 ml/s (-38.35 ml/s, -1.25 ml/s) in forced expiratory volume in 1 s, forced vital capacity, peak expiratory flow, and maximal mid-expiratory flow, respectively. The corresponding lung function estimates for every 5-µg/m3 increase in the ambient NO2 concentration were - 2.70 ml (-6.05 ml, 0.60 ml), - 1.40 ml (-5.40 ml, 2.60 ml), - 6.60 ml/s (-19.75 ml/s, 6.55 ml/s), and - 3.05 ml/s (-11.10 ml/s, 5.00 ml/s), respectively. We did not observe significant associations between PM2.5/NO2 exposure and most respiratory diseases and symptoms. Stratified analyses by sex and age showed that the associations between exposure to air pollution and lung function parameters were stronger in male participants and older participants (11-14 year old group) than in female participants and younger participants (6-10 year old group), respectively. Our results suggest that chronic exposure to air pollution is detrimental to the respiratory health of schoolchildren, especially that of older boys. Our findings reinforce the importance of air pollution mitigation to protect schoolchildren's respiratory health.

Temporal trend of population structure, burden of diseases, healthcare resources and expenditure in China, 2000-2019.

OBJECTIVES: To explore the evolutionary trend of population structure, disease burden, healthcare resources and expenditure in China, and to identify key domains that are most in need of intervention. DESIGN: A cross-sectional and longitudinal analysis. DATA SOURCE: Population and healthcare data from China Statistical Yearbook, and disease burden attributable to causes and risk factors from the Global Burden of Diseases between 2000 and 2019. MEASURES AND METHODS: We used the Joinpoint Regression Program to measure trends in population composition, population change, dependency ratio, healthcare institution, personnel, expenditure and disease burden from 2000 to 2019. RESULTS: Regarding the population in China between 2000 and 2019, a decreasing trend was observed among youth aged 0-14 years (average annual percent change (AAPC): -1.17), a slow rising trend was observed among individuals aged 15-64 years (AAPC: 1.10) and a rapidly increasing trend was observed among individuals older than 65 years (AAPC: 3.67). Astonishing increasing trends in healthcare institutions (AAPC: 3.97), medical personnel (AAPC: 3.26) and healthcare expenditures (AAPC: 15.28) were also observed. Among individuals younger than 70 years, neoplasms (AAPC: 0.54) and cardiovascular diseases (AAPC: 0.67) remained among the top three causes, while tobacco (AAPC: 0.22) remained a top three risk factor. However, while musculoskeletal disorders (AAPC: 1.88) were not a top three cause in 2000, they are a top three cause in 2019. CONCLUSION: Comprehensive age/cause/risk factor-specific strategies are key to reconcile the tension among the triad of population ageing, disease burden and healthcare expenditure. The disease burden from cardiometabolic diseases, neoplasms and musculoskeletal disorders was identified as key domains that require intervention to reduce an increasing disease burden among individuals currently older than 70 years, as well as those approaching this age group.

Association between paternal age at childbirth and autism spectrum disorder in offspring. / çˆ¶äº²ç”Ÿè‚²å¹´é¾„ä¸Žå„¿ç«¥å­¤ç‹¬ç—‡è°±ç³»éšœç¢çš„ç›¸å ³æ€§.

OBJECTIVES: To study the association between paternal age at childbirth and the risk of autism spectrum disorder (ASD) in offspring. METHODS: In this cross-sectional study, 71 children with ASD who were diagnosed in the Department of Child Healthcare in six hospitals in Guangzhou, Foshan, Beijing, Wuhan, Hangzhou, and Chongqing of China from August 2016 to March 2017 were enrolled as subjects, and 284 typically developing children matched for age, sex, and maternal age at childbirth with the ASD children served as controls. A self-design questionnaire was used to collect the data on social demography, maternal pregnancy, and delivery. The association between paternal age at childbirth and the development of ASD in offspring was evaluated by the logistic regression analysis. RESULTS: After control for demographic factors and pregnancy- and delivery-related factors, the logistic regression analysis showed that a relatively high paternal age at childbirth was significantly associated with the increased risk of ASD in offspring (OR=1.12, 95%CI: 1.02-1.23, P<0.05). After grouping based on the paternal age, the logistic regression analysis showed that paternal age at childbirth of ≥40 years was significantly associated with the risk of ASD in offspring (before adjustment: OR=7.08, 95%CI: 1.77-28.32, P<0.05; after adjustment: OR=8.50, 95%CI: 1.71-42.25, P<0.05). CONCLUSIONS: High paternal age at childbirth is significantly associated with the increased risk of ASD in offspring, and paternal age at childbirth ≥40 years may be the high-risk age group for ASD in offspring.

Disruption of ß-catenin-mediated negative feedback reinforces cAMP-induced neuronal differentiation in glioma stem cells.

Accumulating evidence supports the existence of glioma stem cells (GSCs) and their critical role in the resistance to conventional treatments for glioblastoma multiforme (GBM). Differentiation therapy represents a promising alternative strategy against GBM by forcing GSCs to exit the cell cycle and reach terminal differentiation. In this study, we demonstrated that cAMP triggered neuronal differentiation and compromised the self-renewal capacity in GSCs. In addition, cAMP induced negative feedback to antagonize the differentiation process by activating ß-catenin pathway. Suppression of ß-catenin signaling synergized with cAMP activators to eliminate GSCs in vitro and extended the survival of animals in vivo. The cAMP/PKA pathway stabilized ß-catenin through direct phosphorylation of the molecule and inhibition of GSK-3ß. The activated ß-catenin translocated into the nucleus and promoted the transcription of APELA and CARD16, which were found to be responsible for the repression of cAMP-induced differentiation in GSCs. Overall, our findings identified a negative feedback mechanism for cAMP-induced differentiation in GSCs and provided potential targets for the reinforcement of differentiation therapy for GBM.

Long-term Exposure to Fine Particulate Matter and Mortality A Longitudinal Cohort Study of 400,459 Adults.

BACKGROUND: Cohort studies on the association between long-term exposure to fine particulate matter (PM2.5) and mortality have been well established for America and Europe, but limited and inconsistent in Asia with much higher air pollution. This study aims to investigate the associations between ambient PM2.5 and all-cause and cause-specific mortality over a period of rising and then declining PM2.5. METHODS: We enrolled a total of 400,459 adults from an open cohort between 2001 and 2016, and followed them up until 31 May 2019. We obtained mortality data from the National Death Registry maintained by the Ministry of Health and Welfare in Taiwan. We estimated ambient PM2.5 exposures using a satellite-based spatiotemporal model. We performed a Cox regression model with time-dependent covariates to investigate the associations of PM2.5 with deaths from all causes and specific causes. RESULTS: This study identified 14,627 deaths and had a total of 5 million person-years of follow-up. Each 10 µg/m3 increase in PM2.5 was associated with an increased hazard risk of 29% (95% confidence interval: 24%-35%) in all-cause mortality. Risk of death increased by 30% for natural causes, 20% for cancer, 42% for cardiovascular disease (CVD) causes, and 53% for influenza and pneumonia causes, for each 10 µg/m3 increase in PM2.5. Sensitivity analyses generally yielded similar results. CONCLUSION: Long-term exposure to ambient PM2.5 was associated with increased risks of all-cause mortality and deaths from cancers, natural causes, CVD, and influenza and pneumonia. Longitudinal study design should be encouraged for air pollution epidemiologic investigation.