Changes in tuberculosis burden and its associated risk factors in Guizhou Province of China during 2006-2020: an observational study.

BACKGROUND: Understanding the trends of tuberculosis (TB) burden and its risk factors at the provincial level in the context of global End TB targets is crucial to identify the progress and challenges in TB control. We aimed to estimate the burden of TB and risk factors for death from 2006 to 2020 for the first time in Guizhou Province, China. METHODS: Data were collected from the national TB surveillance system. Four indicators of TB burden and their corresponding age-standardized rates (ASRs), including incidence (ASIR), prevalence (ASPR), mortality (ASMR) and disability-adjusted life years (DALYs) (ASDR), were estimated and stratified by year, age, gender and prefecture. Temporal trends of ASRs were presented by locally weighted regression, and the annual percentage change was calculated. The correlation between gross domestic product (GDP) per capita and ASRs was evaluated by Pearson correlation analysis. The associated risk factors for death in PTB patients were determined using logistic regression models. RESULTS: A total of 557,476 pulmonary TB (PTB) cases and 11,234 deaths were reported, including 2233 (19.9%) TB specific deaths and 9001 (80.1%) deaths from other causes. The 15-year average incidence, prevalence and mortality rates were 94.6, 102.6 and 2.1 per 100,000 population, respectively. The average DALY rate was 0.60 per 1000 population. The ASIR and ASPR have shown downward trends since 2012, with the largest percentage decrease in 2020 (ASIR: -29.8%; ASPR: -30.5%). The number in TB specific deaths consistently decreased during the study period (P<0.001), while the increase in deaths from other causes drove the overall upward trend in ASMR and ASDR. Four ASRs remained high in males and 5 prefectures. GDP per capita was negatively associated with the ASIR, ASPR and ASDR (P<0.05). Among PTB patients, men, patients with no fixed job, those with a low GDP level, patients with increasing age, those previously treated, those with severe symptoms, those transferred in and those receiving directly observed treatment were more likely to suffer death. CONCLUSION: Guizhou has made progress in reducing PTB cases and TB specific deaths over the last 15 years. Targeted interventions are needed to address these risk factors for death in PTB patients and high-risk areas.

Age-stratified analysis of HTO and UKA clinical effects in cross-indicated anterior medial osteoarthritis.

PURPOSE: To compare clinical outcomes of high tibial osteotomy (HTO) and unicompartmental knee arthroplasty (UKA) for anterior medial osteoarthritis (AMOA) as well as offer surgical recommendations through age stratification. METHODS: Between May 2019 and May 2021, 68 cross-indicated AMOA patients were analyzed. The patients were divided into HTO and UKA groups and further into two age groups of 55-60 and 60-65 years. Additionally, general data, visual analog scale (VAS) score, and Hospital for Special Surgery knee score (HSS) were analyzed. RESULTS: All the patients were followed up for 18 months. Knee joint HSS significantly improved, and VAS score decreased in both groups (P < 0.05). In the 55-60 age group, HTO showed superior knee HSS at 1 and 3 months (P < 0.05), with no significant difference at 6, 12, and 18 months. HTO had a significantly lower VAS score at one month, and the VAS scores of the two groups decreased gradually with no significant difference. In the 60-65 age group, the UKA group showed superior knee joint HSS at one month, with no significant difference at 3, 6, 12, and 18 months. The UKA group had a significantly lower VAS score at one month, and both groups' VAS scores decreased gradually with no significant difference. CONCLUSION: Both methods yield satisfactory results for AMOA cross-indications, improving knee joint function. The observed recovery trends have implications for personalized surgical recommendations, guiding interventions based on age-specific considerations for optimal outcomes in anterior medial osteoarthritis cases.

SAMLDroid: A Static Taint Analysis and Machine Learning Combined High-Accuracy Method for Identifying Android Apps with Location Privacy Leakage Risks.

Insecure applications (apps) are increasingly used to steal users' location information for illegal purposes, which has aroused great concern in recent years. Although the existing methods, i.e., static and dynamic taint analysis, have shown great merit for identifying such apps, which mainly rely on statically analyzing source code or dynamically monitoring the location data flow, identification accuracy is still under research, since the analysis results contain a certain false positive or true negative rate. In order to improve the accuracy and reduce the misjudging rate in the process of vetting suspicious apps, this paper proposes SAMLDroid, a combined method of static code analysis and machine learning for identifying Android apps with location privacy leakage, which can effectively improve the identification rate compared with existing methods. SAMLDroid first uses static analysis to scrutinize source code to investigate apps with location acquiring intentions. Then it exploits a well-trained classifier and integrates an app's multiple features to dynamically analyze the pattern and deliver the final verdict about the app's property. Finally, it is proved by conducting experiments, that the accuracy rate of SAMLDroid is up to 98.4%, which is nearly 20% higher than Apparecium.

Synthesis and therapeutic effect of styrene-maleic acid copolymer-conjugated pirarubicin.

Previously, we prepared a pirarubicin (THP)-encapsulated micellar drug using styrene-maleic acid copolymer (SMA) as the drug carrier, in which active THP was non-covalently encapsulated. We have now developed covalently conjugated SMA-THP (SMA-THP conjugate) for further investigation toward clinical development, because covalently linked polymer-drug conjugates are known to be more stable in circulation than drug-encapsulated micelles. The SMA-THP conjugate also formed micelles and showed albumin binding capacity in aqueous solution, which suggested that this conjugate behaved as a macromolecule during blood circulation. Consequently, SMA-THP conjugate showed significantly prolonged circulation time compared to free THP and high tumor-targeting efficiency by the enhanced permeability and retention (EPR) effect. As a result, remarkable antitumor effect was achieved against two types of tumors in mice without apparent adverse effects. Significantly, metastatic lung tumor also showed the EPR effect, and this conjugate reduced metastatic tumor in the lung almost completely at 30 mg/kg once i.v. (less than one-fifth of the maximum tolerable dose). Although SMA-THP conjugate per se has little cytotoxicity in vitro (1/100 of free drug THP), tumor-targeted accumulation by the EPR effect ensures sufficient drug concentrations in tumor to produce an antitumor effect, whereas toxicity to normal tissues is much less. These findings suggest the potential of SMA-THP conjugate as a highly favorable candidate for anticancer nanomedicine with good stability and tumor-targeting properties in vivo.

Stages of change, determinants, and mortality for smoking cessation in adult Taiwanese screenees.

We aimed to investigate the associations between three smoking-related constructs (pros and cons of smoking, temptation to smoke, and self-efficacy of resisting smoking) and stage of change (precontemplation, contemplation, preparation, and action) based on the transtheoretical model among smokers attending a community-based screening program. We also assessed their effects on long-term all-cause mortality. A prospective cohort study, with an average of 7 years of follow-up, was conducted by enrolling 454 male smoking screenees. The comparisons of the mean score of each variable pertaining to three smoking-related constructs across four stages of smoking cessation were assessed by analysis of variance. The impacts of both smoking-related constructs and smoking cessation stage measured at baseline on 7-year mortality were assessed by using proportional hazards regression model. The differences in the mean scores of pros and cons of smoking, temptation to smoke, and self-efficacy of resisting smoking across four stages of smoking cessation were statistically significant (P < 0.01). The precontemplation group and the contemplation group as opposed to the action group increased the risk for all-cause mortality, but the size of effect was not statistically significant (P = 0.39) when age, duration of smoking, and three smoking- related constructs were controlled. Those with a lower social aspect of self-efficacy were approximately threefold [adjusted hazard ratio = 3.22 (95 % CI 1.26-8.21)] risk for all-cause death compared with those with a higher one. Three smoking-related constructs were highly associated with smoking cessation stage, and low self-efficacy was independently predictive of long-term mortality among male smokers attending a community-based screening program.

Molecular cloning and functional characterization of the hepcidin gene from the convict cichlid (Amatitlania nigrofasciata) and its expression pattern in response to lipopolysaccharide challenge.

The hepcidin gene is widely expressed in many fish species and functions as an antimicrobial peptide, suggesting that it plays an important role in the innate immune system of fish. In the present study, the Amatitlania nigrofasciata hepcidin gene (AN-hepc) was cloned from the liver and its expression during an immune response was characterized. The results of quantitative PCR and RT-PCR showed that the AN-hepc transcript was most abundant in the liver. The expression of AN-hepc mRNA was significantly increased in the liver, stomach, heart, intestine, gill and muscle but was not significantly altered in the spleen, kidney, brain or skin after lipopolysaccharide challenge. The synthetic AN-hepc peptide showed a wide spectrum of antimicrobial activity in vitro toward gram-positive and gram-negative bacteria. In particular, this peptide demonstrated potent antimicrobial activity against the aquatic pathogens Vibrio alginolyticus, V. parahaemolyticus, V. vulnificus, Aeromonas hydrophila and Streptococcus agalactiae. The in vivo bacterial challenge results demonstrated that the synthetic AN-hepc peptide significantly improved the survival rate of S. agalactiae- and V. vulnificus-infected zebrafish. Taken together, these data indicate an important role for AN-hepc in the innate immunity of A. nigrofasciata and suggest its potential application in aquaculture for increasing resistance to disease.

Upregulation of heme oxygenase-1 in colorectal cancer patients with increased circulation carbon monoxide levels, potentially affects chemotherapeutic sensitivity.

BACKGROUND: Heme oxygenase-1 (HO-1) and its major product carbon monoxide (CO) are known to be involved in the development and progression of many tumors. The present study was to elucidate the expression and function of HO-1 in colorectal cancer (CRC), specially focusing on the circulation CO levels in CRC patients and the possible roles of HO-1 in chemoresistance of colon cancer cells. METHODS: One hundred and eighteen patients received resection for colorectal cancer and polyps at China Medical University Sheng Jing Hospital, were collected in this study. HO-1 expression in CRC tissues was analyzed by immnuohistochemical staining; circulation CO levels as carboxyhemoglobin (COHb) in CRC patients were analyzed by an ABL800 FLEX blood gas analyzer. HO-1 expression in murine colon cells C26 and human colon cancer cells HT29 and DLD1 under HO-1 inducer hemin and anticancer drug pirarubicin (THP) treatment was examined by RT-PCR, and the cell viability after each treatment was investigated by MTT assay. Data were analyzed by student's t-test or one-way ANOVA followed by Bonferroni t-test or Fisher's exact test. RESULTS: HO-1 expression in tumor tissues of CRC (61.0%) was significantly higher than in normal colorectal tissues and polyps tissues (29.7%, P < 0.01); well-differentiated CRC seemed to express more HO-1 (81.5%) than moderately/poorly-differentiated cancers (59.5%, P < 0.05). However, the nuclear HO-1 expression is apparently higher in moderately/poorly differentiated CRC than well-differentiated CRC probably suggesting a new mechanism of function involved in HO-1 in cancer. In parallel with HO-1 expression, circulation CO levels in CRC patients also significantly accelerated. Moreover, HO-1 expression/induction also related to the chemosensitivity of colon cells; HO inhibitor zinc protoporphyrin significantly increased cytotoxicities of THP (i.e., 2.6 - 5.3 folds compared to cells without zinc protoporphyrin treatment). CONCLUSIONS: These findings strongly suggested HO-1/COHb is a useful diagnostic and prognostic indicator for CRC, and inhibition of HO-1 may be a option to enhance the chemotherapeutic effects of conventional anticancer drugs toward CRC.

Protection from inflammatory bowel disease and colitis-associated carcinogenesis with 4-vinyl-2,6-dimethoxyphenol (canolol) involves suppression of oxidative stress and inflammatory cytokines.

Oxidative stress is associated with various pathological processes including inflammatory bowel disease, which is a major cause of colon cancer. Here, we examined the antioxidative and anti-inflammatory effects of 4-vinyl-2,6-dimethoxyphenol (canolol), a potent antioxidant compound obtained from crude canola oil. Oral administration of 2% dextran sulfate sodium (DSS) resulted in the progression of colitis with shortening of the large bowel length. Administering a diet containing canolol significantly suppressed pathogenesis; diarrhea markedly improved and the length of large bowel returned to almost normal. Pathological examination clearly revealed improvement of colonic ulcers. Production of inflammatory cytokines, i.e. interleukin-12 and tumor necrosis factor-α, was significantly increased during this pathological process; their production was markedly inhibited by canolol. In the azoxymethane/DSS-induced colon cancer model, mice receiving canolol had a reduced occurrence of cancer, to 60%, compared with control mice, 100% of which had colon cancer. The numbers of tumors in each mouse were also significantly reduced in mice receiving the canolol-containing diet (5.6±2.0) compared with azoxymethane/DSS control mice (10.8±4.2). No apparent toxicity of canolol was observed. Moreover, inflammatory cytokines (i.e. cyclooxygenase-2, inducible nitric oxide synthase and tumor necrosis factor-α) and oxidative responding molecules, i.e. heme oxygenase-1, in colon were suppressed during this treatment. In a mouse colon 26 solid tumor model, canolol significantly suppressed cyclooxygenase-2 expression; however, no significant tumor growth inhibition was observed, suggesting that canolol preferably shows chemopreventive effects during the stages of initiation/promotion. Canolol may, thus, be considered a potential cancer preventive agent or supplement.

Comparison of the clinical effects for different positions of the weight-bearing axis after high tibial osteotomy.

PURPOSE: To analyze the clinical effects of different positions of the weight-bearing axis (WBA) after high tibial osteotomy (HTO). METHODS: The clinical data of 90 patients who underwent HTO in the Department of Orthopedics at our hospital from June 2018 to June 2021 were retrospectively analyzed. Patients were divided into groups A and B (n = 45 per group) according to different post-HTO WBA positions of the affected side. WBAs in both groups were at 50-60% and 62-66% of the tibial plateau, from inside to outside, respectively. American Hospital for Special Surgery Knee Score (HSS), visual analog scale (VAS) score, femorotibial angle (FTA), and medial proximal tibial angle (MPTA) were recorded and analyzed. RESULTS: All patients were followed up with for 12 months. HSS scores increased gradually and VAS scores decreased gradually in both groups preoperatively, and at 3 months, 6 months, and 1 year postoperatively (P < 0.05). Compared to group A, group B had better HHS scores at 6 months and 1 year postoperatively (P < 0.05). There was no significant between-group difference in VAS scores at all aforementioned timepoints (P > 0.05). Postoperative MPTA and FTA were 89.56° ± 2.18° and 177.11° ± 2.63° in group A, and 89.07° ± 1.98° and 177.07° ± 2.36° in group B, respectively, with no significant between-group difference (P > 0.05). CONCLUSION: Patients with post-HTO WBA ranges of 50-60% and 62-66% achieved knee joint function improvement and pain relief. Half a year later, those with a WBA range of 62-66% had better knee joint function scores. However, a comparison of long-term effects warrants further investigation.

Genome-wide CRISPR/Cas9 screening identifies a targetable MEST-PURA interaction in cancer metastasis.

BACKGROUND: Metastasis is one of the most lethal hallmarks of esophageal squamous cell carcinoma (ESCC), yet the mechanisms remain unclear due to a lack of reliable experimental models and systematic identification of key drivers. There is urgent need to develop useful therapies for this lethal disease. METHODS: A genome-wide CRISPR/Cas9 screening, in combination with gene profiling of highly invasive and metastatic ESCC sublines, as well as PDX models, was performed to identify key regulators of cancer metastasis. The Gain- and loss-of-function experiments were taken to examine gene function. Protein interactome, RNA-seq, and whole genome methylation sequencing were used to investigate gene regulation and molecular mechanisms. Clinical significance was analyzed in tumor tissue microarray and TCGA databases. Homology modeling, modified ELISA, surface plasmon resonance and functional assays were performed to identify lead compound which targets MEST to suppress cancer metastasis. FINDINGS: High MEST expression was associated with poor patient survival and promoted cancer invasion and metastasis in ESCC. Mechanistically, MEST activates SRCIN1/RASAL1-ERK-snail signaling by interacting with PURA. miR-449a was identified as a direct regulator of MEST, and hypermethylation of its promoter led to MEST upregulation, whereas systemically delivered miR-449a mimic could suppress tumor metastasis without overt toxicity. Furthermore, molecular docking and computational screening in a small-molecule library of 1,500,000 compounds and functional assays showed that G699-0288 targets the MEST-PURA interaction and significantly inhibits cancer metastasis. INTERPRETATION: We identified the MEST-PURA-SRCIN1/RASAL1-ERK-snail signaling cascade as an important mechanism underlying cancer metastasis. Blockade of MEST-PURA interaction has therapeutic potential in management of cancer metastasis. FUNDING: This work was supported by National Key Research and Development Program of China (2021YFC2501000, 2021YFC2501900, 2017YFA0505100); National Natural Science Foundation of China (31961160727, 82073196, 81973339, 81803551); NSFC/RGC Joint Research Scheme (N_HKU727/19); Natural Science Foundation of Guangdong Province (2021A1515011158, 2021A0505030035); Key Laboratory of Guangdong Higher Education Institutes of China (2021KSYS009).

Lysine 2-hydroxyisobutyrylation of NAT10 promotes cancer metastasis in an ac4C-dependent manner.

Posttranslational modifications add tremendous complexity to proteomes; however, gaps remain in knowledge regarding the function and regulatory mechanism of newly discovered lysine acylation modifications. Here, we compared a panel of non-histone lysine acylation patterns in metastasis models and clinical samples, and focused on 2-hydroxyisobutyrylation (Khib) due to its significant upregulation in cancer metastases. By the integration of systemic Khib proteome profiling in 20 paired primary esophageal tumor and metastatic tumor tissues with CRISPR/Cas9 functional screening, we identified N-acetyltransferase 10 (NAT10) as a substrate for Khib modification. We further showed that Khib modification at lysine 823 in NAT10 functionally contribute to metastasis. Mechanistically, NAT10 Khib modification enhances its interaction with deubiquitinase USP39, resulting in increased NAT10 protein stability. NAT10 in turn promotes metastasis by increasing NOTCH3 mRNA stability in an N4-acetylcytidine-dependent manner. Furthermore, we discovered a lead compound #7586-3507 that inhibited NAT10 Khib modification and showed efficacy in tumor models in vivo at a low concentration. Together, our findings bridge newly identified lysine acylation modifications with RNA modifications, thus providing novel insights into epigenetic regulation in human cancer. We propose that pharmacological inhibition of NAT10 K823 Khib modification constitutes a potential anti-metastasis strategy.

New insights into the interplay between long non-coding RNAs and RNA-binding proteins in cancer.

With the development of proteomics and epigenetics, a large number of RNA-binding proteins (RBPs) have been discovered in recent years, and the interaction between long non-coding RNAs (lncRNAs) and RBPs has also received increasing attention. It is extremely important to conduct in-depth research on the lncRNA-RBP interaction network, especially in the context of its role in the occurrence and development of cancer. Increasing evidence has demonstrated that lncRNA-RBP interactions play a vital role in cancer progression; therefore, targeting these interactions could provide new insights for cancer drug discovery. In this review, we discussed how lncRNAs can interact with RBPs to regulate their localization, modification, stability, and activity and discussed the effects of RBPs on the stability, transport, transcription, and localization of lncRNAs. Moreover, we explored the regulation and influence of these interactions on lncRNAs, RBPs, and downstream pathways that are related to cancer development, such as N6-methyladenosine (m6A) modification of lncRNAs. In addition, we discussed how the lncRNA-RBP interaction network regulates cancer cell phenotypes, such as proliferation, apoptosis, metastasis, drug resistance, immunity, tumor environment, and metabolism. Furthermore, we summarized the therapeutic strategies that target the lncRNA-RBP interaction network. Although these treatments are still in the experimental stage and various theories and processes are still being studied, we believe that these strategies may provide new ideas for cancer treatment.

Targeting PFKL with penfluridol inhibits glycolysis and suppresses esophageal cancer tumorigenesis in an AMPK/FOXO3a/BIM-dependent manner.

As one of the hallmarks of cancer, metabolic reprogramming leads to cancer progression, and targeting glycolytic enzymes could be useful strategies for cancer therapy. By screening a small molecule library consisting of 1320 FDA-approved drugs, we found that penfluridol, an antipsychotic drug used to treat schizophrenia, could inhibit glycolysis and induce apoptosis in esophageal squamous cell carcinoma (ESCC). Gene profiling and Ingenuity Pathway Analysis suggested the important role of AMPK in action mechanism of penfluridol. By using drug affinity responsive target stability (DARTS) technology and proteomics, we identified phosphofructokinase, liver type (PFKL), a key enzyme in glycolysis, as a direct target of penfluridol. Penfluridol could not exhibit its anticancer property in PFKL-deficient cancer cells, illustrating that PFKL is essential for the bioactivity of penfluridol. High PFKL expression is correlated with advanced stages and poor survival of ESCC patients, and silencing of PFKL significantly suppressed tumor growth. Mechanistically, direct binding of penfluridol and PFKL inhibits glucose consumption, lactate and ATP production, leads to nuclear translocation of FOXO3a and subsequent transcriptional activation of BIM in an AMPK-dependent manner. Taken together, PFKL is a potential prognostic biomarker and therapeutic target in ESCC, and penfluridol may be a new therapeutic option for management of this lethal disease.

Anti-HIV Drug Elvitegravir Suppresses Cancer Metastasis via Increased Proteasomal Degradation of m6A Methyltransferase METTL3.

N6-methyladenosine (m6A) methylation is an abundant modification in eukaryotic mRNAs. Accumulating evidence suggests a role for RNA m6A methylation in various aspects of cancer biology. In this study, we aimed to explore the biological role of RNA m6A modification in tumor metastasis and to identify novel therapeutic strategies for esophageal squamous cell carcinoma (ESCC). Integration of genome-wide CRISPR/Cas9 functional screening with highly invasive and metastatic ESCC subline models led to the identification of METTL3, the catalytic subunit of the N6-adenosine-methyltransferase complex, as a promoter of cancer metastasis. METTL3 expression was upregulated in ESCC tumors and metastatic tissues. In vitro and in vivo experiments indicated that METTL3 increased m6A in EGR1 mRNA and enhanced its stability in a YTHDF3-dependent manner, activating EGR1/Snail signaling. Investigation into the regulation of METTL3 expression found that KAT2A increased H3K27 acetylation levels in the METTL3 promoter region and activated transcription of METTL3, whereas SIRT2 exerted the opposite effects. Molecular docking and computational screening in a Food and Drug Administration-approved compound library consisting of 1,443 small molecules identified compounds targeting METTL3 to suppress cancer metastasis. Elvitegravir, originally developed to treat human immunodeficiency virus (HIV) infection, suppressed metastasis by directly targeting METTL3 and enhancing its STUB1-mediated proteasomal degradation. Overall, RNA m6A modifications are important in cancer metastasis, and targeting METTL3 with elvitegravir has therapeutic potential for treating ESCC. SIGNIFICANCE: This study finds that METTL3 promotes cancer metastasis by activating EGR1/Snail signaling in an m6A-dependent manner, revealing vulnerability to METTL3 blockade in esophageal squamous cell carcinoma.

Blockade of Nuclear ß-Catenin Signaling via Direct Targeting of RanBP3 with NU2058 Induces Cell Senescence to Suppress Colorectal Tumorigenesis.

Colorectal cancer (CRC) is one of the most common malignant tumors in the world, with high prevalence and low 5-year survival. Most of the CRC patients show excessive activation of the Wnt/ß-catenin pathway which is a vital target for CRC treatment. Based on multiple CRC cell lines with different nuclear expression of ß-catenin, NU2058 is identified from a small molecule library consisting of 280 bioactive compounds and found to selectively inhibit the proliferation of CRC cells with nuclear ß-catenin activation in vitro and in vivo. The translational significance of NU2058 alone or in combination with chemotherapeutic drugs oxaliplatin and irinotecan (SN38) in CRC is demonstrated in orthotopic tumor model and patient-derived xenograft models. By integrating limited proteolysis-small molecule mapping (LiP-SMap) and mass spectrometry (MS), Ran-binding protein 3 (RanBP3) is identified as the direct target of NU2058. The results show that RanBP3 is a tumor suppressor in CRC and is associated with patient survival. Mechanistically, NU2058 increases the interaction of RanBP3 and ß-catenin to promote nuclear export of ß-catenin, which further inhibits transcription of c-Myc and cyclin D1 to induce cell senescence. Collectively, NU2058 may serve as a promising therapeutic agent for CRC patients with selective disruption of pathologic Wnt/ß-catenin signaling.

Mortality and suicide after self-harm: community cohort study in Taiwan.

BACKGROUND: Little is known about outcomes after self-harm in East Asia. AIMS: To investigate mortality after self-harm in a Taiwanese population. METHOD: Between 2000 and 2003, 1083 individuals who self-harmed were identified through a population self-harm register in Nantou County, Taiwan, and followed until 2007 for date and cause of death on a national mortality database. RESULTS: In total, 145 individuals died, 48 through suicide. The risks of all-cause and suicide mortality in the first year were 4.7% and 2.1% respectively, representing 8- and 131-fold age- and gender-standardised increases. Male gender and older age were independent risk factors for both suicide and non-suicide mortality. Use of more lethal methods in the index episode was associated with higher mortality but this was accounted for by gender. CONCLUSIONS: Results in this sample support the recommendation that people with a history of recent self-harm should be a major target for suicide prevention programmes.

Targeting PP2A with lomitapide suppresses colorectal tumorigenesis through the activation of AMPK/Beclin1-mediated autophagy.

Colorectal cancer (CRC) is one of the most common malignancies worldwide, and effective therapy remains a challenge. In this study, we take advantage of a drug repurposing strategy to screen small molecules with novel anticancer activities in a small-molecule library consisting of 1056 FDA-approved drugs. We show, for the first time, that lomitapide, a lipid-lowering agent, exhibits antitumor properties in vitro and in vivo. Activated autophagy is characterized as a key biological process in lomitapide-induced CRC repression. Mechanistically, lomitapide stimulated mitochondrial dysfunction-mediated AMPK activation, resulting in increased AMPK phosphorylation and enhanced Beclin1/Atg14/Vps34 interactions, provoking autophagy induction. Autophagy inhibition or AMPK silencing significantly abrogated lomitapide-induced cell death, indicating the significance of AMPK-regulated autophagy in the antitumor activities of lomitapide. More importantly, PP2A was identified as a direct target of lomitapide by limited proteolysis-mass spectrometry (LiP-SMap), and the bioactivity of lomitapide was attenuated in PP2A-deficient cells, suggesting that the anticancer effect of lomitapide occurs in a PP2A-dependent manner. Taken together, the results of the study reveal that lomitapide can be repositioned as a potential therapeutic drug for CRC treatment.

Anti-allergic drug azelastine suppresses colon tumorigenesis by directly targeting ARF1 to inhibit IQGAP1-ERK-Drp1-mediated mitochondrial fission.

This study aimed to screen novel anticancer strategies from FDA-approved non-cancer drugs and identify potential biomarkers and therapeutic targets for colorectal cancer (CRC). Methods: A library consisting of 1056 FDA-approved drugs was screened for anticancer agents. WST-1, colony-formation, flow cytometry, and tumor xenograft assays were used to determine the anticancer effect of azelastine. Quantitative proteomics, confocal imaging, Western blotting and JC-1 assays were performed to examine the effects on mitochondrial pathways. The target protein of azelastine was analyzed and confirmed by DARTS, WST-1, Biacore and tumor xenograft assays. Immunohistochemistry, gain- and loss-of-function experiments, WST-1, colony-formation, immunoprecipitation, and tumor xenograft assays were used to examine the functional and clinical significance of ARF1 in colon tumorigenesis. Results: Azelastine, a current anti-allergic drug, was found to exert a significant inhibitory effect on CRC cell proliferation in vitro and in vivo, but not on ARF1-deficient or ARF1-T48S mutant cells. ARF1 was identified as a direct target of azelastine. High ARF1 expression was associated with advanced stages and poor survival of CRC. ARF1 promoted colon tumorigenesis through its interaction with IQGAP1 and subsequent activation of ERK signaling and mitochondrial fission by enhancing the interaction of IQGAP1 with MEK and ERK. Mechanistically, azelastine bound to Thr-48 in ARF1 and repressed its activity, decreasing Drp1 phosphorylation. This, in turn, inhibited mitochondrial fission and suppressed colon tumorigenesis by blocking IQGAP1-ERK signaling. Conclusions: This study provides the first evidence that azelastine may be novel therapeutics for CRC treatment. ARF1 promotes colon tumorigenesis, representing a promising biomarker and therapeutic target in CRC.

Non-fatal repetition of self-harm: population-based prospective cohort study in Taiwan.

BACKGROUND: Repeated self-harm is relatively common and is linked with an elevated risk of eventual suicide. There has been no study of this involving a large sample from the Far East. AIMS: To estimate the risk over the medium term of non-fatal repetition of self-harm and identify predictive factors in those carrying out self-harm. METHOD: A total of 970 individuals who had self-harmed were recruited from a community-based suicide behaviour register system in Nantou, Taiwan from July 2000 to February 2003. Information regarding demography and suicide methods was collected. Individuals were followed-up until December 2005 to examine the risk of repeated self-harm and independent predictive factors. RESULTS: Ninety cohort members had repeated self-harm during the follow-up period (accounting for 131 repeated self-harm episodes in all). The cumulative risks were 5.7% for the first year, 7.8% for the second year and 9.5% for the fourth year. The risk was highest within the first year after the self-harm event. Independent risk factors included female gender and self-cutting as well as self-poisoning with drugs. Effect of younger age was mediated through the choice of methods. CONCLUSIONS: Individuals with self-harm have a high risk of repetition, especially within the first year. Suicide prevention strategies need to focus on intervening with this population to reduce their repetition.

Echinatin suppresses esophageal cancer tumor growth and invasion through inducing AKT/mTOR-dependent autophagy and apoptosis.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with poor survival. It is urgent to search for new efficient drugs with good stability and safety for clinical therapy. This study aims to identify potential anticancer drugs from a compound library consisting of 429 natural products. Echinatin, a compound isolated from the Chinese herb Glycyrrhiza uralensis Fisch, was found to markedly induce apoptosis and inhibit proliferation and colony-formation ability in ESCC. Confocal fluorescence microscopy data showed that echinatin significantly induced autophagy in ESCC cells, and autophagy inhibitor bafilomycinA1 attenuated the suppressive effects of echinatin on cell viability and apoptosis. Mechanistically, RNA sequencing coupled with bioinformatics analysis and a series of functional assays revealed that echinatin induced apoptosis and autophagy through inactivation of AKT/mTOR signaling pathway, whereas constitutive activation of AKT significantly abrogated these effects. Furthermore, we demonstrated that echinatin had a significant antitumor effect in the tumor xenograft model and markedly suppressed cell migration and invasion abilities of ESCC cells in a dose-dependent manner. Our findings provide the first evidence that echinatin could be a novel therapeutic strategy for treating ESCC.