High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is ...rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9
tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.
Previous studies have shown a relationship between type 2 diabetes mellitus and birth weight. We performed this meta-analysis to resolve the problem of inconsistent results. We conducted a literature ...search of PubMed, Embase and the Cochrane Library using “Diabetes Mellitus, Type 2,” “Birth Weight,” and some related free words. Twenty-one studies were included in accordance with inclusion and exclusion criteria, involving a total of 313,165 participants and 22,341 type 2 diabetes mellitus cases. A modified version of the Newcastle-Ottawa Scale was used to evaluate the methodological quality of studies included. We used Review Manager 5.3 for data merging and statistical analysis. Results were expressed as odds ratio (OR) and 95% confidence interval (95% CI). The risk of diabetes with low birth weight (<2,500 g) was higher than that with birth weight ≥2,500 g, (OR = 1.51, 95% CI: 1.43, 1.58). Compared with normal birth weight (2,500–4,000 g), low birth weight, but not high birth weight, increased the risk of diabetes (OR = 1.41, 95% CI: 1.26, 1.58). There is a negative association between birth weight and the future risk of type 2 diabetes mellitus.
Over the last two decades, there has been an increasing awareness of the role of eicosanoids in the development and progression of several types of cancer, including breast, prostate, lung, and ...colorectal cancers. Several processes involved in cancer development, such as cell growth, migration, and angiogenesis, are regulated by the arachidonic acid derivative thromboxane A2 (TXA2). Higher levels of circulating TXA2 are observed in patients with multiple cancers, and this is accompanied by overexpression of TXA2 synthase (TBXAS1, TXA2S) and/or TXA2 receptors (TBXA2R, TP). Overexpression of TXA2S or TP in tumor cells is generally associated with poor prognosis, reduced survival, and metastatic disease. However, the role of TXA2 signaling in the stroma during oncogenesis has been underappreciated. TXA2 signaling regulates the tumor microenvironment by modulating angiogenic potential, tumor ECM stiffness, and host immune response. Moreover, the by-products of TXA2S are highly mutagenic and oncogenic, adding to the overall phenotype where TXA2 synthesis promotes tumor formation at various levels. The stability of synthetic enzymes and receptors in this pathway in most cancers (with few mutations reported) suggests that TXA2 signaling is a viable target for adjunct therapy in various tumors to reduce immune evasion, primary tumor growth, and metastasis.
Abstract Background Cesarean section-induced postpartum hemorrhage (PPH) potentially causes anemia and hypovolemic shock in pregnant women. Hence, it is helpful for obstetricians and ...anesthesiologists to prepare pre-emptive prevention when predicting PPH occurrence in advance. However, current works on PPH prediction focus on whether PPH occurs rather than assessing PPH amount. To this end, this work studies quantitative PPH prediction with machine learning (ML). Methods The study cohort in this paper was selected from individuals with PPH who were hospitalized at Shijiazhuang Obstetrics and Gynecology Hospital from 2020 to 2022. In this study cohort, we built a dataset with 6,144 subjects covering clinical parameters, anesthesia operation records, laboratory examination results, and other information in the electronic medical record system. Based on our built dataset, we exploit six different ML models, including logistic regression, linear regression, gradient boosting, XGBoost, multilayer perceptron, and random forest, to automatically predict the amount of bleeding during cesarean section. Eighty percent of the dataset was used as model training, and 20 $$\%$$ % was used for verification. Those ML models are constantly verified and improved by root mean squared error(RMSE) and mean absolute error(MAE). Moreover, we also leverage the importance of permutation and partial dependence plot (PDP) to discuss their feasibility. Result The experiment results show that random forest obtains the highest accuracy for PPH amount prediction compared to other ML methods. Random forest reaches the mean absolute error of 21.7, less than 5.4 $$\%$$ % prediction error. It also gains the root mean squared error of 33.75, less than 9.3 $$\%$$ % prediction error. On the other hand, the experimental results also disclose indicators that contributed most to PPH prediction, including Ca, hemoglobin, white blood cells, platelets, Na, and K. Conclusion It effectively predicts the amount of PPH during a cesarean section by ML methods, especially random forest. With the above insight, ML predicting PPH amounts provides early warning for clinicians, thus reducing complications and improving cesarean sections’ safety. Furthermore, the importance of ML and permutation, complemented by incorporating PDP, promises to provide clinicians with a transparent indication of individual risk prediction.
Macrophage activation is a hallmark of atherosclerosis, accompanied by a switch in core metabolism from oxidative phosphorylation to glycolysis. The crosstalk between metabolic rewiring and histone ...modifications in macrophages is worthy of further investigation. Here, we find that lactate efflux-associated monocarboxylate transporter 4 (MCT4)-mediated histone lactylation is closely related to atherosclerosis. Histone H3 lysine 18 lactylation dependent on MCT4 deficiency activated the transcription of anti-inflammatory genes and tricarboxylic acid cycle genes, resulting in the initiation of local repair and homeostasis. Strikingly, histone lactylation is characteristically involved in the stage-specific local repair process during M1 to M2 transformation, whereas histone methylation and acetylation are not. Gene manipulation and protein hydrolysis-targeted chimerism technology are used to confirm that MCT4 deficiency favors ameliorating atherosclerosis. Therefore, our study shows that macrophage MCT4 deficiency, which links metabolic rewiring and histone modifications, plays a key role in training macrophages to become repair and homeostasis phenotypes.
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•MCT4 is highly expressed in macrophages of atherosclerotic plaque•Macrophage MCT4 deficiency enhances p300-mediated histone lactylation•H3K18la initiates macrophage repair and promotes inflammatory resolution
Zhang et al. show that MCT4 deficiency can enhance H3K18la level, which favors a reparative environment through improving anti-inflammatory activity and metabolic rewiring. They also show that administration of MCT4 inhibitors decreases atherosclerosis progression, demonstrating the therapeutic potential of MCT4 inhibitors in atherosclerosis.
Atherosclerosis is a chronic inflammatory disease of the vasculature characterised by the infiltration of activated neutrophils and macrophages at sites of damage within the vessel wall, which ...contributes to lesion formation and plaque progression. Selenomethionine (SeMet) is an organic form of selenium (Se), an essential trace element that functions in the regulation of the immune response by both bolstering the endogenous thioredoxin and glutathione antioxidant defence systems and by directly scavenging damaging oxidant species. This study evaluated the effect of dietary SeMet supplementation within a high fat diet fed apolipoprotein E deficient (ApoE−/-) mouse model of atherosclerosis. Dietary supplementation with SeMet (2 mg/kg) increased the tissue concentration of Se, and the expression and activity of glutathione peroxidase, compared to non-supplemented controls. Supplementation with SeMet significantly reduced atherosclerotic plaque formation in mouse aortae, resulted in a more stable lesion phenotype and improved vessel function. Concurrent with these results, SeMet supplementation decreased lesion accumulation of M1 inflammatory type macrophages, and decreased the extent of extracellular trap release from phorbol myristate acetate (PMA)-stimulated mouse bone marrow-derived cells. Importantly, these latter results were replicated within ex-vivo experiments on cultured neutrophils isolated from acute coronary syndrome patients, indicating the ability of SeMet to alter the acute inflammatory response within a clinically-relevant setting. Together, these data highlight the potential beneficial effect of SeMet supplementation as a therapeutic strategy for atherosclerosis.
Adverse childhood experiences (ACEs) are associated with an increased risk of poly-substance use among drug-using adults. However, there is a paucity of literature on a direct or indirect ...relationship between ACEs and drug use patterns. We thus aimed to identify the pathway of effects of ACEs on drug use patterns in adults by the structural equation model (SEM).
A cross-sectional study was conducted by respondent-driving sampling and consecutive sampling among adult drug users in Southwest China in 2021. Descriptive, univariate, and SEM analyses were performed by R software 4.2.1.
Of 406 participants recruited from a drug abuse clinic, the average age was 34 years. The majority of the participants were male patients (98.3%) from ethnic minorities (79.6%), who were unmarried (71.6%) and employed (81.2%). Nearly 95.5% experienced ACEs with 46.6% of them reporting four or more ACEs. The median value of self-perception of drug abuse score, friend drug use score, and drug use score was 8.0 (3.0, 11.0), 1.0 (0.0, 1.0), and 1.0 (1.0, 2.0) respectively. In the confirmatory analysis part of SEM, the construct of latent variables fitted well with the data. Poly-drug use was significantly and directly affected by three predictors including monthly incomes (β = 0.09), friend drug use (β = 0.50), and ACEs (β = 0.11). The indirect effect of ACEs passing through self-perception of drugs (β = 0.09) was not significant.
ACEs have an independent and direct effect on the drug user for poly-drug use apart from the effect of drug-using friends and family income.
Background
Oral allergy syndrome is a unique type of food allergy caused by cross-sensitivity between inhalant allergens and food allergens. Despite its significant prevalence and potentially serious ...outcome, the knowledge base and practice patterns on OAS are not well known among otolaryngologists. Our study is designed to understand the practice patterns of otolaryngologists in screening, testing, and treating OAS through a web-based survey.
Methods
Three thousand otolaryngologists were randomly selected from a membership list of the American Academy of Otolaryngology – Head and Neck Surgery. A survey was designed to include demographic questions and questions about OAS understanding, screening, and management. Surveys were sent to selected otolaryngologists via mail. Responses were de-identified and analyzed using SPSS.
Results
Out of the 50 survey responses, 46 reported treating environmental allergy in their practices. Twenty eight out of 46 reported knowing about OAS (60.9%). Fifteen out of the 28 physicians screened for OAS (53.6%). Out of the responders who knew about OAS, 12 (42.9%) reported diagnosing under 5 cases in the past year, 7 (25%) diagnosed 5 to 10 cases, and 7 (25%) reported diagnosed more than 10 cases in the past year. Eleven (39.3%) reported ordering component allergy testing for food allergies. Twenty six (92.9%) reported using avoidance, 18 (64.3%) prescribed oral antihistamine medications, 14 (50%) prescribed epi-pen, and 19 (67.9%) desensitized patients to environmental allergies as a treatment for OAS. 26 (93%) reported using more than one of the listed treatments. 10 (36%) reported using all four methods.
Conclusion
Only 60.9% of the responders had a knowledge of OAS. Only 53.6% of those screened for OAS. Current treatment for OAS includes avoidance of allergens, desensitization of environmental allergens, prescription of oral antihistamine and epi-pen. Nearly everyone (93%) reported using more than one treatment method.
Amphetamine-type stimulants (ATS) use has become popular in China. This study explored ATS use status and related risk factors of hepatitis C virus (HCV) infection among ATS users in Jinghong City, ...Xishuangbanna Prefecture, Yunnan Province, China.
A cross-sectional study was conducted by questionnaires from January to July 2021 in border area in Yunnan. Respondent driving sampling and consecutive sampling was carried out among border drug users, and blood samples were tested for HCV antibodies. HCV infection and related risk factors among ATS users were measured. Descriptive, univariate and multivariate analysis were conducted separately by Software SPSS 26.0.
The ATS users accounted for 85.82% (345/402) among drug users, while anti-HCV antibody prevalence was 6.38% (22/345) among ATS users. The combined use of other types of drugs (
= 7.29,
: 1.982-26.81,
= 0.003), injection drug use (
= 6.823,
: 1.898-24.525,
= 0.003), average monthly income (
= 4.825,
: 1.325-17.566,
= 0.017) might increase the risk of HCV infection among ATS users. ATS users with high school or above had higher HCV infection rates than those with primary school or below (
= 5.718,
: 1.172-27.908,
= 0.031).
Taken together, among drug users using ATS in Jinghong City, Xishuangbanna Autonomous Prefecture, Yunnan Province, combined use of multiple drugs and intravenous drug use was the high risk factor for HCV infection. Therefore, corresponding education and intervention measures should be taken.
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