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Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.

The aim of study was to address the effects of manganese and iron, alone and in combination, on apoptosis of BV2 microglia cells, and to determine if combined exposure to these metals augments their individual toxicity. We used a murine microglial BV2 cell line. Cell cytotoxicity was analyzed by propidium iodide (PI) exclusion assay. Cell ROS production was analyzed by 2′, 7′-dichlorofluorescin diacetate (DCFH-DA) probe staining. Pro-inflammatory cytokine production was monitored by ELISA. Cell apoptosis was analyzed by PE Annexin V/7-AAD staining. Mitochondrial membrane integrity was analyzed by flow cytometry. We used immunoblotting to analyze the effect of manganese, iron alone, or their combined exposure on the activation of caspase9, P53, Bax, and Bcl2 apoptosis signaling pathways. Caspase3 activity was determined using a Colorimetric. Manganese, iron, and their combined exposure for 24 h induced the activation of BV2 microglia cells and increased ROS production and the expression of the inflammatory cytokines, IL-1β and TNF-α. And we also found that the apoptosis rate increased, mitochondrial membrane potential decreased, apoptosis-related proteins caspase9, P53, Bax, and Bcl2 expression increased, and caspase3 activity increased. Furthermore, we found that combined manganese-iron cytotoxicity was lower than that induced by manganese exposure alone. Manganese, iron alone, or their combination exposure can induce apoptosis in glial cells. Iron can reduce the toxicity of manganese, and there is an antagonistic effect between manganese and iron.

Background Microdissection testicular sperm extraction (micro-TESE) is an effective method to retrieve sperm from non-obstructive azoospermia (NOA) patients. However, the predictive factors for sperm retrieval rate (SRR) remain confused. The goal of our study was to identify the role of testicular pathological morphometric parameters, including diameter of tubule (DT), height of spermatogenic epithelium (HSE), and thickness of basement-membrane (TBM) in NOA patients, and to develop a predictive model and nomogram to predict SRR based on these morphometric parameters. Methods This study involved two cohorts including 406 men with NOA. A retrospective cohort of 313 males with NOA who underwent micro-TESE at Northwest Women’s and Children’s Hospital (Xi’an, China) were included to build a prediction model of SRR. Then, another retrospective cohort of 93 males with NOA from Ren Ji Hospital (Shanghai, China) were recruited to validate the prediction model. The measurement of testicular morphometric parameters as well as the assessment of Johnsen score and pathological diagnostic types were performed by at least two pathologists. Testicular volumes as well as level of serum hormones including follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) were also measured. Logistic regressions were used to test potential predictors of SRR. Area under curve (AUC) estimates was used to evaluate the predictive accuracy. The validation datasets were used to validate the prediction model by prediction accuracy. Results Our study demonstrated that DT and HSE were significantly longer in successful sperm retrieval group than in failed sperm retrieval group. In addition, DT and HSE were positively correlated with Johnsen score, testicular volume, and serum T, while, were negatively correlated with serum FSH and serum LH. On the contrary, TBM demonstrated exact opposite results. Moreover, univariate logistic analyses illustrated that longer DT and HSE was associated with a high SRR, respectively. Further multivariate logistic analyses constructed multi-variables models with better predictive abilities compared with single-variables models. A multi-variables model (predicting score = -0.612–0.018 × DT + 0.040 × HSE + 0.097 × Johnsen score-0.004 × serum FSH) was finally constructed with the best predictive ability (AUC = 0.839, sensitivity = 71.4% specificity = 77.5%, cut-off value = 0.489). A higher predicting score indicated a higher possibility of successful sperm retrieval. The predictive accuracy was 89.25% in the external validation dataset. Conclusion We report for the first time that DT and HSE have pretty ability to predict SRR in NOA patients.

Background This study aimed at investigating the relationship between the weekend catch-up outdoor duration (WCOD) and prevalence of myopia among students in China. Methods This cross-sectional study recruited participants in 107 schools (six cities, 30 districts) from China from May to June 2021. Demographic characteristics (age, grade, sex, ethnicity, BMI, resident, and parents’ myopia), optically habits (bad writing habits, working/studying time per day, continuous working/studying time per day, and screen time per day) and outdoor duration (weekday and weekend) were obtained from questionnaire. WCOD was defined as outdoor time 1 h longer on weekends than on weekdays. Spherical equivalent (SE) of refractive error were measured with non-cycloplegic refraction. Adjusted multivariate logistic regression analysis was performed to evaluate the relationship between WCOD and prevalence of myopia. Results Students with myopia had shorter WCOD compared with those without myopia ( P  < 0.001). Adjusted multivariate logistic regression analyses showed negative associations between WCOD and prevalence of myopia in Chinese students, especially in students with WCOD of 2–3 h (OR = 0.577, P  < 0.001) and 3–4 h (OR = 0.571, P  = 0.004) when the weekday outdoor duration was 0.5–1 h, as well as students with WCOD of 2–3 h (OR = 0.614, P  = 0.003) when the weekday outdoor duration was 1–2 h. Similar results were observed in students with high myopia. Students with high myopia had shorter WCOD compared with those without high myopia ( P  = 0.001). Negative associations between WCOD and prevalence of high myopia were significant in students with WCOD of 1–2 h when the weekday outdoor duration was < 0.5 h (OR = 0.585, P  = 0.007) and 0.5–1 h (OR = 0.537, P  = 0.018). Conclusion Our study, for the first time, reported that a WCOD have a potential to reduce the prevalence of myopia and high myopia in Chinese students.

Neurodevelopmental disorders are currently one of the major complications faced by patients with congenital heart disease (CHD). Chronic hypoxia in the prenatal and postnatal preoperative brain may be associated with neurological damage and impaired long-term cognitive function, but the exact mechanisms are unknown. In this study, we find that delayed neuronal migration and impaired synaptic development are attributed to altered Atoh1 under chronic hypoxia. This is due to the fact that excessive Atoh1 facilitates expression of Kif21b, which causes excess in free-state α-tubulin, leading to disrupted microtubule dynamic stability. Furthermore, the delay in neonatal brain maturation induces cognitive disabilities in adult mice. Then, by down-regulating Atoh1 we alleviate the impairment of cell migration and synaptic development, improving the cognitive behavior of mice to some extent. Taken together, our work unveil that Atoh1 may be one of the targets to ameliorate hypoxia-induced neurodevelopmental disabilities and cognitive impairment in CHD. Atoh1 hinders neuronal dendritic branching, cell migration and long-term cognitive functions by modulating Kif21b to disrupt microtubule’s dynamic stability under perinatal chronic hypoxia.

Dissimilarity nitrate reduction to ammonium (DNRA) is of significance in agriculture ecosystems as the process is beneficial to N retention in soils. However, how fertilization regimes influence DNRA rates and functional microbes in agriculture was rarely estimated. In the present study, a 2-year pot experiment was conducted in two contrasting paddy soils to evaluate the effects of straw and nitrogen addition on DNRA process and the related functional microbes, using stable isotope tracer and molecular ecology techniques. The results showed that the abundance and transcription activity of nitrite reductase encoding gene ( nrfA) involved in DNRA process and DNRA rates were significantly higher in alkaline soils than in acidic soils. Straw incorporation significantly enhanced nrfA gene abundance and transcription activity, with a greater effect in alkaline soil than in acidic soil. The rates of DNRA, abundance and transcription activity of nrfA gene positively correlated to soil C/N and C/NO 3 − induced by straw application. Sequencing analysis based on nrfA gene transcript showed that Deltaproteobacteria was the most dominant group in both soil types (30.9% -67.4%), while Gammaproteobacteria, Chloroflexi, Actinobacteria were selectively enriched by straw incorporation. These results demonstrated that DNRA activity can be improved by straw return practice in paddy soils while the effect will vary among soil types due to differentiated functional microbial communities and edaphic properties.

N3 gastric cancer (GC) is characterized by a heavy burden of lymph node metastasis and a high postoperative recurrence rate. The role of radiotherapy in this group of patients remains undetermined. The purpose of this study was to compare the effectiveness of adjuvant chemoradiotherapy (CRT) and adjuvant chemotherapy (ChT) for N3 GC after D2/R0 resection. From January 2004 to December 2015, patients with N3 GC in the database of Fudan University Shanghai Cancer Center were retrospectively reviewed. The eligible patients were enrolled in an adjuvant CRT group and an adjuvant ChT group. Four different methods based on a propensity score model were used to balance the baseline characteristics. Then, survival analyses between the two groups were performed in addition to patterns of recurrence and subgroup analyses. In total, 175 and 365 eligible patients were enrolled into the CRT and ChT groups, respectively. After balancing, the disease-free survival (DFS) of patients in the CRT group was significantly better than that of patients in the ChT group ( =0.021). Subgroup analyses showed that patients with N3a GC benefitted from adjuvant CRT. Compared with adjuvant ChT, adjuvant CRT can further improve the DFS of patients with N3 GC after D2/R0 resection. Patients with lymph node metastases should be further stratified when selecting patients for adjuvant CRT.