Lactic acid (LA) accumulation in tumor microenvironments (TME) has been implicated in immune suppression and tumor progress. Diverse roles of LA have been elucidated, including microenvironmental pH regulation, signal transduction, post-translational modification, and metabolic remodeling. This review summarizes LA functions within TME, focusing on the effects on tumor cells, immune cells, and stromal cells. Reducing LA levels is a potential strategy to attack cancer, which inevitably affects the physiological functions of normal tissues. Alternatively, transporting LA into the mitochondria as an energy source for immune cells is intriguing. We underscore the significance of LA in both tumor biology and immunology, proposing the burning of LA as a potential therapeutic approach to enhance antitumor immune responses.
Humans ; Tumor Microenvironment/immunology* ; Neoplasms/therapy* ; Lactic Acid/immunology* ; Mitochondria/metabolism* ; Animals ; Signal Transduction

The dysregulation of cyclin-dependent kinase 12 (CDK12), which may result from genomic alterations or modulation by upstream effectors, is implicated in cancer oncogenesis and progression. CDK12 overexpression or activation is sufficient to induce tumor initiation, recurrence, and therapeutic resistance. However, CDK12 may also exert tumor-suppressive functions in a context-dependent manner. Therefore, caution is warranted when targeting CDK12 in future clinical trials. A comprehensive elucidation of the dual roles and underlying mechanisms of CDK12 in carcinogenesis is urgently needed to advance precision oncology. This review provides an overview of the current understanding of the dysregulation and biological roles of CDK12 in cancer. Subsequently, we systematically summarize the functions and mechanisms of the oncogenic and tumor-suppressive roles of CDK12 in different contexts. Finally, we discuss the potential of CDK12 as a novel therapeutic target and its implications in clinical oncology, offering insights into future directions for innovative cancer treatment strategies.

Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such drugs. To address this challenge, we developed a smart theranostic prodrug system that combines a fluorophore and an anticancer drug, specifically 6-diazo-5-oxo-l-norleucine (DON), using a thioketal linkage (TK). This system enables imaging, chemotherapy, photodynamic therapy, and on-demand drug release upon radiation exposure. The optimized prodrug, DON-TK-BM3, incorporating cyanine dyes as the fluorophore, displayed potent reactive oxygen species release and efficient tumor cell killing. Unlike the parent drug DON, DON-TK-BM3 exhibited no toxicity toward normal cells. Moreover, DON-TK-BM3 demonstrated high tumor accumulation and reduced side effects, including gastrointestinal toxicity, in mice. This study provides a practical strategy for designing prodrugs of metabolic inhibitors with significant toxicity stemming from their lack of tissue selectivity.

Background Studies on the relationships of environmental noise exposure with negative emotions and sleep quality have long been reported. Self-perceived noise intensity is not only related to environmental noise exposure, but also reflects an individual's susceptibility to noise; however, few studies on self-perceived noise intensity, negative emotions, and sleep quality have been reported, and it is not clear whether negative emotions play a mediating role in the relationship between self-perceived noise intensity and sleep quality. Objective To analyze the mediating role of negative emotions (anxiety, depression, and stress) in the relationship between self-perceived noise intensity and sleep quality in noise-exposed workers, and to provide a scientific basis for addressing psychological problems and sleep quality induced by noise exposure. Methods Stratified cluster sampling was used to select noise-exposed workers from a large equipment manufacturing plant in Chengdu from May to June 2023, and demographic characteristics were investigated using a self-designed general information questionnaire; self-perceived noise intensity was reported by the study subjects as the noise intensity of their workplaces; sleep quality was synthesized from three indicators: night sleep duration, self-perceived sleep quality, and sleep-related symptoms; the Anxiety-Depression-Stress Scale (DASS-21 scale) was used to evaluate anxiety, depression, and stress of a worker. Structural equation modeling was used to analyze the pathways of negative emotions (anxiety, depression, and stress) between self-perceived noise intensity and sleep quality. Results The positive rates of negative emotions were 33.1% (anxiety symptoms, 215/649), 26.0% (depression symptoms, 169/649), and 14.0% (stress symptoms, 91/649), respectively in a total of 649 noise-exposed workers. Self-perceived noise intensity was positively correlated with sleep quality score (r=0.218, P<0.001) and negative emotions (anxiety, depression, and stress) (r=0.167, 0.145, 0.167, P<0.001); sleep quality score was positively correlated with negative emotions (anxiety, depression, and stress) (r=0.512, 0.447, 0.513, P<0.001). The results of path analysis showed that the negative emotions (anxiety, depression, and stress) partially mediated between self-perceived noise intensity and sleep quality (β=0.123，P<0.001). Self-perceived noise intensity was positively correlated with negative emotions and sleep quality, and there was a path of self-perceived noise intensity → negative emotion → sleep quality (P<0.001), and the mediating effect accounted for 42.71%. Conclusion The positive rates of anxiety, depression, and stress are high among the noise-receiving workers in this manufacturing industry, and negative emotions characterized by anxiety, depression, and stress partially mediate the relationship between self-perceived noise intensity and sleep quality.

Objective:To establish a nomogram model for predicting the hyper-progression recurrence after hepatectomy in patients with hepatocellular carcinoma (HCC) based on circulating tumor cells (CTC).Methods:Clinical data of 231 HCC patients undergoing hepatectomy at the Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital from January 2013 to December 2022 were retrospectively analyzed, including 200 males and 31 females, aged 46(39, 52) years old. Patients were divided into two groups: the modeling group ( n=154) and the validation group ( n=77). According to the state of postoperative hyper-progression recurrence, patients in the modeling group were subdivided into hyper-progression recurrence ( n=39) and non-hyper-progression recurrence group ( n=115). Patients in the validation group were also subdivided into hyper-progression recurrence ( n=16) and non-hyper-progression recurrence group ( n=61). Clinicopathological data such as the total CTC count, alpha-fetoprotein, and postoperative pathology were collected. Logistic regression analysis was used to analyze the influencing factors of postoperative hyper-progression recurrence. A nomogram model was established based on the results of multivariate logistic regression analysis. The receiver operating characteristic (ROC) curve, calibration curve, decision curve analysis (DCA) and clinical impact curve (CIC) were used to validate the nomogram model. Results:Multivariate logistic regression analysis showed that HCC patients with age ≤45 years old ( OR=6.704, 95% CI: 1.619-27.760, P=0.009), incomplete tumor capsule ( OR=13.292, 95% CI: 3.084-57.295, P=0.001), high total numbers of CTC ( OR=1.101, 95% CI: 1.023-1.186, P=0.011) and high Ki67 index ( OR=52.659, 95% CI: 3.215-862.604, P=0.005) had a high risk of hyper-progression recurrence after hepatectomy. The above three preoperative variables were integrated to construct a nomogram model. The calibration curve showed that the predicted results of the nomogram model were in good agreement with the actual results. The ROC curves of the nomogram model for predicting hyper-progression recurrence after hepatectomy in HCC patients were plotted, and the area under the curve was 0.907 (95% CI: 0.856-0.959) and 0.833 (95% CI: 0.721-0.945) in the modeling group and validation group, respectively. DCA showed that the nomogram model could be used as a valuable predictive tool for the hyper-progression recurrence after hepatectomy. The CIC showed that the population judged by the nomogram model was highly matched with the actual population with hyper-progression recurrence. Conclusions:This study established a nomogram model based on age, tumor capsular integrity and total CTC count, which could accurately predict the postoperative hyper-progression recurrence in HCC patients before hepatectomy. The model is promising in guiding clinical practice after further validation.

Objective To analyze the seroepidemiology characteristics of Epstein-Barr virus(EBV)infection in children in Shenyang.Methods From June 2022 to May 2023,serum was collected from 12 083 children at Shengjing hospital of China Medical University.Serum capsid antigen(VCA)-IgM,VCA-IgG,EBV nuclear antigen-IgG(EBNA-IgG),and early antigen-IgG(EA-IgG)antibodies were detected using the LIAISION chemiluminescence immunoassay.EBV-DNA was detected using real-time PCR.Differences in antibody positivity rates between sexes,ages,and seasons of onset were compared.Results In 12 083 patients,the positive rates of VCA-IgM,VCA-IgG,EBNA-IgG,and EA-IgG were 9.95％(1 202/12 083),50.57％(6 110/12 083),46.03％(5 562/12 083)and 4.93％(596/12 083).The positive rates of VCA-IgM and EA-IgG were lower in male patients(9.09％and 4.44％,respectively)than in female patients(11.10％,5.60％;all P＜0.05).The differences in the positive rates for VCA-IgM,VCA-IgG,EBNA-IgG,and EA-IgG antibodies in children of different ages were statistically significant(all P＜0.05).Differences in the positive rates of VCA-IgG,EBNA-IgG,and EA-IgG antibodies were statistically significant when compared between seasons(all P＜0.05).Fourteen EBV antibody-positive combinations were detected,of which the main combination was VCA-IgG and EBNA-IgG double-positive,with a total of 4 741 cases(39.24％).Of the 3 712 children who underwent EBV-DNA detection testing,3 034(81.73％)were EBV-DNA-negative and 678(18.27％)were EBV-DNA-posi-tive.VCA-IgG and EBNA-IgG double positivity was the most common in EBV-DNA-negative and EBV-DNA-positive children,accounting for 983(26.48％)and 194 cases(5.23％),respectively.Conclusion Both VCA-IgG and EBNA-IgG antibodies are main positive in children with EBV infection in Shenyang.The positive rate of EBV antibodies is lower in boys than in girls.The positive rates of EBV anti-bodies differ in children of different ages and seasons of onset.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is an independent risk factor for colorectal cancer (CRC), and the patients with CRC and T2DM have worse survival. The human gut microbiota (GM) is linked to the development of CRC and T2DM, respectively. However, the GM characteristics in patients with CRC and T2DM remain unclear. METHODS: We performed fecal metagenomic and targeted metabolomics studies on 36 samples from CRC patients with T2DM (DCRC group, n = 12), CRC patients without diabetes (CRC group, n = 12), and healthy controls (Health group, n = 12). We analyzed the fecal microbiomes, characterized the composition and function based on the metagenomics of DCRC patients, and detected the short-chain fatty acids (SCFAs) and bile acids (BAs) levels in all fecal samples. Finally, we performed a correlation analysis of the differential bacteria and metabolites between different groups. RESULTS: Compared with the CRC group, LefSe analysis showed that there is a specific GM community in DCRC group, including an increased abundance of Eggerthella , Hungatella , Peptostreptococcus , and Parvimonas , and decreased Butyricicoccus , Lactobacillus , and Paraprevotella . The metabolomics analysis results revealed that the butyric acid level was lower but the deoxycholic acid and 12-keto-lithocholic acid levels were higher in the DCRC group than other groups ( P < 0.05). The correlation analysis showed that the dominant bacterial abundance in the DCRC group ( Parvimonas , Desulfurispora , Sebaldella , and Veillonellales , among others) was negatively correlated with butyric acid, hyodeoxycholic acid, ursodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, cholic acid and glycocholate. However, the abundance of mostly inferior bacteria was positively correlated with these metabolic acid levels, including Faecalibacterium , Thermococci , and Cellulophaga . CONCLUSIONS Unique fecal microbiome signatures exist in CRC patients with T2DM compared to those with non-diabetic CRC. Alterations in GM composition and SCFAs and secondary BAs levels may promote CRC development.
Humans ; Gastrointestinal Microbiome/genetics* ; Diabetes Mellitus, Type 2 ; Microbiota ; Bacteria/genetics* ; Fatty Acids, Volatile ; Colorectal Neoplasms/metabolism* ; Butyrates ; Feces/microbiology*

Objective : To explore the method of using high-fat diet combined with angiotensin-Ⅱ ( Ang-Ⅱ) and β-aminopropionitrile (BAPN) to establish the model of aortic dissection in mice． Methods : 24 C57BL /6J mice (4 weeks old，male) were randomly divided into control group［intraperitoneal injection of 0．9% sodium chloride solu- tion 10 ml / (kg · d) ］and experimental groups［Ang-Ⅱ 4 mg / ( kg · d) group，Ang-Ⅱ 4 mg / ( kg · d) + BAPN 0. 33 g / (kg · d) group］，each group with 8 mice ; all mice were given a high-fat diet and the mice weights were measured at the same time point and administered according to the weight standard．The dead mice were dissected immediately and the aorta was taken out for pathological section，then observed under the microscope．The morphology of aorta was detected by small animal ultrasound and the mice with obvious dissection were killed and dissected directly. Results : After administration，the activity and appetite of mice in the high-fat diet combined with Ang-Ⅱ + BAPN group decreased most significantly，and the mortality rate of aortic dissection rupture and the success rate of modeling in this group were higher than those in the high-fat diet combined with Ang-Ⅱ group，while there was no significant change in the control group．Under the ultrasound of small animals，compared with the other two groups，the mice in the high-fat diet combined with Ang-Ⅱ + BAPN group showed the formation of abdominal aortic vascular false lumen and vascular enlargement．The mice that died during the administration were dissected immediately，and a large number of blood clots in the abdominal cavity and around the blood vessels could be seen．The mice with aortic dissection or aortic aneurysm could be seen under ultrasound in small animals，and severe adhesion between the vascular wall and the surrounding tissues could be found when dissected，while no obvious abnormalities were found in the blood vessels of the control group．The results of the staining showed that the false lumen of blood vessel wall was formed and the arrangement of elastin and collagen was disordered in the mice of high fat diet com- bined with Ang-Ⅱ + BAPN group．The thickness of blood vessel wall in each group was statistically analyzed，and it was found that the blood vessels in the two experimental groups were thicker than those in the control group，which was statistically significant (P＜0. 001) ．The vascular wall of Ang-Ⅱ + BAPN + high-fat diet group showed severe elastin degradation． Conclusion High-fat diet combined with Ang-Ⅱ 4 mg / (kg · d) and BAPN 0. 33 g / (kg · d) can establish an efficient model of aortic dissection in mice.

Background/Aims: Depression and anxiety are associated with poorer outcomes in patients with hepatocellular carcinoma (HCC). However, the prevalence of depression and anxiety in HCC are unclear. We aimed to establish the prevalence of depression and anxiety in patients with HCC. Methods: MEDLINE and Embase were searched and original articles reporting prevalence of anxiety or depression in patients with HCC were included. A generalized linear mixed model with Clopper-Pearson intervals was used to obtain the pooled prevalence of depression and anxiety in patients with HCC. Risk factors were analyzed via a fractional-logistic regression model. Results: Seventeen articles involving 64,247 patients with HCC were included. The pooled prevalence of depression and anxiety in patients with HCC was 24.04% (95% confidence interval [CI], 13.99–38.11%) and 22.20% (95% CI, 10.07–42.09%) respectively. Subgroup analysis determined that the prevalence of depression was lowest in studies where depression was diagnosed via clinician-administered scales (16.07%;95% CI, 4.42–44.20%) and highest in self-reported scales (30.03%; 95% CI, 17.19–47.01%). Depression in patients with HCC was lowest in the Americas (16.44%; 95% CI, 6.37–36.27%) and highest in South-East Asia (66.67%; 95% CI, 56.68–75.35%). Alcohol consumption, cirrhosis, and college education significantly increased risk of depression in patients with HCC. Conclusions One in four patients with HCC have depression, while one in five have anxiety. Further studies are required to validate these findings, as seen from the wide CIs in certain subgroup analyses. Screening strategies for depression and anxiety should also be developed for patients with HCC.

Background/Aims: Non-alcoholic fatty liver disease (NAFLD) is associated with the development of cardiovascular disease. While existing studies have examined cardiac remodeling in NAFLD, there has been less emphasis on the development of carotid atherosclerosis and stroke. We sought to conduct a meta-analysis to quantify the prevalence, risk factors, and degree of risk increment of carotid atherosclerosis and stroke in NAFLD. Methods: Embase and Medline were searched for articles relating to NAFLD, carotid atherosclerosis, and stroke. Proportional data was analysed using a generalized linear mixed model. Pairwise meta-analysis was conducted to obtain odds ratio or weighted mean difference for comparison between patients with and without NAFLD. Results: From pooled analysis of 30 studies involving 7,951 patients with NAFLD, 35.02% (95% confidence interval [CI], 27.36–43.53%) had carotid atherosclerosis with an odds ratio of 3.20 (95% CI, 2.37–4.32; P<0.0001). Pooled analysis of 25,839 patients with NAFLD found the prevalence of stroke to be 5.04% (95% CI, 2.74–9.09%) with an odds ratio of 1.88 (95% CI, 1.23–2.88; P=0.02) compared to non-NAFLD. The degree of steatosis assessed by ultrasonography in NAFLD was closely associated with risk of carotid atherosclerosis and stroke. Older age significantly increased the risk of developing carotid atherosclerosis, but not stroke in NAFLD. Conclusions This meta-analysis shows that a stepwise increment of steatosis of NAFLD can significantly increase the risk of carotid atherosclerosis and stroke development in NAFLD. Patients more than a third sufferred from carotid atherosclerosis and routine assessment of carotid atherosclerosis is quintessential in NAFLD.