The cellular and molecular components of the tumor immune microenvironment (TIME) and their information exchange processes significantly influence the trends of anti-tumor immunity. In recent years, numerous studies have begun to evaluate TIME in the context of previous cancer treatment strategies. This review will systematically summarize the compositional characteristics of TIME and, based on this foundation, explore the impact of current cancer therapies on the remodeling of TIME, aiming to provide new insights for the development of innovative immune combination therapies that can convert TIME into an anti-tumor profile.
Tumor Microenvironment/immunology* ; Humans ; Neoplasms/therapy* ; Immunotherapy/methods* ; Animals

Elemene is widely recognized as an effective anti-cancer compound and is routinely administered in Chinese clinical settings for the management of several solid tumors, including non-small cell lung cancer (NSCLC). However, its detailed molecular mechanism has not been adequately demonstrated. In this research, it was demonstrated that elemene effectively curtailed NSCLC growth in the patient-derived xenograft (PDX) model. Mechanistically, employing high-throughput screening techniques and subsequent biochemical validations such as microscale thermophoresis (MST), microRNA-145-5p (miR-145-5p) was pinpointed as a critical target through which elemene exerts its anti-tumor effects. Interestingly, elemene serves as a binding stabilizer for miR-145-5p, demonstrating a strong binding affinity (dissociation constant (K _D) = 0.39 ± 0.17 μg/mL) and preventing its degradation both in vitro and in vivo, while not interfering with the synthesis of the primary microRNA transcripts (pri-miRNAs) and precursor miRNAs (pre-miRNAs). The stabilization of miR-145-5p by elemene resulted in an increased level of this miRNA, subsequently suppressing NSCLC progression through the miR-145-5p/mitogen-activated protein kinase kinase kinase 3 (MAP3K3)/nuclear factor kappaB (NF-κB) pathway. Our findings provide a new perspective on revealing the interaction patterns between clinical anti-tumor drugs and miRNAs.

Objective:Drug safety assessments based on real-world data are often challenged by both treatment switching and rare events. In this study, we used statistical simulations to investigate the effects of switching rates and treatment effects on the statistical performance of commonly used analytical strategies and methods under overlapping scenarios of treatment switching and rare events.Methods:The simulation scenario was set up as a bidirectional treatment switching (allowing the control group to switch to the treatment group and the treatment group to switch to the control group), and the event rates were set at approximately 2%, 5%, and 20%. Different simulation scenarios were generated with sufficient sample size to consider switching rate and relative treatment effect. The simulated datasets were analyzed using three types of analysis strategy, i.e. intention to treat (ITT), per protocol (PP), and as treated (AT). The performance of five indicators, namely percentage bias, mean square error, empirical standard error, coverage, and rejection rate, were compared among the different methods in different scenarios, and recommendations for method selection were given.Results:In terms of analytical strategies and methods, AT analysis were relatively optimal in terms of percentage bias and accuracy, followed by PP analysis and ITT analysis. When the relative treatment effects converged (e.g. HR=1.0), both the ITT analysis and the time-dependent AT approaches (marginal structural model, time-dependent Cox regression model or time-dependent propensity score matching) performed well; when the relative treatment effects were small (e.g. HR=0.8), the marginal structural model was the most optimal; when the relative treatment effects were large (e.g. HR=0.6 or 0.4), the approaches of using a censored treatment for switchers in the AT analysis were more accurate. In addition, the time-dependent AT approaches had the highest rejection rate when there was a difference in treatment effect between the two groups, and the ITT analysis had the lowest rejection rate. Conclusions:For the dual challenges of bidirectional switching and rare events in real-world drug safety evaluations, adequate sample size is a prerequisite for accurate estimation of treatment effects, while switching rates and effect sizes of switched drugs might also affect estimation accuracy. Appropriate strategies and methods should be selected for the analysis. It is necessary to consider whether the event is rare or not, the switching rate and the expected treatment effect size of the two types of treatment to select appropriate analysis strategies and methods.

Objective:To explore the association between serum selenium levels and total cancer risk in humans.Methods:A systematic search was conducted for Chinese and English literature on the association between selenium and cancer risk published up to December 2023 in the Chinese National Knowledge Infrastructure (CNKI), Wanfang, PubMed, EMbase, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases by using “neoplasms” “selenium” “prospective-studies” (both in English and Chinese) as keywords. The meta-analysis was performed using a random-effect model. The linear dose-response relationship was analyzed using a generalized least squares regression model, and the non-linear dose-response relationship was analyzed using a restricted cubic spline regression model. Publication bias was assessed by funnel plots and Egger′s regression asymmetry test.Results:A total of 12 prospective studies were included from 16 408 articles retrieved, including seven studies from Europe, four from America, and one from Asia, with a total of 4 586 cancer cases reported. Meta-analysis revealed an inverse association between baseline serum selenium levels and total cancer risk ( RR=0.68, 95% CI: 0.57-0.82, P=0.000). Furthermore, serum selenium was found to have a protective effect on both the incidence ( RR=0.66, 95% CI: 0.53-0.84, P=0.001) and mortality ( RR=0.70, 95% CI: 0.50-0.98, P=0.035) of total cancer. The inverse association between serum selenium and the incidence of total cancer was more pronounced in populations with low baseline serum selenium levels ( RR=0.65, 95% CI: 0.48-0.89, P=0.007). Additionally, dose-response meta-analysis showed that for every 10 μg/L increase in baseline serum selenium concentration, there was a 26% reduction in incidence of total cancer ( RR=0.74, 95% CI: 0.46-0.83, P=0.229) and a 6% reduction in mortality of total cancer ( RR=0.94, 95% CI: 0.86-0.96, P=0.229). Conclusion:Serum selenium is negatively associated with the incidence and mortality of total cancer.

Objective:To investigate the epidemiological characteristics, disease spectrum, and laboratory characteristics of human immunodeficiency virus/cytomegalovirus (HIV/CMV) co-infection, to provide references for clinical diagnosis and treatment.Methods:A cross-sectional study was conducted. Clinical information of 544 HIV/acquired immune deficiency syndrome (AIDS) patients who underwent CMV-DNA tests in Beijing Ditan Hospital in 2023 was collected. Participants were categorized into CMV-infection group (126 cases) and non-CMV-infection group (418 cases). The prevalence of CMV infection was analyzed. Univariate and multivariate logistic regression analysis were performed to identify risk factors for CMV/AIDS co-infection. The disease spectrum, laboratory characteristics, serum CMV-DNA load changes, treatment prognosis and outcomes in the CMV-infected group were evaluated. SPSS 27.0 was used for statistical analysis including the χ 2 test, Mann-Whitney U test, and Kruskal-Wallis H test. Results:The CMV infection rate among HIV/AIDS patients was 23.16% (126/544). Multivariate analysis identified low CD4 +T-lymphocyte count [<50 cells/μl; OR=27.962, 95% confidence interval( CI) 11.957-65.389] and high HIV RNA load (>1×10 5 copies/ml; OR=2.057, 95% CI 1.237-3.420) as independent risk factors for CMV co-infection in HIV/AIDS patients. Among the 126 HIV/CMV co-infected patients, CMV viremia was the most common manifestation (38.10%, 48/126), followed by CMV pneumonia (33.33%, 42/126) and CMV retinitis (11.90%, 15/126), which were mainly observed in patients with CD4 +T-lymphocyte counts <50 cells/μl. Of the patients receiving anti-CMV therapy, 80.70% (46/57) exhibited reduced CMV-DNA loads compared with baseline. Totally 29.82% (17/57) of those patients initiating antiretroviral therapy alone achieved CMV-DNA reduction compared with baseline. Overall, 80.16% (101/126) of patients achieved favorable prognosis. Conclusion:CMV co-infection is high in HIV/AIDS patients. Disease spectrum of HIV/CMV co-infection are dominated by CMV viremia and CMV pneumonia. Timely anti-CMV therapy is pivotal for reducing CMV-DNA loads and improving prognosis.

Objective:To investigate the alterations in the brain structural network properties related to cognitive emotion regulation strategies in young, first-episode and drug-naive (FEDN) patients with major depressive disorder (MDD).Methods:One hundred and twelve young patients who were diagnosed with FEDN MDD were enrolled in the Second Xiangya Hospital of Central South University between October 2019 and October 2023, and 143 healthy controls (HC) were recruited for reference during the same period. Clinical data and T 1 structural images of high-resolution magnetic resonance imaging were collected from all participants, and the cognitive emotion regulation was assessed using the Chinese version of the Cognitive Emotion Regulation Questionnaire (CERQ-C). The brain structural alterations related to cognitive emotion regulation strategies were explored using whole-brain voxel-based morphometry (VBM) group analysis and individual differential structural covariance network (IDSCN) analysis. Partial correlation analysis was performed between the IDSCN anomalous structural concatenated edge and subdimensions of the CERQ-C. Results:The scores on the sub-dimension of negative cognitive emotion regulation (self-condemnation, rumination, catastrophization, blaming others) in the young FEDN MDD patients in CERQ-C were significantly higher than those in HC (14.28±2.30 vs 12.45±2.00, t=6.501, P<0.001;14.40±2.97 vs 11.31±2.93, t=7.934, P<0.001;12.19±3.75 vs 7.59±2.58, t=10.553, P<0.001;10.26±3.00 vs 8.74±2.89, t=3.916, P<0.001; respectively). There was no statistically significant difference in the VBM group analysis (all P>0.05). However, IDSCN single sample t test results showed significant group differences between the left orbitofrontal inferior gyrus and the left supplementary motor area, the left orbitofrontal middle gyrus and the bilateral precuneus, and the left superior temporal gyrus and the bilateral hippocampus (all P<0.05). With controlling for age, sex, and other factors, partial correlation analysis results showed that the left orbital inferior frontal gyrus-left supplementary motor area connection in patients with MDD was positively correlated with the self-condemnation and acceptance scores of the CERQ-C ( r=0.226, P=0.027; r=0.216, P=0.035), while negatively correlated with the score of blaming others ( r=-0.252, P=0.013). Additionally, connections between the right hippocampus and left superior temporal gyrus were significantly associated with the scores on catastrophization subdimension of the CERQ-C ( r=0.229, P=0.025). Conclusion:Due to its sensitivity to individualized analyses, the IDSCN analysis found that abnormal topological property changes were mainly manifested in the limbic system, the sensorimotor system, and the default network in young FEDN MDD patients, and were linked to their negative cognitive emotion regulation strategies, even though the VBM group analysis did not yield any significant results.

To describe the incidence and mortality of adult head and neck cancer (HNC) in different regions worldwide and their temporal trends.

Objective: To investigate the effects of “Three Methods and Three Acupoints” (TMTP) Tuina therapy on spinal microcirculation in sciatic nerve injury (SNI). Methods: Thirty-six Sprague–Dawley rats were randomly assigned to four groups: normal, sham operation, model, and TMTP Tuina. Successful model induction was confirmed by observable hind limb lameness. After 20 sessions, hind limb grip strength and motor nerve conduction velocity (MNCV) were measured at baseline and following the 10th and 20th intervention. CD31 and α-SMA in the ventral horn of SNI model rats were detected using immunofluorescence. Motor neurons in the ventral horn were detected by Nissl staining. PTEN levels in the ventral horn were measured by ELISA, and PI3K, Akt, BDNF, VEGF, and HIF-1α expression was determined by RT-PCR. Spinal cord microcirculation was evaluated by western blotting analysis of the levels of Akt, p-Akt, BDNF, and VEGF. Results: Hind limb grip strength and MNCV significantly improved in the TMTP Tuina group compared to the model group (both P < .001). Morphology of ventral horn motor neurons in the TMTP Tuina group improved compared to the model group, with increased expressions of α-SMA (P = .002) and CD31 (P = .006). Western blot analysis indicated increased expression of VEGF (P = .005), p-Akt (P < .001), and BDNF (P = .008) in the ventral horn following Tuina treatment. RT-PCR analysis revealed increased expression of PI3K, Akt, BDNF, VEGF and HIF-1α (all P < .05). In contrast, expression of PTEN decreased compared to the model group (P < .001). Conclusion TMTP Tuina therapy may restore motor function in rats, enhance ventral horn motor neuron morphology, and promote angiogenesis and vascular smooth muscle proliferation. The mechanism may involve the activation of the PI3K/Akt signaling pathway.

Objective: To explore the brain-predicted age difference (Brain-PAD) in patients with type 2 diabetes mellitus (T2DM) by a machine learning prediction model based on structural magnetic resonance ( sMRI) in the Southwest University Adult Lifespan Dataset (SALD) , and to reveal the relationship between Brain-PAD and dura- tion of T2DM and cognition . Methods: Group comparisons about demographic variables and cognitive function were conducted respectively in local database of 104 T2DM patients and 83 healthy controls (HC) . The prediction model via Gaussian process regression (GPR) was constructed by training sMRI data of 329 healthy volunteers in SALD , then its performance was validated and evaluated . Furthermore , Brain-PAD ( predicted age-chronological age) in the local database was calculated . Group comparisons of Brain-PAD between T2DM patients and HCs were conducted by Mann-Whitney U test. Finally , Pearson correlation coefficient (r) was calculated between Brain-PAD and duration of disease and cognition . Results: Poor performance in auditory verbal learning test (AVLT)-delayed recall , AVLT-recognition , symbol digital modalities test (SDMT) (P < 0. 05) , and increased Brain-PAD were ob- served in T2DM patients , compared with HCs [1 . 619 ( - 4. 001 , 8. 272) years vs - 1 . 289 ( - 4. 128 , 4. 134) years , Z = 2. 056 , P = 0. 034] . Notably , the median of Brain-PAD in T2DM group was positive , indicating that the brain of T2DM patient maybe relatively “older”than his chronological age . Brain-PAD in T2DM group was as- sociated with performance in AVLT-immediate recall ( r = 0. 291 , P = 0. 003) , AVLT-delayed recall ( r = 0. 248 , P = 0. 011) , SDMT( r = 0. 376 , P = 0. 001) and trail making test (TMT)-A ( r = - 0. 206 , P = 0. 036) . However , the relationships between Brain-PAD and duration of T2DM were not explored . Conclusion Decreased cognitive function in patients with T2DM is demonstrated in this study . The machine learning prediction model based on sMRI supports the identification of brain aging objectively in patients with T2DM .

Elemene is widely recognized as an effective anti-cancer compound and is routinely administered in Chinese clinical settings for the management of several solid tumors,including non-small cell lung cancer(NSCLC).However,its detailed molecular mechanism has not been adequately demonstrated.In this research,it was demonstrated that elemene effectively curtailed NSCLC growth in the patient-derived xenograft(PDX)model.Mechanistically,employing high-throughput screening techniques and subsequent biochemical validations such as microscale thermophoresis(MST),microRNA-145-5p(miR-145-5p)was pinpointed as a critical target through which elemene exerts its anti-tumor effects.Inter-estingly,elemene serves as a binding stabilizer for miR-145-5p,demonstrating a strong binding affinity(dissociation constant(KD)=0.39±0.17 μg/mL)and preventing its degradation both in vitro and in vivo,while not interfering with the synthesis of the primary microRNA transcripts(pri-miRNAs)and precursor miRNAs(pre-miRNAs).The stabilization of miR-145-5p by elemene resulted in an increased level of this miRNA,subsequently suppressing NSCLC progression through the miR-145-5p/mitogen-activated pro-tein kinase kinase kinase 3(MAP3K3)/nuclear factor kappaB(NF-κB)pathway.Our findings provide a new perspective on revealing the interaction patterns between clinical anti-tumor drugs and miRNAs.