Manipulating nanostructure assemblies is important in using them as structural and functional materials. Carbon nanotubes (CNTs) lack the ability to reconstruct their entangled network. In this work, we report a strategy with which to realize efficient manipulation of CNT networks by forming double networks with branched polyethylenimine (PEI). The double network was highly viscoelastic and ductile and enabled efficient film stretching or creeping for CNT alignment, which dramatically improved the mechanical strength of the CNT films. Due to the viscous drag from the polymer network, the CNTs showed enhanced movability in reconstructing new networks, which made the film repairable. The repairability resulted from the branched polymeric structure. This double-networking strategy provides a new way to manipulate CNT assemblies for high-performance applications.

Due to the difficulties in precisely manipulating DNA repair pathways, high-fidelity targeted integration of large transgenes triggered by double-strand breaks is inherently inefficient. Here, we exploit prime editors to devise a robust knock-in (KI) strategy named primed micro-homologues-assisted integration (PAINT), which utilizes reverse-transcribed single-stranded micro-homologues to boost targeted KIs in different types of cells. The improved version of PAINT, designated PAINT 3.0, maximizes editing efficiency and minimizes off-target integration, especially in dealing with scarless in-frame KIs. Using PAINT 3.0, we target a reporter transgene into housekeeping genes with editing efficiencies up to 80%, more than 10-fold higher than the traditional homology-directed repair method. Moreover, the use of PAINT 3.0 to insert a 2.5-kb transgene achieves up to 85% KI frequency at several therapeutically relevant genomic loci, suggesting its potential for clinical applications. Finally, PAINT 3.0 enables high-efficiency non-viral genome targeting in primary T cells and produces functional CAR-T cells with specific tumor-killing ability. Thus, we establish that the PAINT method is a powerful gene editing tool for large transgene integrations and may open new avenues for cell and gene therapies and genome writing technologies.

There are few studies focus on post-neoadjuvant treatment in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-)/lymph node-positive (LN+) breast cancer, a multi-center, open-label, randomized, controlled phase III trial was conducted to evaluate pathological response-guided non-cross-resistant adjuvant chemotherapy in patients with HR+/HER2-/LN+ breast cancer who were non-responsive to primary chemotherapy. Patients received four cycles of non-cross-resistant adjuvant chemotherapy plus endocrine therapy (ET), or ET alone. Forty patients responsive to neoadjuvant chemotherapy and with Miller and Payne G4 or G5 and LN- status were assigned to the observation group. Distant disease-free survival was the primary endpoint. The final intention-to-treat analysis comprised 379 patients. After a median follow-up period of 72.4 months, the 5-year distant disease-free survival was 92% and 90% in the chemotherapy plus ET and ET-alone groups, respectively. Comparatively, the observation group showed a trend towards better distant disease-free survival. For patients non-responsive to neoadjuvant chemotherapy, adjuvant non-cross-resistant chemotherapy did not significantly improve distant disease-free survival compared to ET alone.

Metabolic reprogramming is a hallmark of human malignancies. Dysregulation of glutamine metabolism is essential for tumorigenesis, microenvironment remodeling, and therapeutic resistance. Based on the untargeted metabolomics sequencing, we identified that the glutamine metabolic pathway was up-regulated in the serum of patients with primary DLBCL. High levels of glutamine were associated with inferior clinical outcomes, indicative of the prognostic value of glutamine in DLBCL. In contrast, the derivate of glutamine alpha-ketoglutarate (α-KG) was negatively correlated with the invasiveness features of DLBCL patients. Further, we found that treatment with the cell-permeable derivative of α-KG, known as DM-αKG, significantly suppressed tumor growth by inducing apoptosis and non-apoptotic cell death. Accumulation of a-KG promoted oxidative stress in double-hit lymphoma (DHL), which depended on malate dehydrogenase 1 (MDH1)-mediated 2-hydroxyglutarate (2-HG) conversion. High levels of reactive oxygen species (ROS) contributed to ferroptosis induction by promoting lipid peroxidation and TP53 activation. In particular, TP53 overexpression derived from oxidative DNA damage, further leading to the activation of ferroptosis-related pathways. Our study demonstrated the importance of glutamine metabolism in DLBCL progression and highlighted the potential application of α-KG as a novel therapeutic strategy for DHL patients.

T cells are crucial for immune functions to maintain health and prevent disease. T cell development occurs in a stepwise process in the thymus and mainly generates CD4+ and CD8+ T cell subsets. Upon antigen stimulation, naïve T cells differentiate into CD4+ helper and CD8+ cytotoxic effector and memory cells, mediating direct killing, diverse immune regulatory function, and long-term protection. In response to acute and chronic infections and tumors, T cells adopt distinct differentiation trajectories and develop into a range of heterogeneous populations with various phenotype, differentiation potential, and functionality under precise and elaborate regulations of transcriptional and epigenetic programs. Abnormal T-cell immunity can initiate and promote the pathogenesis of autoimmune diseases. In this review, we summarize the current understanding of T cell development, CD4+ and CD8+ T cell classification, and differentiation in physiological settings. We further elaborate the heterogeneity, differentiation, functionality, and regulation network of CD4+ and CD8+ T cells in infectious disease, chronic infection and tumor, and autoimmune disease, highlighting the exhausted CD8+ T cell differentiation trajectory, CD4+ T cell helper function, T cell contributions to immunotherapy and autoimmune pathogenesis. We also discuss the development and function of γδ T cells in tissue surveillance, infection, and tumor immunity. Finally, we summarized current T-cell-based immunotherapies in both cancer and autoimmune diseases, with an emphasis on their clinical applications. A better understanding of T cell immunity provides insight into developing novel prophylactic and therapeutic strategies in human diseases.

BackgroundA workplace-based primary prevention intervention be an effective approach to reducing the incidence of hypertension (HTN). However, few studies to date have addressed the effect among the Chinese working population. We assessed the effect of a workplace-based multicomponent prevention interventions program for cardiovascular disease on reducing the occurrence of HTN through encouraging employees to adopt a healthy lifestyle.MethodsIn this post hoc analysis of cluster randomized controlled study, 60 workplaces across 20 urban regions in China were randomized to either the intervention group (n = 40) or control group (n = 20). All employees in each workplace were asked to complete a baseline survey after randomization for obtaining sociodemographic information, health status, lifestyle, etc. Employees in the intervention group were given a 2-year workplace-based primary prevention intervention program for improving their cardiovascular health, including (1) cardiovascular health education, (2) a reasonable diet, (3) tobacco cessation, (4) physical environment promotion, (5) physical activity, (6) stress management, and (7) health screening. The primary outcome was the incidence of HTN, and the secondary outcomes were improvements of blood pressure (BP) levels and lifestyle factors from baseline to 24 months. A mix effect model was used to assess the intervention effect at the end of the intervention in the two groups.ResultsOverall, 24,396 participants (18,170 in the intervention group and 6,226 in the control group) were included (mean [standard deviation] age, 39.3 [9.1] years; 14,727 men [60.4%]). After 24 months of the intervention, the incidence of HTN was 8.0% in the intervention groups and 9.6% in the control groups [relative risk (RR) = 0.66, 95% CI, 0.58 ~ 0.76, P < 0.001]. The intervention effect was significant on systolic BP (SBP) level (β =  − 0.7 mm Hg, 95% CI, − 1.06 ~  − 0.35; P < 0.001) and on diastolic BP (DBP) level (β =  − 1.0 mm Hg, 95% CI, − 1.31 ~  − 0.76; P < 0.001). Moreover, greater improvements were reported in the rates of regular exercise [odd ratio (OR) = 1.39, 95% CI, 1.28 ~ 1.50; P < 0.001], excessive intake of fatty food (OR = 0.54, 95% CI, 0.50 ~ 0.59; P < 0.001), and restrictive use of salt (OR = 1.22, 95% CI, 1.09 ~ 1.36; P = 0.001) in intervention groups. People with a deteriorating lifestyle had higher rates of developing HTN than those with the same or improved lifestyle. Subgroup analysis showed that the intervention effect of BP on employees with educational attainment of high school above (SBP: β =  − 1.38/ − 0.76 mm Hg, P < 0.05; DBP: β =  − 2.26/ − 0.75 mm Hg, P < 0.001), manual labor workers and administrative worker (SBP: β =  − 1.04/ − 1.66 mm Hg, P < 0.05; DBP: β =  − 1.85/ − 0.40 mm Hg, P < 0.05), and employees from a workplace with an affiliated hospital (SBP: β =  − 2.63 mm Hg, P < 0.001; DBP: β =  − 1.93 mm Hg, P < 0.001) were significantly in the intervention group.ConclusionsThis post hoc analysis found that workplace-based primary prevention interventions program for cardiovascular disease were effective in promoting healthy lifestyle and reducing the incidence of HTN among employees.Trial registrationChinese Clinical Trial Registry No. ChiCTR-ECS-14004641.