STYK1 mediates NK cell anti-tumor response through regulating CCR2 and trafficking.

The serine/threonine/tyrosine kinase 1 (STYK1) is a receptor protein-tyrosine kinase (RPTK)-like molecule that is detected in several human organs. STYK1 plays an important role in promoting tumorigenesis and metastasis in various cancers. By analyzing the expression of RTKs in immune cells in the database of 2013 Immunological Genome Project, we found that STYK1 was principally expressed in NK cells. In order to investigate the function of STYK1, we used CRISPR/Cas9 technology to generate STYK1-deleted mice, we found STYK1 deletion mice have normal number, development, and function of NK cells in spleen and bone marrow in tumor-free resting state. To examine the tumor surveillance of STYK1 in vivo, we utilized a variety of tumor models, including NK cell-specific target cell (ß2M and RMA-S) clearance experiments in vivo, subcutaneous and intravenous injection of B16F10 melanoma model, and the spontaneous breast cancer model MMTV-PyMT. Surprisingly, we discovered that deletion of the oncogenic STYK1 promoted the four-model tumor progression, and we observed a reduction of NK cell accumulation in the tumor tissues of STYK1 deletion mice compared to WT mice. In order to study the mechanism of STYK1 in NK, RNA sequence of STYK1-/- and WT NK have unveiled a disparity in the signaling pathways linked to migration and adhesion in STYK1-/- NK cells. Further analysis of chemokine receptors associated with NK cell migration revealed that STYK1-deficient NK cells exhibited a significant reduction in CCR2 expression. The STYK1 expression was negatively associated with tumor progression in glioma patients. Overall, our study found the expression of STYK1 in NK cell mediates NK cell anti-tumor response through regulating CCR2 and infiltrating into tumor tissue.

Biocompatible Synthesis of Macrocyclic Thiazol(in)e Peptides.

Macrocyclic peptides containing a thiazole or thiazoline in the backbone are considered privileged structures in both natural compounds and drug discovery, owing to their enhanced bioactivity, stability, and permeability. Here, we present the biocompatible synthesis of macrocyclic peptides from N-terminal cysteine and C-terminal nitrile. While the N-terminal cysteine is incorporated during solid-phase peptide synthesis, the C-terminal nitrile is introduced during cleavage with aminoacetonitrile, utilizing a cleavable benzotriazole linker. This method directly yields the fully functionalized linear peptide precursor. The biocompatible cyclization reaction occurs in buffer at physiological pH and room temperature. The resulting thiazoline heterocycle remains stable in buffer but hydrolyzes under acidic conditions. While such hydrolysis enables access to macrocyclic peptides with a complete amide backbone, mild oxidation of the thiazoline leads to the stable thiazole macrocyclic peptide. While conventional oxidation strategies involve metals, we developed a protocol simply relying on alkaline salt and air. Therefore, we offer a rapid and metal-free pathway to macrocyclic thiazole peptides, featuring a biocompatible key cyclization step.

Effect of suspended particulate matter on physiological, biochemical and photosynthetic characteristics of Chlorella pyrenoidosa in the Jinjiang Estuary (Fujian, China).

Suspended particulate matter (SPM), an important component of the natural water environment, can act as a carrier of many pollutants that affect aquatic organisms. In the present study, the effect of SPM obtained from Jinjiang Estuary on the physiological, biochemical, and photosynthetic properties of typical freshwater algae (Chlorella pyrenoidosa) was investigated. The results showed that under different concentrations of SPM treatment, the superoxide dismutase (SOD), catalase (CAT) activities, and malondialdehyde (MDA) content of C. pyrenoidosa increased, but the soluble protein content decreased. SPM with different particle sizes had less effect on SOD of C. pyrenoidosa, but showed a promoting effect on CAT and MDA as well as soluble protein content. In terms of photosynthetic activity, high concentrations (70, 90 mg/L) and small particle sizes (0-75, 75-120 µm) of SPM had a greater effect on the chlorophyll a content of C. pyrenoidosa. In addition, different concentrations of SPM had no significant effect on the potential photosynthetic activity of PS II (Fv/F0) and the maximum quantum yield of PS II (Fv/Fm), but the inhibition of the initial slope (alpha), the maximum photosynthetic rate (ETRmax) and the semi-light saturation point (Ik) increased with the increase of SPM concentration. Fv/F0, ETRmax, and Ik of C. pyrenoidosa showed some degree of recovery after inhibition in the presence of SPM of different particle sizes.

Flow-Based Fmoc-SPPS Preparation and SAR Study of Cathelicidin-PY Reveals Selective Antimicrobial Activity.

Antimicrobial peptides (AMPs) hold promise as novel therapeutics in the fight against multi-drug-resistant pathogens. Cathelicidin-PY (NH2-RKCNFLCKLKEKLRTVITSHIDKVLRPQG-COOH) is a 29-residue disulfide-cyclised antimicrobial peptide secreted as an innate host defence mechanism by the frog Paa yunnanensis (PY) and reported to possess broad-spectrum antibacterial and antifungal properties, exhibiting low cytotoxic and low hemolytic activity. Herein, we detail the total synthesis of cathelicidin-PY using an entirely on-resin synthesis, including assembly of the linear sequence by rapid flow Fmoc-SPPS and iodine-mediated disulfide bridge formation. By optimising a synthetic strategy to prepare cathelicidin-PY, this strategy was subsequently adapted to prepare a bicyclic head-to-tail cyclised derivative of cathelicidin-PY. The structure-activity relationship (SAR) of cathelicidin-PY with respect to the N-terminally positioned disulfide was further probed by preparing an alanine-substituted linear analogue and a series of lactam-bridged peptidomimetics implementing side chain to side chain cyclisation. The analogues were investigated for antimicrobial activity, secondary structure by circular dichroism (CD), and stability in human serum. Surprisingly, the disulfide bridge emerged as non-essential to antimicrobial activity and secondary structure but was amenable to synthetic modification. Furthermore, the synthetic AMP and multiple analogues demonstrated selective activity towards Gram-negative pathogen E. coli in physiologically relevant concentrations of divalent cations.

Hypoxia-related gene signature for predicting LUAD patients' prognosis and immune microenvironment.

Lung adenocarcinoma (LUAD) is a prevalent lung cancer histology with high morbidity and mortality. Moreover, assessment approaches for patients' prognoses are still not effective. Based on mRNA expression and clinical data from the Cancer Genome Atlas (TCGA)-LUAD data set, we utilized hypoxia-related gene set in MsigDB database to identify hypoxia-related differentially expressed genes (DEGs). On the basis of levels of hypoxia-related DEGs, K-means consensus clustering was introduced to divide LUAD patients into subgroups. After hypoxia-related DEGs were analyzed through univariate, Lasso and multivariate Cox regression analyses, 6 of them were determined to be used for evaluating LUAD patients' prognostic signature. With median risk score obtained from hypoxia-related gene signature as threshold, LUAD patients were divided into high- and low-risk groups. Besides, Kaplan-Meier curves, receiver operator characteristic (ROC) curves, univariate and multivariate Cox regression analyses verified that hypoxia-related gene signature was an important prognostic factor independent of clinical features. Gene set enrichment analysis (GSEA) displayed that pathways which showed differences between high- and low-risk groups in activation of pentose-phosphate pathway and p53 signaling pathway. CIBERSORT was utilized to assess infiltration level of each immune cell from two groups, indicating the differences in infiltration abundance of Plasma cells, T cells CD4+ memory activated and Macrophages M1 cells between high- and low-risk groups. We drew a nomogram for predicting one-, three- and five-year survival of LUAD patients following risk scores of hypoxia-related gene signature and six clinical factors. Calibration curves showed a high fit between survival predicted by nomogram and actual survival. In conclusion, hypoxia-related gene signature can be introduced for predicting LUAD patients' prognosis and assessment of the patients' immune microenvironment, guiding clinicians to make appropriate decisions during diagnosis and treatment of LUAD patients.

Laparoscopic central hepatectomy using a parenchymal-first approach: how we do it.

BACKGROUND: Laparoscopic central hepatectomy (LCH) is a difficult and challenging procedure. This study aimed to describe our experience with LCH using a parenchymal-first approach. METHODS: Between July 2017 and June 2021, 19 consecutive patients underwent LCH using a parenchymal-first approach at our institution. Herein, the details of this procedural strategy are described, and the demographic and clinical data of the included patients were retrospectively analyzed. RESULTS: There were 1 female and 18 male patients, all with hepatocellular carcinoma without major vascular invasion. The mean age was 57 ± 10 years. No patients underwent conversion to open surgery, and no blood transfusions were needed intraoperatively. The average operative duration and the average Pringle maneuver duration were 223 ± 65 min and 58 ± 11 min. respectively. The median blood loss was 200 ml (range: 100-800 ml). Postoperative morbidities occurred in 3 patients (15.8%), including 2 cases of bile leakage and 1 case of acquired pulmonary infection; there were no postoperative complications happened such as bleeding, hepatic failure, or mortality. The average postoperative hospital stay was 10 ± 3 days. CONCLUSION: The optimized procedure of LCH using a parenchymal-first approach is not only feasible but also expected to provide an advantage in laparoscopic anatomical hepatectomy.

Distribution characteristics of microplastics in the soil of mangrove restoration wetland and the effects of microplastics on soil characteristics.

The dense vegetation in the wetland could effectively retain microplastic particles, and the distribution of microplastics varied significantly under different planting densities. In addition, microplastics in the soil environment can affect soil properties to a certain extent, which in turn can affect soil functions and biodiversity. In this study, we investigated the distribution of soil microplastics in a mangrove restoration wetland under different planting densities and their effects on wetland soil properties. The results indicated that the average abundance of soil microplastics was 2177.5 n/500 g, of which 70.9% exhibited a diameter ranging from 0.038-0.05 mm, while the remaining soil microplastics accounted for less than 20% of all microplastics, indicating that smaller-diameter microplastics were more likely to accumulate in wetland soil. The microplastic abundance could be ranked based on the planting density as follows: 0.5 × 0.5 m > 1.0 × 0.5 m > 1.0 × 1.0 m > control area. Raman spectroscopy revealed that the predominant microplastic categories in this region included polyethylene terephthalate (PET, 52%), polyethylene (PE, 24%) and polypropylene (PP, 15%). Scanning electron microscopy (SEM) images revealed fractures and tears on the surface of microplastics. EDS energy spectra indicated a large amount of metal elements on the surface of microplastics. Due to the adsorptive features of PET, this substance could influence the soil particle size distribution and thus the soil structure. All physicochemical factors, except for the soil pH, were significantly affected by PET. In addition, the CV analysis results indicated that soils in vegetated areas are more susceptible to PET than are soils in bare ground areas, leading to greater variation in their properties.

Clearing Persistent Extracellular Antigen of Hepatitis B Virus: An Immunomodulatory Strategy To Reverse Tolerance for an Effective Therapeutic Vaccination.

Development of therapeutic vaccines/strategies to control chronic hepatitis B virus (HBV) infection has been challenging because of HBV-induced tolerance. In this study, we explored strategies for breaking tolerance and restoring the immune response to the HBV surface Ag in tolerant mice. We demonstrated that immune tolerance status is attributed to the level and duration of circulating HBsAg in HBV carrier models. Removal of circulating HBsAg by a monoclonal anti-HBsAg Ab in tolerant mice could gradually reduce tolerance and reestablish B cell and CD4(+) T cell responses to subsequent Engerix-B vaccination, producing protective IgG. Furthermore, HBsAg-specific CD8(+) T cells induced by the addition of a TLR agonist resulted in clearance of HBV in both serum and liver. Thus, generation of protective immunity can be achieved by clearing extracellular viral Ag with neutralizing Abs followed by vaccination.

Major hepatectomy for primary hepatolithiasis: a comparative study of laparoscopic versus open treatment.

BACKGROUND: Due to higher technical requirements, laparoscopic major hepatectomy (LMH) for primary hepatolithiasis have been limited to a few institutions. This retrospective study was performed to evaluate the therapeutic safety, and perioperative and long-term outcomes of LMH versus open major hepatectomy (OMH) for hepatolithiasis. METHODS: From January 2012 to December 2016, 61 patients with hepatolithiasis who underwent major hepatectomy were enrolled, including 29 LMH and 32 OMH. The perioperative outcomes and postoperative complications, as well as long-term outcomes, including the stone clearance and recurrence rate, were evaluated. RESULTS: There was no difference of surgical procedures between the two groups. The mean operation time was (262 ± 83) min in the LMH group and (214 ± 66) min in the OMH group (p = 0.05). There is no difference of intra-operative bleeding (310 ± 233) ml versus (421 ± 359) ml (p = 0.05). In the LMH group, there were shorter time to postoperative oral intake ((1.1 ± 0.6) days versus (3.1 ± 1.8) days, p = 0.01) and shorter hospital stay [(7.2 ± 2.3) days versus (11.8 ± 5.5) days, p = 0.03] than the open group. The LMH group had comparable stone clearance rate with the OMH group during the initial surgery (82.8% vs. 84.4%, p = 0.86). CONCLUSIONS: LMH could be an effective and safe treatment for selected patients with hepatolithiasis, with an advantage over OMH in the field of less intra-operative blood loss, less intra-operative transfusion, less overall complications, and faster postoperative recovery.

Prevalence and genotype distribution of human papillomavirus infection in Harbin, Northeast China.

This study aimed to investigate the overall prevalence of human papillomavirus (HPV) infection among women examined at a hospital in Harbin and to evaluate the impact of HPV types on the natural outcome and state of cervical cytology. A total of 2,938 female outpatients from the affiliated hospital of Harbin Medical University were enrolled. Rapid hybridization gene chip and liquid-based cytology tests were used to detect HPV genotypes and cervical cytology. The overall prevalence of HPV in women who came to this hospital was 36.45 %. The majority were infected with a single strain, and the high-risk HPV (HR-HPV) type constituted the largest proportion. HPV16 and 58 were the most common types, while the genotypes of single low-risk HPV (LR-HPV) were not the same in different age groups. HPV53, 16 and 81 were the most common types in multiple HR-HPV infection; HR-HPV16, 33, 81 and LR-HPV 6, 44, 43 were the most common in HR and LR-HPV infection. In total, 44.1 % of the women with HSIL and 44.0 % with ASCUS were positive for HR-HPV16. Multiple HPV infections and single HPV infections had no effect on the natural outcome after half a year. HPV16, 81 and 35 had a better natural outcome, followed by HPV52 and 53, but HPV58, 59 and 18 had a bad outcome after half a year. This is the first study to show that the distribution of HPV types is different in Harbin than it is in other regions. These findings will provide guidance for the vaccination program in this area.

Biocompatible strategies for peptide macrocyclisation.

Peptides are increasingly important drug candidates, offering numerous advantages over conventional small molecules. However, they face significant challenges related to stability, cellular uptake and overall bioavailability. While individual modifications may not address all these challenges, macrocyclisation stands out as a single modification capable of enhancing affinity, selectivity, proteolytic stability and membrane permeability. The recent successes of in situ peptide modifications during screening in combination with genetically encoded peptide libraries have increased the demand for peptide macrocyclisation reactions that can occur under biocompatible conditions. In this perspective, we aim to distinguish biocompatible conditions from those well-known examples that are fully bioorthogonal. We introduce key strategies for biocompatible peptide macrocyclisation and contextualise them within contemporary screening methods, providing an overview of available transformations.

SLAM-family receptors promote resolution of ILC2-mediated inflammation.

Type 2 innate lymphoid cells (ILC2) initiate early allergic inflammation in the lung, but the factors that promote subsequent resolution of type 2 inflammation and prevent prolonged ILC2 activation are not fully known. Here we show that SLAM-family receptors (SFR) play essential roles in this process. We demonstrate dynamic expression of several SFRs on ILC2s during papain-induced type 2 immunity in mice. SFR deficiency exacerbates ILC2-driven eosinophil infiltration in the lung, and results in a significant increase in IL-13 production by ILC2s exclusively in mediastinal lymph nodes (MLN), leading to increased dendritic cell (DC) and TH2 cell numbers. In MLNs, we observe more frequent interaction between ILC2s and bystander T cells, with T cell-expressed SFRs (especially SLAMF3 and SLAMF5) acting as self-ligands to suppress IL-13 production by ILC2s. Mechanistically, homotypic engagement of SFRs at the interface between ILC2s and T cells delivers inhibitory signaling primarily mediated by SHIP-1. This prevents activation of NF-κB, driven by IL-7 and IL-33, two major drivers of ILC2-mediated type 2 immunity. Thus, our study shows that an ILC2-DC-TH2 regulatory axis may promote the resolution of pulmonary type 2 immune responses, and highlights SLAMF3/SLAMF5 as potential therapeutic targets for ameliorating type 2 immunity.

Dual Activity of Type III PI3K Kinase Vps34 is Critical for NK Cell Development and Senescence.

Vps34 is the unique member of the class III phosphoinositide 3-kinase family that performs both vesicular transport and autophagy. Its role in natural killer (NK) cells remains uncertain. In this study, a model without Vps34 (Vps34fl/fl/CD122Cre/+) is generated, deleting Vps34 during and after NK-cell commitment. These mice exhibit a nearly 90% decrease in NK cell count and impaired differentiation. A mechanistic study reveals that the absence of Vps34 disrupts the transport of IL-15 receptor subunit alpha CD122 to the cell membrane, resulting in reduced responsiveness of NK cells to IL-15. In mice lacking Vps34 at the terminal stage of NK-cell development (Vps34fl/fl/Ncr1Cre/+), NK cells gradually diminish during aging. This phenotype is associated with autophagy deficiency and the stress induced by reactive oxygen species (ROS). Therefore, terminally differentiated NK cells lacking Vps34 display an accelerated senescence phenotype, while the application of antioxidants effectively reverses the senescence caused by Vps34 deletion by neutralizing ROS. In summary, this study unveils the dual and unique activity of Vps34 in NK cells. Vps34-mediated vesicular transport is crucial for CD122 membrane trafficking during NK cell commitment, whereas Vps34-mediated autophagy can delay NK cell senescence.

Eomesodermin spatiotemporally orchestrates the early and late stages of NK cell development by targeting KLF2 and T-bet, respectively.

Eomesodermin (Eomes) is a critical factor in the development of natural killer (NK) cells, but its precise role in temporal and spatial coordination during this process remains unclear. Our study revealed that Eomes plays distinct roles during the early and late stages of NK cell development. Specifically, the early deletion of Eomes via the CD122-Cre transgene resulted in significant blockade at the progenitor stage due to the downregulation of KLF2, another important transcription factor. ChIP-seq revealed direct binding of Eomes to the conserved noncoding sequence (CNS) of Klf2. Utilizing the CHimeric IMmune Editing (CHIME) technique, we found that deletion of the CNS region of Klf2 via CRISPRi led to a reduction in the NK cell population and developmental arrest. Moreover, constitutive activation of this specific CNS region through CRISPRa significantly reversed the severe defects in NK cell development caused by Eomes deficiency. Conversely, Ncr1-Cre-mediated terminal deletion of Eomes expedited the transition of NK cell subsets from the CD27+CD11b+ phenotype to the CD27-CD11b+ phenotype. Late-stage deficiency of Eomes led to a significant increase in T-bet expression, which subsequently increased the expression of the transcription factor Zeb2. Genetic deletion of one allele of Tbx21, encoding T-bet, effectively reversed the aberrant differentiation of Eomes-deficient NK cells. In summary, we utilized two innovative genetic models to elucidate the intricate mechanisms underlying Eomes-mediated NK cell commitment and differentiation.

A single-cell analysis of the NK-cell landscape reveals that dietary restriction boosts NK cell antitumor immunity via Eomesdermin.

Abnormal metabolism in tumor cells represents a potential target for tumor therapy. In this regard, dietary restriction (DR) or its combination with anticancer drugs is of interest as it can impede the growth of tumor cells. In addition to its effects on tumor cell, DR also plays an extrinsic role in restricting tumor growth by regulating immune cells. Natural killer (NK) cells are innate immune cells involved in tumor immunosurveillance. However, it remains uncertain whether DR can assist NK cells in controlling tumor growth. Herein, we demonstrate that DR effectively inhibits metastasis of melanoma cells to the lung. Consistent with this, the regression of tumors induced by DR was minimal in mice lacking NK cells. Single-cell RNA sequencing analysis revealed that DR enriched a rejuvenated subset of CD27+CD11b+ NK cells. Mechanistically, DR activated a regulatory network involving the transcription factor Eomesodermin (Eomes), which is essential for NK-cell development. Firstly, DR promoted the expression of Eomes by optimizing mTORC1 signaling. The upregulation of Eomes revived the subset of functional CD27+CD11b+ NK cells by counteracting the expression of T-bet and downstream Zeb2. Moreover, DR enhanced the function and chemotaxis of NK cells by increasing the accessibility of Eomes to chromatin, leading to elevated expression of adhesion molecules and chemokines. Consequently, we conclude that DR therapy enhances tumor immunity through non-tumor autonomous mechanisms, including promoting NK-cell tumor immunosurveillance and activation.

Multilayer Fluorine-Free MoBTx MBene with Hydrophilic Structural-Modulating for the Fabrication of a Low-Resistance and High-Resolution Humidity Sensor.

2D transition metal borides (MBenes) with abundant surface terminals hold great promise in molecular sensing applications. However, MBenes from etching with fluorine-containing reagents present inert -fluorine groups on the surface, which hinders their sensing capability. Herein, the multilayer fluorine-free MoBTx MBene (where Tx represents O, OH, and Cl) with hydrophilic structure is prepared by a hydrothermal-assisted hydrochloric acid etching strategy based on guidance from the first-principle calculations. Significantly, the fluorine-free MoBTx-based humidity sensor is fabricated and demonstrates low resistance and excellent humidity performance, achieving a response of 90% to 98%RH and a high resolution of 1%RH at room temperature. By combining the experimental results with the first-principles calculations, the interactions between MoBTx and H2O, including the adsorption and intercalation of H2O, are understood first in depth. Finally, the portable humidity early warning system for real-time monitoring and early warning of infant enuresis and back sweating illustrates its potential for humidity sensing applications. This work not only provides guidance for preparation of fluorine-free MBenes, but also contributes to advancing their exploration in sensing applications.

Self-Healing, Laminated, and Low Resistance NH3 Sensor Based on 6,6',6″-(Nitrilotris(benzene-4,1-diyl))tris(5-phenylpyrazine-2,3-dicarbonitrile) Sensing Material Operating at Room Temperature.

With the rapid development of the concept of the Internet of Things (IoT), gas sensors with the function of simulating the human sense of smell became irreplaceable as a key element. Among them, ammonia (NH3) sensors played an important role in respiration tests, environmental monitoring, safety, and other fields. However, the fabrication of the high-performance device with high stability and resistance to mechanical damages was still a challenge. In this work, polyurethane (PU) with excellent self-healing ability was applied as the substrate, and the sensor was designed from new sensitive material design and device structure optimization, through applying the organic molecule with groups which could absorb NH3 and the laminated structure to shorten the electronic transmission path to achieve a low resistance state and favorable sensing properties. Accordingly, a room temperature flexible NH3 sensor based on 6,6',6″-(nitrilotris(benzene-4,1-diyl))tris(5-phenylpyrazine-2,3-dicarbonitrile) (TPA-3DCNPZ) was successfully developed. The device could self-heal by means of a thermal evaporation assisted method. It exhibited a detection limit of 1 ppm at 98% relative humidity (RH), as well as great stability, selectivity, bending flexibility, and self-healing properties. The improved NH3 sensing performance under high RH was further investigated by complex impedance plots (CIPs) and density functional theory (DFT), attributing to the enhanced adsorption of NH3. The TPA-3DCNPZ based NH3 sensors proved to have great potential for application on simulated exhaled breath to determine the severity of kidney diseases and the progress of treatment. This work also provided new ideas for the construction of high-performance room temperature NH3 sensors.

Tenofovir versus entecavir on the prognosis of hepatitis B virus-related hepatocellular carcinoma: a reconstructed individual patient data meta-analysis.

Background: Hepatitis B, often leading to Hepatocellular carcinoma (HCC), poses a major global health challenge. While Tenofovir (TDF) and Entecavir (ETV) are potent treatments, their comparative effectiveness in improving recurrence-free survival (RFS) and overall survival (OS) rates in HBV-related HCC is not well-established. Methods: We conducted an individual patient data meta-analysis using survival data from randomized trials and high-quality propensity score-matched studies to compare the impact of Tenofovir (TDF) and Entecavir (ETV) on RFS and OS in HBV-related HCC patients. Data from six databases and gray literature up to 30 August 2023, were analyzed, utilizing Kaplan-Meier curves, stratified Cox models, and shared frailty models for survival rate assessment and to address between-study heterogeneity. The study employed restricted mean survival time analysis to evaluate differences in RFS and OS between TDF-treated and ETV-treated patients. Additionally, landmark analyses compared early (<2 years) and late (≥2 years) tumor recurrence in these cohorts. Results: This study incorporated seven research articles, covering 4,602 patients with HBV-related HCC (2,082 on TDF and 2,520 on ETV). Within the overall cohort, TDF recipients demonstrated significantly higher RFS (p = 0.042) and OS (p < 0.001) than those on ETV. The stratified Cox model revealed significantly improved OS for the TDF group compared to the ETV group (hazard ratio, 0.756; 95% confidence interval, 0.639-0.896; p = 0.001), a result corroborated by the shared frailty model. Over a follow-up period of 1-8 years, no significant difference was noted in the mean time to death between the TDF and ETV groups. The rates of early recurrence did not significantly differ between the groups (p = 0.735). However, TDF treatment was significantly associated with a reduced risk of late recurrence compared to ETV (p < 0.001). In the HCC resection subgroup, the disparities in OS, early, and late recurrence rates between the two treatments paralleled those seen in the overall cohort. Conclusion: Compared to ETV, TDF may enhance OS and reduce late tumor recurrence risk in HBV-related HCC patients receiving curative treatment. However, there was no statistically significant distinction in the timing of tumor recurrence and mortality between patients administered TDF and those prescribed ETV. Systematic Review Registration: http://www.crd.york.ac.uk/prospero/.

Vps34 sustains Treg cell survival and function via regulating intracellular redox homeostasis.

The survival and suppressive function of regulatory T (Treg) cells rely on various intracellular metabolic and physiological processes. Our study demonstrates that Vps34 plays a critical role in maintaining Treg cell homeostasis and function by regulating cellular metabolic activities. Disruption of Vps34 in Treg cells leads to spontaneous fatal systemic autoimmune disorder and multi-tissue inflammatory damage, accompanied by a reduction in the number of Treg cells, particularly eTreg cells with highly immunosuppressive activity. Mechanistically, the poor survival of Vps34-deficient Treg cells is attributed to impaired endocytosis, intracellular vesicular trafficking and autophagosome formation, which further results in enhanced mitochondrial respiration and excessive ROS production. Removal of excessive ROS can effectively rescue the death of Vps34-deficient Treg cells. Functionally, acute deletion of Vps34 within established Treg cells enhances anti-tumor immunity in a malignant melanoma model by boosting T-cell-mediated anti-tumor activity. Overall, our results underscore the pivotal role played by Vps34 in orchestrating Treg cell homeostasis and function towards establishing immune homeostasis and tolerance.

Dihydroartemisinin Sensitizes Lung Cancer Cells to Cisplatin Treatment by Upregulating ZIP14 Expression and Inducing Ferroptosis.

BACKGROUND: Despite significant advances in lung cancer treatment, cisplatin (DDP)-based chemotherapy remains a cornerstone for managing the disease. However, the prevalence of chemoresistance presents a major challenge, limiting its effectiveness and contributing to poor outcomes. This underscores the urgent need for novel therapeutic strategies to overcome chemoresistance and improve chemotherapy efficacy in lung cancer patients. Exploring approaches to sensitize tumors to cisplatin could enhance treatment responses and overall survival rates. METHODS AND RESULTS: Our study utilized a variety of lung cancer models, including cell lines, mouse models, and patient-derived organoids, to validate the synergistic cytotoxic effects of dihydroartemisinin (DHA) and cisplatin (DDP). When combined with DDP, we demonstrate that DHA is a promising therapeutic agent that effectively triggers ferroptosis in lung cancer cells, offering a potential strategy for overcoming chemoresistance. Mechanistically, the combination of DHA and DDP synergistically enhances ZIP14 expression, modulating iron homeostasis and upregulating oxidative stress, leading to both in vitro and in vivo ferroptosis. Notably, our findings revealed that the sequential administration of DDP followed by DHA significantly increases ZIP14 expression and induces superior therapeutic outcomes compared to the simultaneous administration or DHA followed by DDP. This observation underscores the importance of the drug administration order in optimizing treatment efficacy, providing new insights into enhancing chemotherapy response in lung cancer. CONCLUSION: Our findings suggest that combining dihydroartemisinin (DHA) with cisplatin (DDP) presents a promising strategy to overcome chemoresistance in lung cancer patients. Importantly, administering DHA during chemotherapy intervals could further optimize treatment outcomes, enhancing the overall efficacy of lung cancer chemotherapy.