The Transcription Factor Zfp335 Promotes Differentiation and Survival of Effector Th1 Cells by Directly Regulating Lmna Expression.

Ag-specific effector CD4+ T cells play a crucial role in defending against exogenous pathogens. However, the mechanisms governing the differentiation and function of IFN-γ-producing effector CD4+ Th1 cells in immune responses remain largely unknown. In this study, we elucidated the pivotal role of zinc finger protein 335 (Zfp335) in regulating effector Th1 cell differentiation and survival during acute bacterial infection. Mice with Zfp335 knockout in OT-II cells exhibited impaired Ag-specific CD4+ T cell expansion accompanied by a significant reduction in resistance to Listeria infection. Furthermore, Zfp335 deficiency restricted the effector CD4+ Th1 cell population and compromised their survival upon Listeria challenge. The expression of T-bet and IFN-γ was accordingly decreased in Zfp335-deficient Th1 cells. Mechanistically, Zfp335 directly bound to the promoter region of the Lmna gene and regulated its expression. Overexpression of Lmna was able to rescue the survival and function of Zfp335-deficient effector Th1 cells. Therefore, our study provides novel insights into the mechanisms governing effector Th1 cell differentiation and survival during acute infection.

Med1 controls thymic T-cell migration into lymph node through enhancer-based Foxo1-Klf2 transcription program.

The migration is the key step for thymic T cells to enter circulation and then lymph nodes (LNs), essential for future immune surveillance. Although promoter-based transcriptional regulation through Foxo1, Klf2, Ccr7, and Sell regulates T-cell migration, it remains largely unexplored whether and how enhancers are involved in this process. Here we found that the conditional deletion of Med1, a component of the mediator complex and a mediator between enhancers and RNA polymerase II, caused a reduction of both CD4+ and CD8+ T cells in LNs, as well as a decrease of CD8+ T cells in the spleen. Importantly, Med1 deletion hindered the migration of thymic αßT cells into the circulation and then into LNs, accompanied by the downregulation of KLF2, CCR7, and CD62L. Mechanistically, Med1 promotes Klf2 transcription by facilitating Foxo1 binding to the Klf2 enhancer. Furthermore, forced expression of Klf2 rescued Ccr7 and Sell expression, as well as αßT-cell migration into LNs. Collectively, our study unveils a crucial role for Med1 in regulating the enhancer-based Foxo1-Klf2 transcriptional program and the migration of αßT cells into LNs, providing valuable insights into the molecular mechanisms underlying T-cell migration.

The compensatory role of T cells from lymph nodes in mice with splenectomy.

The spleen is a vital organ for the immune system, while splenectomy may be necessary for various reasons. However, there is limited research on the impact of splenectomy on T cell function in peripheral lymph nodes as a compensatory mechanism in preventing infections. This study aimed to investigate the characteristics and function of CD8+ and CD4+ T cells in different peripheral lymph nodes during viral infection using a well-established splenectomy model. The results revealed that splenectomy caused an increase in CD8+GP33+ T cells in the mesenteric lymph nodes (MLN). Moreover, we demonstrated that splenectomy resulted in an increase of effector KLRG1+ T cells in the MLN. Additionally, the number of CD4+ cytotoxic T cells (CD4 CTLs) was also elevated in the peripheral lymph nodes of mice with splenectomy. Surprisingly, aged mice exhibited a stronger compensatory ability than adult mice, as evidenced by an increase in effector CD8+ T cells in all peripheral lymph nodes. These findings provide compelling evidence that T cells in MLN play a crucial role in protecting individuals with splenectomy against viral infections. The study offers new insights into understanding the changes in the immune system of individuals with splenectomy and highlights the potential compensatory mechanisms involved by T cells in peripheral lymph nodes.

Progress and Challenges in Tumor Ferroptosis Treatment Strategies: A Comprehensive Review of Metal Complexes and Nanomedicine.

Ferroptosis is a new form of regulated cell death featuring iron-dependent lipid peroxides accumulation to kill tumor cells. A growing body of evidence has shown the potential of ferroptosis-based cancer therapy in eradicating refractory malignancies that are resistant to apoptosis-based conventional therapies. In recent years, studies have reported a number of ferroptosis inducers that can increase the vulnerability of tumor cells to ferroptosis by regulating ferroptosis-related signaling pathways. Encouraged by the rapid development of ferroptosis-driven cancer therapies, interdisciplinary fields that combine ferroptosis, pharmaceutical chemistry, and nanotechnology are focused. First, the prerequisites and metabolic pathways for ferroptosis are briefly introduced. Then, in detail emerging ferroptosis inducers designed to boost ferroptosis-induced tumor therapy, including metal complexes, metal-based nanoparticles, and metal-free nanoparticles are summarized. Subsequently, the application of synergistic strategies that combine ferroptosis with apoptosis and other regulated cell death for cancer therapy, with emphasis on the use of both cuproptosis and ferroptosis to induce redox dysregulation in tumor and intracellular bimetallic copper/iron metabolism disorders during tumor treatment is discussed. Finally, challenges associated with clinical translation and potential future directions for potentiating cancer ferroptosis therapies are highlighted.

The Transcription Factor Zfp335 Promotes Differentiation and Persistence of Memory CD8+ T Cells by Regulating TCF-1.

Memory CD8+ T cells play an essential role in providing effective and lifelong protection against pathogens. Comprehensive transcriptional and epigenetic networks are involved in modulating memory T cell development, but the molecular regulations of CD8+ memory T cell formation and long-term persistence remain largely unknown. In this study, we show that zinc finger protein 335 (Zfp335) is indispensable for CD8+ T cell memory establishment and maintenance during acute infections. Mice with Zfp335 deletion in CD8+ T cells exhibit a significant reduction of memory T cells and memory precursor cells in the contraction phase. Zfp335 deficiency in CD8+ T cells resulted in decreased expression of memory featured genes Eomes and IL-2Rß, leading to a loss of memory identity and an increase of apoptosis in response to IL-7 and IL-15. Mechanistically, Zfp335 directly binds to and regulates TCF-1, known to be critical for memory T cell development. Importantly, overexpression TCF-1 could rescue the defects in the survival of both CD8+ memory precursors and memory T cells caused by Zfp335 deficiency. Collectively, our findings reveal that Zfp335 serves as a novel transcriptional factor upstream of TCF-1 in regulating CD8+ T cell memory.

Med1 Controls Effector CD8+ T Cell Differentiation and Survival through C/EBPß-Mediated Transcriptional Control of T-bet.

Effector CD8+ T cells are crucial players in adaptive immunity for effective protection against invading pathogens. The regulatory mechanisms underlying CD8+ T cell effector differentiation are incompletely understood. In this study, we defined a critical role of mediator complex subunit 1 (Med1) in controlling effector CD8+ T cell differentiation and survival during acute bacterial infection. Mice with Med1-deficient CD8+ T cells exhibited significantly impaired expansion with evidently reduced killer cell lectin-like receptor G1+ terminally differentiated and Ly6c+ effector cell populations. Moreover, Med1 deficiency led to enhanced cell apoptosis and expression of multiple inhibitory receptors (programmed cell death 1, T cell Ig and mucin domain-containing-3, and T cell immunoreceptor with Ig and ITIM domains). RNA-sequencing analysis revealed that T-bet- and Zeb2-mediated transcriptional programs were impaired in Med1-deficient CD8+ T cells. Overexpression of T-bet could rescue the differentiation and survival of Med1-deficient CD8+ effector T cells. Mechanistically, the transcription factor C/EBPß promoted T-bet expression through interacting with Med1 in effector T cells. Collectively, our findings revealed a novel role of Med1 in regulating effector CD8+ T cell differentiation and survival in response to bacterial infection.

Biologically informed machine learning modeling of immune cells to reveal physiological and pathological aging process.

The immune system undergoes progressive functional remodeling from neonatal stages to old age. Therefore, understanding how aging shapes immune cell function is vital for precise treatment of patients at different life stages. Here, we constructed the first transcriptomic atlas of immune cells encompassing human lifespan, ranging from newborns to supercentenarians, and comprehensively examined gene expression signatures involving cell signaling, metabolism, differentiation, and functions in all cell types to investigate immune aging changes. By comparing immune cell composition among different age groups, HLA highly expressing NK cells and CD83 positive B cells were identified with high percentages exclusively in the teenager (Tg) group, whereas unknown_T cells were exclusively enriched in the supercentenarian (Sc) group. Notably, we found that the biological age (BA) of pediatric COVID-19 patients with multisystem inflammatory syndrome accelerated aging according to their chronological age (CA). Besides, we proved that inflammatory shift- myeloid abundance and signature correlate with the progression of complications in Kawasaki disease (KD). The shift- myeloid signature was also found to be associated with KD treatment resistance, and effective therapies improve treatment outcomes by reducing this signaling. Finally, based on those age-related immune cell compositions, we developed a novel BA prediction model PHARE ( https://xiazlab.org/phare/ ), which can apply to both scRNA-seq and bulk RNA-seq data. Using this model, we found patients with coronary artery disease (CAD) also exhibit accelerated aging compared to healthy individuals. Overall, our study revealed changes in immune cell proportions and function associated with aging, both in health and disease, and provided a novel tool for successfully capturing features that accelerate or delay aging.

[Effects of different exercise modes on neuromuscular junction and metabolism of skeletal muscle-related proteins in aging rats].

The present study aimed to explore the effects of different exercise modes on neuromuscular junction (NMJ) and metabolism of skeletal muscle-related proteins in aging rats. Ten from 38 male Sprague-Dawley (SD) rats (3-month-old) were randomly selected into young (Y) group, while the rest were raised to 21 months old and randomly divided into elderly control (O), endurance exercise (EN) and resistance exercise (R) groups. After 8 weeks of corresponding exercises training, the gastrocnemius muscles of rats were collected, and the expression of S100B in Schwann cells was detected by immunofluorescence staining. Western blot was used to detect the protein expression levels of agglutinate protein (Agrin), low-density lipoprotein receptor-related protein 4 (Lrp4), muscle- specific kinase protein (MuSK), downstream tyrosine kinase 7 (Dok7), phosphorylated protein kinase B (p-Akt), phosphorylated mammalian target rapamycin (p-mTOR), and phosphorylated forkhead box O1 (p-FoxO1) in rat gastrocnemius muscles. The results showed that, endurance and resistance exercises increased the wet weight ratio of gastrocnemius muscle in the aging rats. The protein expression of S100B in the R group was significantly higher than those in the O and EN groups. Proteins related to NMJ function, including Agrin, Lrp4, MuSK, and Dok7 were significantly decreased in the O group compared with those in the Y group. Resistance exercise up-regulated these four proteins in the aging rats, whereas endurance exercise could not reverse the protein expression levels of Lrp4, MuSK and Dok7. Regarding skeletal muscle-related proteins, the O group showed down-regulated p-Akt, and p-mTOR protein expression levels and up-regulated p-FoxO1 protein expression level, compared to the Y group. Resistance and endurance exercises reversed the changes in p-mTOR and p-FoxO1 protein expression in the aging rats. These findings demonstrate that both exercise modes can enhance NMJ function, increase protein synthesis and reduce the catabolism of skeletal muscle-related proteins in aging rats, with resistance exercise showing a more pronounced effect.

Effects of ultrasound-guided stellate ganglion block on postoperative sore throat and postoperative sleep disturbance after lumbar spine surgery: a randomized controlled trial.

BACKGROUND: Postoperative sore throat and sleep disturbance are prevalent among patients undergoing spinal surgery, and these conditions can substantially impact their postoperative satisfaction and quality of life. The present study aimed to examine the impact of ultrasound-guided stellate ganglion block (SGB) on the occurrence of postoperative sore throat (POST) and postoperative sleep disturbance (PSD) in patients who undergo lumbar spine surgery under general anesthesia. METHODS: Sixty patients were randomly assigned to either the experimental group (SGB group) or the control group (CG). Both groups received the same induction and maintenance drugs. However, the SGB group received a right SGB under ultrasound guidance 15 min before anesthesia induction, while the CG did not receive any block anesthesia intervention before anesthesia induction. We monitored the incidence and severity of POST at 1, 6, 24, and 48 h after surgery in both groups. Additionally, we evaluated the deep sleep quality score on the first, second, and fifth days after surgery in both groups. RESULTS: The incidence of POST at 1 h and 6 h after surgery was significantly lower in the SGB group (10.0% and 13.3%) than in the CG (43.3% and 36.7%) (P < 0.05). The postoperative sore throat scores of the SGB group (0.10 ± 0.31 and 0.17 ± 0.46) at 1 h and 6 h after surgery were lower than those of the CG (0.57 ± 0.73 and 0.50 ± 0.77) (P < 0.05). Moreover, the deep sleep quality score on the first, second, and fifth days after surgery were significantly higher in the CG (5.40 ± 3.37, 4.70 ± 3.19, 4.53 ± 3.44) than in the SGB group (3.87 ± 2.30, 3.13 ± 1.77, 3.03 ± 1.84) (P < 0.05). CONCLUSION: Ultrasound-guided SGB can reduce the incidence and severity of POST and improve PSD in patients undergoing lumbar spine surgery. TRIAL REGISTRATION: This study was registered on Chinese Clinical Trial Registry, (ChiCTR2200065279) on 01/11/2022.

Effects of intraoperative Magnesium sulfate infusion on emergency agitation during general anesthesia in patients undergoing radical mastectomy: a randomized controlled study.

BACKGROUND: Emergency agitation is a common postoperative complication in patients under general anesthesia, which can lead to unpredictable damages such as shedding of drainage tube and bleeding from the wound. The purpose of the study is to investigate whether intraoperative infusion of Magnesium Sulfate reduces the incidence of emergency agitation (EA) in patients undergoing radical mastectomy, and to evaluate its safety and efficacy. METHODS: A total of 70 patients were randomly assigned to two groups: the Magnesium group (M group) and the control group (C group). After a routine intravenous anesthetic induction, patients in the M group received a 30 mg/kg bolus of intravenous magnesium during the first hour and then a continuous infusion of 10 mg/kg ×h until the end of the surgery, patients in the C group received 0.9% saline at the same volume and rate. The sedation-agitation scale (SAS) and the visual analogue scale were used to assess agitation and pain, respectively. RESULTS: Compared to the C group, the M group reduced the incidence of EA significantly (odds ratio 0.26, 95% confidence interval 0.09-0.71, P = 0.009). The postoperative pain score of the magnesium sulfate group(0(0,1)) was lower than that of the control group(2(0,3)) at T0 (P = 0.011). Additionally, the M group required a lower dosage of remifentanil during surgery compared to the C group(300.4 ± 84 versus 559.3 ± 184 µg, respectively, P<0.001). CONCLUSIONS: the intraoperative infusion of magnesium sulfate is a safe and effective method for reducing the incidence of emergency agitation in patients undergoing radical mastectomy. TRAIL REGISTRATION: The study was registered in Chictr.org with the identifier: ChiCTR2300070595 on 18/04/2023.

Pbrm1 intrinsically controls the development and effector differentiation of iNKT cells.

Under static condition, the pool size of peripheral invariant natural killer T (iNKT) cells is determined by their homeostatic proliferation, survival and thymic input. However, the underlying mechanism is not fully understood. In the present study, we found that the percentage and number of iNKT cells were significantly reduced in the spleen, but not in the thymus of mice with deletion of polybromo-1 (Pbrm1) compared to wild type (WT) mice. Pbrm1 deletion did not affect iNKT cell proliferation and survival, instead significantly impaired their development from stage 1 to stage 2. Importantly, loss of Pbrm1 led to a dysfunction of RORγt expression and iNKT17 cell differentiation, but not iNKT1 and iNKT2 proportion. Collectively, our study reveals a novel mechanism of Pbrm1 controlling the peripheral size of iNKT cells through regulating their development and differentiation.

Arid1a promotes thymocyte development through ß-selection-dependent and ß-selection-independent mechanisms.

Early T-cell development from CD4-  CD8- double-negative (DN) stage to CD4+  CD8+ double-positive (DP) stage in the thymus is regulated through multiple steps involving a batch of sequentially expressed factors. Our preliminary data and a recent report showed that AT-rich interaction domain 1A (Arid1a) is required for the transition from DN to DP stages, but the mechanism is not fully understood. In this study, we consolidated that conditional deletion of Arid1a in T-cell lineage intrinsically caused developmental blocks from DN3 to DN4 stages, as well as from DN4 to DP stages using both in vivo adoptive T-cell transfer model and in vitro culture system. The expression of intracellular TCRß is significantly decreased in Arid1a-deficient DN4 cells compared with WT cells. OT1 transgenic TCR can rescue the defect in the transition from DN3 to DN4 stages, but not from DN to DP stages. Furthermore, we observed a comparable or stronger proliferation capacity accompanied by a significant increase in cell death in Arid1a-/- DP cells compared with that in WT controls. RNA-Seq analysis shows a significant enrichment of apoptotic pathway within differentially expressed genes between Arid1a-/- and WT DP cells, including the upregulation of Bim, Casp3 and Trp53 and the downregulation of Rorc, Bcl-XL and Mcl1. Therefore, our study reveals a novel mechanism that Arid1a controls early T-cell development by maintaining intracellular TCRß expression-mediated ß-selection and activating parallel cell survival pathways.

Med1 controls CD8 T cell maintenance through IL-7R-mediated cell survival signalling.

Under steady-state conditions, the pool size of peripheral CD8+ T cells is maintained through turnover and survival. Beyond TCR and IL-7R signals, the underlying mechanisms are less well understood. In the present study, we found a significant reduction of CD8+ T cell proportion in spleens but not in thymi of mice with T cell-specific deletion of Mediator Subunit 1 (Med1). A competitive transfer of wild-type (WT) and Med1-deficient CD8+ T cells reproduced the phenotype in the same recipients and confirmed intrinsic role of Med1. Furthermore, we observed a comparable degree of migration and proliferation but a significant increase of cell death in Med1-deficient CD8+ T cells compared with WT counterparts. Finally, Med1-deficient CD8+ T cells exhibited a decreased expression of interleukin-7 receptor α (IL-7Rα), down-regulation of phosphorylated-STAT5 (pSTAT5) and Bim up-regulation. Collectively, our study reveals a novel role of Med1 in the maintenance of CD8+ T cells through IL-7Rα/STAT5 pathway-mediated cell survival.

Analysis of the clinical characteristics of insulin autoimmune syndrome induced by alpha-lipoic acid.

WHAT IS KNOWN AND OBJECTIVE: Alpha-lipoic acid (ALA) is widely used as a dietary supplement and antiageing agent. Insulin autoimmune syndrome (IAS) is the most serious adverse reaction reported with the use of ALA. The purpose of this study was to explore the clinical characteristics of ALA-induced IAS and provide a scientific reference for clinical diagnosis, treatment and prevention. METHODS: We collected literature on IAS cases induced by ALA for retrospective analysis in Chinese and English. RESULTS AND DISCUSSION: The median age of 37 patients (28 females and 9 males) was 61 years (range 32-82). The symptoms occurred at night and in the early morning (60.7%), in the late postprandial period (50.0%) or after fasting (35.7%), within hours in some patients and up to 2 months in others after stopping ALA or during medication treatment. Autonomic nervous system symptoms (81.1%) and neurological hypoglycaemia (64.9%) are the main clinical manifestations of hypoglycaemia. The blood glucose concentration at the onset of hypoglycaemia was 2.19 mmol/L (median, range 1.09-3.52), the insulin concentration was ≥100 µIU/ml (94.6%), and the C-peptide concentration was ≤20 ng/ml (83.3%). Testing for IgG insulin autoantibodies (IAAs) was positive in 37 patients. Pancreatic imaging was unremarkable on computed tomography (CT), magnetic resonance imaging (MRI) and abdominal sonography. Hypoglycaemia disappeared within 5 days to 8 months after withdrawing ALA alone or using corticosteroid treatment. IAA turned negative in 7 months (median; range 2-36). Follow-up showed no recurrent hypoglycaemic episodes at 7.25 months (median; range 1-36). WHAT IS NEW AND CONCLUSION: ALA-induced IAS is a clinically rare autoimmune disease with hypoglycaemia that occurs during medication treatment or after drug withdrawal that should be treated promptly.

Effect of Capecitabine Maintenance Therapy Using Lower Dosage and Higher Frequency vs Observation on Disease-Free Survival Among Patients With Early-Stage Triple-Negative Breast Cancer Who Had Received Standard Treatment: The SYSUCC-001 Randomized Clinical Trial.

Importance: Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of relapse and death are needed. Objective: To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer. Design, Setting, and Participants: Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy. Interventions: Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m2 twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy. Main Outcomes and Measures: The primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events. Results: Among 443 women who were randomized, 434 were included in the full analysis set (mean [SD] age, 46 [9.9] years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio [HR] for risk of recurrence or death, 0.64 [95% CI, 0.42-0.95]; P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92]; P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19]; P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 [95% CI, 0.46-1.13]; P = .15). The most common capecitabine-related adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event. Conclusions and Relevance: Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01112826.

Efficacy of Moxifloxacin plus Treatment of Physician's Choice in Patients with Metastatic Breast Cancer.

LESSONS LEARNED: Moxifloxacin plus continuation of the previous treatment of physician's choice shows promising efficacy in patients with metastatic breast cancer. The addition of moxifloxacin shows well-tolerated toxicities. BACKGROUND: Recent studies have confirmed bacterial infection as an important contributor in cancer. Elimination of tumor-associated microbes may lead to a reduction in tumors and improved survival. Moxifloxacin is an orally administrated fourth-generation quinolone with broad-spectrum coverage against tumor-associated bacteria. METHODS: In this study, we assessed the efficacy and safety of moxifloxacin in combination with treatment of physician's choice (TPC) in patients with metastatic breast cancer (MBC). In this single-arm, phase II study, we recruited 30 patients with MBC who had a trend toward disease progression (stable disease [SD] with increased tumor size) during TPC before enrollment at Sun Yat-sen University Cancer Center between January 1 and July 30, 2018. Eligible patients were given moxifloxacin once daily at a dose of 400 mg from days 1 to 7 of a 28-day cycle, in addition to continuing to receive the therapy previously selected by their physicians. Tumor response was determined according to RECIST (version 1.1). Progression-free survival (PFS) was calculated using the Kaplan-Meier method. RESULTS: The concomitant use of moxifloxacin and previous TPC yielded a median PFS of 6.6 months (95% confidence interval [CI]: 4.0-9.1) and a 1-year PFS of 25.9% (95% CI: 10.0%-41.9%). Objective responses were achieved in seven (23.3%, 95% CI: 7.3%-39.4%) patients. The clinical benefit rate was 46.7% (95% CI: 27.7%-65.6%). No grade 4 adverse events (AEs) and four grade 3 AEs were observed, none of which were considered to have definite relation to moxifloxacin. CONCLUSION: The combination of moxifloxacin with previous TPC shows promising efficacy and well-tolerated toxicities in patients with MBC.

Prostate tumour overexpressed-1 promotes tumourigenicity in human breast cancer via activation of Wnt/ß-catenin signalling.

Breast cancer is the most common malignancy in females. The presence of cancer stem cells (CSCs) is the main cause of local and distant tumour recurrence and is associated with poor outcome in breast cancer. However, the molecular mechanisms underlying the maintenance of CSCs remain largely unknown. This study demonstrates that prostate tumour overexpressed-1 (PTOV1) enhances the CSC population and augments the tumourigenicity of breast cancer cells both in vitro and in vivo. Moreover, PTOV1 suppresses transcription of Dickkopf-1 (DKK1) by recruiting histone deacetylases and subsequently reducing DKK1 promoter histone acetylation, followed by activation of Wnt/ß-catenin signalling. Restoration of DKK1 expression in PTOV1-overexpressing cells counteracts the effects of PTOV1 on Wnt/ß-catenin activation and the CSC population. Collectively, these results suggest that PTOV1 positively regulates the Wnt/ß-catenin signalling pathway and enhances tumourigenicity in breast cancer; this novel mechanism may represent a therapeutic target for breast cancer. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[The changes of p-Akt/MuRF1/FoxO1 proteins expressions in the conditions of training and immobilization in rats' gastrocnemius muscle].

This study was aimed to investigate the changes of muscle protein synthesis and degradation under different movement conditions, so as to provide theoretical basis for muscle atrophy mechanism. Sprague Dawley (SD) rats were randomly divided into control, endurance training (treadmill training), hind limb overhanging and eccentric training (treadmill training, angle -16º) groups. The gastrocnemius muscles of rats were taken and weighed. The muscle was sectioned, and HE staining was employed to determine the cell's cross-sectional area. Protein expression of p-Akt was measured by immunohistochemistry; and the expressions of MuRF1 and FoxO1 were determined by Western blot. The results showed that, compared with control group, hind limb overhanging and eccentric training groups exhibited decreased muscle weight and cross-sectional area, but endurance training group did not show any changes. The expressions of p-Akt in endurance and eccentric training groups, not in hind limb overhanging group, were significantly higher than that in control group. Compared with that of control, MuRF1 protein remained unchanged in endurance training groups, but was increased in eccentric training and hind limb overhanging groups; FoxO1 protein was decreased in endurance training group, but was increased in eccentric training and hind limb overhanging groups. These results indicate that movement (endurance and eccentric training) can activate Akt expression, but does not increase muscle weight, whereas eccentric training and hind limb overhanging can increase the expressions of MuRF1 and FoxO1, and induce amyotrophy, suggesting MuRF1 and FoxO1 are major determinant factors in muscle atrophy.

Immunogenic PANoptosis-Initiated Cancer Sono-Immune Reediting Nanotherapy by Iteratively Boosting Cancer Immunity Cycle.

The cancer-immune cycle conceptualized the mechanisms of driving T cell responses to tumors, but w as limited by immunological ignorance elicited by tumor inherent immunoediting, which failed to initiate and maintain adaptive immunity. Targeting specific vulnerabilities of cell death patterns may provide unique opportunities to boost T cell antitumor immunological effects. Here an ultrasound nanomedicine-triggered tumor immuno-reediting therapeutic strategy using nano/genetically engineered extracellular vesicles, which can induce tumor highly immunogenic PANoptosis and iteratively start-up the energization of cancer innate immunity cycle by repeatedly liberating damage-associated molecular patterns, thereby priming sufficient antigen-specific T cells and shaping protective immune response through activating cGAS-STING signaling pathways, is reported. Aided by immune checkpoint blockade, the reprogramming of immune microenvironment further facilitated a prompt bridging of innate and adaptive immunity, and remarkably suppressed metastatic and rechallenged tumor growth. Thus, targeting PANoptotic cell death provides a catcher against immune escape and a positive-feedback immune activation gateway for overcoming immune resistance to intractable cancers.

Emerging Role of Sorting Nexin 17 in Human Health and Disease.

The distortion of the cellular membrane transport pathway has a profound impact on cell dynamics and can drive serious physiological consequences during the process of cell sorting. SNX17 is a member of the Sorting Nexin (SNX) family and plays a crucial role in protein sorting and transport in the endocytic pathway. SNX17, SNX27, and SNX31 belong to the SNX-FERM subfamily and possess the FERM domain, which can assist in endocytic transport and lysosomal degradation. The binding partners of SNX27 have been discovered to number over 100, and SNX27 has been linked to the development of Alzheimer's disease progression, tumorigenesis, cancer progression, and metastasis. However, the role and potential mechanisms of SNX17 in human health and disease remain poorly understood, and the function of SNX17 has not been fully elucidated. In this review, we summarize the structure and basic functions of SNX protein, focusing on providing current evidence of the role and possible mechanism of SNX17 in human neurodegenerative diseases and cardiovascular diseases.