Therapeutic potential of resveratrol through ferroptosis modulation: insights and future directions in disease therapeutics.

Resveratrol, a naturally occurring polyphenolic compound, has captivated the scientific community with its promising therapeutic potential across a spectrum of diseases. This review explores the complex role of resveratrol in modulating ferroptosis, a newly identified form of programmed cell death, and its potential implications for managing cardiovascular and cerebrovascular disorders, cancer, and other conditions. Ferroptosis is intricately linked to the pathogenesis of diverse diseases, with resveratrol exerting multifaceted effects on this process. It mitigates ferroptosis by modulating lipid peroxidation, iron accumulation, and engaging with specific cellular receptors, thereby manifesting profound therapeutic benefits in cardiovascular and cerebrovascular conditions, as well as oncological settings. Moreover, resveratrol's capacity to either suppress or induce ferroptosis through the modulation of signaling pathways, including Sirt1 and Nrf2, unveils novel therapeutic avenues. Despite resveratrol's limited bioavailability, advancements in molecular modification and drug delivery optimization have amplified its clinical utility. Future investigations are poised to unravel the comprehensive mechanisms underpinning resveratrol's action and expand its therapeutic repertoire. We hope this review could furnish a detailed and novel insight into the exploration of resveratrol in the regulation of ferroptosis and its therapeutic prospects.

Retrievable dual-chamber leadless pacemaker implant (Aveir DR) in an adult patient with congenital heart disease.

Leadless pacemakers have demonstrated potential as a transvenous pacing option in Adult Congenital Heart Disease patients. Aveir™ single-chamber (VR) leadless pacemakers have demonstrated safety in patients without congenital heart disease in a dual chamber approach. We present a case of dual-chamber pacing using the Aveir dual-chamber (DR) leadless pacemaker in a patient with repaired dextro-transposition of the great arteries with ventricular septal defect (VSD) surgical closure. A 26-year-old male patient with a history of transposition of the great arteries status post arterial switch and VSD repair neonatally had complicated second degree atrioventricular block and sinus node dysfunction necessitating pacemaker placement. Epicardial single-chamber ventricular pacemaker was placed neonatally, which was switched to dual-chamber pacemaker at age 17 due to malfunction. Recent fracture of pacemaker leads led to implantation of new dual chamber leadless pacemaker. Removal of previous pacemaker leads via mechanical extraction occurred and implantation of Aveir DR leadless pacemaker was performed under anesthesia via right femoral vein access without complication. Follow-up demonstrated Aveir VR threshold of 1.0V@0.2 ms, R-wave of 8.9mV, impedance of 490Ω, and the Aveir AR threshold of 0.75V@0.2 ms, P-wave of 3.7mV, and impedance of 400Ω. This case demonstrates safety and efficacy of dual chamber leadless pacemaker implantation in an ACHD patient.

Oleanane-type triterpenoids from Sabia limoniacea and their anti-inflammatory activities.

Eighteen new oleanane-type triterpenoids were isolated from the stems of Sabia limoniacea, including sabialimon A (1), a triterpenoid with an unprecedented 6/6/6/7/7 pentacyclic skeleton and seventeen undescribed triterpenoids, sabialimons B-R (2 - 18), along with six previously described analogs (19 - 24). Their structures were fully elucidated via extensive spectroscopic analysis including 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), experimental electronic circular dichroism measurements and X-ray crystallographic studies. Compound 1 is the first triterpenoid that possesses a rare ring system (6/6/6/7/7) with an oxygen-bearing bridge between C-17 and C-18 and a hemiketal form at C-17, which is generated a larger ring by the degradation of C-28 and D/E-ring expansion. Biological evaluation revealed that sabialimon I (9), sabialimon K (11), sabialimon P (16) and 11,13(18)-oleanadien-28-hydroxymethyl 3-one (20) exhibited significantly inhibitory activities against nitric oxide (NO) release with IC50 values of 29.65, 23.41, 18.12 and 26.64 µM, respectively, as compared with the positive control (dexamethasone, IC50 value: 40.35 µM). Furthermore, sabialimon P markedly decreased the secretion of TNF-α, iNOS, IL-6 and NF-κB and inhibited the expression of COX-2 and NF-κB/p65 in LPS-induced RAW264.7 cells in a dose-dependent manner.

Helicobacter pylori-Induced Angiopoietin-Like 4 Promotes Gastric Bacterial Colonization and Gastritis.

Helicobacter pylori infection is characterized as progressive processes of bacterial persistence and chronic gastritis with features of infiltration of mononuclear cells more than granulocytes in gastric mucosa. Angiopoietin-like 4 (ANGPTL4) is considered a double-edged sword in inflammation-associated diseases, but its function and clinical relevance in H. pylori-associated pathology are unknown. Here, we demonstrate both pro-colonization and pro-inflammation roles of ANGPTL4 in H. pylori infection. Increased ANGPTL4 in the infected gastric mucosa was produced from gastric epithelial cells (GECs) synergistically induced by H. pylori and IL-17A in a cagA-dependent manner. Human gastric ANGPTL4 correlated with H. pylori colonization and the severity of gastritis, and mouse ANGPTL4 from non-bone marrow-derived cells promoted bacteria colonization and inflammation. Importantly, H. pylori colonization and inflammation were attenuated in Il17a -/-, Angptl4 -/-, and Il17a -/- Angptl4 -/- mice. Mechanistically, ANGPTL4 bound to integrin αV (ITGAV) on GECs to suppress CXCL1 production by inhibiting ERK, leading to decreased gastric influx of neutrophils, thereby promoting H. pylori colonization; ANGPTL4 also bound to ITGAV on monocytes to promote CCL5 production by activating PI3K-AKT-NF-κB, resulting in increased gastric influx of regulatory CD4+ T cells (Tregs) via CCL5-CCR4-dependent migration. In turn, ANGPTL4 induced Treg proliferation by binding to ITGAV to activate PI3K-AKT-NF-κB, promoting H. pylori-associated gastritis. Overall, we propose a model in which ANGPTL4 collectively ensures H. pylori persistence and promotes gastritis. Efforts to inhibit ANGPTL4-associated pathway may prove valuable strategies in treating H. pylori infection.

Splicing factor hnRNPA1 regulates alternative splicing of LOXL2 to enhance the production of LOXL2Δ13.

Lysyl oxidase-like 2 (LOXL2) is a member of the lysyl oxidase family and has the ability to catalyze the cross-linking of extracellular matrix collagen and elastin. High expression of LOXL2 is related to tumor cell proliferation, invasion, and metastasis. LOXL2 contains 14 exons. Previous studies have found that LOXL2 has abnormal alternative splicing and exon skipping in a variety of tissues and cells, resulting in a new alternatively spliced isoform denoted LOXL2Δ13. LOXL2Δ13 lacks LOXL2WT exon 13, but its encoded protein has greater ability to induce tumor cell proliferation, invasion, and metastasis. However, the molecular events that produce LOXL2Δ13 are still unclear. In this study, we found that overexpression of the splicing factor hnRNPA1 in cells can regulate the alternative splicing of LOXL2 and increase the expression of LOXL2Δ13. The exonic splicing silencer exists at the 3' splice site and 5' splice site of LOXL2 exon 13. HnRNPA1 can bind to the exonic splicing silencer and inhibit the inclusion of exon 13. The RRM domain of hnRNPA1 and phosphorylation of hnRNPA1 at S91 and S95 are important for the regulation of LOXL2 alternative splicing. These results show that hnRNPA1 is a splicing factor that enhances the production of LOXL2Δ13.

Analysis of Influencing Factors and Strategies for Premature Breast Development in Female Children based on Logistic Regression Analysis: A Randomized Double-blind Controlled Clinical Trial.

Objective: To investigate and analyze the influencing factors of simple early breast development in girls, to discover the dangers and triggers of PT conversion to ICPP, and the time point of transformation in order to detect and prevent the occurrence of transformation in advance and reduce the incidence of idiopathic central precocious puberty. Ensure children's physical and mental health and normal growth and development. Methods: A total of 50 children with PT admitted to our hospital from April 2019 to December 2020 were included in the study group, and 50 children with physical examination during the same period were selected as the control group. All children were tested for vitamin D, androstenedione, dehydroepiandrosterone, 17-hydroxyprogesterone, leptin, IGF-I., and IGFBp-3 at 3, 6, 9 and 12 months after the diagnosis of PT. Results: Vitamin D levels decreased in the child, indicating that vitamin D deficiency was closely related to the age of breast development in ICPP girls and may be related to serum P-FSH, P-LH and E2 levels. Increased levels of IGFBp-3 indicate that these indicators are involved in the onset of ICPP. Children have a higher BMI, watch idol dramas or play mobile games longer, often eat snacks containing preservatives, have a fishy diet, are more irritable and sensitive, and dry stools are also risk factors affecting the early development of simple breasts in girls. Conclusion: The influencing factors leading to simple, early breast development in girls include vitamin D, androstenedione, dehydroepiandrosterone, 17-hydroxyprogesterone, leptin, IGF-I., IGFBp-3, and should be combined with the progression of breast Tanner staging (complete regression, recurrent, and persistent), height growth rate, bone age, Uterine and ovarian B ultrasound, sex hormones, etc., warn of the conversion of PT to ICPP, and ensure children's physical and mental health and normal growth and development.

CD39 expression defines exhausted CD4+ T cells associated with poor survival and immune evasion in human gastric cancer.

Objectives: CD4+ T cell helper and regulatory function in human cancers has been well characterised. However, the definition of tumor-infiltrating CD4+ T cell exhaustion and how it contributes to the immune response and disease progression in human gastric cancer (GC) remain largely unknown. Methods: A total of 128 GC patients were enrolled in the study. The expression of CD39 and PD-1 on CD4+ T cells in the different samples was analysed by flow cytometry. GC-infiltrating CD4+ T cell subpopulations based on CD39 expression were phenotypically and functionally assessed. The role of CD39 in the immune response of GC-infiltrating T cells was investigated by inhibiting CD39 enzymatic activity. Results: In comparison with CD4+ T cells from the non-tumor tissues, significantly more GC-infiltrating CD4+ T cells expressed CD39. Most GC-infiltrating CD39+CD4+ T cells exhibited CD45RA-CCR7- effector-memory phenotype expressing more exhaustion-associated inhibitory molecules and transcription factors and produced less TNF-α, IFN-γ and cytolytic molecules than their CD39-CD4+ counterparts. Moreover, ex vivo inhibition of CD39 enzymatic activity enhanced their functional potential reflected by TNF-α and IFN-γ production. Finally, increased percentages of GC-infiltrating CD39+CD4+ T cells were positively associated with disease progression and patients' poorer overall survival. Conclusion: Our study demonstrates that CD39 expression defines GC-infiltrating CD4+ T cell exhaustion and their immunosuppressive function. Targeting CD39 may be a promising therapeutic strategy for treating GC patients.

CD39hi identifies an exhausted tumor-reactive CD8+ T cell population associated with tumor progression in human gastric cancer.

The ectonucleotidase CD39 has been regarded as a promising immune checkpoint in solid tumors. However, the expression of CD39 by tumor-infiltrating CD8+ T cells as well as their potential roles and clinical implications in human gastric cancer (GC) remain largely unknown. Here, we found that GC-infiltrating CD8+ T cells contained a fraction of CD39hi cells that constituted about 6.6% of total CD8+ T cells in tumors. These CD39hi cells enriched for GC-infiltrating CD8+ T cells with features of exhaustion in transcriptional, phenotypic, metabolic and functional profiles. Additionally, GC-infiltrating CD39hiCD8+ T cells were also identified for tumor-reactive T cells, as these cells expanded in vitro were able to recognize autologous tumor organoids and induced more tumor cell apoptosis than those of expanded their CD39int and CD39-CD8+ counterparts. Furthermore, CD39 enzymatic activity controlled GC-infiltrating CD39hiCD8+ T cell effector function, and blockade of CD39 efficiently enhanced their production of cytokines IFN-γ and TNF-α. Finally, high percentages of GC-infiltrating CD39hiCD8+ T cells correlated with tumor progression and independently predicted patients' poor overall survival. These findings provide novel insights into the association of CD39 expression level on CD8+ T cells with their features and potential clinical implications in GC, and empowering those exhausted tumor-reactive CD39hiCD8+ T cells through CD39 inhibition to circumvent the suppressor program may be an attractive therapeutic strategy against GC.

Oxidative stress is associated with Aß accumulation in chronic sleep deprivation model.

Amyloid-ß (Aß) accumulation is the main pathological change in Alzheimer's disease (AD), which results from the imbalance of production and clearance of Aß in the brain. Our previous study found that chronic sleep deprivation (CSD) led to the deposition of Aß in the brain by disrupting the balance of Aß production and clearance, but the specific mechanism was not clear. In the present study, we investigated the effects of oxidative stress on Aß accumulation in CSD rats. We found that the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) significantly increased after CSD, while superoxide dismutase (SOD) decreased in the brain. Furthermore, the serum ROS was elevated and SOD declined after CSD. The levels of oxidative stress in the brain were significantly correlated with ß-site APP-cleaving enzyme 1 (BACE1), low-density lipoprotein receptor-related protein-1 (LRP1), and receptor of advanced glycation end products (RAGE) levels in hippocampus and prefrontal lobe, and the concentration of serum oxidative mediators were strongly correlated with plasma levels of soluble LRP1 (sLRP1) and soluble RAGE (sRAGE). These results suggested that the oxidative stress in the brain and serum may involved in the CSD-induced Aß accumulation. The underlying mechanism may be associated with disrupting the balance of Aß production and clearance.

Diagnostic value of matrix metalloproteinases 2, 7 and 9 in urine for early detection of colorectal cancer.

BACKGROUND: A noninvasive biomarker with high diagnostic performance is urgently needed for the early diagnosis of colorectal cancer (CRC). AIM: To evaluate the diagnostic value of matrix metalloproteinases (MMPs) 2, 7 and 9 in urine for CRC. METHODS: Of 59 healthy controls, 47 patients with colon polyps and 82 patients with CRC were included in this study. Carcinoembryonic antigen (CEA) in serum and MMP2, MMP7, and MMP9 in urine were detected. The combined diagnostic model of the indicators was established by binary logistic regression. The receiver operating characteristic curve (ROC) of the subjects was used to evaluate the independent and combined diagnostic value of the indicators. RESULTS: The MMP2, MMP7, MMP9, and CEA levels in the CRC group differed significantly from levels in the healthy controls (P < 0.05). The levels of MMP7, MMP9, and CEA also differed significantly between the CRC group and the colon polyps group (P < 0.05). The area under the curve (AUC) distinguishing between the healthy control and the CRC patients using the joint model with CEA, MMP2, MMP7 and MMP9 was 0.977, and the sensitivity and specificity were 95.10% and 91.50%, respectively. For early-stage CRC, the AUC was 0.975, and the sensitivity and specificity were 94.30% and 98.30%, respectively. For advanced stage CRC, the AUC was 0.979, and the sensitivity and specificity were 95.70% and 91.50%, respectively. Using CEA, MMP7 and MMP9 to jointly established a model distinguishing the colorectal polyp group from the CRC group, the AUC was 0.849, and the sensitivity and specificity were 84.10% and 70.20%, respectively. For early-stage CRC, the AUC was 0.818, and the sensitivity and specificity were 76.30% and 72.30%, respectively. For advanced stage CRC, the AUC was 0.875, and the sensitivity and specificity were 81.80% and 72.30%, respectively. CONCLUSION: MMP2, MMP7 and MMP 9 may exhibit diagnostic value for the early detection of CRC and may serve as auxiliary diagnostic markers for CRC.

Effects of thoracic paravertebral nerve block on postoperative pain and postoperative delirium in elderly patients undergoing thoracoscopic lobectomy.

OBJECTIVES: To evaluate the effects of ultrasound-guided thoracic paravertebral nerve block on perioperative pain and postoperative delirium in elderly patients undergoing thoracoscopic lobotomy. METHODS: Patients aged 60 to 80 years who underwent the surgery of thoracoscopic lobectomy were selected; ASA grades I to III and New York Heart Association (NYHA) grades I to II. Patients were randomly divided into two groups: group C (group Compaired) and group T (group Thoracic Paravertebral Nerve Block TPVB). Patients in group T received ultrason-guided TPVB while those in group C didn't received TPVB. Postoperative patient-controlled intravenous analgesia was administered to all the patients. The consumption of intraoperative opioids, cases of hipoxemia, operative time, and extubation time was also recorded. Pain scores (static and dynamic) were assessed at 2, 4, 6, 24, 48, 72, 96, and 120 hours point after the operation. Pain scores, occurrence of postoperative delirium occurrence, postoperative complications, total amount of analgesic drugs, length of hospital stay, rescue analgesic requirement, and side effects were recorded within 5 days. RESULTS: Intraoperative dosages of sufentanil and remifentanil were significantly lower in group T (Table 1). The postoperative recovery time in group T was significantly shortened (Table 1). The VAS pain scores of group T at 2, 4, 6, and 24 hours after surgery were much lower. The consumption of intraoperative opioids, number of rescue analgesic requirements, and the occurrence of postoperative delirium incidence in group T was significantly reduced (Table 2). There were no differences in hipoxemia events, postoperative nausea, vomiting and pulmonary complications between the two groups (Table 2). CONCLUSION: Preoperative ultrasound-guided thoracic paravertebral nerve block (TPVB) can obviously decrease the intraoperative and postoperative opioids consumption, shorten the recovery time, reduce the number of rescue analgesia and the incidence of postoperative delirium in elderly patients undergoing thoracoscopic lobotomy.

Cost-effectiveness of immune checkpoint inhibition and targeted treatment in combination as adjuvant treatment of patient with BRAF-mutant advanced melanoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and targeted treatments have improved the health outcomes of patients with advanced melanoma. However, due to the high cost of novel therapies, it is crucial to evaluate their value by considering both effectiveness and cost. To compare the cost-effectiveness of these novel agents (atezolizumab-vemurafenib-cobimetinib, vemurafenib-plus-cobimetinib, dabrafenib-plus-trametinib, and encorafenib-plus-binimetinib) for first-line treatment of metastatic melanoma with the BRAFV600 mutation. METHODS: A patient-level model was developed to project the health outcomes of 4 strategies for patients with advanced melanoma. We estimated transition probabilities from the IMspire150 (ClinicalTrials.gov, NCT02908672), COMBI-AD (NCT01682083), and COLUMBUS (NCT01909453) trials using a parametric survival model. All health outcomes, including direct cost, quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER), were estimated from the US payer perspective. Lifetime cost, QALYs, life-years (LYs), and ICERs were calculated. Univariable and probabilistic sensitivity analyses were performed to test model robustness, along with multiple scenario analyses. RESULTS: Of the 4 competing strategies, atezolizumab-vemurafenib-cobimetinib produced the best health outcomes, and the vemurafenib-cobimetinib strategy was the least expensive option. Atezolizumab-vemurafenib-cobimetinib, dabrafenib-plus-trametinib, and vemurafenib-cobimetinib formed the cost-effective frontier, indicating that the ordered ICERs were $325,113/QALYs for dabrafenib-plus-trametinib vs. vemurafenib-cobimetinib strategies and $2,247,500/QALYs for atezolizumab-vemurafenib-cobimetinib vs. dabrafenib-plus-trametinib strategies. Encorafenib-plus-binimetinib was dominated by the other 3 competing strategies. The drug price and first-line utility significantly influenced the model utcomes. CONCLUSIONS: For BRAF-mutant advanced melanoma, the vemurafenib-cobimetinib strategy could be considered the most cost-effective treatment at the willingness-to-pay threshold of $150,000.

Structural stability of the evolving developer collaboration network in the OSS community.

The structural stability of the developer collaboration network is critical to the success of the OSS (Open Source Software) community. However, research on the structural stability of the evolving developer collaboration network in OSS communities is relatively insufficient. In this paper, according to the software version sequence, we construct the corresponding developer collaboration network of the Angular OSS community and then analyse this network's structural stability during network evolution. The results show that the network always presents an economical modular small-world structure during its evolution. The maintenance of the structure is related to a cohesive core, which is composed of two types of nodes (i.e., hubs and connectors). The hubs organize noncore nodes to form modules, while connectors facilitate the formation of inter-module connections. The overall results highlight the important role of core developers in the sustainable development of OSS communities and may provide a reference for community initiators to implement protection strategies for core developers.

Evaluation of a recombinant five-antigen Staphylococcus aureus vaccine: The randomized, single-centre phase 1a/1b clinical trials.

BACKGROUND: Staphylococcus aureus is an important pathogen that causes hospital and community infections. To control Staphylococcus aureus infection and reduce the usage of antibiotics, we evaluated the safety and immunogenicity of a recombinant five-antigen Staphylococcus aureus vaccine (rFSAV) in healthy adults. METHODS: We conducted a randomized, double-blind, placebo-controlled phase 1a study and a randomized, open-label phase 1b study. In phase 1a, we randomly allocated 144 healthy participants in a ratio of 1:1:1:1 to receive the low-(60 µg), middle-(120 µg), and high-dose (240 µg) vaccine or placebo at day 0, 3, 7 and 14. In phase 1b, 144 healthy participants were randomly allocated at a ratio of 1:1:1:1 to receive 0-3-7, 0/0-7, 0/0-3-7, 0/0-7-14 regimens to estimate the optimal strategy. The primary study endpoint was the incidence of solicited adverse events post-vaccination. The immunogenicity endpoints included the level of specific antibodies to five antigens after vaccination, as well as the cellular immune responses and functional antibodies. RESULTS: There were 31 (86%), 30 (83%), and 32 (89%) of 36 participants in the low-, middle-, and high-dose group reported solicited adverse events, respectively, most of the adverse events were mild or moderate. In phase 1b, the dose-adjusted rFSAV (90 µg) showed a better safety profile in the four immune procedures, and no vaccine-related serious adverse events were reported. The antigen-specific binding antibodies started to increase at day 7 and reached the peak around day 14 to 21. The cellular immune responses and functional antibodies also were substantially above background levels. CONCLUSIONS: rFSAV is safe, well tolerated in healthy adults, elicits rapid and robust specific humoral and cellular immune responses with unconventional immunization procedure in phase 1a and 1b. It deserves to be noted and further explored. CLINICAL TRIALS REGISTRATION: NCT02804711 and NCT03966040.

FasL+ PD-L2+ Identifies a Novel Immunosuppressive Neutrophil Population in Human Gastric Cancer That Promotes Disease Progression.

Neutrophils constitute abundant cellular components in human gastric cancer (GC) tissues, but their protumorigenic subset in pathogenesis of GC progression is unclear. Here, it is found that patients with GC show significantly higher neutrophil infiltration in tumors that is regulated by CXCL12-CXCR4 chemotaxis. These tumor-infiltrating neutrophils express high level immunosuppressive molecules FasL and PD-L2, and this FasL+ PD-L2+ neutrophil subset with a unique phenotype constitutes at least 20% of all neutrophils in advanced GC and predicts poor patient survival. Tumor induces neutrophils to express FasL and PD-L2 proteins with similar phenotype to those in GC tumors in both time-dependent and dose-dependent manners. Mechanistically, Th17 cell-derived IL-17A and tumor cell-derived G-CSF can significantly induce neutrophil FasL and PD-L2 expression via activating ERK-NF-κB and JAK-STAT3 signaling pathway, respectively. Importantly, upon over-expressing FasL and PD-L2, neutrophils acquire immunosuppressive functions on tumor-specific CD8+ T-cells and promote the growth and progression of human GC tumors in vitro and in vivo, which can be reversed by blocking FasL and PD-L2 on these neutrophils. Thus, the work identifies a novel protumorigenic FasL+ PD-L2+ neutrophil subset in GC and provides new insights for human cancer immunosuppression and anti-cancer therapies targeting these pathogenic cells.

Distribution, phenotype, functional and clinical relevance of CD8+CD103+ tissue-resident memory T cells in human gastric cancer.

CD8+CD103+ tissue-resident memory T cells (TRMs) are involved in tumor immune response and linked to favorable clinical outcome in human cancer. However, the distribution, phenotype, functional properties and clinical relevance of these cells in gastric cancer (GC) remain elusive. Here, our data show that, in comparison to non-tumor tissues, the percentages of CD8+CD103+ TRMs in tumors are significantly decreased. Most tumor-infiltrating CD8+CD103+ TRMs are CD45RA-CCR7- effector-memory cells with higher PD-1 and 4-1BB expression than those from non-tumor tissues. Further, tumor-infiltrating CD8+CD103+ TRMs show impaired cytolytic capacity due to decreased granzyme B and perforin expression. Moreover, ex vivo PD-1 blockade could restore the cytolytic capacity of tumor-infiltrating CD8+CD103+ TRMs, and such anti-PD-1-mediated reinvigoration of CD8+CD103+ TRMs could be further enhanced by 4-1BB co-stimulation. Finally, lower levels of Tumor-infiltrating CD8+CD103+ TRMs are positively correlated with GC progression and poor patients' survival. Our data suggest that restoring CD8+CD103+ TRM function by combining PD-1 blockade and 4-1BB co-stimulation may be a promising strategy for treating GC.

Helicobacter pylori-induced REDD1 modulates Th17 cell responses that contribute to gastritis.

OBJECTIVE: Regulated in development and DNA damage responses-1 (REDD1) is a conserved and ubiquitous protein, which is induced in response to multiple stimuli. However, the regulation, function and clinical relevance of REDD1 in Helicobacter pylori-associated gastritis are presently unknown. APPROACH: Immunohistochemistry, real-time PCR and Western blot analyses were performed to examine the levels of REDD1 in gastric samples from H. pylori-infected patients and mice. Gastric tissues from Redd1-/- and wildtype (WT, control) mice were examined for inflammation. Gastric epithelial cells (GECs), monocytes and T cells were isolated, stimulated and/or cultured for REDD1 regulation and functional assays. RESULTS: REDD1 was increased in gastric mucosa of H. pylori-infected patients and mice. H. pylori induced GECs to express REDD1 via the phosphorylated cytotoxin associated gene A (cagA) that activated MAPKp38 pathway to mediate NF-κB directly binding to REDD1 promoter. Human gastric REDD1 increased with the severity of gastritis, and mouse REDD1 from non-marrow chimera-derived cells promoted gastric inflammation that was characterized by the influx of MHCII+ monocytes. Importantly, gastric inflammation, MHCII+ monocyte infiltration, IL-23 and IL-17A were attenuated in Redd1-/- mice. Mechanistically, REDD1 in GECs regulated CXCL1 production, which attracted MHCII+ monocytes migration by CXCL1-CXCR2 axis. Then H. pylori induced MHCII+ monocytes to secrete IL-23, which favored IL-17A-producing CD4+ cell (Th17 cell) polarization, thereby contributing to the development of H. pylori-associated gastritis. CONCLUSIONS: The present study identifies a novel regulatory network involving REDD1, which collectively exert a pro-inflammatory effect within gastric microenvironment. Efforts to inhibit this REDD1-dependent pathway may prove valuable strategies in treating of H. pylori-associated gastritis.

Chest CT imaging characteristics and their evolution of 48 patients with COVID-19 in Hengyang, China.

The novel coronavirus 2019 (2019 nCoV), appeared in Wuhan in December 2019, can cause a novel coronavirus pneumonia (Corona Virus Disease 2019, COVID-19). COVID-19 is highly infectious and easy to infect people. The epidemic has gradually spread to all parts of the country. In order to provide a basis for clinical diagnosis, this study retrospectively analyzed the imaging characteristics, evolution and related imaging manifestations of COVID-19 patients in different stages of the disease. The results suggest that the imaging findings of 48 COVID-19 patients from Hengyang, Hunan Province are comparable in different stages of the disease. Chest CT showed no pneumonia in one mild patient. Chest CT findings of moderate type (n=38) and severe type (n=9) had comparable characteristics. The main manifestations were ground-glass opacity (GGO) (18/38, 47.37%; 1/9, 11.11%), and GGO with consolidation (16/38, 42.11%; 5/9, 55.56%), which respectively presented in bilateral lungs (34/38, 89.47%; 9/9, 100.00%), and multi-lobe distribution (involving 5 lobes) (17/38, 44.74%; 8/9, 88.89%). After treatment, 28 patients were isolated for 14 days and returned to the hospital for re-examination; among them, the pulmonary lesion was completely absorbed in 15 moderate patients, while 13 patients mainly manifested as GGO. The CT imaging findings of patients with COVID-19 can detect the lesions early, observe the scope of the lesions, evaluate the severity of the lesions, and assist the clinician in completing rapid isolation, diagnosis and treatment. At the same time, it can help to understand the performance of COVID-19 in different stages and dynamically detect changes in the patient's condition.

Acupuncture: A therapeutic approach against acne.

Acne is a common but chronic skin disease that influence large population especially juvenile. Acne can continue, begin, or grow into severe form in adult age, affecting face, back, and chest. It may be a serious issue if not cared or treated timely. Even if acne got treated it leaves a persistent scar, which is difficult to alleviate. These acne lesions are long-lasting and result in significant impact on mental and physical health of an individual. There are four mechanisms that are involved in acne lesion formation. However, the accurate series of events of the interaction among the factors in acne pathogenesis is still unsettled. Pubescent acne is due to increase hormone levels, when in fact adult acne is due to fluctuation in hormone levels. There are various approaches for the treatment of acne, including oral medications, creams or gels, acupuncture. Traditional Chinese Medicine stated acne as a infection that is associated with the pathogenic influence of damp heat and heat on specific meridians. As an ancient and integral part of Chinese medicine acupuncture therapy is employed in the treatment of many diseases including acne. It functions by ameliorating the deep-rooted mechanisms playing crucial role in acne development. In this review, we have explained the acne causes, pathogenesis, and its available treatment options. Additionally, we also discussed the acupuncture therapy methods, devices, different techniques. and its mechanism of action in treating acne. Furthermore, clinical trials studies motivated us to highlight the scope of acupuncture in the growing system of medicine.

STAT3ß disrupted mitochondrial electron transport chain enhances chemosensitivity by inducing pyroptosis in esophageal squamous cell carcinoma.

The clinical efficacy of cisplatin in the treatment of esophageal squamous cell carcinoma (ESCC) is undesirable. Signal transducer and activator of transcription 3ß (STAT3ß), a splice variant of STAT3, restrains STAT3α activity and enhances chemosensitivity in ESCC. However, the underlying molecular mechanisms remain poorly understood. Here, we found that high expression of STAT3ß contributes to cisplatin sensitivity and enhances Gasdermin E (GSDME) dependent pyroptosis in ESCC cells after exposure to cisplatin. Mechanistically, STAT3ß was located into the mitochondria and its high expression disrupts the activity of the electron transport chain, resulting in an increase of ROS in cisplatin treatment cells. While high levels of ROS caused activation of caspase-3 and GSDME, and induced cell pyroptosis. STAT3ß blocked the phosphorylation of STAT3α S727 in mitochondria by interacting with ERK1/2 following cisplatin treatment, disrupting electron transport chain and inducing activation of GSDME. Clinically, high expression of both STAT3ß and GSDME was strongly associated with better overall survival and disease-free survival of ESCC patients. Overall, our study reveals that STAT3ß sensitizes ESCC cells to cisplatin by disrupting mitochondrial electron transport chain and enhancing pyroptosis, which demonstrates the prognostic significance of STAT3ß in ESCC therapy.