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Introduction: Necroptosis has emerged as a promising biomarker for predicting immunotherapy responses across various cancer types. Its role in modulating immune activation and therapeutic outcomes offers potential for precision oncology. Methods: A comprehensive pan-cancer analysis was performed using bulk RNA sequencing data to develop a necroptosis-related gene signature, termed Necroptosis.Sig. Multi-omics approaches were employed to identify critical pathways and key regulators of necroptosis, including HMGB1. Functional validation experiments were conducted in A549 lung cancer cells to evaluate the effects of HMGB1 knockdown on tumor proliferation and malignancy. Results: The Necroptosis.Sig gene signature effectively predicted responses to immune checkpoint inhibitors (ICIs). Multi-omics analyses highlighted HMGB1 as a key modulator of necroptosis, with potential to enhance immune activation and therapeutic efficacy. Functional experiments demonstrated that HMGB1 knockdown significantly suppressed tumor proliferation and malignancy, reinforcing the therapeutic potential of targeting necroptosis. Discussion: These findings underscore the utility of necroptosis as a biomarker to guide personalized immunotherapy strategies. By advancing precision oncology, necroptosis provides a novel avenue for improving cancer treatment outcomes. [ABSTRACT FROM AUTHOR]

The response rates to immunotherapy vary widely depending on the type of cancer and the specific treatment used and can be disappointingly low for many solid tumors. Fortunately, due to their complementary mechanisms of action, immunotherapy and anti-angiogenic therapy have synergistic effects in cancer treatment. By normalizing the tumor vasculature, anti-angiogenic therapy can improve blood flow and oxygenation to facilitate better immune cell infiltration into the tumor and enhance the effectiveness of immunotherapy. It also reduces immunosuppressive factors and enhances immune activation, to create a more favorable environment for immune cells to attack the tumor. Their combination leverages the strengths of both therapies to enhance anti-tumor effects and improve patient outcomes. This review discusses the vasculature-immunity crosstalk in the tumor microenvironment and summarizes the latest advances in combining anti-angiogenic therapy and immune checkpoint inhibitors to treat digestive system tumors. [ABSTRACT FROM AUTHOR]

Background and Objective: Durvalumab plus tremelimumab (Durva/Treme) has recently been approved as a first-line or later-line treatment for patients with unresectable hepatocellular carcinoma (u-HCC) in Japan. We assessed the real-world outcomes of Durva/Treme for u-HCC, with a focus on treatment efficacy and safety. Methods: We retrospectively evaluated 22 patients with u-HCC treated with Durva/Treme at Iwate Medical University during the period from 2023 to 2024, with a comparison of the clinical outcomes between patients who received Durva/Treme as first-line and later-line treatments. We further evaluated changes in the modified albumin-bilirubin (mALBI) grade during treatment. Results: There were 10 patients in the first-line group and 12 patients in the later-line treatment group. During the follow-up with a median duration of 7.6 months, the median progression-free survival (first-line versus later-line: 4.7 months versus 2.9 months, p = 0.85), the objective response rate (0.0% versus 16.7%, p = 0.48), the disease control rate (60.0% versus 58.4%, p = 1.00), and the incidence of any adverse event (50.0% versus 75.0%, p = 0.38) were not statistically different between the two groups. The changes in the mALBI scores were not statistically significant (p = 0.75). Conclusions: Durva/Treme may be effective and safe for patients with u-HCC, even in patients who receive Durva/Treme as a later-line treatment. [ABSTRACT FROM AUTHOR]

In the realm of cancer research, the tumor microenvironment (TME) plays a crucial role in tumor initiation and progression, shaped by complex interactions between cancer cells and surrounding non-cancerous cells. Cytokines, as essential immunomodulatory agents, are secreted by various cellular constituents within the TME, including immune cells, cancer-associated fibroblasts, and cancer cells themselves. These cytokines facilitate intricate communication networks that significantly influence tumor initiation, progression, metastasis, and immune suppression. Pyroptosis contributes to TME remodeling by promoting the release of pro-inflammatory cytokines and sustaining chronic inflammation, impacting processes such as immune escape and angiogenesis. However, challenges remain due to the complex interplay among cytokines, pyroptosis, and the TME, along with the dual effects of pyroptosis on cancer progression and therapy-related complications like cytokine release syndrome. Unraveling these complexities could facilitate strategies that balance inflammatory responses while minimizing tissue damage during therapy. This review delves into the complex crosstalk between cytokines, pyroptosis, and the TME, elucidating their contribution to tumor progression and metastasis. By synthesizing emerging therapeutic targets and innovative technologies concerning TME, this review aims to provide novel insights that could enhance treatment outcomes for cancer patients. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs), an essential component of the human immune system, are a heterogeneous group of T lymphocytes with the ability to suppress immune responses and maintain immune homeostasis. Recent evidence indicates that Tregs may impair antitumor immunity and facilitate cancer progression by weakening functions of effector T cells (Teffs). Consequently, targeting Tregs to eliminate them from tumor microenvironments to improve Teffs' activity could emerge as an effective strategy for cancer immunotherapy. This review outlines the biology of Tregs, detailing their origins, classification, and crucial markers. Our focus lies on the complex role of Tregs in cancer's development, progression and treatment, particularly on their suppressive role upon antitumor responses via multiple mechanisms. We delve into Tregs' involvement in immune checkpoint blockade (ICB) therapy, their dual effect on cancer immunotherapy and their potential biomarkers for ICB therapy effectiveness. We also summarize advances in the therapies that adjust Tregs to optimize ICB therapy, which may be crucial for devising innovative cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Acetaminophen (APAP) overdose is a significant cause of drug-induced liver injury (DILI). N-acetylcysteine (NAC) is the first-line agent used in the clinic. However, it rarely benefits patients with advanced APAP toxicity. Mesenchymal stromal cells (MSCs) have demonstrated potential in treating DILI. However, the specific mechanism by which MSCs protect against APAP-induced liver injury remains unclear. Methods: APAP was injected intraperitoneally to induce a liver injury model. We then detected histopathology, biochemical indices, and inflammatory cytokine levels to assess the efficacy of MSCs and MSC extracellular vesicles (MSC-EVs). Flow cytometry was performed to reveal the immunoregulatory effects of MSCs and MSC-EVs on the neutrophils. RNA sequencing (RNA-Seq) of liver tissues was used to identify critical target genes for MSC treatment. Results: MSC and MSC-EV treatment effectively alleviated APAP-induced liver injury and inhibited neutrophil infiltration. RNA-Seq analysis and ELISA data indicated that C-X-C motif chemokine 1 (CXCL1), a chemoattractant for neutrophils, was a key molecule in the MSC-mediated amelioration of APAP-induced liver damage. In addition, neutralization of CXCL1 reduced APAP-induced liver damage, which was accompanied by decreased neutrophil infiltration. Importantly, we verified that MSC-EV-derived miR-186-5p directly binds to the 3'-UTR of Cxcl1 to inhibit its expression in hepatocytes. The agomir miR-186-5p showed excellent potential for the treatment of DILI. Conclusions: Our findings suggest that MSCs and MSC-EVs are an effective approach to mitigate DILI. Targeting the miR-186-5p/CXCL1 axis is a promising approach to improve the efficacy of MSCs and MSC-EVs in the treatment of DILI. [ABSTRACT FROM AUTHOR]

Background and Objectives The aim of this study was to investigate the Effect of eight weeks of selected Pilates training on lipid profile, fasting blood sugar, blood pressure and fat percentage of women with non-alcoholic fatty liver disease in Ahvaz city. Subjects and Methods In this semi-experimental study, 20 women with non-alcoholic fatty liver were randomly simple divided into two groups: Pilates training (N=10) with an average age of 42.2±8.68 years and an average weight of 79.8±4.7 kg, and control group (N=10) with an average age of 40.1±8.97 years and an average weight of 80.4±5.10 kg. The training group did Pilates training for 60 minutes three days a week for eight weeks. The control group did not participate in any sports activities. Following data collection, independent samples t-test and analysis of covariance were run and the data were analyzed using SPSS26 software at a significance level of P<0.05. Results The results of this study showed that eight weeks of selected Pilates training increased HDL levels and as well as significantly decreased the levels of TC, TG, LDL, VLDL, FBS and indicators blood pressure (systolic and diastolic) and body fat percentage in the Pilates training group compared to the control group (P<0.05). Conclusion According to the results of this research Pilates training can be used to reduce the levels of TC, TG, LDL,VLDL, FBS, blood pressure (systolic and diastolic) and fat percentage and increase HDL levels [ABSTRACT FROM AUTHOR]

Background: Aerobic exercise plays an influential role in improving mental health. Aerobics, as a form of efficient aerobic exercise, is suitable for various individuals and promotes the mental health of college students. Objectives: The purpose of this study was to explore whether aerobic exercise has a positive effect on the mental health and Body Mass Index (BMI) of obese college students. Methods: Sixty obese college students with a BMI ≥ 28 were selected and divided into two groups. Each group consisted of 30 students, 15 boys and 15 girls. The experimental group received aerobic exercise training three times a week for 12 weeks, while the control group received prescribed aerobic training. Data before and after the experiment were recorded. Results: The BMI of the experimental group decreased from 30.19 ± 0.73 before the experiment to 27.32 ± 0.84 after the experiment, with a change range of 2.86 ± 0.11. The experimental group showed significant differences before and after the experiment (P < 0.01). The BMI of the control group decreased from 30.16 ± 0.73 before the experiment to 28.62 ± 0.89 after the experiment, with a change range of 1.54 ± 0.84. The control group also showed significant differences before and after the experiment (P < 0.05). The experimental group had a better effect. The 12 dimensions of the mental health test changed in both the experimental group and the control group, and the results were statistically significant (P < 0.05), with the experimental group showing better improvement. Conclusions: The statistically significant impact of aerobics on the mental health of obese college students holds practical significance. Notably, the observed reduction in anxiety and depression symptoms, coupled with notable enhancements in self-esteem and self-confidence, underscores the tangible benefits of incorporating aerobics into the lifestyle of this demographic. [ABSTRACT FROM AUTHOR]

Introduction: Hyperlipidemia, a chronic metabolic disorder marked by elevated blood lipid levels, significantly increases the risk of cardiovascular disease in individuals with diabetes, hypertension, and obesity. While pharmacological interventions exist, factors such as medication side effects, cost considerations, and a growing interest in complementary and alternative medicine have stimulated research into the therapeutic potential of medicinal plants in managing hyperlipidemia. This study aims to assess the efficacy and safety of these botanical agents in reducing blood lipid levels. Methods: A comprehensive literature search was conducted across reputable databases, including PubMed, ScienceDirect, Google Scholar, and other relevant online platforms. Keywords such as "hyperlipidemia," "herbal medicine," "traditional medicine," "herbal extract," and "herbal therapy" were employed to identify studies published up to 2024. Inclusion criteria were established to select studies that reported the impact of medicinal plants on lipid profile modifications. Results: Based on the results, the study revealed that various medicinal plants, including Thymus vulgaris, Apium graveolens, Cichorium intybus, Fumaria officinalis, Heracleum rawianum, Anthemis altissima, Gundelia tourneforttii, Cynodon dactylon, Anthriscus sylvestrianum, Solanum nigrum, Arum elongatum, Glycyrrhiza glabra, Berberis vulgaris, Rheum ribes, and Mentha spicata, are commonly used in traditional medicine to address hyperlipidemia. Conclusions: The use of indigenous Iranian medicinal plants for managing hyperlipidemia is deeply rooted in the country’s ancient history and has been increasingly validated by contemporary scientific research. These natural compounds can help lower blood lipid levels by inhibiting fat absorption and boosting lipid metabolism. The growing interest in traditional medicine and medicinal plants can be attributed to their inherent advantages, such as a lower incidence of side effects compared to synthetic drugs. Ongoing scientific research in this field offers promising avenues for developing innovative and effective herbal-based therapies. [ABSTRACT FROM AUTHOR]

Background: Cancer remains a major global health concern, with conventional treatments often limited by side effects and resistance. Bojungikki-tang (BJIKT), a traditional herbal formula, has shown promise in alleviating cancer-related symptoms and enhancing anti-cancer effects when combined with conventional treatments. As immune checkpoint inhibitors (ICIs) have become the standard for cancer treatment, a combination of BJIKT and ICIs may exhibit immune-mediated anti-cancer effects. This review aims to summarize the recent evidence on BJIKT use in cancer treatment, investigate its immunomodulatory effects, and identify research gaps. Methods: This review was conducted and reported following the Arksey and O'Malley framework and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Scoping Review. A comprehensive search of six electronic databases was conducted, and studies published between 2013 and 2022 were identified. Reports on oral administration of BJIKT to patients with cancer were included and analyzed by two reviewers. The extracted data were synthesized using descriptive reporting and meta-analysis. Results: Overall, 56 studies met the inclusion criteria: 36 human studies, 14 experimental studies, and 6 reviews on clinical and preclinical investigations. The use of BJIKT in restoring immune function and improving fatigue, cancer-related fever, and quality of life after chemotherapy has been reported in clinical studies. The different medication forms of BJIKT included decoction, extract granules, pills, and water extract. The meta-analysis revealed a significantly higher Karnofsky Performance Scale score in the BJIKT plus chemotherapy group than in the chemotherapy alone group. Preclinical studies have demonstrated that BJIKT has anti-cancer effects, enhances gastrointestinal function and immunomodulatory effects, and supports favorable chemotherapy outcomes. Conclusion: In recent clinical research on BJIKT, its impact on fatigue, quality of life, and alleviating cancer-related fever has mostly been examined. The direct anti-cancer activities and immunomodulatory mechanisms of BJIKT have been reported in preclinical studies; however, clinical research on BJIKT-induced enhancement of immune function is lacking. Further research on the efficacy and safety of ICI combined with BJIKT and the association of immunomarker changes with clinical outcomes is required to precisely identify the effect of BJIKT on immune system modulation. [ABSTRACT FROM AUTHOR]

Method: Twenty inactive males (BMI 27.67 ± 0.88 kg/m2, age 49.15 ± 2.58 years) participated in an eight-week were randomly assigned to one of three intervention groups (combined (CT), resistance (RT), and aerobic (AT)) exercise modalities to assess within-subject and between group changes in glycolipid profile. Data were analyzed using repeated measures ANCOVA. Result: Pre-post mean values of body fat percentage (%BF), area under the curve (AUC), low density lipoprotein (LDL), high density lipoprotein (HDL) and total cholesterol (TC) decreased in all three groups. The main effect of exercise modality on the AUC (F (2, 26) = 10.577, P = 0.001, η2 = 0.569) was significant. Post-hoc analyses revealed that the RT group (-30.653 ± 6.766, p = 0.001) with 11.53% and the CT group (M = -0.896, SE = 3.347, P = 0.015) with 3.79% exhibited significantly greater reductions in AUC compared to the AT group. LDL levels showed significant different between groups (F (2, 26) = 6.33, p = 0.009, η2 = 0.442), specially significantly 3.7% lowered in AT (MD = 4.783, SE = 1.563, P = 0.002) and 3.79% lower in CT (MD = 4.57, SE = 1.284, P = 0.008) groups compared to the RT group. AT significantly reduced TC by 17.716 ± 5.705 mg/dL (p = 0.02) compared to RT, representing a 7.97% decrease. Conclusion: Exercise type significantly influences lipid profiles and glycemic control. Notably, both aerobic and combined training demonstrated a superior ability to modulate the lipid profile, and resistance training and combined training were more effective in reducing the AUC. Trial registration: May, 31st 2024. Registration no: PACTR202405463745521 "Retrospectively registered". [ABSTRACT FROM AUTHOR]

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Objective: To investigate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on the efficacy of immune checkpoint inhibitor (ICI)-based therapy in patients with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). Methods: A total of 155 patients with CHB-related HCC who received ICI–based therapy (in the Department of Hepatology, Tianjin Second People’s Hospital and Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Institute & Hospital) between April 2021 and December 2023 were evaluated. Patients were divided into two groups: MASLD concurrent with CHB [MASLD-CHB] (n = 38), and CHB (n = 117). Results: The median progression-free survival (PFS, 6.9 months vs. 9.3 months; P = 0.001), progressive disease (57.89% vs. 37.61%; P = 0.028), and disease control rate (42.11% vs. 62.39%; P = 0. 028) in the MASLD-CHB group were significantly worse than the CHB group. The median overall survival was not attained. The percentage of CD4+PD1+ (17. 56% vs. 8.89%; P < 0.001) and CD8+PD1+ T cells (10.50% vs. 7.42%; P = 0.005) in patient samples from the MASLD-CHB group were significantly higher than the CHB group. Concurrent MASLD [hazard ratio (HR) = 1.921; 95% CI, 1.138–3.245; P = 0.015] and alpha-fetoprotein levels after 3 months of treatment (HR = 2.412; 95% CI, 1.360–4.279; P = 0.003) were independent risk factors for PFS in all patients. Conclusions: ICI-based therapy in patients with CHB-related HCC and concurrent MASLD resulted in poorer efficacy and shorter PFS compared to patients with CHB-related HCC alone. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) remains a significant global health burden, emphasizing the need for innovative treatment strategies. 95% of the CRC population are microsatellite stable (MSS), insensitive to classical immunotherapies such as anti-PD-1; on the other hand, responders can become resistant and relapse. Recently, the use of cancer vaccines enhanced the immune response against tumor cells. In this context, we developed a therapeutic vaccine based on Stimulated Tumor Cells (STC) platform technology. This vaccine is composed of selected tumor cell lines stressed and haptenated in vitro to generate a factory of immunogenic cancer-related antigens validated by a proteomic cross analysis with patient’s biopsies. This technology allows a multi-specific education of the immune system to target tumor cells harboring resistant clones. Here, we report safety and antitumor efficacy of the murine version of the STC vaccine on CT26 BALB/c CRC syngeneic murine models. We showed that one cell line (1CL)-based STC vaccine suppressed tumor growth and extended survival. In addition, three cell lines (3CL)-based STC vaccine significantly improves these parameters by presenting additional tumor-related antigens inducing a multi-specific anti-tumor immune response. Furthermore, proteomic analyses validated that the 3CL-based STC vaccine represents a wider quality range of tumor-related proteins than the 1CL-based STC vaccine covering key categories of tumor antigens related to tumor plasticity and treatment resistance. We also evaluated the efficacy of STC vaccine in an MC38 anti-PD-1 resistant syngeneic murine model. Vaccination with the 3CL-based STC vaccine significantly improved survival and showed a confirmed complete response with an antitumor activity carried by the increase of CD8+ lymphocyte T cells and M1 macrophage infiltration. These results demonstrate the potential of this technology to produce human vaccines for the treatment of patients with CRC. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor macrophage (CAR-MΦ) represents a significant advancement in immunotherapy, especially for treating solid tumors where traditional CAR-T therapies face limitations. CAR-MΦ offers a promising approach to target and eradicate tumor cells by utilizing macrophages' phagocytic and antigen-presenting abilities. However, challenges such as the complex tumor microenvironment (TME), variability in antigen expression, and immune suppression limit their efficacy. This review addresses these issues, exploring mechanisms of CAR-MΦ action, optimal construct designs, and interactions within the TME. It also delves into the ex vivo manufacturing challenges of CAR-MΦ, discussing autologous and allogeneic sources and the importance of stringent quality control. The potential synergies of integrating CAR-MΦ with existing cancer therapies like checkpoint inhibitors and conventional chemotherapeutics are examined to highlight possible enhanced treatment outcomes. Furthermore, regulatory pathways for CAR-MΦ therapies are scrutinized alongside established protocols for CAR-T cells, identifying unique considerations essential for clinical trials and market approval. Proposed safety monitoring frameworks aim to manage potential adverse events, such as cytokine release syndrome, crucial for patient safety. Consolidating current research and clinical insights, this review seeks to refine CAR-MΦ therapeutic applications, overcome barriers, and suggest future research directions to transition CAR-MΦ therapies from experimental platforms to standard cancer care options. Highlights: CAR-MΦ offers an innovative approach to treating solid tumors, addressing the limitations of traditional CAR-T therapies. CAR-MΦ eliminates tumor cells and boosts other immune cells' effectiveness. Strategies are being t developed to improve CAR-MΦ targeting and cancer cell eradication. CAR-MΦ is combined with other treatments to enhance overall efficacy. Challenges and safety concerns, including side effects of CAR-MΦ therapies, are Beijing addressed. [ABSTRACT FROM AUTHOR]

Background: Leiomyosarcoma (LMS) is an uncommon type of tumour found in the uterus, comprising about one percent of cancers in women and playing a substantial role in uterine cancer fatalities. The resemblance to benign leiomyomas complicates pre-surgery detection, possibly leading to improper use of myomectomy and morcellation, causing concerns. Managing Uterine Leiomyosarcoma (ULMS) is particularly challenging due to its aggressive nature and resistance to standard therapies. Predictive algorithms provide accurate forecasts, although the time of diagnosis is critical for survival. Aim of the study: This study evaluates the effectiveness of existing surgical and medicinal treatments for ULMS, concentrating on targeted therapy and examining the influence of uterine morcellation on gynaecologic surgical practices. The main goal is to improve knowledge of ULMS, investigate early detection techniques, and assess new treatments. Materials and Methods: Study employs a comprehensive analysis of existing literature, emphasizing surgical techniques, medicinal approaches, and the effects of certain medicines including olaratumab, trabectedin, and pazopanib. The current examination focuses on aromatase inhibitors and immunotherapies. Results: However, treating ULMS is challenging, Food and Drug Administration (FDA)-approved targeted therapies have shown efficacy against uterine and other LMSs. The present research concentrates on creating methods for detecting diseases at an early stage and exploring new treatments, such as aromatase inhibitors and immunotherapies. Conclusion: Study emphasizes the necessity for enhanced detection methods for ULMS due to its deceptive resemblance to benign tumours. Investigation of new treatments and the effects of uterine morcellation on surgical techniques is crucial for improving the management of ULMS, even with the effectiveness of FDA-approved therapies. [ABSTRACT FROM AUTHOR]

Stem cell-based therapies have emerged as a promising approach for treating various neurological disorders by harnessing the regenerative potential of stem cells to restore damaged neural tissue and circuitry. This comprehensive review provides an in-depth analysis of the current state of stem cell applications in primary neurological conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other related disorders. The review begins with a detailed introduction to stem cell biology, discussing the types, sources, and mechanisms of action of stem cells in neurological therapies. It then critically examines the preclinical evidence from animal models and early human trials investigating the safety, feasibility, and efficacy of different stem cell types, such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs). While ESCs have been studied extensively in preclinical models, clinical trials have primarily focused on adult stem cells such as MSCs and NSCs, as well as iPSCs and their derivatives. We critically assess the current state of research for each cell type, highlighting their potential applications and limitations in different neurological conditions. The review synthesizes key findings from recent, high-quality studies for each neurological condition, discussing cell manufacturing, delivery methods, and therapeutic outcomes. While the potential of stem cells to replace lost neurons and directly reconstruct neural circuits is highlighted, the review emphasizes the critical role of paracrine and immunomodulatory mechanisms in mediating the therapeutic effects of stem cells in most neurological disorders. The article also explores the challenges and limitations associated with translating stem cell therapies into clinical practice, including issues related to cell sourcing, scalability, safety, and regulatory considerations. Furthermore, it discusses future directions and opportunities for advancing stem cell-based treatments, such as gene editing, biomaterials, personalized iPSC-derived therapies, and novel delivery strategies. The review concludes by emphasizing the transformative potential of stem cell therapies in revolutionizing the treatment of neurological disorders while acknowledging the need for rigorous clinical trials, standardized protocols, and multidisciplinary collaboration to realize their full therapeutic promise. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) remains an unsolved challenge in oncology, signifying a substantial global health burden. While considerable progress has been made in recent years through the emergence of immunotherapy modalities, such as immune checkpoint inhibitors (ICIs), monotherapies often yield limited clinical outcomes. The rationale behind combining various immunotherapeutic or other anticancer agents, the mechanistic underpinnings, and the clinical evidence supporting their utilization is crucial in NSCLC therapy. Regarding the synergistic potential of combination immunotherapies, this study aims to provide insights to help the landscape of NSCLC treatment and improve clinical outcomes. In addition, this review article discusses the challenges and considerations of combination regimens, including toxicity management and patient selection. [ABSTRACT FROM AUTHOR]

Background: The Prognostic Nutritional Index (PNI) has become an important predictive tool for assessing patients' nutritional status and immune competence. It is widely used in prognostic evaluations for various cancer patients. However, the prognostic relevance of the Prognostic Nutritional Index (PNI) in gastric or gastro-esophageal junction cancer patients (GC/GEJC) undergoing immune checkpoint inhibitors (ICIs) treatment remains unclear. This meta-analysis aimed to determine the prognostic impact of PNI in this specific patient cohort. Methods: We conducted a thorough literature search, covering prominent databases such as PubMed, Embase, Web of Science, SpringerLink, and the Cochrane Library. The search spanned from the inception of these databases up to December 5, 2023. Employing the 95% confidence interval and Hazard Ratio (HR), the study systematically evaluated the relationship between PNI and key prognostic indicators, including the objective remission rate (ORR), disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) in GC/GEJC patients undergoing ICI treatment. Results: Eight studies comprising 813 eligible patients were selected. With 7 studies consistently demonstrating superior Overall Survival (OS) in the high- Prognostic Nutritional Index (PNI) group compared to their low-PNI counterparts (HR 0.58, 95% CI: 0.47-0.71, P<0.001). Furthermore, the results derived from 6 studies pointed out that the significant correlation between he low-PNI and poorer progression-free survival (PFS) (HR 0.58, 95% CI: 0.47-0.71, P<0.001). Subgroup analyses were performed to validate the robustness of the results. In addition, we conducted a meta-analysis of three studies examining the correlation between PNI and objective response rate/disease control rate (ORR/DCR) and found that the ORR/DCR was significantly superior in the high PNI group (ORR: RR: 1.24, P=0.002; DCR: RR: 1.43, P=0.008). Conclusion: This meta-analysis indicates that the low-PNI in GC/GEJC patients undergoing ICI treatment is significantly linked to worse OS and PFS. Therefore, PNI can serve as a prognostic indicator of post-treatment outcomes in patients with GC receiving ICIs. Further prospective studies are required to assess the reliability of these findings. Systematic review registration: https://inplasy.com/, identifier INPLASY202450133. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) promote antitumour immune responses by blocking inhibitory signals expressed by T cells and have significant clinical benefits in the treatment of oral squamous cell carcinoma (OSCC). With the advancement of immunotherapy, an increasing number of ICIs have been developed or are in clinical trial stages. However, drug resistance and immune-related adverse events (irAEs) associated with ICIs have limited the clinical application of immunotherapy in OSCC, and the optimal drug regimen for ICIs and the optimal duration of ICIs administration also deserves to be further discussed. New therapeutic regimens and drug delivery technologies are key to promoting the further development of ICIs. This article elucidates the mechanism of ICIs' action and presents a review of their clinical applications and current development status in OSCC. Additionally, it summarizes the current challenges and outlines future research directions for ICIs therapy, with the aim of offering fresh insights to researchers. [ABSTRACT FROM AUTHOR]

Objectives: The prognostic relevance of the platelet-to-lymphocyte ratio (PLR) in gastric cancer (GC) patients undergoing immune checkpoint inhibitor (ICI) treatment remains unclear. This meta-analysis aimed to determine the prognostic impact of PLR in this specific patient cohort. Methods: We searched the PubMed, Cochrane Library, CNKI, and EMBASE databases, including literature published up to September 2023, to investigate the prognostic implications of PLR in patients with gastric cancer undergoing immune checkpoint inhibitor therapy. Outcome measures encompassed overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rates (DCR). Results: Nine studies from seven articles comprising 948 eligible patients were selected. The results revealed a significant correlation between elevated PLR and poorer OS and progression-free survival (PFS) (OS: HR 1.67, 95% CI 1.39–2.00, p < 0.001; PFS: HR 1.51, 95% CI 1.29–1.76, p < 0.001). Subgroup analyses were performed to validate the robustness of the results. Moreover, a meta-analysis of four studies investigating the correlation between the PLR in gastric cancer (GC) patients and the objective response rate/disease control rate (ORR/DCR), showed no significant association between the PLR and ORR/DCR (ORR: RR = 1.01, p = 0.960; DCR: RR = 0.96, p = 0.319). Conclusions: This meta-analysis indicates that elevated PLR in GC patients undergoing ICI treatment is significantly linked to worse OS and PFS. Therefore, PLR can serve as a prognostic indicator of post-treatment outcomes in patients with GC receiving ICIs. Further prospective studies are required to assess the reliability of these findings. [ABSTRACT FROM AUTHOR]

The emergence of antiparasitic drug resistance poses a concerning threat to animals and humans. Mesenchymal Stem Cells (MSCs) have been widely used to treat infections in humans, pets, and livestock. Although this is an emerging field of study, the current review outlines possible mechanisms and examines potential synergism in combination therapies and the possible harmful effects of such an approach. The present study delved into the latest pre-clinical research on utilizing MSCs to treat parasitic infections. As per investigations, the introduction of MSCs to patients grappling with parasitic diseases like schistosomiasis, malaria, cystic echinococcosis, toxoplasmosis, leishmaniasis, and trypanosomiasis has shown a reduction in parasite prevalence. This intervention also alters the levels of both pro- and anti-inflammatory cytokines. Furthermore, the combined administration of MSCs and antiparasitic drugs has demonstrated enhanced efficacy in combating parasites and modulating the immune response. Mesenchymal stem cells are a potential solution for addressing parasitic drug resistance. This is mainly because of their remarkable immunomodulatory abilities, which can potentially help combat parasites' resistance to drugs. [ABSTRACT FROM AUTHOR]

The article discusses the combination of Janus kinase (JAK) inhibitors and immune checkpoint inhibitors in clinical trials, showing promising results in treating Hodgkin lymphoma and non-small cell lung cancer. The combination therapy aims to enhance antitumor immunity by reversing T-cell exhaustion, modulating the tumor microenvironment, and enhancing antigen presentation. Challenges such as safety, patient selection, dosing, and resistance mechanisms need to be addressed for the full potential of this therapy. While the studies provide encouraging results, further research is needed to apply this approach to a wider range of cancer types and explore combination with other emerging therapies. [Extracted from the article]

Inflammation plays a critical role in conditions such as acute liver failure, acute-on-chronic liver failure, and ischemia–reperfusion-induced liver injury. Various pathogenic pathways contribute to liver inflammation, involving inflammatory polarization of macrophages and Küpffer cells, neutrophil infiltration, dysregulation of T cell subsets, oxidative stress, and activation of hepatic stellate cells. While mesenchymal stromal cells (MSCs) have demonstrated beneficial properties, their clinical translation is limited by their cellular nature. However, MSC-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free therapeutic approach for immunomodulation. MSC-EVs naturally mirror their parental cell properties, overcoming the limitations associated with the use of MSCs. In vitro and in vivo preclinical studies have demonstrated that MSC-EVs replicate the beneficial effects of MSCs in liver injury. This includes the reduction of cell death and oxidative stress, improvement of hepatocyte function, induction of immunomodulatory effects, and mitigation of cytokine storm. Nevertheless, MSC-EVs face challenges regarding the necessity of defining consistent isolation methods, optimizing MSCs culture conditions, and establishing quality control measures for EV characterization and functional assessment. By establishing standardized protocols, guidelines, and affordable cost mass production, clinicians and researchers will have a solid foundation to conduct further studies, validate the therapeutic efficacy of MSC-EVs, and ultimately pave the way for their clinical implementation in acute liver injury. [ABSTRACT FROM AUTHOR]

Penile squamous cell carcinoma (PSCC) occurs more frequently in some developing countries compared to developed countries. Infection with HIV and/or high-risk human papillomavirus (hrHPV) are risk factors for penile cancer development. The tumor microenvironment of PSCC may predict prognosis and may inform on the best targets for immunotherapy. We evaluated the immune microenvironment of penile tumors histologically, and determined whether and/or how HIV and/or hrHPV infections affect this tumor microenvironment. We conducted a prospective analytical cross-sectional study in which penile cancer tumors from 35 patients presenting at the University Teaching Hospital in Lusaka, Zambia were histologically staged and assessed for presence of tumor infiltrating immune cells and expression of immune checkpoints. Immunohistochemistry was used to evaluate immune checkpoints and infiltrating immune cells, while multiplex real-time polymerase chain reaction was used for hrHPV genotyping. The median age of all participants was 55 years. About 24% had advanced histological stage, 83% were HIV+, and 63% had hrHPV detected in their tumors using multiplex real-time polymerase chain reaction. PDL1 expression was significantly higher in HIV- participants than HIV+ participants (p = 0.02). Tumors with multiple hrHPV infections had a significantly higher number of cells expressing TIM3 than those with one hrHPV (p = 0.04). High grade tumors had a significantly higher infiltrate of FoxP3+ cells (p = 0.02), CD68+ cells (p = 0.01), CD163+ cells (p = 0.01), LAG3+ cells (p = 0.01), PD1+ cells (p = 0.01) and TIM3+ cells (p = 0.03) when compared with low grade tumours. There was significant moderate to strong positive correlation of cells expressing PD1 and LAG3 (⍴ = 0.69; p = 0.0001), PD1 and TIM3 (⍴ = 0.49; p = 0.017) and TIM3 and LAG3 PDL1 (⍴ = 0.61; p = 0.001). In conclusion, the tumor microenvironment of penile squamous cell carcinoma seems to be affected by both HIV and HPV infections. TIM3 appears to be a potential therapeutic target in PSCC patients with hrHPV infections. [ABSTRACT FROM AUTHOR]

T cell immunity is central to contemporary cancer and autoimmune therapies, encompassing immune checkpoint blockade and adoptive T cell therapies. Their diverse characteristics can be reprogrammed by different immune challenges dependent on antigen stimulation levels, metabolic conditions, and the degree of inflammation. T cell-based therapeutic strategies are gaining widespread adoption in oncology and treating inflammatory conditions. Emerging researches reveal that clustered regularly interspaced palindromic repeats–associated protein 9 (CRISPR–Cas9) genome editing has enabled T cells to be more adaptable to specific microenvironments, opening the door to advanced T cell therapies in preclinical and clinical trials. CRISPR–Cas9 can edit both primary T cells and engineered T cells, including CAR-T and TCR-T, in vivo and in vitro to regulate T cell differentiation and activation states. This review first provides a comprehensive summary of the role of CRISPR–Cas9 in T cells and its applications in preclinical and clinical studies for T cell-based therapies. We also explore the application of CRISPR screen high-throughput technology in editing T cells and anticipate the current limitations of CRISPR–Cas9, including off-target effects and delivery challenges, and envisioned improvements in related technologies for disease screening, diagnosis, and treatment. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is a significant public health concern in India, with one of the highest disability burdens worldwide. For the success of the disease prevention and control program that aims to reduce prevalence through health promotion and screening, the public's prior knowledge of the disease is important. Hence, this study was conducted to assess baseline knowledge of the disease and effects of health education and community mobilization program in the SCD endemic tribal community of Gujarat. This quasi-experimental study was conducted in three phases at Chhotaudepur district of Gujarat, India. Knowledge of the community was assessed through the administration of pretested quantitative questionnaire in 1646 and 1631 individuals respectively during formative and evaluation phases. Differences between the proportions of two phases were statistically assessed by chi-square tests. Despite 75.3% of respondents having heard of SCD before, only 20% could perceive the correct cause. It was improved by 42% post-intervention. During the evaluation, 83% respondents recognized the most common symptom of extreme pain, whereas 86.8% identified the correct diagnostic method. Seventy-seven percent respondents reported modern medicine as a treatment for SCD at endline. Knowledge and awareness about SCD were found inadequate in the community. However, health education intervention strategies effectively improved knowledge related to the disease and its causes, diagnosis, and treatment. Hence, urgent action is required to incorporate community mobilization and awareness generation strategies to mitigate the disease burden. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Tissue Engineering Research / Zhongguo Zuzhi Gongcheng Yanjiu is the property of Chinese Journal of Tissue Engineering Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Context: Peroxisome proliferator-activated receptor γ (PPAR-γ) plays a crucial role in regulating oxidative phosphorylation and energy utilization, both of which are diminished in obesity and type 2 diabetes (T2DM), major risk factors for cardiovascular disease (CVD). It is well established that exercise, as one of the significant modifiable lifestyle factors, is associated with the expression and activity of PPAR-γ-controlled genes. Evidence Acquisition: In this systematic review, we conducted comprehensive searches across various databases, including PubMed, ScienceDirect, and Google Scholar, for relevant literature published between January 2000 and May 2022. This study focused on published articles (in-vivo and human) in English. This review encompasses 16 studies (4 involving humans and 12 involving animals). Results: The findings from 14 studies indicated that various types of exercise programs, including regular exercise, resistance exercise, swimming, climbing, and treadmill running, effectively improved PPAR-γ levels in individuals with T2DM, obese populations, and healthy subjects. Only two studies reported no significant improvement in PPAR-γ levels following physical activity. Notably, all studies involving subjects with T2DM showed improved PPAR-γ levels after exercise training. Conclusions: Upon comparing various types of exercise training, the collected data suggest that all forms of aerobic exercise, regardless of their type and duration, have the potential to up-regulate PPAR-γ messenger ribonucleic acid (mRNA) expression. This study lays the foundation for further research into the association between different types of exercise training and PPAR-γ levels/activity across various human populations. However, given the limited number of human studies, further high-quality research is necessary to draw firm conclusions. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade (ICB) targeting the programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) fails to provide clinical benefit for most cancer patients due to primary or acquired resistance. Drivers of ICB resistance include tumor antigen processing/presentation machinery (APM) and IFNγ signaling mutations. Thus, there is an unmet clinical need to develop alternative therapies for these patients. To this end, we have developed a CRISPR/Cas9 approach to generate murine tumor models refractory to PD-1/-L1 inhibition due to APM/IFNγ signaling mutations. Guide RNAs were employed to delete B2m, Jak1, or Psmb9 genes in ICB-responsive EMT6 murine tumor cells. B2m was deleted in ICB-responsive MC38 murine colon cancer cells. We report a detailed development and validation workflow including whole exome and Sanger sequencing, western blotting, and flow cytometry to assess target gene deletion. Tumor response to ICB and immune effects of gene deletion were assessed in syngeneic mice. This workflow can help accelerate the discovery and development of alternative therapies and a deeper understanding of the immune consequences of tumor mutations, with potential clinical implications. [ABSTRACT FROM AUTHOR]

Copyright of Turkish Journal of Geriatrics / Türk Geriatri Dergisi is the property of Turkish Geriatrics Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background and aims: Hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) has an extremely poor prognosis. A previous study proved that low-dose radiotherapy (RT) could prolong the prognosis of HCC patients with PVTT. This study aims to explore the sensitivity of PVTT to RT treatment. Methods: Patients were selected based on imaging diagnosis of HCC accompanied by PVTT and received combined treatment of radiotherapy, antiangiogenic drugs and immune checkpoint inhibitors, followed by hepatectomy or liver transplantation from January 2019 to August 2022. The efficacy was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines and pathological assessment. The sensitivity of tumor cells to the treatment was compared between the primary tumor (PT)and PVTT by analyzing their residual tumor and pathologic complete remission (PCR) incidence. Results: Data from 14 patients were collected in the study. After combined treatment, the size of PVTT decreased more significantly than that of the primary tumor in the imaging study (p < 0.05). The residual cancer was significantly more restrictive than that of primary tumor in paired patients based on pathological measurement (p = 0.008). The PCR incidence of the primary tumor (21.42%) was significantly lower (p = 0.008) than that of PVTT in the pathologic study (78.57%). Conclusion: PVTT is more sensitive to radiotherapy treatment than the primary tumor in patients with HCC. This combination therapy might be an effective option as a downstaging therapy for patients with HCC with PVTT. [ABSTRACT FROM AUTHOR]

Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with the ability to communicate with other tissues and cell types over long distances. Their use in regenerative medicine has gained tremendous momentum recently due to their ability to be utilized as therapeutic options for a wide array of diseases/conditions. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be developed. Today exosomes have been applied in numerous contexts including neurodegenerative disorders (Alzheimer's disease, central nervous system, depression, multiple sclerosis, Parkinson's disease, post‐traumatic stress disorders, traumatic brain injury, peripheral nerve injury), damaged organs (heart, kidney, liver, stroke, myocardial infarctions, myocardial infarctions, ovaries), degenerative processes (atherosclerosis, diabetes, hematology disorders, musculoskeletal degeneration, osteoradionecrosis, respiratory disease), infectious diseases (COVID‐19, hepatitis), regenerative procedures (antiaging, bone regeneration, cartilage/joint regeneration, osteoarthritis, cutaneous wounds, dental regeneration, dermatology/skin regeneration, erectile dysfunction, hair regrowth, intervertebral disc repair, spinal cord injury, vascular regeneration), and cancer therapy (breast, colorectal, gastric cancer and osteosarcomas), immune function (allergy, autoimmune disorders, immune regulation, inflammatory diseases, lupus, rheumatoid arthritis). This scoping review is a first of its kind aimed at summarizing the extensive regenerative potential of exosomes over a broad range of diseases and disorders. [ABSTRACT FROM AUTHOR]

Background: Despite the utilization of immune checkpoint inhibitors (ICIs) in treating numerous types of cancers being approved, their efficacy in tumor control in the clinic is not satisfactory. Since adoptive cell therapy (ACT) can alter the tumor microenvironment, we hypothesized that ACT potentially synergized with ICI in tumor control and examined this hypothesis via a murine allograft model. Methods: Female C57BL/6 mice were stimulated with interleukin 15 and granulocyte monocyte-colony stimulating factor, followed by collecting their bone marrow cells for murine NKDC cultivation. Then, female C57BL/6 mice, inoculated with lymphoma cancer cell line E.G7-OVA, were administrated with murine NKDC cells, murine anti-program cell death ligand-1 antibody (α-mPD-L1), or both for 28 days. After 28 days of treatment, mice were sacrificed whose inoculated tumors, spleen, sentinel lymph nodes, and peripheral blood were collected to measure tumor size, lymphocyte infiltration, and change of immune cell profile. Results: Combined treatment of NKDCs with α-mPD-L1 exhibited significantly stronger tumor control efficacy than treatment of NKDCs or α-mPD-L1 alone. NKDCs/α-mPD-L1 combination increased migration of dendritic cells, CD4, CD8 T cells, and activated CD8 T cells to the tumor-bedding site, and promoted endogenous tumor-specific cytotoxic T-cell response. Conclusion: The current study confirmed our hypothesis that combining NKDC ACT with ICI therapy can potentiate tumor control efficacy by manipulating the tumor microenvironment. This study provided a novel circumstance on tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major heart failure events, an action that is statistically linked to enhanced erythropoiesis, suggesting that stimulation of erythropoietin and cardioprotection are related to a shared mechanism. Four hypotheses have been proposed to explain how these drugs increase erythropoietin production: (i) renal cortical reoxygenation with rejuvenation of erythropoietin-producing cells; (ii) counterregulatory distal sodium reabsorption leading to increased tubular workload and oxygen consumption, and thus, to localized hypoxia; (iii) increased iron mobilization as a stimulus of hypoxia-inducible factor-2α (HIF-2α)-mediated erythropoietin synthesis; and (iv) direct HIF-2α activation and enhanced erythropoietin gene transcription due to increased sirtuin-1 (SIRT1) signaling. The first two hypotheses assume that the source of increased erythropoietin is the interstitial fibroblast-like cells in the deep renal cortex. However, SGLT2 inhibitors do not alter regional tissue oxygen tension in the non-diabetic kidney, and renal erythropoietin synthesis is markedly impaired in patients with anemia due to chronic kidney disease, and yet, SGLT2 inhibitors produce an unattenuated erythrocytic response in these patients. This observation raises the possibility that the liver contributes to the production of erythropoietin during SGLT2 inhibition. Hypoxia-inducible factor-2α and erythropoietin are coexpressed not only in the kidney but also in hepatocytes; the liver is a major site of production when erythropoietin stimulation is maintained for prolonged periods. The ability of SGLT2 inhibitors to improve iron mobilization by derepressing hepcidin and ferritin would be expected to increase cytosolic ferrous iron, which might stimulate HIF-2α expression in both the kidney and liver through the action of iron regulatory protein 1. Alternatively, the established ability of SGLT2 inhibitors to enhance SIRT1 might be the mechanism of enhanced erythropoietin production with these drugs. In hepatic cell lines, SIRT1 can directly activate HIF-2α by deacetylation, and additionally, through an effect of SIRT in the liver, peroxisome proliferator-activated receptor-γ coactivator-1α binds to hepatic nuclear factor 4 to promote transcription of the erythropoietin gene and synthesis of erythropoietin. Since SIRT1 up-regulation exerts direct cytoprotective effects on the heart and stimulates erythropoietin, it is well-positioned to represent the shared mechanism that links erythropoiesis to cardioprotection during SGLT2 inhibition. [ABSTRACT FROM AUTHOR]

Purpose of Review: This article sumarizes pathopysiological consequencies between obesity and dyslipidemia and aims to bring some practical approach. Recent Findings: Dyslipidemia is often present in individuals with obesity and simultaneusly, many obese individuals have lipid metabolism disorders. Especially the abdominal obesity increases the cardiometabolic risk because of the presence of atherogenic dyslipidemia while the total low density lipoprotein cholesterol (LDL-C) may be normal. LDL-C is the primary goal in dyslipidemia treatment. Apoliprotein B (Apo B) and non – high density lipoprotein cholesterol (non-HDL-C) should be estimated to precise the cardiovascular risk and represents the secondary goal in treatment. Weight loss either with diet or antiobestic medication induces the decrease in triglycerides (TG) and LDL-C and the increase in HDL-C. Composition of nutrients, esp. fatty acids, influences lipid levels. Bariatric surgery is efficient in weight loss and has a significant effect on serum lipids. Summary: Dyslipidemia and obesity present common diseases that must be managed to decrease the cardiovascular risk and the risk of obesity-related complications. [ABSTRACT FROM AUTHOR]

Objective: The predictive biomarkers of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) still need to be further explored. This study aims to establish a new immune prognosis biomarker to predict the clinical outcomes of hepatocellular carcinoma patients receiving immune checkpoint inhibitors. Methods: The subjects of this study were 151 HCC patients receiving ICIs at Harbin Medical University Cancer Hospital from January 2018 to December 2021. This study collected a wide range of blood parameters from patients before treatment and used Cox's regression analysis to identify independent prognostic factors in blood parameters, as well as their β coefficient. The hepatocellular carcinoma immune prognosis score (HCIPS) was established through Lasso regression analysis and COX multivariate analysis. The cut-off value of HCIPS was calculated from the receiver operating characteristic (ROC) curve. Finally, the prognostic value of HCIPS was validated through survival analysis, stratified analyses, and nomograms. Results: HCIPS was composed of albumin (ALB) and thrombin time (TT), with a cut-off value of 0.64. There were 56 patients with HCIPS < 0.64 and 95 patients with HCIPS ≥ 0.64, patients with low HCIPS were significantly related to shorter progression-free survival (PFS) (13.10 months vs. 1.63 months, P < 0.001) and overall survival (OS) (14.83 months vs. 25.43 months, P < 0.001). HCIPS has also been found to be an independent prognostic factor in this study. In addition, the stratified analysis found a significant correlation between low HCIPS and shorter OS in patients with tumor size ≥ 5 cm (P of interaction = 0.032). The C-index and 95% CI of the nomograms for PFS and OS were 0.730 (0.680–0.779) and 0.758 (0.711–0.804), respectively. Conclusions: As a new score established based on HCC patients receiving ICIs, HCIPS was significantly correlated with clinical outcomes in patients with ICIs and might serve as a new biomarker to predict HCC patients who cloud benefit from ICIs. [ABSTRACT FROM AUTHOR]

PSA is a type of proto-oncogene that is specifically and highly expressed in embryonic and prostate cancer cells, but not expressed in normal prostate tissue cells. The specific expression of prostate-specific antigen (PSA) is found to be related with the conditional transcriptional regulation of its promoter. Clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9-KRAB is a newly developed transcriptional regulatory system that inhibits gene expression by interupting the DNA transcription process. Induction of CRISPR-dCas9-KRAB expression through the PSA promoter may help feedback inhibition of cellular PSA gene expression via single guide RNA (sgRNA), thereby monitoring and suppressing the malignant state of tumor cells. In this study, we examined the transcriptional activity of the PSA promoter in different prostate cancer cells and normal prostate epithelial cells and determined that it is indeed a prostate cancer cell-specific promoter.Then we constructed the CRISPR-dCas9-KRAB system driven by the PSA promoter, which can inhibit PSA gene expression in the prostate cancer cells at the transcriptional level, and therefore supress the malignant growth and migration of prostate cancer cells and promote their apoptosis in vitro. This study provides a potentially effective anti-cancer strategy for gene therapy of prostate cancer. [ABSTRACT FROM AUTHOR]

The differentiation, survival, and effector function of tumor-specific CD8+ cytotoxic T cells lie at the center of antitumor immunity. Due to the lack of proper costimulation and the abundant immunosuppressive mechanisms, tumor-specific T cells show a lack of persistence and exhausted and dysfunctional phenotypes. Multiple coinhibitory receptors, such as PD-1, CTLA-4, VISTA, TIGIT, TIM-3, and LAG-3, contribute to dysfunctional CTLs and failed antitumor immunity. These coinhibitory receptors are collectively called immune checkpoint receptors (ICRs). Immune checkpoint inhibitors (ICIs) targeting these ICRs have become the cornerstone for cancer immunotherapy as they have established new clinical paradigms for an expanding range of previously untreatable cancers. Given the nonredundant yet convergent molecular pathways mediated by various ICRs, combinatorial immunotherapies are being tested to bring synergistic benefits to patients. In this review, we summarize the mechanisms of several emerging ICRs, including VISTA, TIGIT, TIM-3, and LAG-3, and the preclinical and clinical data supporting combinatorial strategies to improve existing ICI therapies. [ABSTRACT FROM AUTHOR]

Background: Obesity carries great risks related to health, such as the development and progression of chronic inflammation and obvious metabolic disorders. This study aimed to examine the effect of eight weeks of moderateintensity resistance training with garlic supplementation on the lipid profile in overweight women. Methods: The present research was a semi-experimental study and the participants were 60 overweight women from Gachsaran City with (body mass index: 28.45±6.72) who were randomly divided into four groups (n = 15): supplemental exercise, placebo exercise, garlic supplemental, and placebo. Two training groups performed moderate-intensity resistance training for eight weeks and three sessions per week. One day before the start of training and 48 hours after the last training session, blood samples were collected to measure total cholesterol (TC), triglyceride (TG), LDL-C, and HDL-C variables. Data were analyzed by one-way ANOVA and LSD post-hoc test. Results: Findings showed that there is a significant decrease in the serum levels of TC, TG, and LDL-C and a significant increase in HDL-C (P-Value < 0.001) serum levels in three groups of supplemental exercise, placebo exercise, and garlic supplemental compared to the placebo group. Conclusion: Moderate-intensity resistance training with and without consuming garlic improves overweight women's lipid profile, and when exercise is accompanied by consuming garlic, the amount of these changes and improving the lipid profile is greater. [ABSTRACT FROM AUTHOR]

Background: Premature ovarian failure (POF) is one of the leading causes of female infertility and is accompanied by abnormal endocrine, seriously affecting female quality of life. Previous studies have demonstrated that mesenchymal stem cells (MSCs) transplantation is a promising therapeutic strategy for POF. However, the mechanism remains obscure. This study aims to investigate the therapeutic effect of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on ovarian function in the POF rat model and explore the underlying mechanisms. Methods: The ovarian function was evaluated by ovarian morphology, histology, estrous cycle, hormone levels (AMH, E2, FSH, and LH), and fertility ability to investigate the effect of hUC-MSCs on the POF rats model. The cytokines levels were assayed in serum using protein array to explore the mechanisms of hUC-MSCs therapy for POF. The excessive autophagy levels were evaluated using a co-culture system of 3D MSCs spheroids with human ovarian granulosa cell line (KGN) or primary ovarian granulosa cells (GCs) to understand the paracrine effect of hUC-MSCs on GCs. The related proteins expression of autophagy and PI3K/AKT/mTOR pathway was detected using Western Blotting and/or in various inhibitors supplement to further demonstrate that vascular endothelial growth factor A (VEGFA) secreted by hUC-MSCs can alleviate excessive autophagy of ovarian GCs via PI3K/AKT/mTOR signaling pathway. The ovarian culture model in vitro was applied to confirm the mechanism. Results: The ovarian function of POF and the excessive autophagy of ovarian GCs were restored after hUC-MSCs transplantation. The protein array result demonstrated that VEGF and PI3K/AKT might improve ovarian function. in vitro experiments demonstrated that VEGFA secreted by hUC-MSCs could decrease oxidative stress and inhibit excessive autophagy of ovarian GCs via PI3K/AKT/mTOR pathway. The ovarian culture model results confirmed this mechanism in vitro. Conclusion: The hUC-MSCs can alleviate excessive autophagy of ovarian GCs via paracrine VEGFA and regulate the PI3K/AKT/mTOR signaling pathway, thereby improving the ovarian function of POF. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) is characterized by rapid liver cell destruction. It is a multi-etiological and fulminant complication with a clinical mortality of over 80%. Therapy using mesenchymal stem cells (MSCs) or MSCs-derived exosomes can alleviate acute liver injury, which has been demonstrated in animal experiments and clinical application. However, similar to other stem cells, different cell sources, poor stability, cell senescence and other factors limit the clinical application of MSCs. To achieve mass production and quality control on stem cells and their exosomes, transfecting umbilical cord mesenchymal stem cell (UCMSC) with lentivirus overexpressing human telomerase reverse transcriptase (hTERT) gene, the hTERT-UCMSC was constructed as an immortalized MSC cell line. Compared with the primary UCMSC (P3) and immortalized cell line hTERT-UCMSC at early passage (P10), the hTERT-UCMSC retained the key morphological and physiological characteristics of UCMSC at the 35th passage (P35), and showed no signs of carcinogenicity and toxic effect in mice. There was no difference in either exosome production or characteristics of exosomes among cultures from P3 primary cells, P10 and P35 immortalized hTERT-UCMSCs. Inoculation of either hTERT-UCMSC (P35) or its exosomes improved the survival rate and liver function of ALF mice induced by thioacetamide (TAA). Our findings suggest that this immortalized cell line can maintain its characteristics in long-term culture. Inoculation of hTERT-UCMSC and its exosomes could potentially be used in clinics for the treatment of liver failure in the future. [ABSTRACT FROM AUTHOR]

Background: Photodynamic therapy (PDT) plays an immunoregulatory role in tumours. Here, we conducted a retrospective patient analysis to evaluate the effectiveness of PDT plus immune checkpoint inhibitors (ICIs) in gastric cancer. Further, we performed a dynamic analysis of gastric cancer patients receiving PDT to clarify its effects on anti-tumour immunity. Methods: Forty ICI-treated patients that received PDT or not were retrospectively analysed. Five patients with gastric adenocarcinoma were enrolled for sample collection before and after PDT. Single-cell RNA/T cell receptor (TCR) sequencing, flow cytometry and histological exanimation were used to analyse the collected specimens. Results: Patients in PDT group had a significantly better OS after ICI treatment than those in No PDT group. Single-cell analysis identified ten cell types in gastric cancer tissues and four sub-populations of T cells. Immune cell infiltration increased in the tumours after PDT and the circular immune cells showed consistent alterations. TCR analysis revealed a specific clonal expansion after PDT in cytotoxic T lymphocytes (CTL), but a constriction in Tregs. The B2M gene is upregulated in tumour cells after PDT and is associated with immune cell infiltration. Several pathways involving the positive regulation of immunity were enriched in tumour cells in the post-PDT group. The interactions following PDT were increased between tumour cells and effector cells but decreased between Tregs and other immune cells. Some co-stimulatory signaling emerged, whereas co-inhibitory signaling disappeared in intercellular communication after PDT. Conclusions: PDT elicits an anti-tumour response through various mechanisms and is promising as an adjuvant to enhance ICI benefit. [ABSTRACT FROM AUTHOR]

To investigate the mechanism of sodium tanshinone IIA sulfonate inhibiting hypoxia induced retinal neovascularization in rats. Forty 7 d old clean grade C57BL/6J male neonatal rats were randomly divided into control group, model group, low-dose group and high-dose group. The control group was kept in normal air for 10 d. Oxygen-induced retinopathy was studied in the model group, low-dose group, and high-dose group 30 mg/kg sodium tanshinone IIA sulfonate. The body weight of mice in all groups was measured on the 12th and 17th d after birth, and the area without perfusion around the optic disc was observed and calculated. The number of neovascular endothelial cells was calculated using hematoxylin and eosin staining. The expression of vascular endothelial growth factor, vascular endothelial growth factor-2 and hypoxia-inducible factor-1 were detected by Western blot. The no perfusion area around the optic disc in the model group was raised than that in the control group, and the no perfusion area around the optic disc in the low-dose group, and high-dose group was reduced than that in the model group (p<0.01). In the model group, the inner limiting membrane of retina was proliferated and disordered, and the surface was not smooth; in low-dose group, smooth limiting membrane of the retina, and a small number of endothelial cells could be seen breaking through the limiting membrane; in the high-dose group, the limiting membrane of retina was relatively complete and smooth, and the tissue structure of each layer could be seen. The number of neovascular endothelial cells in the model group was raised than that in the control group, and the number of neovascular endothelial cells in the lowdose group, and high-dose group was reduced than that in the model group, as the dose increased, it decreased (p<0.01). Vascular endothelial growth factor, vascular endothelial growth factor-2 and hypoxia-inducible factor-1 in low-dose group, and high-dose group were raised than those in control group, and those proteins expression level of in model group was reduced than control group, as the dose increased, it decreased (p<0.05). Sodium tanshinone IIA sulfonate can inhibit hypoxia induced retinal neovascularization in a dose-dependent manner, and its mechanism may be related to the regulation of vascular endothelial growth factor pathway related proteins by sodium tanshinone IIA sulfonate. [ABSTRACT FROM AUTHOR]