The Prognostic and therapeutic value and clinical implications of fibroblast activation protein-α as a novel biomarker in colorectal cancer.

The identification of contributing factors leading to the development of Colorectal Cancer (CRC), as the third fatal malignancy, is crucial. Today, the tumor microenvironment has been shown to play a key role in CRC progression. Fibroblast-Activation Protein-α (FAP) is a type II transmembrane cell surface proteinase expressed on the surface of cancer-associated fibroblasts in tumor stroma. As an enzyme, FAP has di- and endoprolylpeptidase, endoprotease, and gelatinase/collagenase activities in the Tumor Microenvironment (TME). According to recent reports, FAP overexpression in CRC contributes to adverse clinical outcomes such as increased lymph node metastasis, tumor recurrence, and angiogenesis, as well as decreased overall survival. In this review, studies about the expression level of FAP and its associations with CRC patients' prognosis are reviewed. High expression levels of FAP and its association with clinicopathological factors have made as a potential target. In many studies, FAP has been evaluated as a therapeutic target and diagnostic factor into which the current review tries to provide a comprehensive insight. Video Abstract.

The prognostic and therapeutic potential of HO-1 in leukemia and MDS.

BACKGROUND: Heme oxygenase-1 (HO-1), a heme-degrading enzyme, is proven to have anti-apoptotic effects in several malignancies. In addition, HO-1 is reported to cause chemoresistance and increase cell survival. Growing evidence indicates that HO-1 contributes to the course of hematological malignancies as well. Here, the expression pattern, prognostic value, and the effect of HO-1 targeting in HMs are discussed. MAIN BODY: According to the recent literature, it was discovered that HO-1 is overexpressed in myelodysplastic syndromes (MDS), chronic myeloid leukemia (CML), acute myeloblastic leukemia (AML), and acute lymphoblastic leukemia (ALL) cells and is associated with high-risk disease. Furthermore, in addition to HO-1 expression by leukemic and MDS cells, CML, AML, and ALL leukemic stem cells express this protein as well, making it a potential target for eliminating minimal residual disease (MRD). Moreover, it was concluded that HO-1 induces tumor progression and prevents apoptosis through various pathways. CONCLUSION: HO-1 has great potential in determining the prognosis of leukemia and MDS patients. HO-1 induces resistance to several chemotherapeutic agents as well as tyrosine kinase inhibitors and following its inhibition, chemo-sensitivity increases. Moreover, the exact role of HO-1 in Chronic Lymphocytic Leukemia (CLL) is yet unknown. While findings illustrate that MDS and other leukemic patients could benefit from HO-1 targeting. Future studies can help broaden our knowledge regarding the role of HO-1 in MDS and leukemia. Video abstract.

T-cell immunoglobulin and ITIM domain, as a potential immune checkpoint target for immunotherapy of colorectal cancer.

The importance of the tumor microenvironment in cancer progression has been well studied for many years. Immune checkpoint inhibitors (ICIs) are regarded as potential strategies in enhancing the immune responses in patients with cancer, particularly colorectal cancer (CRC). Notably, CRCs are extraordinarily heterogeneous and mostly are microsatellite-stable (MSS) or cold tumors, which means that the immune response is not usually as strong as that of foreign cells. T-cell immunoglobulin and ITIM domain (TIGIT) is a new immune checkpoint receptor overexpressed inside the CRC tumor-immune microenvironments. Moreover, several studies have shown that TIGIT in combination with other ICIs and/or conventional treatments, can lead to a robust anti-tumor response in CRC. This review looks deep inside TIGIT expression patterns, their various functions, and possible immunotherapy strategies to increase survival rates and decrease immune-related adverse events.

The Impact of Different Modes of Exercise Training on Bone Mineral Density in Older Postmenopausal Women: A Systematic Review and Meta-analysis Research.

Effectiveness of exercise on bone mass is closely related to the mode of exercise training regimen, as well as the study design. This study aimed to determine the effect of different modes of exercise training on lumbar spine and femoral neck bone mineral density (BMD) in older postmenopausal women (PMW). PubMed, CINAHL, Medline, Google Scholar, and Scopus databases and reference lists of included studies were searched up until March 25, 2019 for randomized controlled trials (RCTs) that evaluated the effectiveness of various modes of exercise training in PMW. Sixteen RCTs with 1624 subjects were included. Our study found no significant change in both lumbar spine and femoral neck BMD following exercise training (MD: 0.01 g/cm2; 95% confidence interval (CI) [- 0.01, 0.02] and MD: 0.00 g/cm2; 95% CI [- 0.01, 0.01], respectively). However, subgroup analysis by type of exercise training revealed that lumbar spine BMD (MD: 0.01; 95% CI [0.00, 0.02]) raised significantly when whole-body vibration (WBV) was employed as intervention compared with RCTs that utilized aerobic (MD: - 0.01; 95% CI [- 0.02, - 0.01]), resistance (MD: 0.01; 95% CI [- 0.04, 0.06]), and combined training (MD: 0.03; 95% CI [- 0.01, 0.08]). On the other hand, lumbar spine BMD (MD: - 0.01; 95% CI [- 0.02, - 0.01]) reduced significantly when aerobic exercise training was used as intervention compared with RCTs that utilized resistance training, combined training, and WBV. By contrast, these analyses did not have significant effect on change in femoral neck BMD. WBV is an effective method to improve lumbar spine BMD in older PMW.

Combined cancer immunotherapy based on targeting adenosine pathway and PD-1/PDL-1 axis.

INTRODUCTION: Cancer immunotherapy has revolutionized the field of oncology, offering new hope to patients with advanced malignancies. Tumor-induced immunosuppression limits the effectiveness of current immunotherapeutic strategies, such as PD-1/PDL-1 checkpoint inhibitors. Adenosine, a purine nucleoside molecule, is crucial to this immunosuppression because it stops T cells from activating and helps regulatory T cells grow. Targeting the adenosine pathway and blocking PD-1/PDL-1 is a potential way to boost the immune system's response to tumors. AREAS COVERED: This review discusses the current understanding of the adenosine pathway in tumor immunology and the preclinical and clinical data supporting the combination of adenosine pathway inhibitors with PD-1/PDL-1 blockade. We also discuss the challenges and future directions for developing combination immunotherapy targeting the adenosine pathway and the PD-1/PDL-1 axis for cancer treatment. EXPERT OPINION: The fact that the adenosine signaling pathway controls many immune system processes suggests that it has a wide range of therapeutic uses. Within the next five years, there will be tremendous progress in this area, and the standard of care for treating malignant tumors will have switched from point-to-point therapy to the integration of immunological networks comprised of multiple signaling pathways, like the adenosine axis.

Targeting the CTLA-4/B7 axes in glioblastoma: preclinical evidence and clinical interventions.

INTRODUCTION: Glioblastoma Multiforme (GBM) is one of the fatal cancers of the Central Nervous System (CNS). A variety of reasons exist for why previous immunotherapy strategies, especially Immune Checkpoint Blockers (ICBs), did not work in treating GBM patients. The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a key immune checkpoint receptor. Its overexpression in cancer and immune cells causes tumor cell progression. CTLA-4 suppresses anti-tumor responses inside the GBM tumor-immune microenvironment. AREAS COVERED: It has been attempted to explain the immunobiology of CTLA-4 as well as its interaction with different immune cells and cancer cells that lead to GBM progression. Additionally, CTLA-4 targeting studies have been reviewed and CTLA-4 combination therapy, as a promising therapeutic target and strategy for GBM immunotherapy, is recommended. EXPERT OPINION: CTLA-4 could be a possible supplement for future cancer immunotherapies of GBM. However, many challenges remain such as the high toxicity of CTLA-4 blockers, and the unresponsiveness of most patients to immunotherapy. For the future clinical success of CTLA-4 blocker therapy, combination approaches with other targeted treatments would be a potentially effective strategy. Going forward, predictive biomarkers can be used to reduce trial timelines and increase the chance of success.

The prognostic and therapeutic potentials of CTLA-4 in hematological malignancies.

INTRODUCTION: Hematological Malignancies (HMs) are a group of progressive, difficult-to-treat, and highly recurrent diseases. A suppressed phenotype of the immune system is present in HMs and growing evidence indicates the role of Cytotoxic T lymphocyte-Associated protein 4 (CTLA-4) in the course of HMs. AREAS COVERED: This article reviews the recent literature on the role of CTLA-4 in different subtypes of HMs. Here, the studies on the expression pattern, its effect on the prognosis of different HMs, and polymorphisms of CTLA-4 have been elaborated. Finally, the effect of targeting CTLA-4 in vitro and in vivo, as well as in clinical trials, is discussed. EXPERT OPINION: According to the recent literature, CTLA-4 is overexpressed in different HMs, which is correlated with poor survival, while it is associated with better a prognosis in Chronic Lymphocytic Leukemia (CLL). Targeting CTLA-4 in Acute Myeloid Leukemia (AML), Sezary Syndrome (SS), Hodgkin's Lymphoma (HL), and so on, is helpful. While this is not recommended and may even be harmful in multiple myeloma (MM) and CLL. Also, it seems that certain CTLA-4 gene polymorphisms are efficient factors in the course of HMs. Future studies may broaden our knowledge regarding the role of CTLA-4 in HMs.

The effect of six months aerobic exercise during dialysis on liver enzymes, cystatin C and quality of life of hemodialysis patients.

BACKGROUND: The purpose of this study was to investigate the effect of six-month aerobic exercise during dialysis on hepatic enzymes, cystatin c, glomerular filtration factors and the quality of life of hemodialysis patients. METHODS: The subjects of this study were 30 subjects randomly divided into two groups including experimental groups (N.=15) and control (N.=15). The aerobic exercise program consisted of six months of aerobic exercise, 3 sessions per week, and each session for 30 to 45 minutes with a maximum intensity of 50-70% of the maximum heart rate stored on the minibike. Paired sample t-test and repeated measures (ANOVA) were used to compare between- and within-group variance changes. Significance level was considered less than 0.05. RESULTS: Mass loss, Body Mass Index, body fat percentage, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, cystatin C significantly decreased while the maximum oxygen consumption at the end of the period increased significantly. Changes in intragroup mean in physical, psychological, general health, vitality, social activity, physical function, emotional function, and life satisfaction in the group of men with kidney disease increased significantly at the end of the training period. Phosphorus, calcium, sodium, potassium, urea, creatinine and bilirubin levels decreased significantly. CONCLUSIONS: The results indicate the positive effects of using aerobic exercise as a noninvasive and non-pharmacological method with minimal side effects that can be effective in improving the renal function of these patients. Therefore, due to this, this method can probably be used to improve the condition of patients under hemodialysis.

Anti-Inflammatory Effects of Exercise on Metabolic Syndrome Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Increments in inflammatory indicators and low levels of physical activity are correlated to the expansion of the metabolic syndrome (MetS). OBJECTIVE: The purpose of this study was to establish if exercise training ameliorates inflammatory status in MetS patients. DATA SOURCES: PubMed, CINAHL, and Medline, Google Scholar, and Scopus databases and reference lists of included studies were searched. STUDY SELECTION: Twenty randomized controlled trials (RCTs) of exercise-training impact on inflammatory markers (tumor necrosis factor (TNF) α, C-reactive protein (CRP), interleukin (IL) 6, IL-8, IL-10, and IL-18) with concurrent control groups were included in this analysis. RESULTS: Results demonstrated an overall significant decrease in serum levels of TNF-α (mean difference (MD): -1.21 pg/ml; 95% confidence interval (CI): -1.77, -0.66), CRP (MD: -0.52 mg/l; 95% CI: -0.79, -0.25), IL-8 (MD: -1.31 pg/ml; 95% CI: -2.57, -0.06), and a significant increase in IL-10 (MD: 0.48 pg/ml; 95% CI: 0.10, 0.86). But exercise training did not change the level of IL-6 (MD: -0.69 pg/ml; 95% CI: -1.53, 0.14) and IL-18 (MD: -53.01 pg/ml; 95% CI: -166.64, 60.62). CONCLUSION: Exercise training improves TNF-α, CRP, IL-8, and IL-10 levels in patients with MetS. For some variables, isolated aerobic exercise, and combined aerobic and resistance exercise appears to be optimal. Future research is needed to clarify the mechanisms underlying exercise training's effect on this population's inflammatory markers. More studies are required to confirm these findings.

Simultaneous blockade of TIGIT and HIF-1α induces synergistic anti-tumor effect and decreases the growth and development of cancer cells.

PURPOSE: T-cell immunoglobulin and ITIM domain (TIGIT) is an immune checkpoint that is overexpressed on both immune cells and some cancer cells. TIGIT can alter the anti-tumor responses inside the tumor microenvironment. Hypoxia-inducible factor 1-alpha (HIF-1α) plays a significant role in the TME and involves suppressing the anti-tumor responses. Under hypoxic conditions, HIF-1α can enhance the expression of different immune checkpoints. Accordingly, hypoxic TME and TIGIT overexpression cause cancer development. Thus, we decided to inhibit tumor cell expansion by inhibiting TIGIT and HIF-1α molecules and discovering the relationship between TIGIT and HIF-1α. METHODS: In this research, we utilized superparamagnetic iron oxide-based NPs (SPIONs) combined with chitosan lactate (CL) and folic acid (FA) nanoparticles (NPs) loaded with TIGIT-siRNA and HIF-1α- siRNA for suppressing TIGIT and HIF-1α in tumor cells and evaluated the consequences of this treatment strategy on tumor growth, apoptosis, and metastasis. RESULTS: The results showed that cancer cells treated with TIGIT and HIF-1α siRNA-loaded SPIONs-CL-FA NPs, strongly suppressed the TIGIT and HIF-1α expression, colony formation ability, angiogenesis, and the growth rate of cancer cells. CONCLUSIONS: Present data suggest the combination treatment of TIGIT and HIF-1α as a novel treatment strategy against colorectal and breast cancer, but more researches are required to realize the complete role of TIGIT and HIF-1α inside the TME.

The role of regulatory T cells in the pathogenesis and treatment of prostate cancer.

Despite developments in the treatment of various cancers, prostate cancer is one of the deadliest diseases known to men. Systemic therapies such as androgen deprivation, chemotherapy, and radiation therapy have not been very successful in treating this disease. Numerous studies have shown that there is a direct relationship between cancer progression and inhibition of anti-tumor immune responses that can lead to progression of various malignancies, including prostate cancer. Interestingly, CD4+CD25+FoxP3+ regulatory T cells significantly accumulate and increase in draining lymph nodes and PBMCs of patients with prostate cancer and other solid tumors. In vivo and in vitro studies have shown that Tregs can suppress anti-tumor responses, which is directly related to the increased risk of cancer recurrence. Tregs are essential for preserving self-tolerance and inhibiting extra immune responses harmful to the host. Since the tumor-related antigens are mainly self-antigens, Tregs could play a major role in tumor progression. Accordingly, it has discovered that prostate cancer patients with higher Tregs have poor prognosis and low survival rates. However, anti-tumor responses can be reinforced by suppression of Tregs with using monoclonal antibodies against CD25 and CTLA-4. Therefore, depleting Tregs or suppressing their functions could be one of the effective ways for prostate cancer immunotherapy. The purpose of this review is to investigate the role of Treg cells in the progression of prostate cancer and to evaluate effective strategies for the treatment of prostate cancer by regulating Treg cells.

The effect of aerobic, resistance, and combined training on PPAR-α, SIRT1 gene expression, and insulin resistance in high-fat diet-induced NAFLD male rats.

BACKGROUND: Insulin resistance (IR) is known as the most important cause of Non-alcoholic Fatty Liver Disease (NAFLD), which is accompanied by a decline in gene expression of hepatic's peroxisomes Proliferator-Activated Receptors-alpha (PPAR-α) and Sirtuin-1 (SIRT1). This study aimed to investigate the effect of eight weeks of aerobic, resistance, and combined training on hepatic PPAR-α and SIRT1 expression, IR, serum Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in rats of NAFLD induced by high-fat diet (HFD). METHODS: A total of 37 male NAFLD rats induced 12 weeks of HFD were randomly divided into 4 groups: control, aerobic, resistance, and combined training. All groups continued the HFD until the end of the study. The training groups carried out exercise training with moderate intensity by 8 weeks of running on a treadmill and climbing a ladder for 5 sessions/week. At the end of the trainings, PPAR-α and SIRT1 expressions were examined via qPCR technique in the liver tissue. RESULTS: The 3 types of trainings controlled the weight gain caused by HFD and showed a significant decrease in serum ALT (P<0.05). Post-hoc test results indicated a significant reduction in AST and IR between the control group and HFD+AT, as well as the control group and HFD+RT (P<0.05). Despite a notable increase in hepatic PPAR-α and SIRT1 expression, it was not statistically significant (P ≥ 0.05). CONCLUSION: Doing any aerobic, resistance, and combined training for 8 weeks can control body weight, improve IR, decrease ALT; nevertheless, resistance training is more effective in improving NAFLD.