Association of future cancer metastases with fibroblast activation protein-α: a systematic review and meta-analysis.

Introduction: Fibroblast activation protein-α (FAP-α) is a vital surface marker of cancer-associated fibroblasts, and its high expression is associated with a higher tumor grade and metastasis. A systematic review and a meta-analysis were performed to associate future metastasis with FAP-α expression in cancer. Methods: In our meta-analysis, relevant studies published before 20 February 2024 were systematically searched through online databases that included PubMed, Scopus, and Web of Science. The association between FAP-α expression and metastasis, including distant metastasis, lymph node metastasis, blood vessel invasion, vascular invasion, and neural invasion, was evaluated. A pooled odds ratio (OR) with 95% confidence intervals (CI) was reported as the measure of association. Results: A total of 28meta-analysis. The random-effects model for five parameters showed that a high FAP-α expression was associated with blood vessel invasion (OR: 3.04, 95% CI: 1.54-5.99, I 2 = 63%, P = 0.001), lymphovascular invasion (OR: 3.56, 95% CI: 2.14-5.93, I 2 = 0.00%, P < 0.001), lymph node metastasis (OR: 2.73, 95% CI: 1.96-3.81, I 2 = 65%, P < 0.001), and distant metastasis (OR: 2.59; 95% CI: 1.16-5.79, I 2 = 81%, P < 0.001). However, our analysis showed no statistically significant association between high FAP-α expression and neural invasion (OR: 1.57, 95% CI: 0.84-2.93, I 2 = 38%, P = 0.161). Conclusions: This meta-analysis indicated that cancer cells with a high FAP-α expression have a higher risk of metastasis than those with a low FAP-α expression. These findings support the potential importance of FAP-α as a biomarker for cancer metastasis prediction.

L. plantarum and L. lactis as a promising agent in treatment of inflammatory bowel disease and colorectal cancer.

It has been understood for nearly a century that patients with intestinal inflammatory disease (IBD) have a higher risk of developing colorectal cancer (CRC). Recently, two species of lactic acid bacteria, Lactobacillus plantarum and Lactococcus lactis, have been investigated as therapeutic agents for IBD. These bacteria have been shown to survive gastric transit, to adhere and colonize in the intestinal tract of humans and modulate the intestinal microbiota and immune response. L. plantarum and L. lactis might be used as multifunctional drugs for the treatment of IBD and the prevention or treatment of CRC. This article summarizes current knowledge of L. plantarum and L. lactis as therapeutic and preventative agents for IBD and CRC, respectively.

Expanding CYLD protein in NF-κß/TNF-α signaling pathway in response to Lactobacillus acidophilus in non-metastatic rectal cancer patients.

The CYLD gene is a tumor suppressor, reduced in many cancers. Here, we aimed to investigate CYLD protein level and NF-κß/TNF-α signaling pathway in rectal cancer patients with Lactobacillus acidophilus (L. acidophilus) consumption. One hundred ten patients with non-metastatic rectal cancer were randomly divided into L. acidophilus probiotic (500 mg, three times daily) and placebo groups for 13 weeks. The expression of CYLD, TNF-α, and NF-κB proteins and the genes involved in the NF-κß/TNF-α pathway were evaluated using ELISA and qPCR techniques. The survival rate was measured after five years. Unlike the placebo group, the results showed a significant increase in the expression of CYLD protein and tumor suppressor genes, including FOXP3, ROR-γ, Caspase3, GATA3, T-bet, and a considerable decrease in the expression of NF-Òß and TNF-α proteins and oncogenes, including STAT3, 4, 5, 6, and SMAD 3, in the probiotic group. A higher overall survival rate was seen after L. acidophilus consumption compared to the placebo group (P < 0.05). L. acidophilus consumption can reduce inflammation factors by affecting CYLD protein and its downstream signaling pathways. A schematic plot of probiotic consumption Effects on the CYLD protein in regulating the NF-Ä¸ß signaling pathway in colorectal cancer. NF-Ä¸ß can be activated by canonical and noncanonical pathways, which rely on IκB degradation and p100 processing, respectively. In the canonical NF-κß pathway, dimmers, such as p65/p50, are maintained in the cytoplasm by interacting with an IκBα protein. The binding of a ligand to a cell-surface receptor activates TRAF2, which triggers an IKK complex, containing -α, -ß, -g, which phosphorylates IKK-ß. It then phosphorylates IκB-α, leading to K48-ubiquitination and degradation of this protein. The p65/p50 protein freely enters the nucleus to turn on target genes. The non-canonical pathway is primarily involved in p100/RelB activation. It differs from the classical pathway in that only certain receptor signals activate this pathway. It proceeds through an IKK complex that contains two IKK-α subunits but not NEMO. Several materials including peptidoglycan, phorbol, myristate, acetate, and gram-positive bacteria such as probiotics inhibit NF-κB by inducing CYLD. This protein can block the canonical and noncanonical NF-κß pathways by removing Lys-63 ubiquitinated chains from activated TRAFs, RIP, NEMO, and IKK (α, ß, and γ). Moreover, TNF-α induces apoptosis by binding caspase-3 to FADD.

Strategy of targeting the tumor microenvironment via inhibition of fibroblast/fibrosis remodeling new era to cancer chemo-immunotherapy resistance.

The use of repurposing drugs that may have neoplastic and anticancer effects increases the efficiency and decrease resistance to chemotherapy drugs through a biochemical and mechanical transduction mechanisms through modulation of fibroblast/fibrosis remodeling in tumor microenvironment (TME). Interestingly, fibroblast/fibrosis remodeling plays a vital role in mediating cancer metastasis and drug resistance after immune chemotherapy. The most essential hypothesis for induction of chemo-immunotherapy resistance is via activation of fibroblast/fibrosis remodeling and preventing the infiltration of T cells after is mainly due to the interference between cytoskeleton, mechanical, biochemical, metabolic, vascular, and remodeling signaling pathways in TME. The structural components of the tumor that can be targeted in the fibroblast/fibrosis remodeling include the depletion of the TME components, targeting the cancer-associated fibroblasts and tumor associated macrophages, alleviating the mechanical stress within the ECM, and normalizing the blood vessels. It has also been found that during immune-chemotherapy, TME injury and fibroblast/fibrosis remodeling causes the up-regulation of inhibitory signals and down-regulation of activated signals, which results in immune escape or chemo-resistance of the tumor. In this regard, repurposing or neo-adjuvant drugs with various transduction signaling mechanisms, including anti-fibrotic effects, are used to target the TME and fibroblast/fibrosis signaling pathway such as angiotensin 2, transforming growth factor-beta, physical barriers of the TME, cytokines and metabolic factors which finally led to the reverse of the chemo-resistance. Consistent to many repurposing drugs such as pirfenidone, metformin, losartan, tranilast, dexamethasone and pentoxifylline are used to decrease immune-suppression by abrogation of TME inhibitory signal that stimulates the immune system and increases efficiency and reduces resistance to chemotherapy drugs. To overcome immunosuppression based on fibroblast/fibrosis remodeling, in this review, we focus on inhibitory signal transduction, which is the physical barrier, alleviates mechanical stress and prevents mechano-metabolic activation.

Assessment of iron status and iron deficiency anemia in patients with celiac, a single center experience.

Aim: This study aimed to assess the status of iron stores and the frequency of iron deficiency anemia in Celiac disease (CD) patients referred to the Golestan Research Center of Gastroenterology and Hepatology, Gorgan, Iran. Background: Studies have shown that nutritional deficiencies affect 20-38% of patients with CD due to malabsorption and as a result of a gluten-free diet. Methods: In this study, 59 out of 100 CD patients were assessed. The presence and severity of anemia were determined using the concentration of serum hemoglobin according to WHO criteria. The status of body iron stores was also assessed based on serum ferritin levels. Results: Mean and SD of age, duration of disease, serum hemoglobin, ferritin, TIBC, and serum iron were 39.9±11.9 years, 69.8±45.4 months, 12.6±1.99 g/dl, 54.3±55.3 mg/dL, 365.9±49.1 µg/dL, and 84.1±37.1 µg/dL, respectively. 68.42% had no anemia, 19.3% had mild anemia, 8.77% had moderate anemia, and 3.51% had severe anemia. 25.42% of patients had depleted iron stores, 71.19% had normal iron stores, and 3.39% were exposed to iron overload. There was a statistically significant correlation between serum hemoglobin and the duration of disease diagnosis (P=0.037, r=0.302). Conclusion: In this study, 31.58% of CD patients on a gluten-free diet had some degree of anemia. In addition, 25.42% of patients had depleted iron stores. These results suggest that CD patients should be evaluated for iron status, even with a gluten-free diet.

Unexpected high frequency of anti-thyroid peroxidase (anti-TPO) antibodies in Golestan province, Iran.

Background: Anti-TPO antibodies are one of the characteristic factors in autoimmune thyroiditis (AIT). Previous studies reported a high prevalence of anti-TPO antibodies (Abs) in Iran. We have therefore assessed the prevalence of anti-TPO Abs in Gorgan, Iran. Methods: This cross-sectional study, conducted from 2015 to 2018 in Gorgan city, Northeast of Iran. The Participants included women with Poly cystic ovary syndrome (PCOs), celiac patients, men with hepatitis C infection, and age and sex-matched controls. ELISA method was used for the analysis of laboratory tests. Results: The number of enrolled subjects in PCOs, celiac disease, and Hepatitis C infection groups were 76, 67, and 60, respectively. Anti-TPO Abs positivity was significantly higher in patients with PCOS than in the control group (18.4% vs. 0.00%; p = 0.000). There were no significant differences in the frequency of anti-TPO Abs positive cases between CD patients and the controls (26.9% vs. 21.1% p =0.413). The incidence of anti-TPO Abs positivity was significantly higher in the control group (10% vs. 25%; P = 0.031). Conclusion: Very high level of anti-TPO Abs was observed in both patients and healthy population in Golestan province. Considering this rate and its association with autoimmune disorders, it is suggested to prioritize screening programs for related disease in this area.

Esophageal and gastric cancer incidence trends in Golestan, Iran: An age-period-cohort analysis 2004 to 2018.

Golestan province in the northeast of Iran is part of the Asian esophageal cancer belt and is known as a high-risk area for esophageal (EC) and gastric cancers (GC). Data on incident cases of EC and GC during 2004 to 2018 were obtained from the Golestan Population-based Cancer Registry (GPCR). The age-standardized incidence rates (ASRs) were calculated and presented per 100 000 person-years. The estimated annual percentage change (EAPC) with 95% confidence interval (95% CI) were calculated. We also fitted age-period-cohort (APC) models to assess nonlinear period and cohort effects as incidence rate ratios (IRRs). Overall, 3004 new cases of EC (ASR = 15.7) and 3553 cases of GC (ASR = 18.3) were registered in the GPCR. We found significant decreasing trends in incidence rates of EC (EAPC = -5.0; 95% CI: -7.8 to -2.2) and less marked nonsignificant trends for GC (EAPC = -1.4; 95% CI: -4.0 to 1.4) during 2004 to 2018. There was a strong cohort effect for EC with a consistent decrease in the IRR across successive birth cohorts, starting with the oldest birth cohort (1924; IRR = 1.9 vs the reference birth cohort of 1947) through to the most recent cohort born in 1988 (IRR = 0.1). The marked declines in EC incidence rates in Golestan relate to generational changes in its underlying risk factors. Despite favorable trends, this population remains at high risk of both EC and GC. Further studies are warranted to measure the impact of the major risk factors on incidence with a view to designing effective preventative programs.

The increasing antimicrobial resistance of Shigella species among Iranian pediatrics: a systematic review and meta-analysis.

BACKGROUND: Shigellosis remains one of the global causes of morbidity and mortality. However, the global emergence of antibiotic resistance has become the leading cause of treatment failure in shigellosis. This review aimed to provide an updated picture of the antimicrobial resistance rates in Shigella species in Iranian pediatrics. METHODS: A comprehensive systematic search was performed on PubMed, Scopus, Embase, and Web of Science until 28 July 2021. The meta-analysis was performed by computing the pooled using a random-effects model with Stata/SE software, v.17.1. The discrepancy within articles was surveyed by the forest plot in addition to the I2 statistic. All statistical interpretations were reported on a 95% confidence interval (CI) basis. RESULTS: Totally, of 28 eligible studies published between 2008 and 2021. The pooled prevalence rate of multidrug-resistant (MDR) was 63% (95% CI 50-76). Regarding suggested antimicrobial agents for Shigella species, the prevalence of resistance for ciprofloxacin, azithromycin, and ceftriaxone as first- and second-line treatments for shigellosis were 3%, 30%, and 28%, respectively. In contrast, resistance to cefotaxime, cefixime, and ceftazidime was 39%, 35%, and 20%. Importantly, subgroup analyses indicated that an increase in resistance rates during the periods (2008-2014, 2015-2021) was recognized for ciprofloxacin (0 % to 6%) and ceftriaxone (6% to 42%). CONCLUSION: Our findings revealed that ciprofloxacin is an effective drug for shigellosis in Iranian children. The substantially high prevalence estimation proposes that the first- and second-line treatments for shigellosis are the major threat to public health and active antibiotic treatment policies are essential.

Breast tumor metastasis following filgrastim administration due to the SDF-1/CXCR4 pathway.

Filgrastim, a recombinant type of granulocyte-colony stimulating factor (G-CSF), has a high potential to manage chemotherapy-induced leukopenia. It can increase stromal cell-derived factor 1 (SDF-1) which may stimulate C-X-C chemokine receptor type 4 (CXCR4) to migrate bone marrow-derived stem/progenitor cells to the bloodstream. Here, we aimed to investigate in vitro and in vivo effects of filgrastim on cell migration, invasion, and metastasis. A lentivirus vector of the anti-CXCR4 receptor was first used for the CXCR4 knockout. Effects of filgrastim on cell proliferation and migration were then investigated on 4T1 cells by Transwell migration and wound healing assay. At last, the effects of filgrastim on cell metastasis and the possible involved mechanisms have been investigated in a metastatic murine breast tumor. The knockout of the CXCR4 receptor could lead to a decrease in cell proliferation, migration, and invasion of the 4T1 cells. Filgrastim could directly target SDF-1 and upregulate the expression of the CXCR4 receptor. The knockout of the CXCR4 receptor reduced cell metastasis in an animal model of breast cancer. CXCR4 receptor stimulation by the filgrastim-affected pathways is a conserved evolutionary response that could increase cancer cell proliferation and consequent cell metastasis. Our results suggest that the activation of the CXCR4 receptor is a conserved evolutionary response that can increase cell proliferation, migration, and consequent metastasis. It seems that filgrastim may increase the chance of cancer cell metastasis in people continuously receiving it to increase the number of neutrophils. Filgrastim induces the SDF-1/CXCR4 axis on tumor cell growth. SDF-1 and its receptor CXCR4 are vital targets for filgrastim. The CXCR4 can stimulate the PI3K/AKT, NF-κB, and JAK/STAT signaling pathways. The SDF-1/CXCR4 pathway promotes cell chemotaxis and proliferation via MAPKs signaling. It also enhances cell survival, proliferation, and angiogenesis, increasing tumor cell metastasis. The STAT3-mediated inflammation is essential for tumorigenesis processes, and Akt, Wnt, STAT3, and CXCR4 signaling pathways are all correlated. CXCR4 = C-X-C chemokine receptor type 4, SDF-1 = stromal-derived-factor-1, MAPK = mitogen activated protein kinase; NF-κB = nuclear factor-κB, PI3K = phosphoinositide 3-kinase, JAK = Janus kinase, STAT = signal transducer and activator of transcription, PLC = phospholipase C, PKC = Protein kinase C, GRK = G protein-coupled receptor kinase.

Effect of Adding Intravenous Somatostatin to Rectal Indomethacin on Post-Endoscopic Retrograde Cholangiopancreatography (ERCP) Pancreatitis in High-risk Patients: A Double-blind Randomized Placebo-controlled Clinical Trial.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) has an important role in the treatment of pancreaticobiliary disorders. GOALS: Considering the high prevalence and importance of postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) and the controversial findings, we aimed to determine the effect of adding intravenous somatostatin to rectal indomethacin on the incidence of PEP in high-risk patients. STUDY: In this prospective study, 530 patients underwent ERCP during March 2018 and February 2019. Patients were randomized into 2 groups. The intervention group received a bolus injection of 250 µg somatostatin followed by an infusion of 500 µg of somatostatin for 2 hours. In both groups, 100 mg of pre-ERCP suppository indomethacin was administrated. All patients were screened for PEP symptoms and signs for 24 hours after ERCP (Iranian Registry of Clinical Trials code: IRCT20080921001264N11). RESULTS: A total of 376 patients were finally analyzed. PEP was the most common adverse event with 50 (13.2%) episodes, including 21 (5.5%) mild, 23 (6.1%) moderate, and 6 (1.2%) severe. The rate of PEP was 15.2% in the control group and 11.4% in the intervention group ( P =0.666). The incidence of post-ERCP hyperamylasemia was 21.7% in the control group and 18.2% in the intervention group ( P =0.395). No death occurred. CONCLUSIONS: In this study administration of somatostatin plus indomethacin could safely reduce the rate of post-ERCP hyperamylasemia and PEP in the intervention group compared with the control group, but the differences were not significant. Further studies with larger sample sizes are required.

Primary Biliary Tract Cancers in Golestan, Iran: 13-Year Experience of Golestan Population-Based Cancer Registry.

BACKGROUND: Epidemiological research on the high-risk population might be helpful in early detection and prevention of biliary tract malignancies. This study assesses the prevalence of biliary tract cancer (BTC) in the Golestan province, northeastern Iran, between 2004 and 2016. METHODS: The current study used information from the Golestan Population-based Cancer Registry (GPCR) to access the epidemiology of BTC across a 13-year period while taking into account temporal and geographic differences. The number of cases, crude rates, age-standardized incidence rates (ASRs) per 100,000 person-years, average annual percent change (AAPC), age-specific incidence rates, and 95% confidence intervals (CI) were reported for each year with respect to gender and place of residence. RESULTS: Totally, 224 instances of BTC overall (54% of whom were females) were reported throughout the research period. The ASR of BTC was 1.7 (95% CI: 1.4‒2) for females and 1.4 (95% CI: 1.1‒1.6) for men, respectively. Males exhibited a growing time trend in incidence (AAPC: 7.18; CI: 0.06‒14.81; P-value:0.048), whereas females had a decreasing trend (AAPC: 0.82; CI: -5.94‒4.57; P-value: 0.740). Both sexes saw an increase in age-specific incidence rates starting at the age of 45; however, males experienced a significant increase in incidence in the age group of 75 to 79 while the female rates grew steadily. CONCLUSION: The focus for cancer control in this region may be given to demographic groups with a combination of risk factors, including male gender, older age, and urban residence.

Molecular mechanisms underlying the action of carcinogens in gastric cancer with a glimpse into targeted therapy.

BACKGROUND: Gastric cancer imposes a substantial global health burden despite its overall incidence decrease. A broad spectrum of inherited, environmental and infectious factors contributes to the development of gastric cancer. A profound understanding of the molecular underpinnings of gastric cancer has lagged compared to several other tumors with similar incidence and morbidity rates, owing to our limited knowledge of the role of carcinogens in this malignancy. The International Agency for Research on Cancer (IARC) has classified gastric carcinogenic agents into four groups based on scientific evidence from human and experimental animal studies. This review aims to explore the potential comprehensive molecular and biological impacts of carcinogens on gastric cancer development and their interactions and interferences with various cellular signaling pathways. CONCLUSIONS: In this review, we highlight recent clinical trial data reported in the literature dealing with different ways to target various carcinogens in gastric cancer. Moreover, we touch upon other multidisciplinary therapeutic approaches such as surgery, adjuvant and neoadjuvant chemotherapy. Rational clinical trials focusing on identifying suitable patient populations are imperative to the success of single-agent therapeutics. Novel insights regarding signaling pathways that regulate gastric cancer can potentially improve treatment responses to targeted therapy alone or in combination with other/conventional treatments. Preventive strategies such as control of H. pylori infection through eradication or immunization as well as dietary habit and lifestyle changes may reduce the incidence of this multifactorial disease, especially in high prevalence areas. Further in-depth understanding of the molecular mechanisms involved in the role of carcinogenic agents in gastric cancer development may offer valuable information and update state-of-the-art resources for physicians and researchers to explore novel ways to combat this disease, from bench to bedside. A schematic outlining of the interaction between gastric carcinogenic agents and intracellular pathways in gastric cancer H. pylori stimulates multiple intracellular pathways, including PI3K/AKT, NF-κB, Wnt, Shh, Ras/Raf, c-MET, and JAK/STAT, leading to epithelial cell proliferation and differentiation, apoptosis, survival, motility, and inflammatory cytokine release. EBV can stimulate intracellular pathways such as the PI3K/Akt, RAS/RAF, JAK/STAT, Notch, TGF-ß, and NF-κB, leading to cell survival and motility, proliferation, invasion, metastasis, and the transcription of anti-apoptotic genes and pro-inflammatory cytokines. Nicotine and alcohol can lead to angiogenesis, metastasis, survival, proliferation, pro-inflammatory, migration, and chemotactic by stimulating various intracellular signaling pathways such as PI3K/AKT, NF-κB, Ras/Raf, ROS, and JAK/STAT. Processed meat contains numerous carcinogenic compounds that affect multiple intracellular pathways such as sGC/cGMP, p38 MAPK, ERK, and PI3K/AKT, leading to anti-apoptosis, angiogenesis, metastasis, inflammatory responses, proliferation, and invasion. Lead compounds may interact with multiple signaling pathways such as PI3K/AKT, NF-κB, Ras/Raf, DNA methylation-dependent, and epigenetic-dependent, leading to tumorigenesis, carcinogenesis, malignancy, angiogenesis, DNA hypermethylation, cell survival, and cell proliferation. Stimulating signaling pathways such as PI3K/Akt, RAS/RAF, JAK/STAT, WNT, TGF-ß, EGF, FGFR2, and E-cadherin through UV ionizing radiation leads to cell survival, proliferation, and immortalization in gastric cancer. The consequence of PI3K/AKT, NF-κB, Ras/Raf, ROS, JAK/STAT, and WNT signaling stimulation by the carcinogenic component of Pickled vegetables and salted fish is the Warburg effect, tumorigenesis, angiogenesis, proliferation, inflammatory response, and migration.

Serum and salivary tissue transglutaminase IGA (tTG-IGA) level in celiac patients.

BACKGROUND: Celiac disease (CD) is a genetically determined autoimmune disease triggered by gluten consumption. Patients with these conditions have intraepithelial lymphocytosis, crypt hyperplasia, and severe intestinal atrophy. Gluten elimination is the only way to reduce this chronic inflammation. The diagnosis of CD is usually made by analyzing anti-tTG, anti-DGP, or EMA serological tests, and it is confirmed by biopsy of the duodenum. In people with CD, xerostomia or dry mouth is a common complication. This condition causes the salivary glands to malfunction and, in turn, may result in oral plaque and periodontal disease. By comparing salivary and serum levels of tissue transglutaminase IgA (tTG-IgA), this study aims to suggest a non-invasive method for diagnosis of CD. Furthermore, the present study evaluates the severity of xerostomia symptoms in people with CD. METHODS: In this case-control study, participants were patients referred to the internal ward of Sayyad Shirazi hospital. The control group was selected from healthy people who attended Gorgan Dental College. In this study, an analysis of serum was performed following consent from patients. This was followed by a salivary test, and the results of both tests were compared. The Xerostomia Inventory questionnaire was also used to determine the severity of xerostomia. As part of this study, examination of factors such as total protein concentration of saliva, albumin concentration, amylase level, pH, sodium, calcium, potassium, phosphorus, and interleukin (6, 18, and 21) were conducted. RESULTS: A total of 78 people were studied (aged 15 to 68), 26 were male (33.3%) and 52 were female (66.7%). In comparisons of the serum and saliva of people with and without CD, the level of amylase was higher in the latter group. The average levels of IL-6، IL-18 ،IL-21, and salivary and serum tTG were higher in people with CD. Additionally, CD patients were more likely to develop xerostomia. CONCLUSION: Study findings showed that CD can reduce certain salivary enzymes and elements, as well as increase inflammatory cytokines, salivary, and serum tTG. The management of dry mouth should also be recommended for celiac disease patients in order to prevent its complications.

Innovative targets of the lncRNA-miR-mRNA network in response to low-dose aspirin in breast cancer patients.

This study aimed to investigate innovative targets in breast cancer patients by considering the interaction of the lncRNA-miR-mRNA network in response to low-dose aspirin. The candidate miRs were first taken from the GEO and TCGA databases. Then, the candidate network was constructed using the high-throughput sequencing data. The expression levels of candidate targets were finally measured using Real-Time PCR in luminal A breast cancer patients undergoing aspirin (80 mg daily for three months) and non-aspirin groups during chemotherapy after surgery. The expression levels of TGFß, IL-17, IFNγ, and IL-ß proteins were measured using the ELISA technique. 5 lncRNAs, 12 miRs, and 10 genes were obtained in the bioinformatic phase. A significant expression increase of the candidate tumor suppressor lncRNAs, miRs, and genes and a substantial expression decrease of the candidate onco-lncRNAs, oncomiRs, and oncogenes were achieved after the aspirin consumption. Unlike the non-aspirin group, the expression levels of TGFß, IL-17, IFNγ, and IL-ß proteins were significantly decreased following aspirin consumption. The Kaplan-Meier analysis indicated a longer overall survival rate in the patients after aspirin consumption. Our results showed that the lncRNA-miR-mRNA network might be a significant target for aspirin; their expression changes may be a new strategy with potential efficacy for cancer therapy or prevention.

Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs); where do they stand in tumorigenesis and how they can change the face of cancer therapy?

The tumor microenvironment (TME) and its components have recently attracted tremendous attention in cancer treatment strategies, as alongside the genetic and epigenetic alterations in tumor cells, TME could also provide a fertile background for malignant cells to survive and proliferate. Interestingly, TME plays a vital role in the mediation of cancer metastasis and drug resistance even against immunotherapeutic agents. Among different cells that are presenting in TME, tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) have shown to have significant value in the regulation of angiogenesis, tumor metastasis, and drug-resistance through manipulating the composition as well as the organization of extracellular matrix (ECM). Evidence has shown that the presence of both TAMs and CAFs in TME is associated with poor prognosis and failure of chemotherapeutic agents. It seems that these cells together with ECM form a shield around tumor cells to protect them from the toxic agents and even the adaptive arm of the immune system, which is responsible for tumor surveillance. Given this, targeting TAMs and CAFs seems to be an essential approach to potentiate the cytotoxic effects of anti-cancer agents, either conventional chemotherapeutic drugs or immunotherapies. In the present review, we aimed to take a deep look at the mechanobiology of CAFs and TAMs in tumor progression and to discuss the available therapeutic approaches for harnessing these cells in TME.

Novel targets in rectal cancer by considering lncRNA-miRNA-mRNA network in response to Lactobacillus acidophilus consumption: a randomized clinical trial.

We aimed to explore the lncRNA-miR-mRNA network in response to Lactobacillus acidophilus (L. acidophilus) consumption in rectal cancer patients. The candidate miRs were first taken from the GEO and TCGA databases. We constructed the lncRNA-miR-mRNA network using the high-throughput sequencing data. At last, we created a heatmap based on the experimental data to show the possible correlation of the selected targets. The expression levels of selected targets were measured in the samples of 107 rectal cancer patients undergoing placebo and probiotic consumption and 10 noncancerous subjects using Real-Time PCR. Our analysis revealed a group of differentially expressed 12 miRs and 11 lncRNAs, and 12 genes in rectal cancer patients. A significant expression increase of the selected tumor suppressor miRs, lncRNAs, and genes and a substantial expression decrease of the selected oncomiRs, onco-lncRNAs, and oncogenes were obtained after the probiotic consumption compared to the placebo group. There is a strong correlation between some network components, including miR-133b and IGF1 gene, miR-548ac and MSH2 gene, and miR-21 and SMAD4 gene. In rectal cancer patients, L. acidophilus consumption was associated with improved expression of the lncRNA-miR-mRNA network, which may provide novel monitoring and therapeutic approaches.

Heteroresistance to clarithromycin and metronidazole in patients with a Helicobacter pylori infection: a systematic review and meta-analysis.

BACKGROUND: Antimicrobial resistance of H. pylori can lead to treatment failure. Importantly, several studies have reported on heteroresistance, i.e. the presence of resistant and susceptible H. pylori populations in the same sample and/or a difference in the susceptibility patterns between biopsy samples. This meta-analysis aims to provide comprehensive data on the prevalence of metronidazole and clarithromycin heteroresistance and the approaches to their detection. MATERIAL AND METHODS: A systematic review was performed after the search of MEDLINE, Scopus and Web of Science. The study outcomes were the weighted pooled prevalence of heteroresistance to clarithromycin and metronidazole in H. pylori positive samples and/or isolates with a subanalysis by continent. RESULTS: A total of 22 studies that had investigated 3852 H. pylori positive patients were included in the meta-analysis. Heteroresistance to clarithromycin was reported in 20 studies, with a weighted pooled prevalence of 6.8% (95% CI 5.1-8.6; 3654 H. pylori positive patients; the substantial heterogeneity I2 = 55.6%). Heteroresistance to metronidazole was reported in 12 studies, with a weighted pooled prevalence of 13.8% (95% CI 8.9-18.6; 1670 H. pylori positive patients; the substantial heterogeneity I2 = 60.9%). The weighted pooled prevalence of clarithromycin heteroresistance was similar in Asia and Europe (p = 0.174584), however, metronidazole heteroresistance was detected more often in Europe (p < 0.00001). Clarithromycin heteroresistance was detected more often by phenotype rather than by using genotyping methods (12 vs 8 studies), whereas heteroresistance to metronidazole was detected only by phenotype. CONCLUSION: The prevalence of heteroresistance to clarithromycin and/or metronidazole is not negligible and can be detected in approximately 7 and 14% of H. pylori positive samples, respectively. These findings highlight the need to raise the awareness of gastroenterologists and microbiologists to the heteroresistance to clarithromycin and metronidazole in patients with a H. pylori infection.

Genetic polymorphisms -137 (G > C) (rs187238) and -607 (C > A) (rs1946518) and serum level of interleukin 18 in Fars ethnic groups with metabolic syndrome in Northern Iran.

INTRODUCTION: We aimed to determine the genetic polymorphisms and serum level of interleukin 18 in Fars ethnic groups. MATERIAL AND METHODS: 226 Fars ethnic groups were participated. The ATP III criteria were used to assess MS components. The SNPs of the IL-18 gene were determined with ARMS-PCR. RESULTS: The GG, GC, and CC genotypes of -137 were 50%, 40%, and 10%. The CC, CA, and AA genotypes of -607 were 45%, 37%, and 18%. The GG, GC, and CC genotypes of -137 were 44.20%, 43.40%, and 12.40%, and were 55.75%, 36.28%, and 7.97% in subjects with and without MS, respectively. The CC, CA, and AA genotypes of -607 were 48.70%, 37.20%, and 14.20% and were 41.60%, 37.20%, and 21.20% in both groups, respectively. CONCLUSION: IL-18 gene may different in specific populations, different ethnic groups and geographic regions. The IL-18 polymorphisms might not be used as a marker of metabolic syndrome.

Age- and Gender-Related Serum Level of Interleukin 18 in Iranian Fars Ethnic Group with Metabolic Syndrome.

Background: The purpose of the present study was to investigate the age- and gender-related serum level of interleukin 18 (IL18) in male and female Iranian Fars ethnic group with metabolic syndrome components. Methods: The study included 226 native Iranian Fars ethnic groups. One hundred sixteen females and 110 men were selected. There were 60 females and 50 males with metabolic syndrome and 56 females and 60 males without metabolic syndrome. The serum fasting blood glucose (FBS), lipid profiles, and IL18 were measured. The National Cholesterol Education Program Adult treatment Panel III criteria were used to determine metabolic syndrome components. Results: There were significant differences between the males and females [except high-density lipoprotein (HDL)] with and without metabolic syndrome for the mean body mass index, FBS, HDL-cholesterol, waist circumference (WC), triglyceride (TG), and IL18 levels in all age groups. Serum IL18 was the highest in males and females in age groups 61-70 and 41-50 years with metabolic syndrome, respectively. Serum IL18 levels significantly correlated with TG and waist WC in males (and also correlated with HDL) and females with the metabolic syndrome. There were significant correlations between IL18 and TG and WC in males (and also correlated with HDL) in ages 61-70 years and females in ages 41-50 years with the metabolic syndrome. Conclusions: The increased IL18 level in both gender and different ages may have an important role in the alteration of some metabolic syndrome components. These alterations may be made to happen in different related metabolic diseases. IL18 seems to be a useful biomarker for the management of metabolic syndrome components and the risk factors of cardiovascular disease.

A systematic approach introduced novel targets in rectal cancer by considering miRNA/mRNA interactions in response to radiotherapy.

BACKGROUND: The discovery of miRNA/mRNA interactions in several biological samples prompted the researchers to explore new biomarkers in tumors. OBJECTIVE: We aimed to investigate the interactions of miRNA/mRNA in response to radiotherapy in the plasma samples of rectal cancer patients. METHODS: Five microarray datasets related to cancerous and non-cancerous individuals were first used to construct networks. The databases of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were applied to analyze pathway enrichment. The plasma samples were then collected from 55 patients with recently diagnosed rectal cancer and 10 healthy subjects. For radiotherapy courses, the patients have consecutively received 30 sessions of local radiation for six weeks. At last, the expression of selected genes and miRNAs was experimentally measured before and after radiotherapy by qPCR, and the protein levels of the target genes were measured by ELISA assay. We evaluated the therapeutic responses based on the tumor regression grade of the Dworak classification. RESULTS: We identified 5 up-regulated and 5 down-regulated miRNAs and 8 up-regulated and 3 down-regulated genes of the databases. There was a significant increase in tumor suppressor miRNAs, including miR-101-3p, miR-145-5p, miR-26a-5p, miR-34a-5p, and a significant decrease in oncomiRs, including miR-221-3p and miR-17-5p, after radiotherapy compared to the pre-treatment. Moreover, the up-regulated miR-17-5p and miR-221-5p and the down-regulated miR-101-3p and miR-145-5p were directly related to rectal cancer through the interaction with the Wnt, RAS, PI3K, and TGF-ß signaling pathways. An analysis of receiver operating characteristics showed that miRNAs 221, 17, and 23 were response-related in locally advanced rectal cancer patients. CONCLUSIONS: It seems that monitoring the miRNA/mRNA interactions during radiotherapy can be an appropriate diagnostic tool to track the recovery process and respond to standard therapies.