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Background: Uterine cervical malignancy is one of the commonly detected malignancies related to the human papillomavirus (HPV) and is increasing incidentally in developing countries. Therefore, the use of an efficient diagnostic method is required as an effectual step for cervical cancer prevention and treatment. The purpose of the study was to diagnose various types of HPV in the cervical cytology specimens in the South-East of Iran. Methods: This cross-sectional study was performed on 1079 cervical fluid cytology specimens referred for two years, between 2018-2020. Polymerase chain reaction (PCR) and hybridization (INNO-LiPA HPV Genotyping EXTRA II assay) were used to determine HPV DNA and their genotypes, respectively. Results: HPV was positive in 37.7% (407 of 1079) patients with a mean age of 34.62 ± 8.82. Among positive cases, 252 (62%) had only one HPV genotype and 155 (38.05%) had multiplex HPV genotypes, which included 94 (60.7%), 38 (24.6%), 18 (11.6%) and 5 (3.2%) cases with two, three, four and five or more genotypes, respectively. The samples with multiple strains revealed 31 HPV genotypes with the four most prevalent being HPV6 (14.7%), HPV16 (10.9%), HPV53 (9.6%) and HPV51 (5.9%). Conclusion: HPV infection is the main health challenge for women that requires improved health service programs and appropriate epidemic vaccination.

BackgroundPentavalent antimonial compounds are currently used to treat leishmaniasis and resistance to these drugs is a serious problem. Multidrug resistance protein is an efflux pump of the cell membrane that expels foreign compounds. This study designed to evaluate the mutations in the multi-drug resistance 1 (MDR1) gene, in biopsy specimens ofLeishmania tropica, with high resolution melting (HRM) method. In this experimental study, genomic DNA was extracted from 130 patients with skin leishmaniasis. Then, nucleotide changes were investigated throughout the gene using HRM and sequencing methods. The samples categorized in 5 groups by differences in the melting temperature (Tm).ResultThe nucleotide changes analysis showed that 61% of the samples of different groups that were unresponsive to drug had mutations in the MDR1 gene, which were also confirmed by the sequencing method. These mutations can be one of the factors responsible for non-responsiveness to the treatment.ConclusionAccording to the findings, it seems that mutation in MDR1 gene could be responsible for drug resistance to pentavalent antimonial compounds. Furthermore, HRM method can be used to diagnose drug resistance in leishmaniasis. It is also recommended that further studies be done regarding the importance of drug resistance in theleishmaniaaffected patients.

Background & objective Early detection of malignancies in the serous fluids has been remained an issue. A classic diagnostic tool for the ascites and pleural effusions is cytologic study (morphology) with approximately 98% specificity for the detection of cancer cells. This study aimed to evaluate the diagnostic value of three complementary markers in the serosal fluids of patients with malignant cytology and suspected cases. Methods Seventy two patients with serosal effusion treated in three teaching hospitals were studied. The cases underwent a diagnostic workup to determine the pleural effusion malignancy and etiologies. Complementary markers, including CEA, CA15-3, and CA125 were measured in serosal fluids of three categories of benign, suspicious, and malignant. The study was carried out by Chemiluminescence immunoalayzer. The morphologies were re-evaluated by a consulting Cytopathologist. Results Of 72 serosal fluid specimens, 41 (56.9%) were related to pleural effusion and 31 (43.1%) were related to ascites. The sensitivity of CEA, CA125, and CA15-3 biomarkers were 64, 84, and 68%, respectively, and the specificity of each test was 100, 86, and 96%, respectively. This was statistically achieved for the combination of the area of markers below the curve (AUC), 0.93 and 90% sensitivity and 91% specificity. Conclusion The results suggest that complementary CA125, CA15-3, and CEA markers assayed with well-developed immunoassay method might be useful in the differentiation between malignant and benign effusions while combined with conventional cytology. CA125 yielded a significant correlation between cytomorphology and biomarkers based on the correlation coefficient analysis.

Background & Objective: Reproductive toxicity of cadmium (Cd) as an environmental toxicant has been proved in animals and humans. Exposure to Cd impairs testes organs and can reduce male fertility. The present study was designed to investigate the spectrum of histopathological changes in testicular tissue focusing on Sertoli cells in rats following Cd intoxication. Methods: In the present experiment, acute testicular toxicity was induced by an intraperitoneal injection of 1.2 mg/kg CdCl2 to the animals in the test group, while the control group received normal saline. After 52 days, the animals were euthanized, and testicular tissue was stained by Hematoxylin and Eosin. In addition, immunohistochemical staining was performed on Sertoli cells for Wilms' Tumor, Melan-A, and CD99 to evaluate histopathological changes. Results: Cd caused significant alterations in seminiferous tubules with varying effects on the patterns of spermatozoa production. These histopathological changes were significantly higher in the Cd group, compared to the control group. Conclusion: The Cd-induced stepwise spectrum changes included sloughing, disorganization, hypospermatogenesis, spermatic cell arrest, germ cell hypoplasia, Sertoli cell-only pattern, fibro-hyalinized seminiferous tubules, and calcification. Sertoli cells accumulated and created multinucleated giant cells in the seminiferous tubules during the atrophic process, which could be dependent upon Sertoli cells viability and function.

BACKGROUND: The pathogenesis of the COVID19 pandemic, that has killed one million nine hundred people and infected more the 90 million until end of 2020, has been studied by many researchers. Here, we try to explain its biological behavior based on our recent autopsy information and review of literature. METHODS: In this study, patients with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result were considered eligible for enrollment. Histopathological examinations were done on 13 people who were hospitalized in Afzalipour hospital, Kerman, Iran. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry and electron microscopy. RESULTS: The most frequent co-morbidity in the patients was cardiovascular disease. The common initial symptoms of COVID-19 infection were dyspnea and cough. In all cases, the number of white blood cells was higher than the normal range. Common histopathological findings were variable degrees of vasculitis as degenerative to necrotic changes of endothelium and trafficking of inflammatory cells in the vessel wall with fibrinoid necrosis. Tissue damage included interstitial acute inflammatory cells reaction with degenerative to necrotic changes of the parenchymal cells. CD34 and Factor VIII immunohistochemistry staining showed endothelial cell degeneration to necrosis at the vessel wall and infiltration by inflammatory cells. Electron microscopic features confirmed the degenerative damages in the endothelial cells. CONCLUSION: Our histopathological studies suggest that the main focus of the viral damage is the endothelial cells (endotheliopathica) in involved organs. Also, our findings suggest that degeneration of leukocytes occurs at the site of inflammation and release of cytokines (leukocytoclastica) resulting in a cytokine storm.

Panax ginseng is known to potentiate the immune system via its antioxidant properties. Cadmium as an environmental pollutant has destructive effects on body organs especially the reproductive system. This study investigated the effects of P. ginseng extract against cadmium-induced testicular toxicity in rats. In this experimental study, 50 male adult rats were randomly divided into 5 groups: A significant decrease was observed in sperm count and viability in the cadmium group versus the control group. Ginseng extract could repair these defects. Increases in apoptotic germ cells due to cadmium were significantly reduced by ginseng extract. Our results demonstrated that P. ginseng extract reduces cadmium-induced testicular toxicity, via anti-oxidative and anti-apoptotic processes.

Candida albicans (C. albicans) is the most common cause of candidiasis in humans and animals. This study was established to a new experimental infection model for systemic candidiasis using partridge and embryonated partridge egg. First, we tested the induction of systemic candidiasis in partridge and embryonated partridge egg. Finally, interaction between virulence factors of C. albicans and Bcl-2 family members was predicted. We observed that embryonic infection causes a decrease in survival time and at later embryonic days (11–12th), embryos showed lesions. Morphometric analysis of the extra-embryonic membrane (EEM) vasculature showed that vascular apoptotic effect of C. albicans was revealed by a significant reduction in capillary area. In immunohistochemistry assay, low expression of Bcl-2 and increased expression of Bax confirmed apoptosis. The gene expression of Bax and Bcl-2 was also altered in fungi-exposed EEM. Ourin silico simulation has shown an accurate interaction between aspartic proteinase, polyamine oxidase, Bcl-2 and BAX. We observed that the disease was associated with adverse consequences, which were similar to human candidiasis. Acquired results support the idea that partridge and embryonated partridge egg can be utilized as appropriate preclinical models to investigate the pathological effects of candidiasis.

Background & objective Cervical intraepithelial neoplasia (CIN) is a dysmaturation process in squamous cells in epithelial layer, which highly increases the risk of developing cervical cancer. The aim of this study was to compare the expression of three biomarkers, p16, p63, and CK17 in patients with CIN and in those with atypical squamous metaplasia (ASM). Methods In this study, 100 patients underwent a colposcopy-guided cervix biopsy. Immunostaining for the biomarkers was undertaken on tissue samples presented with ASM (n=50) and CIN (n=50). Results A significant increase in immunostaining for CK7, P63, and P16 in patients with CIN was found compared to ASM subjects. Conclusion Expression of CK17, P63, and P16 in CIN varied from those in ASM. Those biomarkers could be reliable factors to distinguish ASM from CIN; however, all the biomarkers could differentiate CIN from its mimics due to their high degree of sensitivity and specificity.

Our previous studies on cannabinoid type1 receptor (CB1R) activation on Methamphetamine (METH)-induced neurodegeneration and locomotion impairments in male rats suggest an interaction between CB1Rs and METH. However, the role of these receptors in METH-neurotoxicity has not been fully identified. Therefore, the purpose of the present study is to investigate the involvement of CB1Rs in these effects. We conducted an electrophysiological study to evaluate functional interactions between METH and CB1Rs using whole-cell patch current clamp recording. Furthermore, we designed the Nissl staining protocol to assess the effect of METH on the basic cerebellar Purkinje cell structure. Our findings revealed that METH significantly increased the action potential half-width, spontaneous interspike intervals, first spike latency, and decreased the rebound action potential and spontaneous firing frequency. Using CB1R agonist and antagonist, our results showed a significant interaction with some of the electrophysiological alterations induced by METH. Further, Nissl staining revealed that the exposure to the combination of METH and SR141716A resulted in the necrotic cell death. Results of the current study raises the possibility that METH consumption profoundly affect the intrinsic membrane properties of cerebellar Purkinje neurons and cannabinoid system manipulations may counteract some of these effects. In summary, our findings provide further insights into the modulatory role of the endocannabinoid system in METH-induced neurologic changes, which can be used in the development of potential therapeutic interventions for METH dependence.

A heterogeneous group of CNS tumors are characterized by mixed neuroepithelial and mesenchymal features. Glial tumors manifesting this phenomenon are referred to as gliosarcoma. These tumors are usually mistaken for cerebral metastases or meningioma at operation. Their histological studies have revealed an admixture of gliomatous and sarcomatous tissues, which leads to a biphasic pattern. The mesenchymal component can present in different forms such as fibrosarcoma, undifferentiated pleomorphic sarcoma, chondro-osteogenic, and myogenic differentiation, as well as angiosarcomatous and liposarcomatous types. Squamous differentiation, adenoid formations and glandular structures may also be displayed. Herein, we report a rare case who was admitted to the emergency room with decreased consciousness resembling methadone poisoning. Clinical work-up showed a temporoparietal mass on radiological investigation. Histopathological evaluation of the brain mass revealed a gliosarcoma with adenoid formations and a mesenchymal component, which manifested as chondrosarcomatous differentiation. Immunohistochemical studies confirmed the histologic diagnosis through positivity for EMA, GFAP, S100, and vimentin expression in different components.

Background: Given the increasing use of waterpipe tobacco smoking in the world and its unknown effects on bone healing, this study investigated the repairing of femoral bone fractures in rats exposed to waterpipe tobacco smoking (WTS).Main Methods: This study involved 40 male Wistar rats that were divided into two groups, including the femoral fracture (Fx) and the Fx + WTS groups. Each group was divided into two subgroups that were evaluated for bone healing 28 and 42 days after femoral fracture. After fixing the fractured femur, the healing process was evaluated by radiography, pathological indicators, and a measurement of the blood levels of vascular endothelial growth factor (VEGF), parathyroid hormone (PTH), Ca ++, transforming growth factor-beta (TGF-β), and insulin-like growth factor 1 (IGF-1). Additionally, the density of VEGF and CD34 in fracture tissue was investigated by immunohistochemistry.Key Findings: Radiographic findings showed that factors related to the earlier stages of bone healing had higher scores in the Fx + WTS28 and 42 subgroups in comparison to the Fx groups. The density of VEGF and CD34 showed that the angiogenesis processes were different in the bone fracture area and callus tissue in the Fx +WTS subgroups. The serum levels of VEGF, TGF-β, and IGF-1 were significantly lower in the Fx +WTS42 group, and PTH in the Fx +WTS28 group was higher than that in the other groups.Significance: The findings showed the disturbance and delay in the femoral fracture union in rats exposed to hookah smoke. This is partly due to the reduction of molecular stimuli of bone synthesis and the attenuation of quantitative angiogenesis.

The ongoing conventional drugs for leishmaniasis treatment are insufficient. The present study aimed to assess 6-gingerol alone and in combination with amphotericin B on Leishmania major stages using experimental and in vivo murine models. Here, arrays of experimental approaches were designed to monitor and evaluate the 6-gingerol potential therapeutic outcomes. The binding affinity of 6-gingerol and IFN-γ was the basis for docking conformations. 6-Gingerol combined with amphotericin B represented a safe mixture, extremely leishmanicidal, a potent antioxidant, induced a remarkable apoptotic index, significantly increased the expression of the Th1-related cytokines (IL-12p40, IFN-γ, and TNF- α), iNOS, and transcription factors (STAT1, c-Fos, and Elk-1). In contrast, the expression of the Th2-related cytokines was significantly downregulated (p < 0.001). This combination was also potent when the lesion appearance was evaluated following three weeks of treatment. The histopathological and immunohistochemical patterns of the murine model represented clusters of CD4+ and CD8+ T lymphocytes which compressed and deteriorated the macrophages harboring Leishman bodies. The primary mode of action of 6-gingerol and amphotericin B involved broad mechanistic insights providing a coherent basis for further clinical study as a potential drug candidate for CL. In conclusion, 6-gingerol with amphotericin B synergistically exerted anti-leishmanial activity in vitro and in vivo and potentiated macrophages' leishmanicidal activity, modulated Th1- and Th2-related phenotypes improved the histopathological changes in the BALB/c mice infected with L. major. They elevated the leukocyte infiltration into the lesions. Therefore, this combination should be considered for treating volunteer patients with CL in clinical studies.

The emergence of patient-tailored medicine has changed all measurable disease outcomes. Among human diseases, cancers appear to be the most dangerous. Furthermore, lung cancers rank the first among human cancers in both morbidity and mortality. When lung cancer is clinically diagnosed, it is often too late for therapy. The absence of accurate and specific tools for early detection results in a poor prognosis for lung cancer. The discovery of microRNAs and their function in lung cancer offers a new mechanism for the detection of lung cancer cells. These molecules, derived from cancerous cells, circulate in the patient's blood. Recently, a revolutionary technique, i.e., liquid biopsy has shown promise in discovering these circulating microRNAs molecules in body fluids, namely peripheral blood. A liquid biopsy allows the detection and isolation of circulating tumor cells, circulating nucleotides, and cellular exosome as a source of genomic and proteomic information in cancerous patients, especially in the early stages of cancer cell development. In this review, by searching various databases, including PubMed, Google Scholar, and Scopus, we explore liquid biopsy as a novel tool and the application of miRNAs in lung cancer detection in diagnostic pathology.

The classical two-layer anastomosis has been experimentally compared with anastomosis using synthetic TachoSil in terms of pre- and post-surgical symptoms and healing status of the anastomotic area in rats. Thirty-six adult male rats were randomly allocated into two groups: in group C (control), classic anastomosis was performed in the ileum of the small intestine, 10 cm away from the ileocecal valve using Vicryl 5-0 interrupted suture; group S (study) received anastomosis in the same area but with TachoSil using three sutures (mesenteric, anti-mesenteric, and anterior wall as suture-less method). The obtained results were analyzed by SPSS20 software, using Chi-square test. Based on the obtained results, group C had more favorable anastomotic healing than group S. Actually, the fibroblast and collagen were seen in most cases of the control rats, while healing was stopped in group S (TachoSil group) in early stages due to thrombosis and vasculitis gangrene. According to the findings, TachoSil patch cannot be advised for safe use in suturing the less small-bowel anastomosis.

Leishmaniasis is one of the most important parasitic diseases after malaria. The standard treatment of leishmaniasis includes pentavalent antimonials (SbV); however, these drugs are associated with serious adverse effects. There have been very few studies pertaining to their side effects and mechanism of action in the fetus. This investigation examines the effects of meglumine antimoniate (MA) on the survival rate, angiogenesis and cellular apoptosis in the human umbilical vein endothelial cells (HUVECs). HUVECs were treated with varying doses of MA (100-800 μg/ml) for 24, 48 and 72 h and the survival rate was studied by colorimetric assay, flow cytometry, immunocytochemistry, migration (scratch) assay and tube formation assay. The results of quantitative real-time PCR (qPCR) studies indicated that the most important genes involved in presenting angiogenesis included VEGF and its receptors (Kdr and Flt-1), NP1 and Hif-1α genes including the anti-apoptotic gene of Bcl2, were significantly reduced compared to the control group (p 0.05). In contrast, the most leading genes involved in the phenomenon of apoptosis were P53, Bax, Bak, Apaf-1 and caspases 3, 8 and 9, which were significantly up regulated compared to the control group (p 0.05).

Introduction. Leishmaniasis is a neglected tropical and subtropical disease caused by over 20 protozoan species. Hypothesis. Treatment of this complex disease with traditional synthetic drugs is a major challenge worldwide. Natural constituents are unique candidates for future therapeutic development. Aim. This study aimed to assess the in vivo anti-leishmanial effect of the Gossypium hirsutum extract, and its fractions compared to the standard drug (Glucantime, MA) in a murine model and explore the mechanism of action. Methodology. Footpads of BALB/c mice were infected with stationary phase promastigotes and treated topically and intraperitoneally with G. hirsutum extract, its fractions, or Glucantime, 4 weeks post-infection. The extract and fractions were prepared using the Soxhlet apparatus with chloroform followed by the column procedure. Results. The crude extract significantly decreased the footpad parasite load and lesion size compared to the untreated control group (PLeishmania major. Conclusion. This finding suggests that the extract possesses multiple combinatory effects of diverse bioactive phytochemical compositions that exert its mechanisms of action through agonistic-synergistic interactions. The topical extract formulation could be a suitable and unique candidate for future investigation and pharmacological development. Further studies are crucial to evaluate the therapeutic potentials of the extract alone and in combination with conventional drugs using clinical settings.

Purpose: Free radicals such as hydroxyl and peroxide are contributing factors to neuronal destruction in cerebral ischemia. Alpha lipoic acid (ALA) is one of the potent known antioxidants. Preparation of ALA niosomes allows IV injection and can increase bioavailability and penetration into the central nervous system (CNS). Methods: Film hydration method was used to prepare different niosomes composed of Span®, Tween®, and cholesterol at different molar ratio. ALA and niosome-forming compounds were dissolved in chloroform, before removing the organic solvent by rotary evaporator. Animals were randomly divided into four groups: Sham, control group, intravenous (IV) injection of empty niosomes plus intraperitoneal (IP) injection of ALA solution, and finally, IV injection of ALA niosomes. Rats were subjected to deep anesthesia before inducing cerebral ischemia, then, their internal common carotid arteries were clamped for 15 min and reperfusion was done for 30 min. Niosomal ALA was injected intravenously just before declamping. Results: Mean volume diameter of the prepared niosomes was between 4.36 ± 0.82 and 19.95 ± 1.21 µm in different formulations. Encapsulation efficiency percent (EE%) of ALA in the selected formulation, Span60/Tween60/Cholesterol (35:35:30 molar ratio), was 94.5 ± 0.2, and 59.27 ± 5.61% of ALA was released after 4h. In the niosomal group, the rate of reduction in complications of cerebral ischemia such as histopathologic changes and acute damage (from score 3 to 1) in CNS was higher than other groups. Conclusion: The obtained results show that niosomes can be used as effective drug delivery systems for ALA in cerebral ischemia.

Background The relationship between the expressions of matrix metalloproteinases with clinico-pathological data on gastric cancer has been investigated in many countries, but this relationship remains unexplored in Iranian patients. Also, the correlation of the MMPs and the HER-2/neu proto-oncogene with other clinic-pathological variables has been evaluated for several other malignancies, but little effort has been made to shed light on the relationship with gastric cancer. Methods We investigated MMP-2 and MMP-9 expression and HERE-2/neu overexpression in 48 gastric cancer patients referred to Afzalipour Hospital, associated with Kerman Medical University. Immunohistochemistry staining with rabbit polyclonal antibodies was used. Data statistical analysis was done by SPSS software (Version 20.0). Results The mean age was 59, most of the patients were male (79.2%), and the average tumor size was larger than 5 centimeters in its greatest diameter. The majority of tumors were of the intestinal subtype and were located in the pyloric and antrum regions (43.8%). Invasion to muscularis properia was seen in 87.5% of the tumors (T3). MMP-2 and MMP-9 were highly expressed in 58.3% and 50% of cases, respectively, and Her-2/neu positivity was 10.4%. MMP-2, MMP-9 and HER-2 were found to have no relation with any clinicopathological parameters. Conclusion According to the results of this study, MMP-2 and MMP-9 were highly expressed in gastric cancer, but there was no significant association with other clinicopathological variables.

Background Cutaneous leishmaniasis (CL) is a neglected disease with important public health concerns in many parts of the world including Iran. Objectives We aimed to explore the histological changes and immunohistochemical quantification of inflammatory cells and their role in the immunopathology of acute, chronic non-lupoid, and chronic lupoid skin lesions in anthroponotic CL (ACL). Methods In this study, skin biopsies of 53 patients with ACL were taken. Samples were studied by light microscopy and immunohistochemistry to quantify the immune and inflammatory cells. Results Of the 53 skin lesions, 38 were acute, nine chronic non-lupoid and six chronic lupoid. CD68+ macrophages were the most common cells. CD3+ T-lymphocytes were present as diffuse and focal dermal infiltrates and CD8+ cytotoxic T-lymphocytes were the dominant lymphocyte type, constituting more than 50% of the lymphocyte population. CD4+ T-lymphocytes in chronic non-lupoid (10.57 ± 2.37%) and chronic lupoid (14.40 ± 1.28%) lesions were more than those observed in the acute form (8.61 ± 1.31%), but the differences were not statistically significant. CD20+ B-lymphocytes constituted a small percentage of inflammatory cell infiltrates. CD1a + Langerhans cells showed progressively higher percentages from acute to chronic non-lupoid to chronic lupoid lesions. The differences were statistically significant (P CD68 + macrophages were the most common cells and CD8+ T lymphocytes remained the predominant T-lymphocytes in acute, chronic non-lupoid, and chronic lupoid lesions, suggesting their central role in the pathogenesis and possible healing of CL. Conclusion Focusing on the deep dermis, periadnexal and/or peripheral margins or even papillary tip of inflammatory sites of sandfly bites, we sometimes find granuloma inside lymphatic vessels (lymphangiectatic metastatic granuloma) or even infected macrophages with engulfed Leishman bodies faraway. Knowledge of the histopathological and immunohistochemical findings for various forms of ACL is essential in improving clinical and medical strategies and crucial for proper prophylactic and therapeutic plans.

This study aimed to determine any association of KRAS and BRAF mutations in colorectal cancer with clinicopathological features and overall survival (OS) of Southeast Iranian colorectal cancer (CRC) patients. Overall, KRAS and BRAF status were assessed in 100 Iranian CRC subjects. A hundred consecutive stages I–IV CRC patients, who underwent surgical tumor resection from February 2012 to August 2015, were prospectively attained from three centers and were enrolled in the research. Direct sequencing and real-time PCR methods were used to the detection of KRAS and BRAF mutations, respectively. Logistic regression models were used to detect associations of KRAS and BRAF mutations with clinical/clinicopathological features. Kaplan–Meier model was used to estimate overall survival. In total, KRAS and BRAF mutations were detected in 29 (29%) and 7 (7%) of 100 CRC patients, respectively. BRAF mutations that all comprised V600E and KRAS mutations were found in codon 12, 13, and 61 (72.4%, 20.7 and 6.9%), respectively. In a multivariate analysis, older age (≥ 60) was significantly associated with higher KRAS mutations rate and high BRAF mutation rate was significantly associated with older age (≥ 60) and poorly differentiated tumors. KRAS and BRAF mutant vs. wild type of KRAS and BRAF, 5-year OS was 62.1% vs. 71.8% (p value > 0.05) and 57.1% vs. 67.7% (p value > 0.05), respectively. Mutations were found in both KRAS and BRAF genes in Iranian colorectal cancers patients and were associated with clinical/clinicopathologic features. Our data emphasizes the importance of these molecular features in Iranian CRC patients.

Background The methylenetetrahydrofolate reductase (MTHFR) gene is involved in DNA methylation, synthesis and repair, which influences the risk of cancers. Many studies have demonstrated that the MTHFR rs1801133 and rs1801131 polymorphisms are linked with the risks of colorectal cancer (CRC). However, no study has probed the relationship between these polymorphisms and CRC risk in southeast Iranian population. Therefore, the aim of this study was to investigate the association of these two polymorphisms with CRC risk in a case-control investigation. Methods A total of 200 confirmed CRC patients and 200 healthy controls (matched to sex and age) were recruited from the Southeast of Iran between 2014 and 2019. Genomic DNA was extracted and genotyped for the polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism method. The relationship between the polymorphism and CRC risk was evaluated by logistical regression analysis. Results MTHFR 667C>T polymorphism was significantly associated with a lower risk of CRC (TT vs CC: p-value = 0.021; CT vs CC: p-value = 0.047; CT+TT vs CC: p-value = 0.017). The T-allele was associated with decreased risk for CRC (p-value = 0.012). However, we did not observe any association of 1298A>C with CRC. Furthermore, stratified analysis showed that MTHFR 667C>T polymorphism was correlated with tumor location in CRC patients. The frequency of T-A haplotype was significantly higher in the healthy controls compared to CRC patients (p-value = 0.021). Conclusion In conclusion, the T-allele of MTHFR 667C>T polymorphism was related to decreased susceptibility to CRC in this Iranian population. Moreover, the CT-AA and TT-AA combined genotypes and T-A haplotype of MTHFR 667C>T and 1298A>C polymorphisms were associated with decreased risk of CRC.

Background & objective: Breast cancer is the leading cause of cancer related death in females. Sphingosine kinase 1 (SPHK1) and its product sphingosine-1-phosphate (S1P) are the essential key regulator molecules in breast cancer through their ability to promote cell proliferation, angiogenesis, cell proliferation, and lymphagiogenesis. SPHK1 is overexpressed in multiple types of cancer including breast cancer and is associated with resistance to treatment. The current study aimed at investigating the expression of SPHK1 in estrogen and progesterone receptors (ER, PR) negative in comparison to ER, and PR positive breast cancer and their normal controls, and also finding the relationship between SPHK1 expression and high body index (BMI) in the selected groups with breast cancer. Methods: A total of 120 human breast cancer tissue specimens were analyzed for SPHK1 expression using Quantitative Real–Time Polymerase Chain Reaction (q RT-PCR) assay. Detection of hormonal status of breast cancer tissue samples was conducted by immunohistochemical assay. Result: The current study findings showed that the level of SPHK1expression in the breast cancer tissue was significantly higher in patients with estrogen and progesterone negative receptors, compared to the ones without them (P-value< 0.05). The obtained data confirmed that the obesity in patients with ER negative was higher than the ones with positive receptors (BMI> 25). Conclusion: The current study showed that expression of SPHK1gene was higher in the patients with ER and PR negative breast cancer and high BMI, compared with other groups.

Fosfomycin residues are found in the egg following administration in the layer hen. In this regard, some aspects of embryo-toxicity of fosfomycin have been documented previously. The exact mechanism by which fosfomycin causes embryo-toxicity is not clearly understood. We hypothesis that fosfomycin may alter vasculature as well as normal expression of genes, which are associated with vascular development. Therefore, the present study aimed to address these issues through in silico and in vivo investigations. At first, embryo-toxicity and anti-angiogenic effects of fosfomycin were tested using computerized programs. After that, fertile chicken eggs were treated with fosfomycin and chorioallantoic membrane vasculature was assessed through morphometric, molecular and histopathological assays. The results showed that fosfomycin not only interacted with VEGF-A protein and promoter, but also altered embryonic vasculature and decreased expression level of VEGF-A. Reticulin staining of treated group was also confirmed decreased vasculature. The minor groove of DNA was the preferential binding site for fosfomycin with its selective binding to GC-rich sequences. We suggested that the affinity of fosfomycin for VEGF-A protein and promoter as well as alteration of the angiogenic signaling pathway may cause vascular damage during embryonic growth. Hence, veterinarians should be aware of such effects and limit the use of this drug during the developmental stages of the embryo, particularly in breeder farms. Considering the anti-angiogenic activity and sequence selectivity of fosfomycin, a major advantage that seems to be very promising is the fact that it is possible to achieve a sequence-selective binding drug for cancer.

Objective The resistance to antimony-containing glucantime is a major obstacle to successful treatment, especially in endemic areas. Looking the molecular mechanisms involved in this drug resistance will help in choosing the best treatment. The aim of this study was to evaluate the expression of multidrug-resistance 1 (MDR1) and multidrug-resistance protein A (MRPA) genes in acute, chronic non-lupoid, and chronic lupoid forms of dry type cutaneous leishmaniasis (DTCL). Results MDR1 gene was over-expressed as 14.4- and 1.56-folds in the chronic lupoid and acute forms compared with the chronic non-lupoid form, respectively. Results comparison showed P

ObjectiveHistopathological studies suggest that parasite load is different between acute and chronic forms of cutaneous leishmaniasis (CL). However, highly sensitive detection methods are still needed to distinguish different forms of leishmaniasis. In the present study, we developed a quantitative real-time polymerase chain reaction (PCR) to detect and quantifyLeishmania tropicaparasites in paraffin-embedded tissue samples.ResultsThe ability of real-time PCR for leishmania detection was higher than histopathological evaluation. The quantitative real-time PCR (qPCR) quantified parasite loads were highly correlated with microscopic results (r = 0.598;P

Aging causes changes in body composition and energy balance. Estrogen plays an important role in body's metabolism. The aim of this study was to determine whether estrogen has beneficial effects on leptin responsiveness in aged mice. Young 4 months and aged 19-21 female mice fed High Fat Diet (HFD) or Standard Diet (SD) for 12 weeks and following received estrogen for 4 weeks. Responsiveness to leptin was compared by measuring energy balance parameters. Results showed that HFD caused weight gain compared to SD in young, but had no effect on aged animals. Estrogen reduced body weight, energy intake and visceral fat in young, while none of these parameters was affected in aged animals. Although there was leptin sensitivity in aged compared to ovariectomized animals, estrogen only improved the sensitivity of young to leptin. Estrogen prevented increase in TNF-α and a decrease in IL-10 in HFD young and aged animals. Response to estrogen depended on age, and estrogen increased leptin sensitivity only in young animals. Determining the exact mechanism of this action is suggested in future studies.

The application of conventional approaches to diabetic wound regeneration has some limitations. Thus, skin substitutes could be a new therapeutic possibility. In this regard, fibrin scaffolds are promising materials due to their desirable characteristics. Since defective fibroblasts caused by diabetes can disrupt regeneration, it seems that the use of living cells can improve the healing process. Thus, based on this fact, a cellular fibrin membrane was used to evaluate the diabetic wound healing in rats. The fibrin membrane was fabricated using fresh frozen plasma on which isolated fibroblasts were cultured. The wound model was created on 36 diabetic rats that were randomly divided into three groups: control, membrane, and cellular fibrin membrane (CM). Wound photogramography and immuno-histopathological staining were performed during consecutive days after treatment. Macroscopic evaluation of the wounds indicated a noteworthy enhancement of wound closure in the CM group. In the CM group, the re-epithelialization rate on day 7, 10 (p0.001), and 14 (p0.05), the fibroblast percentage on day 3 (p0.01) and 7 (p0.05) and the collagenization in all days were significantly higher than those of other groups (p0.001). The fibroblast number in the CM group on day 10 was significantly (p0.01) lower than that in the other groups. Contrary to the neutrophil and angiogenesis percentages that had no significant difference among the groups at different points of time (p0.05), the macrophage percentage on day 7 (P0.01), 10, and 14 (p0.05) was significantly lower in the CM group as compared to that in other groups. Overall, it seems that the use of a fibroblast-loaded fibrin membrane is an attractive strategy to promote diabetic wound healing.

Objective The objective of the current study was to evaluate the embryo-toxicity of omega-3 fatty acids. Methods Firstly, the embryo-toxicity of docosahexaenoic (DHA) and eicosapentaenoic acids (EPA), as well as their interaction with Bcl-2 family members, were predicted using an in silico assay. In the next step, the embryonic pathological lesions and amniotic fluid biochemical changes following omega-3 treatment were investigated using a chick embryo model. Finally, the drug's vascular apoptotic effect on the chick's yolk sac membrane (YSM) was assessed. Results In silico simulations revealed the embryo-toxicity, tissue-toxicity (respiratory and cardiovascular), and vascular-toxicity (apoptotic activity) of DHA and EPA. There was also an accurate interaction between DHA and EPA with Bax (Binding affinity: -7.6 and -10.6 kcal/mol) and Bcl-2 (Binding affinity: -8.0 and -12.2 kcal/mol), respectively. Moreover, DHA and EPA administrations were related to various adverse consequences, including weight loss and lesions in the respiratory and cardiovascular systems. Histopathological findings consisted of pulmonary edema, airway dilatation, increased interstitial tissue, and hyperemia in the lungs, heart, liver, kidney, and brain. Morphometric evaluation of the YSM vasculature revealed that the vascular apoptotic effect of omega-3was associated with a significant reduction in mean capillary area. In immunohistochemistry assay, increased expression of BAX and low expression of Bcl-2 affirmed apoptosis in YSM vessels. Conclusion According to the results of this study, one could confirm that the possible embryo-toxicity of omega-3 was approved by data presented in this research. The obtained results also support the suspicion that alteration of the apoptotic-related proteins in vessels is an essential pathway in embryo-toxicity of omega-3.

Over the last years, there has been a remarkable increase in the number of unresponsive patients with anthroponotic cutaneous leishmaniasis (ACL) reported worldwide. The primary objective of this study was to explore the role of demographic, clinical and environmental risk related-factors in the development of treatment failure, relapse and chronic cases compared to responsive patients with ACL. Moreover, molecular, histopathological and immunohistochemical (IHC) findings between these forms were explored. This work was undertaken as a prospective and case-control study in southeastern Iran. Culture media and nested PCR were used to identify the causative agent. Univariate multinomial and multiple multinomial logistic regression models and the backward elimination stepwise method were applied to analyze the data. A P, Author summary Negligible data are present related to anthroponotic cutaneous leishmaniasis (ACL) treatment outcome and resultant unresponsiveness risk determinants. The role of demographic, clinical, and environmental risk associated-factors in the development of treatment failure, relapse, and chronic forms of ACL has not been studied. We carried out a case-control study for a period of 4 years (2015–2019) using culture media and nested PCR to identify the causative agent. Afterward, we analyzed the data by univariate multinomial and multiple multinomial logistic regression models and the backward elimination stepwise method. Also, we examined skin punch biopsies to study the histopathological and immunohistochemical (IHC) profile for different comparative groups. The findings identified 8 major risk factors were significantly associated with the creation of unresponsive forms. Clinical practitioners and health surveillance systems should be aware of and monitor such perplexing factors. Awareness of the major determinants for unresponsiveness to the treatment of ACL is critical to improving clinical strategies and public health measures. These multidisciplinary approaches need to address specific barriers that directly affect the treatment outcome.

Introduction Previous studies have shown that some cytokines mediate the effect of IGF-1 on inflammation and also association between IGF-1 and vascular endothelial dysfunction. Due to the discrepancies in the inflammatory and anti-inflammatory roles of IL-27 and IL-35, the effects of these cytokines and their IGF-1-mediating role were investigated regarding chronic joint inflammation and synovial blood flow. Method Male rats were divided into two main groups of histopathology (n = 80) and blood flow (n = 72). These were further divided into ten subgroups of control, vehicle, IGF-1, IL-27, IL-35, their antagonists, IGF-1 + IL-27 antagonist, and IGF-1 + IL-35 antagonist. Inflammation was induced by intra-articular injection of complete Freund adjuvant. Two weeks later (in order to induce chronic inflammation), vehicle or drugs were injected into the joint space every other day until day 28, on which inflammatory indices were assessed histopathologically. In the second subgroups, vehicle or drugs were administered by super-fusion on day 28 and their effects on the joint blood flow (JBF, laser Doppler perfusion method) and the systemic blood pressure were assessed. Results Endogenous IL-27 and IL-35 had inflammatory roles and IGF-1 had no effect. IL-27 and IL-35 antagonists had the highest anti-inflammatory and anti-angiogenesis effects and these effects were inhibited by IGF-1. Total inflammation score was 4.5 ± 0.42, 3.50 ± 0.5, 2.25 ± 0.45 and 1.50 ± 0.42 for vehicle, IGF-1 antagonist, IL-27 antagonist and IL-35 antagonist respectively. A significant increase was induced in JBF by IGF-1 antagonist and combination of IGF-1 + IL-35 antagonist. Conclusion IL-27 and IL-35 antagonists may be suitable goals for the treatment of chronic joint inflammation while their anti-inflammatory effects are not exerted via the changes in JBF.

Recent information demonstrated that BK virus reactivation is a dominant complication after kidney transplantation, which occurs because of immunosuppression. BK virus reactivation is the main reason of transplanted kidney losing. Immune response against BK virus is the major inhibitor of the virus reactivation. Therefore, improving our knowledge regarding the main parameters that fight against BK viruses can shed light on to direct new treatment strategies to suppress BK infection. Innate immunity consists of numerous cell systems and also soluble molecules, which not only suppress virus replication, but also activate adaptive immunity to eradicate the infection. Additionally, it appears that immune responses against reactivated BK virus are the main reasons for induction of BK virus-associated nephropathy (BKAN). Thus, improving our knowledge regarding the parameters and detailed mechanisms of innate immunity and also the status of innate immunity of the patients with BK virus reactivation and its complications can introduce new prospective strategies to either prevent or as therapy of the complication. Therefore, this review was aimed to collate the most recent data regarding the roles played by innate immunity against BK virus and also the status of innate immunity in the patients with reactivation BK virus and BKAN.