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Background & Objective: Angiogenesis is an essential component of tumor growth. Expression of PSMA on the neo-vasculature of many solid tumors, including glioblastoma multi-form, has been determined. The pattern of expression suggests that PSMA may play a functional role in angiogenesis., Methods: expression of PSMA in different grades of brain glioma was evaluated by the immunohistochemistry method to determine the probable usefulness of anti-PSMA antibody as complementary target therapy in different grades of glioma., Results: Overall, 72 cases of low (grade I and II) and high (grade III and IV) grade gliomas were evaluated for expression of PSMA. Positive PSMA staining was observed in 12 (33.3%) of high grade and 3 (8.3%) of low grade gliomas. Although, high grade tumors more commonly had positive result for PSMA (P value=0.009), the intensity of staining was significantly stronger in low-grade tumors (P value=0.009)., Conclusion: Expression of PSMA in different grades of glioma might provide a basis for further investigations focusing on selective target therapy in combination with the current standard care in all glioma grades, to improve treatment efficacy., Competing Interests: The authors declare no financial relationship with any organization regarding this research.

In recent years, for neurodegenerative diseases therapy, research has focused on the stem cells therapy. Due to promising findings in stem cell therapy, there are various sources of stem cells for transplantation in human. The aim of this study was to evaluate sciatic nerve regeneration in the rat after nerve transaction followed by human endometrial stem cells (hEnSCs) treatment into poly (e-caprolactone)/collagen/nanobioglass (PCL/collagen/NBG) nanofibrous conduits. After treatment of animals, the performance in motor and sensory tests, showed significant improvement in rats treated with hEnSCs as an autograft. H&E images provided from cross-sectional and, longitudinal-sections of the harvested regenerative nerve as well as immunohistochemistry results indicated that regenerative nerve fibres had been formed and accompanied with new blood vessels in the conduit cell group. Due to the advantage of high surface area for cell attachment, it is reported that this electrospun nerve conduit could find more application in cell therapy for nerve regeneration in future, to further improve the functional regeneration outcome, especially for longer nerve defect restoration. In conclusion, our results suggest that the PCL/collagen/NBG nanofibrous conduit filled with hEnSCs is a suitable strategy to improve nerve regeneration after a nerve transaction in rat.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination are the major reasons for low survival rate in the patients. The bromodomain and extraterminal domain (BET) proteins are known as epigenetic 'readers,' and their inhibitors are novel epigenetic strategies for cancer treatment. Accumulating body of evidence indicates that epigenetic modifications have critical roles in development of EOC, and overexpression of the BET family is a key step in the induction of important oncogenes. Here, we examined the mechanistic activity of I-BET151, a pan-inhibitor of the BET family, in therapy-resistant EOC cells. Our findings showed that I-BET151 diminished cell growth, clonogenic potential, and induced apoptosis. I-BET151 inhibited cell proliferation through down-modulation of FOXM1 and its targets aurora kinase B and cyclin B1. I-BET151 attenuated migration and invasion of the EOC cells by down-regulation of epithelial-mesenchymal transition markers fibronectin, ZEB2, and N-cadherin. I-BET151 synergistically enhanced cisplatin chemosensitivity by down-regulation of survivin and Bcl-2. Our data provide insights into the mechanistic activity of I-BET151 and suggest that BET inhibition has potential as a therapeutic strategy in therapy-resistant EOC. Further in vivo investigations on the therapeutic potential of I-BET151 in EOC are warranted.

Study Design: This is an animal study., Objectives: Metformin is a safe drug for controlling blood sugar in diabetes. It has been shown that metformin improves locomotor recovery after spinal cord injury (SCI). Neuropathic pain is also a disturbing component of SCI. It is indicated that metformin has neuroprotective and anti-inflammatory effects, which attenuate neuropathic pain and hyperalgesia in injured nerves. Thus, we evaluated metformin's therapeutic effects on SCI neuroinflammation and its sensory and locomotor complications. Meanwhile, results were compared to minocycline, an anti-neuroinflammation therapy in SCI., Setting: Experimental Medicine Research Center, Tehran University of Medical Sciences, Iran METHODS: In an animal model of SCI, 48 male rats were subjected to T9 vertebra laminectomy. Animals were divided into a SHAM-operated group and five treatment groups. The treatments included normal saline as a vehicle control group, minocycline 90 mg/kg and metformin at the doses of 10, 50 and 100 mg/kg. Locomotor scaling, behavioral tests for neuropathic pain and weight changes were evaluated and compared through a 28-days period. At the end of the study, tissue samples were taken to assess neuroinflammatory changes., Results: Metformin 50 mg/kg improved the locomotors ability (p < 0.001) and decreased sensitivity to mechanical and thermal allodynia (p < 0.01). These results were compatible with minocycline effect on SCI (p > 0.05). While metformin led to weight loss, both metformin and minocycline significantly decreased neuroinflammation in the assessment of cord tissue histopathology, and levels of TNF-α and interleukin-1β (p < 0.001)., Conclusions: Metformin could be considered as an alternative therapeutic agent for SCI, as it potentially attenuates neuroinflammation, sensory and locomotor complications of cord injury.

Myocardial infarction (MI) is a major cause of mortality and morbidity in industrialized societies. Myocardial tissue engineering is an alternative and promising approach for substituting injured myocardium through development and seeding of appropriate scaffolds. In this study, we investigated the efficacy of using an acellular pericardium to deliver autologous mesenchymal stem cells (MSCs) to the infarcted site for regeneration of the myocardium. MI was induced in two groups of rats; G1 or MI group, and G2 or patch-implanted group. In G2 group, rats had undergone transplantation of a pericardial patch which was previously seeded with adipose tissue derived MSCs. To evaluate the efficacy of the pericardial patches, biopsies were taken one month after transplantation. In order to evaluate the extent of regeneration, inflammation and fibrosis, histopathological investigations including hematoxylin and eosin (H&E), Sirius Red and trichrome staining were performed. In addition, immunohistochemical investigations by Desmin as well as CD68, CD45 and CD34 antibodies were performed. Furthermore, Tunnel assay was performed to detect the extent of apoptosis. H&E assessments of biopsies from the patch-implanted group confirmed presence of pre-seeded pericardium containing MSCs along with neo-vessels. Immunohistochemical assessments demonstrated higher number of CD34 positive cells and Desmin-positive cells in the patch implanted group (p < 0.05); these findings are suggestive of cardiomyocyte regeneration in G2 rats. This study demonstrates the advantages of application of natural acellular scaffolds as cell delivery devices and it emphasizes neovascularization following this approach. However, further investigations are required to analyze long-term cardiac function in recipients. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2670-2678, 2018., (© 2018 Wiley Periodicals, Inc.)

Medullary thyroid carcinoma (MTC) is a rare neoplasia derived from neural parafollicular C cells. MicroRNAs (miRNAs) are small regulatory RNAs with essential roles in the biology of cancers such as MTC and can be applied as diagnostic markers. According to previous studies, miR-144 and miR-34 and their two oncogenes target, mammalian target of rapamycin (mTOR) and AXL receptor tyrosine kinase (AXL), were selected for further investigations in our study. Thirty MTC samples as well as thirty adjacent normal thyroid tissues were applied in this study including 28 formalin-fixed, paraffin-embedded (FFPE) and 2 fresh-frozen MTC samples. RNA extraction and complementary DNA (cDNA) synthesis were performed for all samples. After primer pairs and probes were designed, real-time polymerase chain reaction (real-time PCR) method was used, and the results were analyzed using 2 -ΔΔCt method. Receiver operating characteristic (ROC) curve analysis was applied to assess the diagnostic value of the two miRNAs. AXL protein level was measured in all clinical samples using enzyme-linked immunosorbent assay (ELISA) method. Both miRNAs were up-regulated in all clinical samples compared to the normal tissues. AXL was up-regulated in most clinical samples while mTOR was down-regulated in most samples. Furthermore, the level of AXL protein increased. ROC curve analysis demonstrated that increased expression of miR-34a and miR-144 in MTC patients had significant predictive value. The results demonstrated that high expression of miR-144 and miR-34a can be considered as biomarkers of MTC. However, there was no statistically significant correlation between the expression of these miRNAs and target genes in MTC clinical samples., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Multiple endocrine neoplasia (MEN) syndromes are infrequent inherited disorders in which more than one endocrine glands develop noncancerous (benign) or cancerous (malignant) tumors or grow excessively without forming tumors. There are 3 famous and well-known forms of MEN syndromes (MEN 1, MEN 2A, and MEN 2B) and a newly documented one (MEN4). These syndromes are infrequent and occurred in all ages and both men and women. Usually, germ line mutations that can be resulted in neoplastic transformation of anterior pituitary, parathyroid glands, and pancreatic islets in addition to gastrointestinal tract can be an indicator for MEN1. The medullary thyroid cancer (MTC) in association with pheochromocytoma and/or multiple lesions of parathyroid glands with hyperparathyroidism can be pointer of MEN2 which can be subgrouped into the MEN 2A, MEN 2B, and familial MTC syndromes. There are no distinct biochemical markers that allow identification of familial versus nonfamilial forms of the tumors, but familial MTC usually happens at a younger age than sporadic MTC. The MEN1 gene (menin protein) is in charge of MEN 1 disease, CDNK1B for MEN 4, and RET proto-oncogene for MEN 2. The focus over the molecular targets can bring some hope for both diagnosis and management of MEN syndromes. In the current review, we look at this disease and responsible genes and their cell signaling pathway involved., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Doublecortin-like kinase 1 (DCLK1) is a protein kinase that is known as a specific cancer stem cell (CSC) marker in colorectal cancer (CRC). Deregulation of DCLK1 expression has been reported in various cancers. We measured the protein expression of DCLK1 in 38 CRC and normal colon samples by immunohistochemistry (IHC). HCT-116 and SW-48 cells were transfected with DCLK1 siRNA and analyzed for expression of DCLK1 and miR-200c. The effects of DCLK1 knockdown on cell migration, invasion, sphere-forming, and apoptosis were explored. It was found that DCLK1 protein expression levels were significantly higher in CRC tissue than in normal colon specimens. Silencing of DCLK1 significantly inhibited cell migration, invasion, and sphere-forming potential; it also induced apoptosis as well as increased expression of miR-200c. Furthermore, silencing of miR-200c significantly up-regulated DCLK1 expression. Overall, our data demonstrated that DCLK1 plays an important role in cancer progression and is involved in the regulation of miR-200c expression., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Thyroid cancer, one of the most widespread malignancies of the endocrine-related system that over the past three decades, has a vivid increasing rate. The diagnosis and management of it is dependent on the tumor type and stage. Thyroid cancer is divided into four main types, including PTC (papillary thyroid carcinoma), FTC (follicular thyroid carcinoma), MTC (medullarly thyroid carcinoma), and ATC (anaplastic thyroid carcinoma). The development of the noninvasive diagnostic tool for plasma genotyping, also known as "liquid biopsy", brings a new insight for cancer diagnosis and prognosis. It is mainly containing circulating tumor DNA (ctDNA), circulating tumor cell (CTC), exosomes and extrachromosomal circular DNA (ecDNA). Liquid biopsy as a new plasma genotyping source brings a new prospective of tumor monitoring and therapy. It beneficially reduces the need of tissue biopsy and made early recognition of relapse as well. This article summarizes its components characteristics and their benefit in diagnosis and treatment of thyroid cancer.

Stem cell-based therapies are attraction approaches for regenerative medicine for treating retinal diseases. One of the limitations in cell therapy is cell death following post-injection whit preventing functional integration with retinal tissue. Fibrin gel, a bio-polymeric material with excellent biocompatibility, provides numerous advantages as a tissue engineering scaffold and a stem cell carrier. Therefore, current research is focusing on developing fibrin hydrogel scaffolds to protect stem cells during delivery and to stimulate endogenous regeneration through interactions of transplanted stem cells and retinal tissue. In this study fibrin gel was used as hydrogel scaffold for immobilization of cells. The structural characteristics of fibrin gel scaffold were examined with SEM. Rheological properties of fibrin gel were measured by rheometer and biodegradation rate of fibrin were assayed for 2 weeks. After isolation of stem cells CJMSCs, the cells were differentiated into photoreceptor-like cells by exposing with taurin for 14 days in tissue culture plate (TCP group) and fibrin hydrogel (3 D group). The attachment of cells was analyzed with SEM and MTT. The expression of rhodopsin, PKC, CRX, recoverin, peripherin, nestin and RPE65 as photoreceptor-like cell markers was evaluated by immunocytochemistry and quantitative real-time PCR (RT-PCR) in TCP and 3 D groups. The results of SEM analysis showed CJMSCs were well attached in fibrin gels and there were good integrity between cells and scaffold. The elastic modulus and constant degradation of the gel contributes to the growth and proliferation of cells. There was no toxicity effect of fibrin hydrogel on cells and the viability of cultured cells was higher in 3 D fibrin gels in comparison with TCP groups. After 2 weeks, the expression of rhodopsin, PKC, CRX, peripherin, recoverin, nestin and RPE65 as special markers of photoreceptor cells were detected by Real time PCR and immunofluorescence that these expressions in 3 D groups were higher than TCP groups. In conclusion, our findings showed that application of readily available sources of adult stem cells like human conjunctiva stem cells encapsulated in fibrin gel could be interesting strategy to enhance photoreceptor progenitor cell numbers for repair and regeneration of retina disease such as photoreceptor injury.

Epithelial ovarian cancer (EOC) has exhibited marginal improvement in survival rate, despite advances in surgical debulking and chemotherapy regimens. Although the majority of EOC patients achieve a clinical remission after induction therapy, over 80% relapse and succumb to chemoresistant disease. In this regard, it is of paramount importance to elucidate molecular mechanisms and signaling pathways which promote therapy resistance in EOC in order to devise novel and more effective treatment strategies. In this study, we showed that activation of nuclear factor-κB (NF-κB) is significantly higher in therapy-resistant EOC cells compared to chemosensitive counterparts, which was positively associated with resistance to cisplatin, carboplatin, paclitaxel and erlotinib. Bay 11-7082, a highly selective NF-κB inhibitor, reduced cell proliferation, clonogenicity and anoikis resistance in the therapy-resistant EOC cells and induced apoptotic cell death. Moreover, Bay 11-7082 decreased the expression of pro-survival, inflammatory and metastatic genes and synergistically increased anti-proliferative efficacy of cisplatin, carboplatin, paclitaxel and erlotinib. Altogether, these findings suggest that NF-κB is an attractive therapeutic target in EOC to be exploited in translational oncology and Bay 11-7082 is a potential anti-cancer drug to overcome chemoresistance and inhibit proliferation of the EOC cells., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In molecular biology covalently closed circular DNAs are able to passthrough double layer of eukaryotic cellular membrane. Very recently the presence of circular extra chromosomal DNA (ecDNA) has been shown which are different in seventeen different types of cancers. In fact, ecDNA are the tricky way of oncogenes to increase their copy number. We hypothesis the presence of ecDNA in the blood of cancer patients as a subpopulation of liquid biopsy. On the occasion of their presence in blood they will be very beneficial to cover the small amount of cell frees DNA (cfDNA). Isolation and characterization of ecDNA will be possible by a sensitive method entitled Circle-Seq. The origin of tumor more than its prognosis and diagnosis will be possible in the easiest way by using ecDNA., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Medullary thyroid carcinoma (MTC) is an infrequent, calcitonin producing neuroendocrine tumor and initiates from the parafollicular C cells of the thyroid gland. Several genetic and epigenetic alterations are collaterally responsible for medullary thyroid carcinogenesis. In this review article, we shed light on all the genetic and epigenetic hallmarks of MTC. From the genetic perspective, RET, HRAS, and KRAS are the most important genes that are characterized in MTC. From the epigenetic perspective, Ras-association domain family member 1A, telomerase reverse transcriptase promoter methylations, overexpression of histone methyltransferases, EZH2 and SMYD3, and wide ranging increase and decrease in non-coding RNAs can be responsible for medullary thyroid carcinogenesis.

The heterogeneity of tumor is considered as a major difficulty to victorious personalized cancer medicine. There is an extremeneed of consistent response evaluation for in vivo tumor heterogeneity anditscoupledconflict mechanisms. In this occasion researchers will be able to keep pace withpredictive, preventive, personalized, and Participatory (P4) medicine for cancer managements. In fact tumor heterogeneity is a central part of cancer evolution,soin order to progress in understanding of the dynamics within a tumor some diagnostic apparatus should be improved. Latest molecular techniques like Next generation Sequencing (NGS) and ultra-deep sequencing could disclose some clones within a liquid tumor biopsy which mainly responsible of treatment resistance. Circulating tumor DNA (ctDNA) as a main component of liquid biopsy is agifted biomarker for cancer mutation tracking as well as profiling. Personalized medicine facilitate learning regarding to genetic pools of tumor and their possible respond to treatment which could be much easier by using of ctDNA.With this information, cliniciansarelooking forward to find the best strategies for prevention, screening, and treatment in the way of precision medicine. Currently, numerous clinical efficacy of such informative improved treatment are in hand. Here we represent the review of plasma-derived ctDNA studies use in personalized cancer managements., Competing Interests: This manuscript does not report on or involve the use of any animal or human data or tissue, so ethical approval is not applicable in this section.This review article does not contain data from any individual person; consequently the consent for publication is “Not applicable” in this section.All authors declare that they have no competing interests” in this section.

Thyroid cancer is a frequent endocrine-related malignancy with continuously increasing incidence, and recently the development in understanding its molecular pathogenesis is mainly through the explanation of the original role of several key signaling pathways and related molecular distributors. Central to these mechanisms are the genetic and epigenetic alterations in these pathways such as mutation and DNA rearrangements. However, it does not mean that all the somatic abnormalities in a cancer genome are involved in cancer development and just driver mutations are concerned in tumor initiation. By way of illustrations, MAPK pathway motivated by BRAF V600E and RAS and RET / PTC rearrangements are suggesting driver genetic alterations in follicular derived thyroid cancers considered in the current review., Competing Interests: The authors declared no conflict of interest.

Pheochromocytomas and paragangliomas (PPGLs) are tumors arising from the adrenal medulla and sympathetic/parasympathetic paraganglia, respectively. According to Th e Cancer Genome Atlas (TCGA), approximately 40% of PPGLs are due to germ line mutations in one of 16 susceptibility genes, and a further 30% are due to somatic alterations in at least seven main genes (VHL, EPAS1, CSDE1, MAX, HRAS, NF1, RET, and possibly KIF1B). Th e diagnosis of malignant PPGL was straight forward in most cases as it was defined as presence of PPGL in non-chromaffin tissues. Accordingly, there is an extreme need for new diagnostic marker(s) to identify tumors with malignant prospective. Th e aim of this study was to review all suggested genetic and epigenetic alterations that are remarkably different between benign and malignant PPGLs. It seems that more than two genetic mutation clusters in PPGLs and other genetic and methylation biomarkers could be targeted for malignancy discrimination in different studies.

Promoter methylation in a number of tumor-suppressor genes (TSGs) can play crucial roles in the development of thyroid carcinogenesis. The focus of the current meta-analysis was to determine the impact of promoter methylation of eight selected candidate TSGs on thyroid cancer and to identify the most important molecules in this carcinogenesis pathway. A comprehensive search was performed using Pub Med, Scopus, and ISI Web of Knowledge databases, and eligible studies were included. The methodological quality of the included studies was evaluated according to the Newcastle Ottawa scale table and pooled odds ratios (ORs); 95% confidence intervals (CIs) were used to estimate the strength of the associations with Stata 12.0 software. Egger's and Begg's tests were applied to detect publication bias, in addition to the "Metatrim" method. A total of 55 articles were selected, and 135 genes with altered promoter methylation were found. Finally, we included eight TSGs that were found in more than four studies (RASSF1, TSHR, PTEN, SLC5A, DAPK, P16, RARβ2, and CDH1). The order of the pooled ORs for these eight TSGs from more to less significant was CDH1 (OR = 6.73), SLC5 (OR = 6.15), RASSF1 (OR = 4.16), PTEN (OR = 3.61), DAPK (OR = 3.51), P16 (OR = 3.31), TSHR (OR = 2.93), and RARβ2 (OR = 1.50). Analyses of publication bias and sensitivity confirmed that there was very little bias. Thus, our findings showed that CDH1 and SCL5A8 genes were associated with the risk of thyroid tumor genesis.

Purpose: PTEN and KLLN are two tumor suppressor genes located in 10q23, share a bidirectional promoter and have roles in carcinogenesis. Formerly, the role of PTEN mutations and KLLN epimutations were identified in incidence of thyroid lesions in individuals with Cowden syndrome, a rare autosomal dominant inherited disorder. This study is the first of its type to assess PTEN and KLLN circulating levels in patients with sporadic papillary thyroid carcinoma (PTC) and compare to patients with multinodular goiter (MNG) and healthy individuals., Methods: Plasma levels of PTEN and KLLN were determined by enzyme-linked immunosorbent assay in three groups consisted of PTC (n = 33), MNG (n = 26) and healthy persons (n = 30). The association of demographic/pathological characteristics with the levels of PTEN and KLLN were evaluated., Results: A significant lower plasma levels of PTEN and KLLN were observed in PTC patients compared with those of healthy persons (PTEN, 9.43 ± 3.20 vs. 16.96 ± 1.28 ng/ml, P = 0.000; KLLN, 1.81 ± 0.83 vs. 2.57 ± 1.09 ng/ml, P = 0.005), while no statistical difference was found between PTC and MNG groups. Patients with MNG lesion had significantly lower levels of PTEN/KLLN (PTEN, 9.62 ± 2.97 vs. 16.96 ± 1.28 ng/ml, P = 0.000; KLLN, 1.34 ± 0.86 vs. 2.57 ± 1.09 ng/ml, P = 0.000) compared to the healthy controls. The demographic/pathological characteristics did not demonstrate an association with the levels of PTEN and KLLN., Conclusions: The study suggests that the lowered levels of PTEN and KLLN are associated with both sporadic PTC and MNG tumorigenesis, but they cannot be considered as circulating biomarkers for differential diagnosis between malignancy and benignity in indeterminate thyroid nodules.

Liposarcoma is regarded as the second most common soft tissue malignant tumour. Metastasis of liposarcoma to the heart is very rare, and to date, less than 40 cases have been reported in the literature. We report a 46 year-old male with myxoid liposarcoma of the lower extremity who developed extensive metastasis to the left ventricle, pulmonary artery, and pericardium. The patient presented with acute symptoms of dyspnea 16 years after surgical resection of the primary tumour, and his dyspnea progressed to cardio-respiratory arrest within the first few days of hospital admission.

Diabetic foot ulcers (DFUs) are a severe and costly complication of diabetes and may result in foot amputation., Case Report: A 69-year-old man with a 10-year history of type 2 diabetes, who was undergoing routine care for diabetes in the authors' clinic, developed a DFU of his right foot of 4 years' duration. The wound did not respond to conventional treatments, and imaging studies were normal. His 2 biopsies tested negative for malignancy. The DFU was fully removed surgically. Following surgical removal, squamous cell carcinoma (SCC) was diagnosed in the histologic study of the wound., Conclusion: Clinicians should consider a diagnosis of SCC in any chronic, nonhealing DFU. Early surgical resection of a chronic, nonhealing DFU may prevent development of SCC in an ulcer.

Pheochromocytomas (PCCs) are rare neuroendocrine tumors. The current diagnostic tools are based on biochemistry and histopathology results, but heterogeneity of diagnostic markers, signs and symptoms of PCCs bring a lot of difficulties for these two current methods. Unfortunately, microscopic understanding of PCCs is not adequate for its confident prognosis and management. There are data linking specific genotypes of PCCs tumors to specific locations, typical biochemical phenotypes or future clinical behaviors. The detection of a germ-line mutation possibly can guide us to an early diagnosis, appropriate treatment, and regular surveillance with better prognosis for patients but also and their family members. Moreover, the latest discoveries in gene sequencing, circulating DNA (ctDNA) and circulating tumor cells (CTCs) will support the exact molecular pathogenesis of PCCs to provide an important basis for future PCCs managements., Competing Interests: The authors declared no conflict of interest.

Epithelial ovarian cancer (EOC) is the most fatal gynaecological malignancy. Despite initial therapeutic response, the majority of advanced-stage patients relapse and succumb to chemoresistant disease. Overcoming drug resistance is the key to successful treatment of EOC. Members of vascular endothelial growth factor (VEGF) family are overexpressed in EOC and play key roles in its malignant progression though their contribution in development of the chemoresistant disease remains elusive. Here we show that expression of the VEGF family is higher in therapy-resistant EOC cells compared to sensitive ones. Overexpression of VEGFR2 correlated with resistance to cisplatin and combination with VEGFR2-inhibitor apatinib synergistically increased cisplatin sensitivity. Tivozanib, a pan-inhibitor of VEGF receptors, reduced proliferation of the chemoresistant EOC cells through induction of G2/M cell cycle arrest and apoptotic cell death. Tivozanib decreased invasive potential of these cells, concomitant with reduction of intercellular adhesion molecule-1 (ICAM-1) and diminishing the enzymatic activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-2 (MMP-2). Moreover, tivozanib synergistically enhanced anti-tumour effects of EGFR-directed therapies including erlotinib. These findings suggest that the VEGF pathway has potential as a therapeutic target in therapy-resistant EOC and VEGFR blockade by tivozanib may yield stronger anti-tumour efficacy and circumvent resistance to EGFR-directed therapies.

Background: Retinitis pigmentosa (RP) and age related macular degeneration (AMD) are two retinal diseases that progress by photoreceptor cells death. In retinal transplantation studies, stem and progenitor cells inject into the sub retinal space or vitreous and then these cells can be migrate to the site of retinal degeneration and locate in the host retina and restitute vision., Presentation of the Hypothesis: Our hypothesis suggests that using human conjunctiva stem cells (as the source for increasing the number of human stem cells progenitor cells in retina dysfunction diseases) with fibrin gel and also assessing its relating in vitro (cellular and molecular processes) and in vivo (vision tests and pathology) could be a promising strategy for treatment of AMD and RP disorders., Testing the Hypothesis: In this idea, we describe a novel approach for retina tissue engineering with differentiation of conjunctiva mesenchymal stem cells (CJMSCs) into photoreceptor-like cells in fibrin gel with induction medium contain taurine. For assessment of differentiation, immunocytochemistry and real time PCR are used for the expression of Rhodopsin, RPE65, Nestin as differentiated photoreceptor cell markers in 2D and 3D culture. The results show that fibrin gel will offer a proper 3D scaffold for CJMSCs derived photoreceptor cell-like cells., Implications of the Hypothesis: Application of immune-privileged, readily available sources of adult stem cells like human conjunctiva stem cells with fibrin gel would be a promising strategy to increase the number of photoreceptor progenitor cells and promote involuntary angiogenesis needed in retina layer repair and regeneration., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Glioblastoma (GBM) remains one of the most fatal human malignancies due to its high angiogenic and infiltrative capacities. Even with optimal therapy including surgery, radiotherapy and temozolomide, it is essentially incurable. GBM is among the most neovascularised neoplasms and its malignant progression associates with striking neovascularisation, evidenced by vasoproliferation and endothelial cell hyperplasia. Targeting the pro-angiogenic pathways is therefore a promising anti-glioma strategy. Here we show that tivozanib, a pan-inhibitor of vascular endothelial growth factor (VEGF) receptors, inhibited proliferation of GBM cells through a G2/M cell cycle arrest via inhibition of polo-like kinase 1 (PLK1) signalling pathway and down-modulation of Aurora kinases A and B, cyclin B1 and CDC25C. Moreover, tivozanib decreased adhesive potential of these cells through reduction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Tivozanib diminished GBM cell invasion through impairing the proteolytic cascade of cathepsin B/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase-2 (MMP-2). Combination of tivozanib with EGFR small molecule inhibitor gefitinib synergistically increased sensitivity to gefitinib. Altogether, these findings suggest that VEGFR blockade by tivozanib has potential anti-glioma effects in vitro. Further in vivo studies are warranted to explore the anti-tumour activity of tivozanib in combinatorial approaches in GBM.

Circulating tumor cells (CTCs) recognition and characterization in the peripheral blood of patients with breast cancer have proven practical and predictive value in different studies. However, the clinical significance of CTCs enumeration and molecular characterization in thepersonalization of breast cancer diagnosis and treatment remains under the debate. A literature search in PubMed, Web of Science and Scopus was performed from October 1990 to June 2016 for studies which evaluating CTCs and its association with clinical and pathological characteristics and medical outcome in the field of breast cancer personalization for both diagnosis and treatment categories. The treatment outcomes were progression-free survival (PFS) and overall survival (OS) or relapse in different patients. Sixty-nine studies met the inclusion criteria. The sample size varies from 1 to 2026. Median follow-up was 15 months (range 3-27). Different molecular techniques have been applied toresearch, but they mostly are based on CTCs enrichment and then detection by using FDA-approved Cell SearchTM. By far the most studies define CTCs as cytokeratins (CK) positive and CD45 negative cells. Despite the differences in methodology, twenty-eight studies for breast cancer diagnosis and prognosis were mainly focused on CTCs isolation and enumeration.Forty-threeresearches were about CTCs count and exact molecular characterization. In the way of precision treatment, CTCs detection before starting the first-line of therapy or during therapy in breast cancer patients is extremely valuable, but in the way of precision medicine it should be supported with some molecular characteristics of CTCs like CTCs phenotypic changes, gene expression analysis of CTCs and molecular characteristics of CTCs.

Splenic hamartoma is an unusual accidental finding with non-neoplastic feature that may be incidentally diagnosed because of its compression effect on surrounding organs. The predominant pathological feature leading diagnosis is circumscribed, un-encapsulated bulging nodules with focal fibrosis or cyst. The histopathological feature of splenic hamartoma is the positivity for CD8, and occasionally for CD31, CD34, and CD68 biomarkers on vascular wall but the cells are frequently negative for CD21. Herein, we describe a case with initial diagnosis of nephrolithiasis due to abdominal pain that was finally confirmed as splenic hamartoma by histopathological assessments and detection of CD8, CD31, CD34, and CD68 positivity.

Diabetic neuropathy (DN) is characterized as Hyperglycemia activates thdisturbed nerve conduction and progressive chronic pain. Inflammatory mediators, particularly cytokines, have a determinant role in the pathogenesis of neuropathic pain. The activity of adenosine monophosphate protein kinase (AMPK), an energy charge sensor with neuroprotective properties, is decreased in diabetes. It has been reported that activation of AMPK reduces the systemic inflammation through inhibition of cytokines. In this study, we aimed to investigate the probable protective effects of AMPK on DN in a rat of diabetes. DN was induced by injection of streptozotocin (65 mg/kg, i.p.). Motor nerve conduction velocities (MNCV) of the sciatic nerve, as an electrophysiological marker for peripheral nerve damage, were measured. Plasma levels of IL-6, TNF-α, CRP were assessed as relevant markers for inflammatory response. Also, the expression of phosphorylated AMPK (p-AMPK) and non-phosphorylated (non-p-AMPK) was evaluated by western blotting in the dorsal root ganglia. Histopathological assessment was performed to determine the extent of nerve damage in sciatic nerve. Our findings showed that activation of AMPK by metformin (300 mg/kg) significantly increased the MNCV and reduced the levels of inflammatory cytokines. In addition, we showed that administration of metformin increased the expression of p-AMPK as well as decline in the level of non p-AMPK. Our results demonstrated that co-administration of dorsomorphin with metformin reversed the beneficial effects of metformin. In conclusion, the results of this study demonstrated that the activation of AMPK signaling pathway in diabetic neuropathy might be associated with the anti-inflammatory response.

Patients with inflammatory bowel disease (IBD) have a high risk for development of colitis-associated cancer (CAC). Serotonin is a neurotransmitter produced by enterochromaffin cells of the intestine. Serotonin and its receptors, mainly 5-HT3 receptor, are overexpressed in IBD and promote development of CAC through production of inflammatory cytokines. In the present study, we demonstrated the in vivo activity of tropisetron, a 5-HT3 receptor antagonist, against experimental CAC. CAC was induced by azoxymethane (AOM)/dextran sodium sulfate (DDS) in BALB/c mice. The histopathology of colon tissue was performed. Beta-catenin and Cox-2 expression was evaluated by immunohistochemistry as well as quantitative reverse transcription-PCR (qRT-PCR). Alterations in the expression of 5-HT3 receptor and inflammatory-associated genes such as Il-1β, Tnf-α, Tlr4 and Myd88 were determined by qRT-PCR. Our results showed that tumor development in tropisetron-treated CAC group was significantly lower than the controls. The qRT-PCR analysis demonstrated that the expression of 5-HT3 receptor was significantly increased following CAC induction. In addition, tropisetron reduced expression of β-catenin and Cox-2 in the CAC experimental group. The levels of Il-1β, Tnf-α, Tlr4 and Myd88 were significantly decreased upon tropisetron treatment in the AOM/DSS group. Taken together, our data show that tropisetron inhibits development of CAC probably by attenuation of inflammatory reactions in the colitis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The strong anticancer activity of disulfiram is hindered by its rapid degradation in blood system. A novel folate-receptor-targeted poly (lactide-co-glycolide) (PLGA)-polyethylene glycol (PEG) nanoparticle (NP) is developed for encapsulation and delivery of disulfiram into breast cancer tumor using passive (EPR effect) and active (folate receptor) targeting. The anticancer activity of disulfiram and its effect on caspase-3 activity and cell cycle are studied. The administration of encapsulated PLGA NPs using intra-peritoneal, intravenous and intra-tumor routes is investigated using animal model. Disulfiram shows strong cytotoxicity against MCF7 cell line. The activity of caspase-3 inhibited with disulfiram via dose dependent manner while the drug causes cell cycle arrest in G0/G1 and S phase time-dependently. The encapsulated disulfiram shows higher activity in apoptosis induction as compared to free drug. In nontoxic dose of encapsulated disulfiram, the highest and lowest efficacy of NPs in tumor growth inhibition is observed for intravenous injection and intraperitoneal injection. It is suggested that administration of disulfiram by targeted PLGA nanoparticles using intravenous injection would present an alternative therapeutic approach for solid tumor treatment., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The present study was designed to clarify whether α2-adrenoceptors of the basolateral amygdala (BLA) are involved in nicotine-induced anxiogenic-like behaviours. Adult male Wistar rats were bilaterally cannulated in the BLA and anxiety-like behaviours were assessed in an elevated plus maze (EPM) task. Systemic intraperitoneal (i.p.) administration of nicotine (0.3, 0.5 and 0.7 mg/kg) dose-dependently decreased open arm time (%OAT) and open arm entry (%OAE), indicating the anxiogenic-like effect of nicotine. The activation of the BLA α2-adrenoceptors by the injection of α2-receptor agonist, clonidine (0.1, 0.3 and 0.5 μg/rat) into the BLA (intra-BLA) reversed nicotine-induced anxiogenic-like behaviours. It is important to note that intra-BLA injection of a higher dose of clonidine (0.5 μg/rat) by itself increased %OAT, but not %OAE which showed an anxiolytic effect of the agonist. On the other hand, intra-BLA injection of different doses of α2-adrenoceptor antagonist, yohimbine (1, 3 and 5 μg/rat) in combination with an ineffective dose of nicotine (0.3 mg/kg) decreased %OAT and %OAE, suggesting a potentiative effect of the antagonist on nicotine response. In addition, intra-BLA injection of the same doses of yohimbine did not alter %OAT and %OAE. Interestingly, intra-BLA injection of yohimbine (0.5 and 1 μg/rat) significantly reversed the inhibitory effect of clonidine on nicotine-induced anxiogenic-like behaviours. It should be considered that the drug treatments had no effect on locomotor activity in all experiments. Taken together, it can be concluded that nicotine produces anxiogenic-like behaviours which may be mediated through the BLA α2-adrenoceptor mechanism., (Copyright © 2016. Published by Elsevier Ltd.)

The aim of the present study was to demonstrate the regaining histological characteristics of bioengineered external anal sphincters (EAS) in rabbit fecal incontinence model. The EAS of 16 rabbits were resected and decellularized. The decellularized scaffolds were transplanted to the terminal rectum following a period of 6 months of fecal incontinency (5 days after sterilization). The rabbits were divided into two groups: in group 1 (n = 8), myogenic satellite cells were injected into the transplanted sphincters. In group 2 (n = 8), the transplanted scaffolds remained in situ without cellular injection. The histological evaluation was performed with desmin, myosin, smooth muscle actin, CD31, and CD34 at 3-month intervals. The rabbits were followed for 2 years. Electromyography (EMG) with needle and electrical stimulation, pudendal and muscle electrical stimulation were also performed after 2 years of transplantation. At the time of biopsy, no evidence of inflammation or rejection was observed and the transplanted EAS appeared histologically and anatomically normal. The immunohistochemistry staining validated that the histological features of EAS was more satisfactory in group 1 in short-term follow-up. However, no statistically significant difference was detected between two groups in long-term follow-ups (p value > 0.05). In both groups, grafted EAS contracted in response to electrical signals delivered to the muscle and the pudendal nerve. However, more signals were detected in group 1 in EMG evaluation. In conclusion, bioengineered EAS with myogenic satellite cells can gain more satisfactory histological outcomes in short-term follow-ups with better muscle electrical stimulation outcomes.

Objectives: Diabetic neuropathy (DN) is a common complication of diabetes that leads to allodynia, impaired nerve conduction, and progressive sensory loss. The aim of this study was to observe the effect of a high-affinity cannabinoid receptors agonist, WIN 55,212-2, on thermal hyperalgesia, nerve conduction velocity and sciatic nerve histopathology in diabetic rats., Materials and Methods: Diabetes was induced in rats using a single dose of streptozotocin (45 mg/kg IP)., Results: Intrathecal (IT) administration of WIN55, 212-2 (1, 10, 100 µg/10 µl, IT), produced antinociceptive effects in the hot plate test and also improved nerve conduction velocity (100 µg/10 µl, IT) and sciatic nerve histology., Conclusion: These data show that cannabinoids have potent antinociceptive effects through direct actions in the spinal dorsal horn of nociceptive pathway. This suggests that intrathecally administered cannabinoids may offer hopeful strategies for the treatment of diabetic neuropathic pain.

To address the hypothesis that using a zirconia (ZrO2)/ β-tricalcium phosphate (β-TCP) composite might improve both the mechanical properties and cellular compatibility of the porous material, we fabricated ZrO2/β-TCP composite scaffolds with different ZrO2/β-TCP ratios, and evaluated their physical and mechanical characteristics, also the effect of three-dimensional (3D) culture (ZrO2/β-TCP scaffold) on the behavior of human endometrial stem cells. Results showed the porosity of a ZrO2/β-TCP scaffold can be adjusted from 65% to 84%, and the compressive strength of the scaffold increased from 4.95 to 6.25 MPa when the ZrO2 content increased from 30 to 50 wt%. The cell adhesion and proliferation in the ZrO2/β-TCP scaffold was greatly improved when ZrO2 decreased. Moreover, in vitro study showed that an osteoblasts-loaded ZrO2/β-TCP scaffold provided a suitable 3D environment for osteoblast survival and enhanced bone regeneration. We thus showed that a porous ZrO2/β-TCP composite scaffold has excellent mechanical properties, and cellular/tissue compatibility, and would be a promising substrate to achieve both bone reconstruction and regeneration needed during in vivo study for treatment of large bone defects.

Incorporation of endothelial cells or their progenitor cells into newly sprouting blood vessels can contribute to tissue vascularization after ischemic injury. However, the interaction of the stem cells-derived endothelial cells with angiogenesis within tumors is not well understood. The aim of this study was to examine the efficiency of endothelial-like cells derived from MSCs in controlling breast tumor growth associated with abnormal angiogenesis. For this purpose, Balb/c mouse model of breast carcinoma was developed and subjected to intra tumor (I.T)/intra venous (I.V) therapy with undifferentiated MSCs or endothelial cells derived from them. The homing of the stem cells was approved by measuring different markers as well as tracing green fluorescence protein (GFP)-labeled MSCs in the tumors. Tumor growth was measured following cell therapy using a digital caliper. At the end of treatment period (30 days) the angiogenesis markers; VEGFR2 expression as well as micro-vessel density (MVD) using CD31 were estimated in tumor tissues. Stem cell transplantation to mice bearing breast tumors resulted in tumor growth suppression in all experimental groups. The endothelial markers; CD31 and VEGFR2 were down regulated following I.T delivery of the endothelial cells. Accordingly, angiogenesis was suppressed following I.T administration of endothelial cells which was associated with increased focal necrosis in the tumors. In conclusion, data show that endothelial cells directly injected into tumors is more efficient compared to undifferentiated MSCs in controlling tumor-associated angiogenesis and tumor growth.

Purpose: To investigate the outcomes of implanting rat decellularized trachea scaffold (DTS) between the paravertebral muscles of nude mice using the body as a bioreactor for total graft recellularization., Methods: The tracheas of four rats were aseptically resected and decellularized. To assess the efficiency of the decellularization procedure, all decellularized scaffolds and native control tissues were evaluated with scanning electron microscopy (SEM), DAPI staining, DNA quantification, biomechanical analyses and hydroxyproline measurement. They were then implanted between the paravertebral muscles of four nude mice. The biopsies were precisely evaluated at 1, 3, 6 and 12 months postoperatively for tracheal cartilage and soft tissue recellularization by staining for TTF1, CD34, S100 and leukocyte common antibody., Results: Hematoxylin and eosin (H&E) staining, SEM and the tensile test confirmed the preservation of the tissue structure and the biophysical and biochemical properties of the DTS. The present study clearly demonstrated that the hydroxyproline content of the DTS was similar to that of the native tissue. On the other hand, in biopsy samples obtained after 12 months, histological evaluation showed superior organization and cell seeding in both the cartilage and connective tissues., Conclusion: This study demonstrated the feasibility of using a natural bioreactor for recellularizing DTS; this may have the potential to facilitate homologous transplantation for repairing segmental trachea defects.

Cirrhosis is associated with vascular dysfunction and endotoxemia. These experiments were designed to investigate the hypothesis that the administration of a low-dose of lipopolysaccharide (LPS) worsens vascular dysfunction in rats subjected to bile-duct ligation (BDL), and to determine whether LPS initiates changes in vascular Toll-like receptor 4 (TLR4) expression. Four weeks after BDL, the animals were given an intraperitoneal injection of either saline or LPS (1.0 mg/kg body mass). Three hours later, the superior mesenteric artery was isolated, perfused, and then subjected to the vasoconstriction and vasodilatation effects of phenylephrine and acetylcholine, respectively. Our results show that phenylephrine-induced vasoconstriction decreased in the cirrhotic vascular bed (BDL rats) compared with the vascular bed of the sham-operated animals, and that the LPS injections in the cirrhotic (BDL) rats worsened this response. LPS injection administered to the sham-operated animals had no such effect. On the other hand, both the BDL procedure and the LPS injection increased acetylcholine-induced vasorelaxation, but LPS administration to the BDL rats had no effect on this response. The mRNA levels of TLR4 did not change, but immunohistochemical studies showed that TLR4 localization switched from the endothelium to vascular smooth muscle cells following chronic BDL. In conclusion, acute endotoxemia in cirrhotic rats is associated with hyporesponsiveness to phenylephrine and tolerance to the effects of acetylcholine. Altered localization of TLR4 may be responsible for these effects.

To report the results of whole liver decellularization by two different methods. To present the results of grafting rat and sheep decellularized liver matrix (DLM) into the normal rat liver and compare natural cell seeding process in homo/xenograft of DLM. To compare the results of in vitro whole liver recellularization with rats' neonatal green fluorescent protein (GFP)-positive hepatic cells with outcomes of in vivo recellularization process. Whole liver of 8 rats and 4 sheep were resected and cannulated via the hepatic vein and perfused with sodium dodecyl sulfate (SDS) or Triton + SDS. Several examinations were performed to compare the efficacy of these two decellularization procedures. In vivo recellularization of sheep and rat DLMs was performed following transplantation of multiple pieces of both scaffolds in the subhepatic area of four rats. To compare the efficacy of different scaffolds in autologous cell seeding, biopsies of homograft and xenograft were assessed 8 weeks postoperatively. Whole DLMs of 4 rats were also recellularized in vitro by perfusion of rat's fetal GFP-positive hepatic cells with pulsatile bioreactor. Histological evaluation and enzymatic assay were performed for both in vivo and in vitro recellularized samples. The results of this study demonstrated that the triton method was a promising decellularization approach for preserving the three-dimensional structure of liver. In vitro recellularized DLMs were more similar to natural ones compared with in vivo recellularized livers. However, homografts showed better characteristics with more organized structure compared with xenografts. In vitro recellularization of liver scaffolds with autologous cells represents an attractive prospective for regeneration of liver as one of the most compound organs. In vivo cell seeding on the scaffold of the same species may have more satisfactory outcomes when compared with the results of xenotransplantation. This study theoretically may pave the road for in situ liver regeneration probably by implantation of homologous DLM or in vitro recellularized scaffolds into the diseased host liver., (© 2014 Wiley Periodicals, Inc.)

Project: Cholestasis liver fibrosis has been increasingly recognized as a cause of high morbidity and mortality in humans. The accumulation of toxic bile salts in a bile duct ligation (BDL) animal model plays a pivotal role in the induction of liver fibrosis. Cholestatic liver fibrosis is characterized by excessive collagen production and deposition, which is mediated by reactive oxygen species (ROS). Molybdenum is an essential micronutrient trace element which acts as a cofactor in many detoxification system enzymes. The aim of the present study was to evaluate the antifibrotic effect of sodium molybdate on liver cholestasis induced by bile duct ligation in rats., Procedure: After BDL, rats were given sodium molybdate (0.05 or 0.1 or 0.2g/kg) or urosodeoxycholic acid (UDCA, 25mg/kg) via intragastric gavage for 45 consecutive days (once per day)., Results: BDL drastically increased the serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin and direct bilirubin, whereas it reduced the levels of antioxidant enzymes, superoxide dismutase and catalase in the liver. Treatment of BDL rats with sodium molybdate significantly attenuated these changes. As determined by Masson's trichrome staining, BDL markedly induced the liver fibrosis. These alterations were also significantly attenuated by sodium molybdate administration., Conclusions: The results of this study indicate the hepatoprotective and antifibrotic effect of sodium molybdate in the cholestatic liver. Sodium molybdate, by inhibiting the activation of Ito cells, decreases the collagen production in the liver. The antifibrotic effect of sodium molybdate is likely due to the antioxidative and free radical scavenging effects of this trace element., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

The aim of this study was to investigate the effects of magnesium sulfate (MgSO4) on cholestasis-induced hepatic injury after bile duct ligation (BDL) in male Wistar rats. In this study, the effects of 28-day, oral administration of MgSO4 (at doses of 0.01, 0.05, 0.1, and 0.2 g/kg bw) were evaluated in normal and BDL-induced cholestatic rats. The BDL group showed significant increases in serum levels of ALP, ALT, AST, GGT and significant decreases in hepatic SOD and catalase activities. BDL rats also had significant decreases in the serum levels of albumin, bilirubin, total cholesterol, triglycerides, and LDL. Administration of MgSO4 significantly attenuated these changes to nearly normal levels. Administrations of MgSO4 did not change these parameters in normal rats. Histopathological studies further confirmed the protective effects of MgSO4 on cholestasis-induced hepatic injury in the BDL rat model. Taken together, the results of this study suggest that MgSO4 treatment may be beneficial in cholestasis-induced hepatotoxicity.

The Distinction between malignant and benign pheochromocytoma has always been a diagnostic challenge over the last decades. To date, the only reliable criterion is metastasis. The aim of the present study was to investigate the possible expression of pituitary-tumor transforming gene (PTTG1) and retinoblastoma (Rb) in benign and malignant pheochromocytoma. Paraffin blocks of 44 and 11 patients diagnosed with benign and malignant pheochromocytoma were collected. Parameters such as sex, age, tumor size, necrosis, and histological features were compared between the benign and malignant groups as well as immunohistochemical labeling using specific antibodies. PTTG1 showed negative expression in all (44) benign and 9 out of 11 (81.8%) malignant tumors with only 2 out of 11 (18.2%) malignant tumors showed positive reactivity for PTTG1 (P: 0.037) with spindle cell histological pattern in both of them (P: 0.013). Although Rb expression in malignant tumors (81.8%) was slightly more than the benign ones (52.3%), no statistically significant correlation was observed (P: 0.087). These results suggest that PTTG1 immunostaining may play a key role in distinguishing between benign and malignant phaeochromocytoma. However, larger studies are necessary to confirm the outcomes of the present study.

Objective: Tissue-engineered prepuce scaffold (TEPS) is a collagen-rich matrix with marvelous mechanical properties, promoting in vivo and in vitro tissue regeneration. In this study, adipose-derived mesenchymal stem cells (ADMSCs) were used to seed TEPS for bladder wall regeneration. Its potential in comparison with other materials such as polyglycolic acid (PGA) and nanofibrous scaffolds were evaluated., Materials and Methods: Rat ADMSCs were cultured and seeded into prepared TEPS. A synthetic matrix of electrospun nanofibrous polyamide was also prepared. Sprague Dawley rats (n=32) underwent bladder wall regeneration using (a) TEPS, (b) TEPS+PGA, (c) TEPS+nanofibrous scaffold, and (d) ADMSC-seeded TEPS, between bladder mucosa and seromuscular layer. Animals were followed for 30 and 90 days post implantation for evaluation of bladder wall regeneration by determining CD31/34 and SMC α-actin. Cystometric evaluation was also performed in all groups and in four separate rats as sham controls 3 months postoperatively., Results: Histopathological analysis showed well-organized muscular wall generation in ADMSC-seeded TEPS and TEPS+three-dimensional (3D) nanofibrous scaffold without significant fibrosis after 90 days, while mild to severe fibrosis was detected in groups receiving TEPS and TEPS+PGA. Immunohistochemistry staining revealed the maintenance of CD34+, CD31+, and α-SMA in ADMSC-seeded TEPS and TEPS+3D nanofibrous scaffold with significantly higher density of CD34+ and CD31+ progenitor cells in ADMSC-seeded TEPS and TEPS+3D nanofibrous scaffold, respectively., Conclusions: This work has crucial functional and clinical implications, as it demonstrates the feasibility of ADMSC-seeded TEPS in enhancing the properties of TEPS in terms of bladder wall regeneration., (Copyright © 2014 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate the association between impaired autophagy in smooth muscle cells and the development of congenital ureteropelvic junction (UPJ) obstruction (UPJO)., Materials and Methods: Tissue specimens were obtained from 40 patients with unilateral UPJO and were divided into 3 sections as renal pelvis, site of obstruction, and the ureter distal to obstruction. Control specimens were obtained from the UPJ of 40 age-matched cadavers. Autophagy was evaluated by image analysis techniques for the expression of light chain 3 (LC3) after immunohistochemical staining of LC3 rabbit polyclonal antibody and Western blot analysis; additionally, myocyte apoptosis was determined using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, 4',6-diamidino-2-phenylindole staining, and p53 immunohistochemical staining. To assess the possible role of cell senescence, P21 and P16 immunohistochemistry staining was applied. Cellular proliferation was assessed by image analysis of proliferating cell nuclear antigen-stained specimens., Results: LC3 expression was significantly increased at the renal pelvis (P <.05). Apoptotic indices of smooth muscle cells and Bcl-2 were significantly greater at the site of UPJO (5.15 ± 0.91) compared with the UPJs of the control group (P <.001). A significant negative correlation was found between TUNEL and LC3 in all sections of the obstructed UPJ complex (P <.05). Proliferating cell nuclear antigen and LC3 were positively correlated in the renal pelvis and UPJ (P <.05); however, no specimen was stained for p16, p21, and p53., Conclusion: In conclusion, impaired autophagy is associated with the development of congenital UPJO. Nonetheless, further studies are mandated to establish its etiologic role., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Recent studies have shown that vagus nerve activation inhibits cytokine production in a variety of non-neural cells though activation of α7 nicotinic acetylcholine receptor (α7nAChR). Since chronic inflammation plays a pivotal role in liver fibrosis, this study was designed to investigate the role of hepatic vagus nerve in the progression of hepatic fibrosis in rats. Cirrhosis was induced by chronic ligation of the bile duct. Hepatic hydroxyproline level, portal pressure, serum transaminase level, hepatic TIMP-1 (tissue inhibitor of metalloproteinase-1) and MCP-1 (monocyte chemoattractant peptide-1) expression were measured in order to assess the progression of liver cirrhosis. α7nAChR expression was assessed using RT-PCR as well as immunostaining. RT-PCR analysis of the liver showed that α7nAChR mRNA is expressed in rat liver. Immunostaining study demonstrated that hepatic α7nAChR is mainly expressed in the hepatocytes of cirrhotic liver with minimum α7nAChR expression in biliary epithelium or myofibroblasts. Bile duct ligation was associated with portal hypertension, increased hepatic hydroxyproline level as well as TIMP-1 and MCP-1 expression in the liver. However neither selective hepatic vagotomy nor methyllycaconitine (an α7nAChR antagonist) could significantly affect development of portal hypertension or hepatic fibrosis in rats. Selective hepatic vagotomy could only attenuate serum aspartate aminotransferase level in bile duct ligated rats but did not have a significant effect on hepatic inflammation as assessed by MCP-1 mRNA expression. Our study provides evidence against a crucial role for the hepatic vagus nerve as an intrinsic protective mechanism in modulation of hepatic fibrosis in a rat model of biliary cirrhosis., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Diabetic nephropathy is a serious complication of T1D (type one diabetes mellitus). Persistent hyperglycemia and subsequent hypomagnesemia is believed to develop kidney damage by activation of oxidative stress. We conducted this study to investigate the renoprotective effect of magnesium sulfate (MgSO4) on renal histopathology and oxidative stress in diabetic rats., Methods: The study included 70 male rats. The animals were divided into seven groups: control (CRL), control receiving MgSO4 (CRL + Mg1 & CRL + Mg8), diabetic (DM1 & DM8) and diabetic receiving MgSO4 (DM + Mg1 & DM + Mg8). Rats were given 20 mg/kg (i.p) Streptozocin (STZ) for 5 consecutive days in (MLD) multiple low doses to induce T1D. At day 10 treatment groups were received MgSO4 (10 g/l) in drinking water, for 1 or 8 weeks. The blood glucose, BUN and creatinine levels were measured. Renal tissue levels of malondialdehyde (MDA) were measured by thiobarbituric acid (TBA) method to evaluate the oxidative stress. Renal histopathology was done using H & E staining method., Results: Treatment with MgSO4 significantly decreased the blood glucose in DM + Mg1 and DM + Mg8 groups as compared with DM1 and DM8. Magnesium treatment also decreased serum BUN and tissue level of MDA significantly in both short and long term treatment. The body weight loss and kidney weight to body weight ratio was improved by MgSO4. Histological results showed there were no differences between DM and DM + Mg groups., Conclusion: Our findings showed that diabetic nephropathy is associated with high blood glucose level and oxidative stress (significant increase in MDA level). The renal dysfunction and oxidative stress can be improved by magnesium sulfate administration. It is suggested that protection against development of diabetic nephropathy by MgSO4 treatment involves changes in the blood glucose and oxidative stress.