Dynamic glucose uptake, storage, and release by human microvascular endothelial cells.

Endothelia determine blood-to-tissue solute delivery, yet glucose transit is poorly understood. To illuminate mechanisms, we tracked [3H]-2-deoxyglucose (2-DG) in human adipose-tissue microvascular endothelial cells. 2-DG uptake was largely facilitated by the glucose transporters GLUT1 and GLUT3. Once in the cytosol, >80% of 2-DG became phosphorylated and ∼20% incorporated into glycogen, suggesting that transported glucose is readily accessible to cytosolic enzymes. Interestingly, a fraction of intracellular 2-DG was released over time (15-20% over 30 min) with slower kinetics than for uptake, involving GLUT3. In contrast to intracellular 2-DG, the released 2-DG was largely unphosphorylated. Glucose release involved endoplasmic reticulum-resident translocases/phosphatases and was stimulated by adrenaline, consistent with participation of glycogenolysis and glucose dephosphorylation. Surprisingly, the fluorescent glucose derivative 2-NBD-glucose (2-NBDG) entered cells largely via fluid phase endocytosis and exited by recycling. 2-NBDG uptake was insensitive to GLUT1/GLUT3 inhibition, suggesting poor influx across membranes. 2-NBDG recycling, but not 2-DG efflux, was sensitive to N-ethyl maleimide. In sum, by utilizing radioactive and fluorescent glucose derivatives, we identified two parallel routes of entry: uptake into the cytosol through dedicated glucose transporters and endocytosis. This reveals the complex glucose handling by endothelial cells that may contribute to glucose delivery to tissues.

Quantitative digital image analysis of somatostatin receptor 2 immunohistochemistry in pancreatic neuroendocrine tumors.

Immunohistochemical analysis of somatostatin receptor 2 (SSTR2) provides important information regarding the potential therapeutic efficacy of somatostatin analogues (SSAs) in patients with neuroendocrine tumors. HER2 scoring has been proposed to interpret SSTR2 immunoreactivity but their reproducibility was relatively low because of its intrinsic subjective nature. Digital image analysis (DIA) has recently been proposed as an objective and more precise method of evaluating immunoreactivity. Therefore, in this study, we used DIA for analyzing SSTR2 immunoreactivity in pancreatic neuroendocrine tumors (PanNETs) to obtain its H score and "(%) strong positive cells" and compared the results with those of manually obtained HER2 scores. Membranous SSTR2 immunoreactivity evaluated by DIA was calculated by two scales as: "Membrane Optical Density" and "Minimum Membrane Completeness". PanNETs with HER2 score of > 2 demonstrated the highest concordance with results of "(%) strong positive cells" obtained by DIA when "Minimum Membrane Completeness" was tentatively set at 80%. The SSTR2 immunoreactivity, evaluated based on all scoring systems, was different between grades G1 and G2 in insulinoma but not in non-functional PanNETs. DIA provided reproducible results of SSTR2 immunoreactivity in PanNETs and yielded important information as to the potential application of SSAs.

Ventilation Prediction for an Industrial Cement Raw Ball Mill by BNN-A "Conscious Lab" Approach.

In cement mills, ventilation is a critical key for maintaining temperature and material transportation. However, relationships between operational variables and ventilation factors for an industrial cement ball mill were not addressed until today. This investigation is going to fill this gap based on a newly developed concept named "conscious laboratory (CL)". For constructing the CL, a boosted neural network (BNN), as a recently developed comprehensive artificial intelligence model, was applied through over 35 different variables, with more than 2000 records monitored for an industrial cement ball mill. BNN could assess multivariable nonlinear relationships among this vast dataset, and indicated mill outlet pressure and the ampere of the separator fan had the highest rank for the ventilation prediction. BNN could accurately model ventilation factors based on the operational variables with a root mean square error (RMSE) of 0.6. BNN showed a lower error than other traditional machine learning models (RMSE: random forest 0.71, support vector regression: 0.76). Since improving the milling efficiency has an essential role in machine development and energy utilization, these results can open a new window to the optimal designing of comminution units for the material technologies.

Progesteron receptor expression in insulin producing cells of neuroendocrine neoplasms.

Progesterone receptor (PgR) inhibits cell proliferation in pancreatic neuroendocrine neoplasms (PanNEN). In non-neoplastic pancreas, loss of PgR induces ß-cell proliferation and insulin production. However, detailed association between PgR and insulin producing PanNENs is poorly understood. Insulin, proinsulin, and PgR were immunolocalized in 82 PanNENs (54 non-functioning PanNENs: NF-PanNENs and 28 insulinomas). The status of immunoreactivity was compared to the clinicopathological factors of the patients. Immunoreactivity was also confirmed by employing the double-immunohistochemistry. These results were also compared with those in non-neoplastic Langerhans islets. PgR immunoreactivity was significantly higher in insulinomas than that in NF-PanNENs (p < 0.001). Insulin and proinsulin immunoreactivity was also detected in 20 (37 %) of (single cell) insulin positive NFs (Inspos-NF-PanNEN), in which PgR expression was higher than in insulin negative NF-PanNENs (Insneg-NF-PanNEN, p = 0.03). The ratio of PgR-insulin double positive cells to overall insulin positive cells, as well as PgR-proinsulin double positive cells to proinsulin positive cells, was detected to the same degree in insulinoma (PgR-insulin 70 %, PgR-proinsulin 66 %), Inspos-NF-PanNENs (PgR-insulin 65 %, PgR-proinsulin 68 %) and normal islet (PgR-insulin 80 %, PgR-proinsulin 72 %). PgR and insulin expressing cells colocalize in tumor cells of the PanNENs regardless of the hormone-related symptoms of the patients. Inhibitory effect of PgR on tumor cells might be associated with the favourable clinical outcome of insulinoma patients.

Endothelial cell barriers: Transport of molecules between blood and tissues.

An endothelial cell monolayer separates interstitia from blood and lymph, and determines the bidirectional transfer of solutes and macromolecules across these biological spaces. We review advances in transport modalities across these endothelial barriers. Glucose is a major fuel for the brain and peripheral tissues, and insulin acts on both central and peripheral tissues to promote whole-body metabolic signalling and anabolic activity. Blood-brain barrier endothelial cells display stringent tight junctions and lack pinocytic activity. Delivery of blood glucose and insulin to the brain occurs through their respective carrier (Glucose transporter 1) and receptor (insulin receptor), enacting bona fide transcytosis. At supraphysiological concentrations, insulin is also likely transferred by fluid phase cellular uptake and paracellular transport, especially in peripheral microvascular endothelia. The lymphatic microvasculature also transports insulin but in this case from tissues to lymph and therefrom to blood. This serves to end the hormone's action and to absorb highly concentrated subcutaneously injected insulin in diabetic individuals. The former function may involve receptor-mediated transcytosis into lymphatic endothelial cells, the latter fluid phase uptake and paracellular transport. Lymphatic capillaries also mediate carrier-dependent transport of other nutrients and macromolecules. These findings challenge the notion that lymphatic capillaries only transport macromolecules through intercellular flaps.

Progesterone arrested cell cycle progression through progesterone receptor isoform A in pancreatic neuroendocrine neoplasm.

In pancreatic neuroendocrine neoplasms (Pan-NEN) progesterone signaling has been shown to have both inhibitory and stimulatory effects on cell proliferation. The ability of progesterone to inhibit tumor proliferation is of particular interest and is suggested to be mediated through the less abundantly expressed progesterone receptor (PR) isoform A (PRA). To date the mechanistic processes underlying this inhibition of proliferation remain unclear. To examine the mechanism of PRA actions, the human Pan-NEN cell line QGP-1, that endogenously expresses PR isoform B (PRB) without PRA, was transfected with PRA. PRA transfection suppressed the majority of cell cycle related genes increased by progesterone including cyclin A2 (CCNA2), cyclin B1 (CCNB1), cyclin-dependent kinase 1 (CDK1) and cyclin-dependent kinase 2 (CDK2). Importantly, following progesterone administration cell cycle distribution was shifted to S and G2/M phases in the naïve cell line but in PRA-transfected cells, this effect was suppressed. To see if these mechanistic insights were confirmed in patient samples PRA, PRB, CCNA2, CCNB, CDK1 and CDK2 immunoreactivities were assessed in Pan-NEN cases. Higher levels of cell cycle markers were associated with higher WHO grade tumors and correlations between the markers suggested formation of cyclin/CDK activated complexes in S and G2/M phases. PRA expression was associated with inverse correlation of all cell cycle markers. Collectively, these results indicate that progesterone signals through PRA negatively regulates cell cycle progression through suppressing S and G2/M phases and downregulation of cell cycle phases specific cyclins/CDKs.

High interlaboratory and interobserver agreement of somatostatin receptor immunohistochemical determination and correlation with response to somatostatin analogs.

Monoclonal antibodies to somatostatin receptors 2A (SSTR2A, UMB-1) and 5 (SSTR5, UMB-4) were reported to be highly reliable for immunohistochemical detection of these receptors in neuroendocrine neoplasms. However, the standardization of either the immunohistochemical procedure and the methods of evaluation has yet to be established. Fifty-two tissues from 38 patients with neuroendocrine neoplasm were retrieved from 2 institutions in Italy and Japan. The tissues were immunostained using 3 staining methodologies: 1 automated and 2 manual protocols from the Italian and Japanese institutions. The slides were independently evaluated by 3 observers (2 experienced pathologists and 1 medical student) using 3 scoring systems (Volante-Score, HER2-Score, and H-Score). The scores obtained from the staining methods were highly correlated with each other (r>0.85, P<.0001). Especially, the Volante- and HER2-Scores were highly concordant (r≥0.95, P≤.0001). Very high interobserver agreement was obtained irrespective of the method used and the experience of the evaluator, with the best concordance obtained by experienced pathologists evaluating automated system-stained slides (SSTR2A, r>0.97; SSTR5, r>0.96). HER2- and H-Scores were reliable to represent the characteristics of the patients. SSTR2A expression evaluated by the HER2-Score was significantly associated with clinical efficacy to somatostatin analogs (P=.04). SSTRs determination is an easily standardizable tool in different laboratories and is highly reproducible irrespective of the method of evaluation used. Given the positive association with clinical efficacy to somatostatin analogs, as well as the simple and widespread use, HER2-Score can be proposed as a standard evaluation procedure of SSTR2A and SSTR5 expression in neuroendocrine neoplasms.

SOX2 and Rb1 in esophageal small-cell carcinoma: their possible involvement in pathogenesis.

Clinicopathological features and pathogenesis of esophageal small-cell carcinoma remain unclear. We hypothesized common cellular origin and pathogenesis in small-cell carcinoma of esophagus and lung associated with SOX2 overexpression and loss of Rb1. Expression of squamous-basal markers (CK5/6 and p40), glandular markers (CK18 and CEA), SOX2, and Rb1 were evaluated in 15 esophageal small-cell carcinomas, 46 poorly differentiated squamous cell carcinomas, and 88 small-cell lung carcinoma, as well as 16 embryonic esophagus. Esophageal small-cell carcinoma expressed higher levels of glandular markers and lower levels of squamous-basal markers than poorly differentiated squamous cell carcinoma. No significant differences were observed in immunohistochemistry profiles between small-cell carcinoma of the esophagus and the lung. SOX2 expression was high in esophageal small-cell carcinoma (70%±33% of nuclei), small-cell lung carcinoma (70%±26%), and the embryonic esophagus (75%±4%), and it was significantly lower in poorly differentiated squamous cell carcinoma (29%±28%). Rb1 expression was significantly lower in esophageal small-cell carcinoma (0.3%±1%), small-cell lung carcinoma (2%±6%), and the embryonic esophagus (7%±5%), and it was significantly higher in poorly differentiated squamous cell carcinoma (51%±24%). The immunohistochemistry profiles of small-cell carcinoma of the esophagus and the lung are highly similar. The loss of Rb1 function is a key contributor to the pathogenesis of both neoplasms. In addition, SOX2 overexpression observed in esophageal and lung small-cell carcinoma as well as in the embryonic esophagus indicated that esophageal small-cell carcinoma may arise from embryonic-like stem cells in the esophageal epithelium. The two distinct differentiation patterns (neuroendocrine and glandular) of esophageal small-cell carcinoma further support the fact that SOX2 has a pivotal role in the differentiation of pluripotent stem cells into esophageal small-cell carcinoma cells.

Progesterone Receptor Isoforms A and B in Pancreatic Neuroendocrine Tumor.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) have been reported to express progesterone receptor (PR), and its expression has been demonstrated to be a favorable prognostic factor in these patients. We examined the status of the PR isoforms PRA and PRB in the human PNET cell line and their association with cell proliferation of the tumor cells, which is closely related to the clinical outcome of PNET patients. METHODS: Quantitative RT-PCR and cell proliferation assays were performed following treatment with progesterone and RU-486 as a PR antagonist in nontransfected and PRA-transfected cells of the NET cell line QGP-1, which expresses PRB in its native state. PRA, PRB and cyclin D1 (CCND1) were immunolocalized in 87 PNET cases, and the results were compared with clinicopathological parameters. RESULTS: CCND1, c-Fos and c-Jun mRNA levels were all significantly increased by treatment with progesterone in QGP-1 cells with PRB expression compared with PRA-transfected cells (p = 0.02, p = 0.007 and p = 0.001, respectively). The proliferative activity of QGP-1 cells with PRB expression was also significantly stimulated by the administration of progesterone (p = 0.008). PRA immunoreactivity was significantly decreased in higher-grade PNETs (p = 0.04), whereas CCND1 was significantly elevated in higher-grade PNETs (p = 0.035). CONCLUSION: The results of the present study demonstrate that PRA could play an inhibitory role in the cell proliferation of PNETs, possibly by inhibiting PRB-mediated signals in the presence of progesterone, which could result in decreased CCND1 expression. In addition, the status of PRA in tumor cells could be a prognostic factor in PNETs.

Pathology diagnosis of pancreatic neuroendocrine tumors.

Histopathology of pancreatic neuroendocrine tumors (PNETs) typically displays characteristic features. However, pathologists may encounter histological variants that may resemble other pancreatic tumors. Immunohistochemistry is a powerful tool in confirming neuroendocrine differentiation and differentiating PNETs with other pancreatic neoplasms. Histopathological features could be associated with inherited syndromes. Once the pathology diagnosis of neuroendocrine tumor was made, an accurate grading based on World Health Organization (WHO) classification is required. This review will focus on histology variants, immunohistochemistry and WHO classification of PNET.

Angiogenesis and vascular maturation in neuroendocrine tumors.

Neuroendocrine tumors (NETs) are highly vascularized, but the process of proliferation and maturation of vascular structures during tumor development and progression has remained unknown. We examined the structural alterations of intratumoral blood vessels in human gastroenteropancreatic NET. Microvessel density was evaluated using the endothelial cell markers vasohibin-1 (VASH-1), CD31, and endoglin in 135 cases. Double immunohistochemistry staining was performed to localize endothelium and pericytes on the same vessels using the pericyte marker nestin. The ratio of Ki-67/CD31 was significantly correlated with that of VASH-1/CD31 positivity (P<.001), indicating that the ratio of VASH-1/CD31 also reflects the status of neovascularization in NET. This ratio was higher in NET than in its nonneoplastic counterpart (P=.10) and tended to increase according to World Health Organization (WHO) grade, although the differences were not statistically significant (P=.32). The ratio of VASH-1/nestin-positive vessels, representing the maturation of neovessels, was also significantly higher in NET than in its nonneoplastic counterparts (P=.003). Among WHO grades, the ratio increased from grade 1 to grade 2 (P=.36) and decreased in neuroendocrine carcinoma (P=.34). Our results demonstrated that VASH-1/CD31 can be an ideal immunohistochemical marker for characterizing neovascularization in NET. The VASH-1/CD31 content increased with WHO grade, and the vessels covered by pericytes decreased in higher grades. These structural changes in the vessels are considered to play an important role in inducing tumor-cell proliferation.

Clinicopathologic significance of immunostaining of α-thalassemia/mental retardation syndrome X-linked protein and death domain-associated protein in neuroendocrine tumors.

α-Thalassemia/mental retardation syndrome X-linked protein (ATRX) and death domain-associated protein (DAXX) genes are tumor suppressors whose mutations have been identified in sporadic pancreatic neuroendocrine tumors as well as in patients with MEN1. However, it is unknown whether ATRX and DAXX alterations are specific for pancreatic neuroendocrine tumor. In addition, the association of ATRX/DAXX protein loss with tumor cell proliferation has not been examined. We, therefore, immunostained ATRX and DAXX in 10 gastric, 15 duodenal, 20 rectal, 70 pancreatic, and 22 pulmonary neuroendocrine tumors with 15 nonneoplastic pancreases and 27 pancreatic adenocarcinomas to elucidate the site-specific roles of ATRX/DAXX abnormalities. At least 1 loss of ATRX and DAXX immunoreactivity was detected in all neuroendocrine tumor cases but not in any of nonneoplastic pancreatic tissues or pancreatic adenocarcinomas. The loss of DAXX protein was correlated with the Ki-67 index (ATRX, P = .904; DAXX, P = .044). The status of DAXX immunoreactivity correlated positively with World Health Organization histologic grade (P = .026). These results suggest that the status of ATRX or DAXX protein loss in neuroendocrine tumor differed among the organs in which these tumors arose, and these proteins may play site-specific roles in the development of these tumors.

Increased expression of transforming growth factor-ß and receptors in primary human airway fibroblasts from chemical inhalation patients.

The widespread use of sulfur mustard (SM) as a chemical warfare agent in the past century has proved its long-lasting toxic effects. Despite a lot of research over the past decades on Iranian veterans, there are still major gaps in the SM literature. Transforming growth factor (TGF-ß), a cytokine that affects many different cell processes, has an important role in the lungs of patients with some of chronic airway diseases, especially with respect to airway remodeling in mustard lung. Primary airway fibroblasts from epibronchial biopsies were cultured, and gene expression of TGF-ß1, TGF-ß2, TbR-I and TbR-II in fibroblasts of SM injured patients and controls were investigated. Expression of TGF-ßs and receptors was measured by RT-PCR. Protein level of TGF-ß1 was surveyed by western blot. Our findings revealed that expression levels of TGF-ß1, TGF-ß2, TbR-I and TbR-II were upregulated in the airway fibroblasts of SM exposed patients in comparison with control samples. TGF-ß1 expression was shown to be markedly increased in primary lung fibroblasts of chemically injured patients. Our novel data, suggested that over-expression of TGF-ß molecule and receptors in primary airway fibroblasts of mustard gas injured patients may be involved in progression of airway remodeling of these patients.

Feature subset selection using constrained binary/integer biogeography-based optimization.

Feature selection plays a crucial role in applications where data consists of hundreds of features due to curse of dimensionality. This paper presents two feature selection methods by modifying the main operators of Biogeography-Based Optimization algorithm. The difference between these methods is in employing binary or integer coding. The simulations perform on datasets with different feature dimensions and classes. The results indicate the effectiveness of the proposed methods in comparison with other most frequently used meta-heuristic strategies in feature selection problems.

Proliferation and maturation of intratumoral blood vessels in non-small cell lung cancer.

Non-small cell lung carcinoma is one of the most common leading causes of cancer mortality, and studying the features of intratumoral vessels, especially their generation and maturation, has become more important because of the recent application of antiangiogenic therapy. Vasohibin-1 has been recently considered one of the immunohistochemical markers for identifying neovascularization in archival materials. In addition, the functional maturation of blood vessels is considered to be related to pericyte formation around endothelial cells. Therefore, in this study, we evaluated the status of angiogenesis and maturation of intratumoral blood vessels in 93 patients with non-small cell lung carcinoma (50 with adenocarcinoma and 43 with squamous cell carcinoma) using immunohistochemistry of vasohibin-1, endoglin, CD31, and nestin. The vasohibin-1/CD31-positive ratio was significantly (P = .03) correlated with the Ki-67/CD31 ratio, confirming that the vasohibin-1/CD31-positive ratio represented the status of neovascularization in lung cancer. There were no statistically significant differences in vasohibin-1/CD31 ratios between adenocarcinoma and squamous cell carcinoma in both inner (P = .39) and outer areas (P = .36) of the tumor. The vasohibin-1/nestin-positive ratio, which represents the degrees of vascular maturation in proliferative vessels, was significantly lower in inner areas of adenocarcinoma (0.4 ± 0.1) than those in squamous cell carcinoma (0.8 ± 0.1) (P = .02). These results demonstrated that the degrees of maturation in newly formed blood vessels were less developed in inner areas of squamous cell carcinoma than adenocarcinoma, which may account partly for the complications of antivascular endothelial growth factor therapy more frequently detected in patients with squamous cell carcinoma.

Smad molecules expression pattern in human bronchial airway induced by sulfur mustard.

Airway remodelling is characterized by the thickening and reorganization of the airways seen in mustard lung patients. Mustard lung is the general description for the chronic obstructive pulmonary disease induced by sulfur mustard(SM). Pulmonary disease was diagnosed as the most important disorder in individuals that had been exposed to sulfur mustard. Sulfur mustard is a chemical warfare agent developed during Wars. Iraqi forces frequently used it against Iranian during Iran -Iraq in the 1980-1988. Peribronchial fibrosis result from airway remodeling that include excess of collagen of extracellular matrix deposition in the airway wall. Some of Smads families in association with TGF-ß are involved in airway remodeling due to lung fibrosis. In the present study we compared the mRNA expression of Smad2, Smad3, and Smad4 and Smad7 genes in airway wall biopsies of chemical-injured patients with non-injured patients as control. We used airway wall biopsies of ten unexposed patients and fifteen SM-induced patients. Smads expression was evaluated by RT-PCR followed by bands densitometry. Expression levels of Smad3 and Smad4 in SM exposed patients were upregulated but Smad2 and Smad7 was not significantly altered. Our results revealed that Smad3, and 4 may be involved in airway remodeling process in SM induced patients by activation of TGF-ß. Smad pathway is the most represented signaling mechanism for airway remodeling and peribronchial fibrosis. The complex of Smads in the nucleus affects a series of genes that results in peribronchial fibrosis in SM-induced patients.

Nuclear factor κB1/RelA mediates the inflammation and/or survival of human airway exposed to sulfur mustard.

CONTEXT: Sulfur mustard (SM) is known as an effective chemical agent and was used in the 1980s during the Iran-Iraq war against Iranians. At the present time, there are more than 40,000 people suffering from pulmonary lesions due to mustard gas in Iran. Though much is known about the gross pathology of SM damage, the molecular and cellular basis for this pathology is not well understood. OBJECTIVE: One of the most important protein groups involved in inflammatory responses is nuclear factor κB protein (NF-κB1) family. They belong to the category of DNA-binding protein factors necessary for transcription of many proinflammatory molecules. In our research, we examined the role of NF-κB1/RelA in the pathophysiology of the lung. MATERIALS AND METHODS: We investigated 10 normal individuals and 20 SM induced patients. Expression of NF-κB1/RelA in controls and the SM exposed samples was measured by real-time polymerase chain reaction and localization of NF-κB1 protein was detected by immunohistochemistry staining. RESULTS: Our results revealed that expression levels of NF-κB1 and RelA were upregulated 0.64-6.50 fold and 0.83-8.34 fold, respectively, in the SM exposed patients in comparison with control samples. DISCUSSION AND CONCLUSION: As far as we know, this is the first finding of induction of NF-κB in patients exposed to SM. NF-κB1/RelA may play a major role in inflammation induced by mustard gas or even in cell survival in the bronchial wall of affected patients.

Toll-like receptors: role of inflammation and commensal bacteria.

TLR ligands are present on both commensal and pathogenic microbes. Intestinal epithelial cells (IECs) have been observed to be largely unresponsive to TLR ligands. This observation has partly been explained by the fact that TLR expression on IECs is sparse. The discovery of the Toll-like receptors finally identified the innate immune receptors that were responsible for many of the innate immune functions that had been studied for many years. Interestingly, TLRs seem only to be involved in the cytokine production and cellular activation in response to microbes, and do not play a significant role in the adhesion and phagocytosis of microorganisms. One member of this group, interleukin-1ß (IL-1ß), together with tumour-necrosis factor (TNF), is defined as an alarm cytokine. It is secreted by macrophages and initiates inflammation on activation of TLRs.

Loss of expression of TGF-ßs and their receptors in chronic skin lesions induced by sulfur mustard as compared with chronic contact dermatitis patients.

BACKGROUND: Sulfur mustard (SM) is a blister-forming agent that has been used as a chemical weapon. Sulfur mustard can cause damage in various organs, especially the skin, respiratory system, and eyes. Generally, the multiple complications of mustard gas result from its alkalizing potency; it reacts with cellular components like DNA, RNA, proteins, and lipid membranes.TGF-ß is a multi-functional cytokine with multiple biological effects ranging from cell differentiation and growth inhibition to extracellular matrix stimulation, immunosuppression, and immunomodulation. TGF-ß has 3 isoforms (TGF-ß 1, 2, 3) and its signaling is mediated by its receptors: R1, R2 and intracellular Smads molecules.TGF-ß has been shown to have anti-inflammatory effects. TGF-ßs and their receptors also have an important role in modulation of skin inflammation, proliferation of epidermal cells, and wound healing, and they have been implicated in different types of skin inflammatory disorders. METHODS: Seventeen exposed SM individuals (48.47 ± 9.3 years), 17 chronic dermatitis patients (46.52 ± 14.6 years), and 5 normal controls (44.00 ± 14.6 years) were enrolled in this study.Evaluation of TGF-ßs and their receptors expressions was performed by semiquantitative RT-PCR. Only TGF1 was analyzed immunohistochemically. RESULTS: Our results showed significant decreases in the expression percentages of TGF-ß 1, 2 and R1, R2 in chemical victims in comparison with chronic dermatitis and normal subjects and significant decreases in the intensity of R1 and R2 expressions in chemical victims in comparison with chronic dermatitis and normal controls. (P value < 0.05) CONCLUSIONS: TGF-ßs and their receptors appear to have a noticeable role in chronic inflammatory skin lesions caused by sulfur mustard.