In this editorial, we focus specifically on the mechanisms by which pancreatic inflammation affects pancreatic cancer. Cancer of the pancreas remains one of the deadliest cancer types. The highest incidence and mortality rates of pancreatic cancer are found in developed countries. Trends of pancreatic cancer incidence and mortality vary considerably worldwide. A better understanding of the etiology and identification of the risk factors is essential for the primary prevention of this disease. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this editorial, we highlight the foundational studies that have driven our understanding of these processes. In our experimental center, we have carefully studied the mechanisms of that link pancreatic inflammation and pancreatic cancer. We focused on the role of mast cells (MCs). MCs contain pro-angiogenic factors, including tryptase, that are associated with increased angiogenesis in various tumors. In this editorial, we address the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma tissue and adjacent normal tissue. The assessment includes the density of c-Kit receptor-positive MCs, the density of tryptase-positive MCs, the area of tryptase-positive MCs, and angiogenesis in terms of microvascularization density.

UNASSIGNED: Melanocytes show antigen expressions characteristic for the immune response effector cells, and the immune reactions in the skin, especially those with inflammation background, significantly affect the function of melanocytes. Among the cytokines produced by keratinocytes, the stem cell factor (SCF) plays a leading role in stimulating melanogenesis.
UNASSIGNED: To compare the expression level of stem cell factor (mSCF, pSCF) and the c-Kit receptor in the centre of the vitiligo patch and in the area of healthy skin adjacent to the vitiligo patch.
UNASSIGNED: The research material consisted of skin samples from a vitiligo lesion and from non-lesional skin adjacent to the vitiligo patch. Real Time PCR analysis (Applied Biosystems 7900HT) was performed to determine the expression level of the studied genes.
UNASSIGNED: The studies showed a statistically significant increase in the amount of mSCF within the vitiligo patch compared to both healthy skin of patients with vitiligo and controls. In patients with vitiligo, c-Kit receptor expression was significantly decreased in the area of the lesional skin compared to the healthy skin of the same patient and the skin of the control group.
UNASSIGNED: The membrane-bound form of the SCF is overexpressed within the vitiligo skin, which may indicate the participation of mSCF in the stimulation of melanogenesis in response to melanocyte damage. Decreased expression of C-Kit receptor by melanocytes in the vitiligo patch disrupts the ligand-receptor interaction and may therefore be related to melanocytes dysfunction and/or loss.

BACKGROUND: Several surveys have reported that patients treated with gonadotropin-releasing hormone antagonist (GnRH-ant) protocol showed a significantly lower rate of implantation and clinical pregnancy compared to GnRH agonist (GnRH-a) protocol during in vitro fertilization-fresh embryo transfer. Subsequent studies imputed this poor outcome to the negative effects of GnRH-ant on endometrial receptive. However, the mechanisms were not fully understood.
METHODS: The clinical data of 2815 patients undergoing fresh embryo transfer in our center were analyzed. Human endometrial stromal cells (ESCs) from healthy women undergoing elective pregnancy termination of a normal pregnancy at 8-10 weeks gestation were treated with GnRH-analogs or imatinib (c-kit receptor inhibitor). CCK8 and Flow cytometry were used to investigated the growth ability of ESCs. Immunofluorescence staining and western blot was used to detected the target proteins.
RESULTS: The clinical data showed that the endometrial thickness on HCG Day were significantly lower in GnRH-ant group. Although no difference of embryo quality in these two groups, GnRH-ant group showed remarkably decreased rate of HCG positive, embryo implantation and pregnancy. Moreover, GnRH-ant significantly reduced the proliferation and induced the apoptosis of ESCs. Furthermore, the expression and activation of c-kit receptor, which played pivotal roles during embryo implantation, were observably decreased by GnRH-ant. Inhibiting the activation of c-kit by imatinib remarkably suppressed the proliferation and promoted the apoptosis of ESCs. Additionally, the phosphorylation of AKT and expression of Cyclin D1, which were closely related with cellular growth, were distinctly lessened after treating with imatinib.
CONCLUSIONS: In summary, our study showed that GnRH-ant weakened the activization of c-kit receptor by decreasing its expression, causing the impaired growth ability of ESCs. Our findings provided a new insight into the effects of GnRH-ant on endometrium.

The pathogenesis of Androctonus autralis hector (Aah) scorpion venom involved cellular and molecular mechanisms resulting in multi-organ dysfunction. However, little is reported about the effects of venom on the gastrointestinal axis. Mast cells (MCs) are known to play a crucial role in modulating immune response of the gut. This study aims to investigate the involvement of this cell type in venom-induced gastric and intestinal disorders in a time course (3 and 24h). The obtained results revealed that Aah scorpion venom induced inflammatory cell infiltration as shown by the increase of the myeloperoxidase and eosinophil peroxidase activities. Overexpression of the c-kit receptor (CD117) severely imbalanced the redox status with depletion of antioxidant systemic accompanied by gastrointestinal tissue damage. Moreover, an increased level of lactate dehydrogenase in the serum was correlated with tissue injuries. Pharmacological inhibition of MCs targeting tyrosine kinase (TK) reduces the generation of reactive oxygen species and normalizes catalase, and gluthation S-transferase activities to their physiological levels. In addition, histopathological alterations were restored after pretreatment with c-kit receptor inhibitor associated with a considerable reduction of MC density. Interestingly, obtained results indicate that MCs might be involved in gastric modulation and intestinal inflammation through c-kit signaling following sub-cutaneous Aah venom injection.

Mast cells (MCs) contain proangiogenic factors, in particular tryptase, associated with increased angiogenesis in several tumours. With special reference to pancreatic cancer, few data have been published on the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma tissue (PDAT) and adjacent normal tissue (ANT). In this study, density of mast cells positive for c-Kit receptor (MCDP-c-KitR), density of mast cells positive for tryptase (MCDPT), area of mast cells positive for tryptase (MCAPT), and angiogenesis in terms of microvascular density (MVD) and endothelial area (EA) were evaluated in a total of 45 PDAT patients with stage T2-3N0-1M0.
For each analysed tissue parameter, the mean ± standard deviation was evaluated in both PDAT and ANT and differences were evaluated by Student\'s t-test (p ranged from 0.001 to 0.005). Each analysed tissue parameter was then correlated to each other one by Pearson t-test analysis (p ranged from 0.01 to 0.03). No other correlation among MCDP-c-KitR, MCDPT, MCAPT, MVD, EA and the main clinical-pathological characteristics was found.
Our results suggest that tissue parameters increased from ANT to PDAT and that mast cells are strongly associated with angiogenesis in PDAT. On this basis, the inhibition of MCs through tyrosine kinase inhibitors, such as masitinib, or inhibition of tryptase by gabexate mesylate may become potential novel antiangiogenetic approaches in pancreatic cancer therapy.

Aim: Stem cell factor (SCF) may be associated with inflammatory processes leading to aspirin-induced asthma. This study evaluated the relationship between serum level of SCF and its soluble receptor with aspirin-induced asthma. Methods & materials: Twenty-five patients and 25 healthy controls were enrolled in this study. The concentration of SCF and mast/stem cell growth factor receptor (C-kit) was determined in serum samples. Spirometry and rhinometry were performed to determine the severity of the disease. p < 0.05 were considered significant. Results: The serum levels of SCF and C-kit receptor were significantly higher in the case group. The serum SCF and C-kit level had a significant positive correlation with the severity of asthma, disease duration and nasal obstruction. Conclusion: Our findings suggest that SCF and C-kit receptors have a direct effect on the severity of aspirin-induced asthma.

Introduction: Systemic Mastocytosis (SM) is a complex family of rare diseases, against which pharmacological therapies are still very few. It is a c-kit driven disease, whose disregulation leads to uncontrolled activation and proliferation of mast cells (MCs) with consequent release of effector molecules which are responsible for its clinical manifestations. Areas covered: Masitinib is a relatively new potential drug against SM and its chemical structure strictly derives from imatinib, the first tyrosine kinase inhibitor which entered the pharmaceutical market about 15 years ago. In this review, the authors present masitinib in all its properties, from chemistry to pharmacology and toxicity to its potential clinical application in SM, focusing the discussion on the few clinical trials in which it has been involved, with a particular attention on the still open challenge to determine how to measure the response to therapy. Expert opinion: In spite of their similarity in chemistry and biological activity against submolecular targets, masitinib is much more selective towards c-kit receptors than other tyrosine kinases, such as Bcl-Abl. Furthermore, its ability to inhibit degranulation, cytokine production and MCs migration from bone marrow gives it a great chance to become an important therapeutic option for selected SM patients.

C-Kit protein is a transmembrane tyrosine kinase (TK) receptor (c-KitR-TK), which is predominantly expressed on mast cells (MCs) playing a role in tumor angiogenesis. It could be also expressed on epithelial breast cancer cells (EBCCs), but no data have been published regarding the correlation between mast cells positive to c-KitR (MCs-c-KitR), EBCCs positive to c-KitR (EBCCs-c-KitR), BC angiogenesis in terms of microvessel density (MVD) and the main clinic-pathological features. This study aims to evaluate the above parameters and their correlations in a series of selected 121 female early BC patients. It has been found a strong correlation between MVD and MCDPT, and MCs-c-KitR, MVD and MCs density positive to tryptase (MCDPT), and MCs-c-KitR and MCDPT by Pearson correlation. These data suggest an involvement of both MCDPT and MCs-c-KitR in BC tumor angiogenesis. Furthermore, BC tissue expressing c-KitR could be a putative predictive factor to c-KitR-TK inhibitors. In this way, selected patients with higher MCs-c-KitR could be candidate to receive c-KitR-TK inhibitors (e.g. masitinib, sunitinib) or tryptase inhibitors (e.g. nafamostat mesilate, gabexate mesilate).

BACKGROUND: Human c-kit-positive cardiac stem cells (CSCs) have been used to treat patients suffering from ischemic cardiomyopathy. This study aimed to investigate whether a long-term storage of cardiac tissues would influence the growth potential of the subsequently isolated CSCs.
METHODS: A total of 34 fresh samples were obtained from various cardiac regions [right atrium (RA), left atrium (LA), and/or left ventricle (LV)] of 21 patients. From 12 of these patients, 18 samples kept frozen for ~2 years were employed to prepare and characterize the CSCs. After confirming the specificity of the cell sorting by c-kit immunolabeling, the growth rate (number of doublings per day), BrdU positivity, and colony forming unit (CFU) were measured in each CSC population; the values were compared among distinct cardiac regions as well as between fresh and frozen tissues from which CSCs were derived.
RESULTS: Among independent measurements indicating growth potential, the growth rate and BrdU positivity remarkably correlated in freshly prepared CSCs. The cells obtained from every examined region displayed a high proliferative capacity with the growth rate of 0.48±0.19 and the BrdU positivity of 15.0%±7.6%. The right atrial CSCs tended to show a greater growth than those in the other two areas. Similarly, the CSCs were isolated from tissue blocks, cryopreserved for ~2 years, and compared with CSCs derived from the fresh specimens of the same patients. Importantly, we were able to obtain and culture CSCs from every frozen material, and their proliferative potential, represented by the growth rate of 0.47±0.22 and the BrdU positivity of 13.7%±7.9%, was not inferior to that of the freshly prepared cells.
CONCLUSIONS: The long-term cryopreservation of cardiac tissues did not affect the growth potential of the derivative CSCs. Our findings should expand the therapeutic applications of these cells over a longer time span.

BACKGROUND: The survival and growth of melanocytes are controlled by the binding of stem cell factor to its cell surface receptor c-kit+ (CD117). We have observed that c-kit+ melanocytes existed in some lesions of vitiligo, while Melan A+ cells were absent.
OBJECTIVE: To verify possible relation between c-kit+ expression and treatment response in non-segmental vitiligo lesions.
METHODS: Skin biopsies were done from the center of the 47 lesions from the 47 patients with non-segmental vitiligo. Expression of c-kit+ and Melan A, and amounts of melanin in the epidermis were assessed in each lesion, and treatment responses to excimer laser were evaluated.
RESULTS: Thirty-five of the 47 lesions (74.5%) had c-kit+ phenotypes. There was significant difference of c-kit staining value between good responders in 3 months of excimer laser treatment (average of 24 sessions) and the others.
CONCLUSIONS: c-Kit expression in vitiliginous epidermis may be related to better treatment responses to excimer laser.