Alpha-melanocyte stimulating hormone (α-MSH): biology, clinical relevance and implication in melanoma.

Alpha-melanocyte stimulating hormone (α-MSH) and its receptor, melanocortin 1 receptor (MC1R), have been proposed as potential target for anti-cancer strategies in melanoma research, due to their tissue specific expression and involvement in melanocyte homeostasis. However, their role in prevention and treatment of melanoma is still debated and controversial. Although a large body of evidence supports α-MSH in preventing melanoma development, some preclinical findings suggest that the α-MSH downstream signalling may promote immune escape and cancer resistance to therapy. Additionally, in metastatic melanoma both MC1R and α-MSH have been reported to be overexpressed at levels much higher than normal cells. Furthermore, targeted therapy (e.g. BRAF inhibition in BRAFV600E mutant tumours) has been shown to enhance this phenomenon. Collectively, these data suggest that targeting MC1R could serve as an approach in the treatment of metastatic melanoma. In this review, we explore the molecular biology of α-MSH with particular emphasis into its tumor-related properties, whilst elaborating the experimental evidence currently available regarding the interplay between α-MSH/MC1R axis, melanoma and antitumor strategies.

Macrophage-Mediated Melanoma Reduction after HP-NAP Treatment in a Zebrafish Xenograft Model.

The Helicobacter pylori Neutrophil Activating Protein (HP-NAP) is endowed with immunomodulatory properties that make it a potential candidate for anticancer therapeutic applications. By activating cytotoxic Th1 responses, HP-NAP inhibits the growth of bladder cancer and enhances the anti-tumor activity of oncolytic viruses in the treatment of metastatic breast cancer and neuroendocrine tumors. The possibility that HP-NAP exerts its anti-tumor effect also by modulating the activity of innate immune cells has not yet been explored. Taking advantage of the zebrafish model, we examined the therapeutic efficacy of HP-NAP against metastatic human melanoma, limiting the observational window to 9 days post-fertilization, well before the maturation of the adaptive immunity. Human melanoma cells were xenotransplanted into zebrafish embryos and tracked in the presence or absence of HP-NAP. The behavior and phenotype of macrophages and the impact of their drug-induced depletion were analyzed exploiting macrophage-expressed transgenes. HP-NAP administration efficiently inhibited tumor growth and metastasis and this was accompanied by strong recruitment of macrophages with a pro-inflammatory profile at the tumor site. The depletion of macrophages almost completely abrogated the ability of HP-NAP to counteract tumor growth. Our findings highlight the pivotal role of activated macrophages in counteracting melanoma growth and support the notion that HP-NAP might become a new biological therapeutic agent for the treatment of metastatic melanomas.

Dysregulation of oncogenic factors by GFI1B p32: investigation of a novel GFI1B germline mutation.

GFI1B is a transcription factor essential for the regulation of erythropoiesis and megakaryopoiesis, and pathogenic variants have been associated with thrombocytopenia and bleeding. Analysing thrombocytopenic families by whole exome sequencing, we identified a novel GFI1B variant (c.648+5G>A), which causes exon 9 skipping and overexpression of a shorter p32 isoform. We report the clinical data of our patients and critically review the phenotype observed in individuals with different GFI1B variants leading to the same effect on the p32 expression. Since p32 is increased in acute and chronic leukemia cells, we tested the expression level of genes playing a role in various type of cancers, including hematological tumors and found that they are significantly dysregulated, suggesting a potential role for GFI1B in carcinogenesis regulation. Increasing the detection of individuals with GFI1B variants will allow us to better characterize this rare disease and determine whether it is associated with an increased risk of developing malignancies.

The effect of weight loss after gastric bypass on C-reactive protein levels.

BACKGROUND: Recent studies have shown a direct correlation between C-reactive protein (CRP) level and obesity. There has also been increasing evidence that elevated CRP level is a significant risk factor for cardiac events and stroke. We wanted to evaluate whether CRP is altered by gastric bypass surgery. In addition, we wanted to investigate whether there was any correlation between reduced body mass index (BMI) and decreased CRP level. METHODS: CRP levels were obtained at 1 week preoperatively and then at 3 and 6 months postoperatively. Measurements of weight (kg), height (cm), and waist and hip circumferences (cm) were also measured at these time points. The BMI and CRP mean levels at the 3 time points were compared using a nonparametric Kruskal-Wallis 1-way analysis of variance test, with post hoc Z tests used for comparisons between the individual time periods. In addition, a linear regression analysis was performed at each time period to determine whether a significant correlation existed between the CRP level and the change in BMI. RESULTS: Twenty subjects (19 females and 1 male) have been studied to date. There were significant decreases in BMI between the preoperative and 3-month periods, with a further significant decrease at 6 months (44.5 +/- 4.7, 35.7 +/- 5.1, and 31.5 +/- 4.3, respectively; P < .05). CRP level decreased significantly between the preoperative and 3-month periods (1.02 +/- 0.7 to 0.49 +/- 0.09, respectively; P < .05). (Normal CRP level is < 0.5 mg/dL.) There was a tendency toward a further decrease in CRP level from 3 to 6 months, although this did not reach statistical significance (6-month mean, 0.39 +/- 0.10; P > .05). There was no statistically significant correlation between the change in BMI and CRP levels at any of the time periods. CONCLUSION: There were significant reductions in BMI and CRP levels after gastric bypass surgery. However, there was no statistically significant correlation between the decrease in BMI and the decrease in CRP levels.