Molecular Profiling and Novel Therapeutic Strategies for Mucosal Melanoma: A Comprehensive Review

Mucosal melanoma is a rare and aggressive subtype of melanoma. Unlike its cutaneous counterpart, mucosal melanoma has only gained limited benefit from novel treatment approaches due to the lack of actionable driver mutations and poor response to immunotherapy. Over the last years, whole-genome and exome sequencing techniques have led to increased knowledge on the molecular landscape of mucosal melanoma. Molecular studies have underlined noteworthy findings with potential therapeutic implications, including the presence of KIT mutations, which are potential targets of tyrosine kinase inhibitors currently in use in the clinic (imatinib), but also SF3B1 mutation, CDK4 amplifications, and CDKN2A gene deletions, which are presently under investigation in clinical trials. Recent results from a pooled analysis of patients with mucosal melanoma treated with immunotherapy have suggested that the combination of immune checkpoint inhibitors might improve survival outcomes in this subset of patients, as compared with single-agent immunotherapy. However, these results are not confirmed across different studies, and combo-immunotherapy correlates with a higher rate of adverse events. In this review, we describe the clinical, biological, and genetic features of mucosal melanoma. We also provide an update on the results of approved systemic treatment in this setting and overview the therapeutic strategies currently under investigation in clinical trials.     

Dystrophin Deficiency Causes Progressive Depletion of Cardiovascular Progenitor Cells in the Heart

Duchenne muscular dystrophy (DMD) is a devastating condition shortening the lifespan of young men. DMD patients suffer from age-related dilated cardiomyopathy (DCM) that leads to heart failure. Several molecular mechanisms leading to cardiomyocyte death in DMD have been described. However, the pathological progression of DMD-associated DCM remains unclear. In skeletal muscle, a dramatic decrease in stem cells, so-called satellite cells, has been shown in DMD patients. Whether similar dysfunction occurs with cardiac muscle cardiovascular progenitor cells (CVPCs) in DMD remains to be explored. We hypothesized that the number of CVPCs decreases in the dystrophin-deficient heart with age and disease state, contributing to DCM progression. We used the dystrophin-deficient mouse model (mdx) to investigate age-dependent CVPC properties. Using quantitative PCR, flow cytometry, speckle tracking echocardiography, and immunofluorescence, we revealed that young mdx mice exhibit elevated CVPCs. We observed a rapid age-related CVPC depletion, coinciding with the progressive onset of cardiac dysfunction. Moreover, mdx CVPCs displayed increased DNA damage, suggesting impaired cardiac muscle homeostasis. Overall, our results identify the early recruitment of CVPCs in dystrophic hearts and their fast depletion with ageing. This latter depletion may participate in the fibrosis development and the acceleration onset of the cardiomyopathy.     

Influence of Shenqing Recipe on Morphology and Quantity of Colonic Interstitial Cells of Cajal in Trinitrobenzene Sulfonic Acid Induced Rat Colitis

Objective To observe the influence of Shenqing Recipe (SQR),a kind of Traditional Chinese Medicine,on the morphology and quantity of colonic interstitial cells of Cajal (ICC) in trinitrobenzene sulfonic acid (TNBS)-induced rat colitis,and to investigate the possible mechanism of SQR in regulating intestinal dynamics.Methods Sixty rats were randomly divided into normal control,model I ,model Ⅱ,mesalazine,and high-dose,and low-dose SQR groups with 10 rats in each group.TNBS (10 mg) dissolved in 50% etha-nol was instilled into the lumen of the rat colon of the latter five groups to induce colitis.On the 4th day after administration of TNBS,each treatment group was administered one of the following formulations by enteroclysis gavage once a day for 7 days:600 mg · kg-1·d-1 mesalazine,2.4 g·kg-1·d-1 SQR,and 1.2 g·kg-1·d-1 SQR.Model Ⅱ rats received normal saline solution.After 7 days colonic samples were collected.While the colonic samples of model I group were collected on the 3rd day after TNBS administered.Ultrastructure of ICC in the damaged colonic tissues was observed with transmission electron microscope.Expression of c-kit protein in colonic tissue was determined by immunohistochemical staining and Western blot.Results The ultrastructure of colonic ICC in the rat model of TNBS-induced colitis showed a severe injury,and administration of SQR or mesalazine reduced the severity of injury.Similarly,the expression of c-kit protein of TNBS-induced colitis rat model was significantly decreased compared with the normal control group (P<0.05).Treatment with SQR or mesalazine significantly increased die expression of c-kit protein compared with the administration of control formulations (P<0.05),especially the high-dose SQR group.Conclusion SQR could alleviate and repair the injured ICC,and improve its quantity,which might be involved in regulating intestinal motility.