Dermokine mutations contribute to epithelial-mesenchymal transition and advanced melanoma through ERK/MAPK pathways.

To discover vulnerabilities associated with dermokine (DMKN) as a new trigger of the epithelial-mesenchymal transition (EMT) -driven melanoma, we undertook a genome-wide genetic screening using transgenic. Here, we showed that DMKN expression could be constitutively increased in human malignant melanoma (MM) and that this correlates with poor overall survival in melanoma patients, especially in BRAF-mutated MM samples. Furthermore, in vitro, knockdown of DMKN inhibited the cell proliferation, migration, invasion, and apoptosis of MM cancer cells by the activation of ERK/MAPK signaling pathways and regulator of STAT3 in downstream molecular. By interrogating the in vitro melanoma dataset and characterization of advanced melanoma samples, we found that DMKN downregulated the EMT-like transcriptional program by disrupting EMT cortical actin, increasing the expression of epithelial markers, and decreasing the expression of mesenchymal markers. In addition, whole exome sequencing was presented with p.E69D and p.V91A DMKN mutations as a novel somatic loss of function mutations in those patients. Moreover, our purposeful proof-of-principle modeled the interaction of ERK with p.E69D and p.V91A DMKN mutations in the ERK-MAPK kinas signaling that may be naturally associated with triggering the EMT during melanomagenesis. Altogether, these findings provide preclinical evidence for the role of DMKN in shaping the EMT-like melanoma phenotype and introduced DMKN as a new exceptional responder for personalized MM therapy.

Low androgen level impairs erectile function of rat by regulating the Ng/CaN/AKT/eNOS pathway in penile corpus cavernosum.

BACKGROUND: The mechanism by which low androgen status inhibit erectile function has not yet been clearly elucidated. Neurogranin (Ng) is a Ca2+ -sensitive calmodulin binding protein that is expressed in endothelial cells and regulates eNOS function. OBJECTIVES: To investigate whether low androgen status inhibit erectile function by regulating the Ng/CaN/AKT/eNOS pathway in the penile cavernous tissue of rats. MATERIALS AND METHODS: Thirty-six 8-week-old male Sprague-Dawley rats were randomly divided into six groups as follows (n = 6): 4-week control group (4w-control), 4-week castration group (4w-cast), 4-week castration+testosterone replacement group (4w-cast+T), 8-week control group (8w-control), 8-week castration group (8w-cast), and 8-week castration+testosterone replacement group (8w-cast+T). Four weeks and eight weeks after surgery, the ratio of the maximum intracavernous pressure/mean arterial pressure (ICPmax/MAP) was examined. The level of NO and the expression of Ng, calcineurin (CaN), AKT, p-AKT(S473), eNOS, and p-eNOS(Ser1177) in the penile cavernous tissue of each group were determined. RESULTS: Ng and CaN were mainly expressed in the membrane and cytoplasm of endothelial cells and smooth muscle cells in the penile cavernous tissue of rats. The ICPmax/MAP and the concentration of NO in the cast group were significantly lower than those in the control group and cast+T replacement group (p < 0.01). The expression of Ng and the ratios of p-AKT/AKT and p-eNOS/eNOS in the penile cavernous tissue of rats in the cast group were significantly lower than those in the control group and cast+T replacement group (p < 0.01). The expression of CaN in the penile cavernous tissue of rats in the cast group was significantly increased compared with that in the control group and the cast+T replacement group (p < 0.01). CONCLUSION: Inhibiting the expression of Ng and subsequently upregulating the expression of CaN in the rat penile cavernous tissue was one of the upstream mechanisms of low androgen status inhibiting erectile function by inhibiting the AKT/eNOS signaling pathway.

Acute improvement in the attention network with repetitive transcranial magnetic stimulation in Parkinson's disease.

PURPOSE: To investigate the effect of two weeks of repetitive transcranial magnetic stimulation (rTMS) on the attention network in Parkinson's disease (PD) patients. MATERIALS AND METHODS: Sixty PD patients were randomly divided into equal-sized active- and sham-rTMS groups. Executive function was assessed by neuropsychological tests including the Trail-Making Test (TMT), word fluency test, digit span, Wisconsin Card Sorting Test (WCST) and Stroop test. The attention network was evaluated by the attention network test (ANT). rTMS (5 Hz) was applied over the left dorsolateral prefrontal cortex (DLPFC) in the active-rTMS group, and the sham-rTMS group underwent sham stimulation, both for two weeks. All tests were performed before and after rTMS. RESULTS: After active rTMS, nonparametric analysis revealed significant improvements in categories completed (CC) (p < 0.001) in the WCST and reaction times (RTs) in part 3 (p = 0.002) and the Stroop interference effect (SIE) (p < 0.001) in the Stroop test. Regarding the ANT, the RTs of the executive control network were significantly reduced (p < 0.001). There was no significant change after sham rTMS. CONCLUSIONS: In the short term, in PD patients, rTMS improved the executive control network involved in resolving conflicting information. However, it showed milder effects on neuropsychological test outcomes assessing executive function, which may involve different neuromechanisms.Implications for rehabilitationCognitive impairment is common in patients with Parkinson's disease (PD), and it is related to functional disability and reduced quality of life.Attention is a main component of the cognitive system, and attention deficits are responsible for disability.This study demonstrates that rTMS is beneficial for cognitive rehabilitation in PD, as patients showed improved performance on the attention network test and neuropsychological tests.