A large proportion of human melanomas harbor a mutation leading to permanent activation of the serine/threonine kinase BRAF, and as a consequence, they have developed dependence on BRAF/mitogen-activated protein kinase signaling. Accordingly, BRAF inhibitors such as Vemurafenib show a good anti-tumorigenic effect on metastases with the BRAF(V600E) mutation. Although an initial period of sustained tumor regression is usually observed after Vemurafenib treatment, tumors often relapse at the same site, and apoptosis induction of melanoma cells in vitro is incomplete. Here, we demonstrate, using a large panel of melanoma cell lines, that Vemurafenib induces features of stress-induced senescence in addition to apoptosis. This senescence phenotype is characterized by heterochromatin formation, changes in cell shape, and increased senescence-associated β-galactosidase activity. Importantly, senescence features induced by BRAF(V600E) inhibition was also detected in human melanoma cells xenografted into nude mice. Our observations provide a possible explanation for the lack of complete and durable pro-apoptotic effect of Vemurafenib in patients.
Impaired nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP signaling is involved in the pathogenesis of ischemic heart diseases, yet the impact of long-term sGC activation on progressive cardiac remodeling and heart failure after myocardial infarction (MI) has not been explored. Moreover, it is unknown whether stimulating the NO/heme-independent sGC provides additional benefits to ACE inhibition in chronic ischemic heart failure. Starting 10 days after MI, rats were treated with placebo, the sGC activator ataciguat (10 mg/kg/twice daily), ramipril (1 mg/kg/day), or a combination of both for 9 weeks. Long-term ataciguat therapy reduced left ventricular (LV) diastolic filling pressure and pulmonary edema, improved the rightward shift of the pressure-volume curve, LV contractile function and diastolic stiffness, without lowering blood pressure. NO/heme-independent sGC activation provided protection over ACE inhibition against mitochondrial superoxide production and progressive fibrotic remodeling, ultimately leading to a further improvement of cardiac performance, hypertrophic growth and heart failure. We found that ataciguat stimulating sGC activity was potentiated in (myo)fibroblasts during hypoxia-induced oxidative stress and that NO/heme-independent sGC activation modulated fibroblast-cardiomyocyte crosstalk in the context of heart failure and hypoxia. In addition, ataciguat inhibited human cardiac fibroblast differentiation and extracellular matrix protein production in response to TGF-β1. Overall, long-term sGC activation targeting extracellular matrix homeostasis conferred cardioprotection against progressive cardiac dysfunction, pathological remodeling and heart failure after myocardial infarction. NO/heme-independent sGC activation may prove to be a useful therapeutic target in patients with chronic heart failure and ongoing fibrotic remodeling.
Cutaneous horn is a relatively uncommon lesion, also known by the Latin name "Cornu cutaneum". Although there are multiple reports of cutaneous horns, giant cutaneous horns are much rarer. Cutaneous horns resemble animal horns at first glance. Most of them develop on face and scalp, but any part of the body can be involved.A 90-year-old woman presented with a nineyear history of a large cutaneous horn arising at her right cheek. No history of trauma could be elicited. The patient had a history of long-term sun exposure due to farm activities and had solar keratosis on face and extremities. Clinical examination revealed actinic keratosis on left forehead and firm keratinized conical lesion with a height of 5 cm (Fig. 1) on right cheek. There was no regional lymphadenopathy. Excision of the lesion with an elliptical incision and primary closure of defect was done. Histopathological examination revealed a completely excised cornu cutaneum with a well-differentiated squamous cell carcinoma at its base (Fig. 2). 27 PHOTOLETTER TO THE EDITOR AbstractA 90-year-old patient presented with a large cutaneous horn (cornu cutaneum) of nine-year duration arising at her right cheek. The lesion was removed by surgery. Histology was reported as cornu cutaneum with a well-differentiated squamous cell carcinoma at its base. Cutaneous horn is morphological designation for protuberant mass of keratin that resembles the horn of an animal. Such lesions appear on sun-exposed skin areas like upper parts of the face and ears in elderly patients. Large cutaneous horns (> 1 cm) tend to be more commonly associated with squamous cell carcinoma compared to smaller cutaneous horns, particularly when present on the face. (J Dermatol Case Rep. 2015; 9(1): 27-28)
p53 is a central tumor suppressor protein and its inhibition is believed to be a prerequisite for cancer development. In approximately 50% of all malignancies this is achieved by inactivating mutations in the p53 gene. However, in several cancer entities, including melanoma, p53 mutations are rare. It has been recently proposed that tyrosinase related protein 2 (TRP2), a protein involved in melanin synthesis, may act as suppressor of the p53 pathway in melanoma. To scrutinize this notion we analyzed p53 and TRP2 expression by immunohistochemistry in 172 melanoma tissues and did not find any correlation. Furthermore, we applied three different TRP2 shRNAs to five melanoma cell lines and could not observe a target specific effect of the TRP2 knockdown on either p53 expression nor p53 reporter gene activity. Likewise, ectopic expression of TRP2 in a TRP2 negative melanoma cell line had no impact on p53 expression. In conclusion our data suggest that p53 repression critically controlled by TRP2 is not a general event in melanoma.
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