Role of Mc1r in UV-induced melanoma in animal models

The role of UV and pigmentation are very difficult to control for in human studies, and mechanisms difficult to infer based on statistical association with melanoma. The animal models are not representative of the human situation. But on the other hand, animal studies can be useful for basic studies that will ultimately help in building up a picture of the overall network of in vivo cellular behavior and intra and inter cellular pathways contributing to melanoma progression and the effects (or not) of UV radiation in individuals with MC1R variants. This review describes that, although the Mc1r is a determinant of coat color phenotype as the MC1R is a determinant of hair and skin color in humans, deficiency of the Mc1r in mice is associated with a paradoxical lower incidence of melanoma

The role of nutrition in oncological prevention

In the global battle against cancer, the second leading cause of death, research aims to identify preventative measures, with over 40% of worldwide cancer fatalities and disability-adjusted life years linked to modifiable lifestyle aspects. Un­derstanding the multi-stage, long-term process of carcinogenesis is vital, as is the identification of contributing factors. By controlling certain lifestyle factors like diet, exercise, smoking and alcohol consumption, we can mitigate cancer risk. Leading institutions such as the World Cancer Research Fund and American Institute for Cancer Research have for­mulated guidelines to reduce cancer risk. These tenets include maintaining a healthy weight, engaging in physical activity, adhering to a balanced diet, limiting alcohol, refraining from smoking, avoiding excessive sunlight and taking breastfeeding into account. Many of these principles centre on dietary habits, advocating for a varied intake of fruit, vegetables, whole grains and legumes, while limiting red and processed meats and alcoholic drinks. Emerging research highlights the considerable influence of diet on cancer risk, leading to the formulation of dietary guidelines to minimize this risk. This paper delves into these recommendations and examines the impact of various dietary components and patterns on cancer development

The role of nutrition in oncological prevention

In the global battle against cancer, the second leading cause of death, research aims to identify preventative measures, with over 40% of worldwide cancer fatalities and disability-adjusted life years linked to modifiable lifestyle aspects. Understanding the multi-stage, long-term process of carcinogenesis is vital, as is the identification of contributing factors. By controlling certain lifestyle factors like diet, exercise, smoking, and alcohol consumption, we can mitigate cancer risk. Leading institutions such as the World Cancer Research Fund and American Institute for Cancer Research have formulated guidelines to reduce cancer risk. These tenets include maintaining a healthy weight, engaging in physical activity, adhering to a balanced diet, limiting alcohol, refraining from smoking, avoiding excessive sunlight, and considering breastfeeding. Many of these principles center on dietary habits, advocating for a varied intake of fruits, vegetables, whole grains, and legumes, and limiting red and processed meats and alcoholic drinks. Emerging research highlights the considerable influence of diet on cancer risk, leading to the formulation of dietary guidelines to minimize this risk. This paper delves into these recommendations and examines the impact of various dietary components and patterns on cancer development

Inhibition of the RIPK4 enhances suppression of human melanoma growth through vitamin D signaling

Downregulation of Receptor-Interacting Protein Kinase 4 (RIPK4) inhibits NF-κB and Wnt/β-catenin signaling in melanoma and xenograft growth in mice. The active form of vitamin D3 (1,25-D3), in addition to regulating calcium and phosphate metabolism in humans through the vitamin D receptor (VDR), can inhibit the NF-κB signaling pathway and can affect the proliferation and differentiation of normal and malignant cells, including melanoma. An hyperactive NF-κB pathway maintains the malignant behavior of melanoma, which can be influenced by both RIPK4 and activated VDR. As their interactions affecting the response to 1,25-D3 in melanoma have not been studied, we tested whether downregulation of RIPK4 affects the sensitivity of melanoma cells to 1,25-D3. Our results have shown that both siRIPK4 and CRISPR/Cas9-mediated RIPK4 knockout increase VDR expression in melanoma cells. Furthermore, a decrease in CYP24A1 expression and an increase in 1,25 D3-induced VDR levels were observed in cells with RIPK4 downregulation. Treatment with 1,25- D3 of RIPK4.KO cells, compared to their wild-type counterparts, significantly reduced proliferation in 2D and 3D culture (MTT or ATP assay) and decreased p-p65 and cyclin D1 levels in melanoma cells. These results indicate that RIPK4 knockout may enhance the therapeutic efficacy of 1,25-D3 against melanoma, which encourages further studies on targeting RIPK4 signaling for anti-melanoma effects in preclinical models

Neurofibromatosis type 1 with interstitial pulmonary lesions diagnosed in adult patient. A case study and literature review

Chory, lat 43 u którego na podstawie kryteriów klinicznych rozpoznano nerwiakowłókniakowatość typu 1 (NF1, choroba van Recklinghausena), został skierowany na oddział chorób płuc w celu przeprowadzenia diagnostyki przyczyn pogorszenia tolerancji wysiłku fizycznego oraz etiologii torbielowatych zmian w płucach uwidocznionych w tomografii komputerowej wysokiej rozdzielczości (HRCT). Od dzieciństwa pacjent był leczony z powodu padaczki, rozpoznano także niedomykalność zastawki trójdzielnej III stopnia, nie stwierdzając nadciśnienia płucnego w trakcie cewnikowania prawego serca. Ostatecznie przyjęto, że w omawianym przypadku zmiany śródmiąższowe w płucach są związane z chorobą zasadniczą i wymagają dalszej obserwacji klinicznej. Obserwowane pogorszenie tolerancji wysiłku fizycznego było związane z towarzyszącym zakażeniem układu oddechowego bakteriami Klebsiella oxytoca i Staphylococcus auresus u chorego za zmianami torbielkowatymi w płucach i niedomykalnością zastawki trójdzielnej bez współistnienia nadciśnienia w tętnicy płucnej. W doniesieniu omówiono kryteria rozpoznania NF1, a także kontrowersje dotyczące współistnienia śródmiąższowych zmian płucnych w obrazie choroby.A case of a 43-year-old man with clinically diagnosed neurofibromatosis type I (NF-1, von Recklinghausen disease), was referred to a lung disease unit in order to diagnosis of worsening tolerance to physical effort, and aetiology of radiological cystic lesions in the lungs, seen in the high-resolution computed tomography (HRCT). Since childhood the patient has been treated for epilepsy, and a 3rd degree tricuspid valve incompetence, without pulmonary hypertension was detected during right heart catheterization. Finally, the interstitial pulmonary lesions were attributed to the primary disease, and it was said they need further clinical observation in order to determine their dynamics. The observed deterioration in patient’s tolerance to physical effort was connected to the accompanying infection of the respiratory system with Klebsiella oxytoca and Staphylococcus aureus, with cystic lesions in lungs and tricuspid valve incompetence. The report describes the criteria for NF-1 diagnosis, as well as points out the controversies of coexistence of interstitial pulmonary lesions in the clinical picture of the disease

RIPK4 downregulation impairs Wnt3A-stimulated invasiveness via Wnt/β\beta-catenin signaling in melanoma cells and tumor growth in vivo

Purpose The role of Wnt signaling in oncogenesis and drug resistance is well known. Receptor-interacting protein kinase (RIPK4) contributing to the increased activity of many signaling pathways, including Wnt/$\beta$-catenin, may be an important target for designing new drugs for metastatic melanoma, but its role in melanoma is not fully understood. Methods We tested the effect of genetic manipulation of RIPK4 (CRISPR/Cas9) on xenograft growth. In addition, immunohistochemistry was used to detect active $\beta$-catenin, Ki67 and necrosis in xenografts. Wnt signaling pathway activity was examined using Western blot and Top-Flash. The effect of RIPK4 knockout on melanoma cells in vitro stimulated Wnt3A on wound overgrowth, migration and invasion ability was then evaluated. Results Our study showed that CRISPR/Cas9-mediated RIPK4 knockout (KO) significantly reduced tumor growth in a mouse model of melanoma, particularly of WM266.4 cells. RIPK4 KO tumors exhibited lower percentages of $Ki67^{+}$ cells as well as reduced necrotic area and decreased levels of active $\beta$-catenin. In addition, we observed that RIPK4 knockout impaired Wnt3A-induced activation of LRP6 and $\beta$-catenin, as manifested by a decrease in the transcriptional activity of $\beta$-catenin in Top-Flash in both tested melanoma cell lines, A375 and WM266.4. Prolonged incubation (48 h) with Wnt3A showed reduced level of MMP9, C-myc, and increased SOX10, proteins whose transcription is also dependent on $\beta$-catenin activity. Moreover, RIPK4 knockout led to the inhibition of scratch overgrowth, migration and invasion of these cells compared to their controls. Conclusion RIPK4 knockdown inhibits melanoma tumor growth and Wnt3A stimulated migration and invasion indicating that RIPK4 might be a potential target for melanoma therapy

Deciphering the functional role of RIPK4 in melanoma

The receptor-interacting protein kinase 4 (RIPK4) plays an important role in the development and maintenance of various tissues including skin, but its role in melanoma has not been reported. Using patient-derived cell lines and clinical samples, we show that RIPK4 is expressed in melanomas at different levels. This heterogenous expression, together with very low level of RIPK4 in melanocytes, indicates that the role of this kinase in melanoma is context-dependent. While the analysis of microarray data has revealed no straightforward correlation between the stage of melanoma progression and RIPK4 expression in vivo, relatively high levels of RIPK4 are in metastatic melanoma cell lines. RIPK4 down-regulation by siRNA resulted in the attenuation of invasive potential as assessed by time-lapse video microscopy, wound-healing and transmigration assays. These effects were accompanied by reduced level of pro-invasive proteins such as MMP9, MMP2, and N-cadherin. Incubation of melanoma cells with phorbol ester (PMA) increased PKC-$1\beta$ level and hyperphosphorylation of RIPK4 resulting in degradation of RIPK4. Interestingly, incubation of cells with PMA for short and long durations revealed that cell migration is controlled by the NF-$\kappa$ signaling in a RIPK4-dependent ($RIPK4^{high}$) or independent ($RIPK4^{low}$) manner depending on cell origin (distant or lymph node metastasis) or phenotype (mesenchymal or epithelial)