TRIP13 Activates the PI3K/AKT Signal Pathway to Promote Melanoma Progression by Interacting With FLNA

Background: Skin melanoma is a malignant tumor originated from skin melanocytes. It is highly malignant and easy to relapse and metastasis. Finding new diagnostic and therapeutic targets has become a hot issue. Accumulating evidence now indicates that thyroid hormone receptor interactor 13 (TRIP13) plays important roles in tumor development. However, its role in melanoma remains unclear.Methods: Bioinformatic analyses were employed to excavate crucial genes in melanoma using several public databases. The expression of TRIP13 was detected by immunohistochemistry. MV3 cell and A2058 cell were steadily transfected with TRIP13 knock-down or overexpression lentiviruses, then the function and potential mechanism of TRIP13 were studied in vitro and in vivo. Co-immunoprecipitation (Co-IP) and mass spectrum were employed to screen out the interacting molecule of TRIP13.Results: Our results showed that TRIP13 was generally upregulated in melanoma tissues and was related to the poor prognosis of melanoma patients. The overexpression of TRIP13 promotes the invasion, migration and EMT transformation of melanoma cells in vitro, and promotes lung metastasis in vivo. Mechanismly, TRIP13 interacts with FLNA, and activates the PI3K/AKT pathway, and then induces melanoma migration, invasion and EMT transformation.Conclusion: Elevated TRIP13 drives tumor progression via the FLNA/PI3K/AKT axis, and TRIP13 is a innovative prognostic molecule and potential target of targeted therapy in melanoma.

Medical and organizational approaches to early diagnosis of skin melanoma

Introduction. The most significant problem is the early diagnosis of skin melanoma (SM). In many countries of the world, there is a constant increase in the incidence rate, and the organization of population screening can help solve this problem. Purpose of the study. Evaluation of the use of multi-agent technology in the diagnosis of SM. Material and methods. Study design: at the 1st stage, primary medical documentation was studied - Charts No. 090/y; 027-2/y, statistical reports of the Samara Regional Clinical Oncological Dispensary - Charts No. 7, No. 35, according to the results revealed at stage 2. There was developed and implemented multi-agent technology for SM diagnostics, including various agents of both qualified and specialized levels, these were both individuals and teams of departments who worked in close contact: a public relations agent; artificial intelligence secondary prevention planning agent; agent for training doctors and nurses, patients in the basics of early diagnosis and assessing their level of training; an agent for evaluating performance indicators. Results. After introducing the multi-agent system, the indicator of the share of 1-2 stages of MC in 2010-2019. increased by 48.3% compared to the period 2000-2009 and outpaced the growth in the total number of patients with SM by 6.96%; from 2010 to 2019 the proportion of patients with SM who were actively identified began to increase; one-year mortality rate from 2010 to 2019 decreased in waves (y = 0.0003x5 - 0.0104x4 - 0.2647x3 + 1.4818x2 - 1.8942x + 10.585; R2 = 0.554). Conclusion. The use of multi-agent technology makes it possible to reduce the one-year mortality rate, to achieve a faster growth rate of the newly detected number of patients with an early stage of SM (stage 1-2) compared to the increase in the number of cases, to improve the indicators of early diagnosis, active detection of skin melanoma, which is a positive result.

Screening of Hibiscus and Cinnamomum Plants and Identification of Major Phytometabolites in Potential Plant Extracts Responsible for Apoptosis Induction in Skin Melanoma and Lung Adenocarcinoma Cells

Carcinogenesis is a major concern that severely affects the human population. Owing to persistent demand for novel therapies to treat and prohibit this lethal disease, research interest among scientists is drawing its huge focus toward natural products, as they have minimum toxicity comparable with existing treatment methods. The plants produce secondary metabolites, which are known to have the anticancer potential for clinical drug development. Furthermore, the use of nanocarriers could boost the solubility and stability of phytocompounds to obtain site-targeting delivery. The identification of potential phytochemicals in natural compounds would be beneficial for the synthesis of biocompatible nanoemulsions. The present study aimed to investigate the potential cytotoxicity of ethanol extracts of Hibiscus syriacus and Cinnamomum loureirii Nees plant parts on human skin melanoma (G361) and lung adenocarcinoma (A549) cells. Importantly, biochemical analysis results showed the presence of high phenol (50–55 µgGAE/mg) and flavonoids [42–45 µg quercetin equivalents (QE)/mg] contents with good antioxidant activity (40–58%) in C. loureirii Nees plants extracts. This plant possesses potent antiproliferative activity (60–90%) on the malignant G361 and A549 and cell lines correlated with the production of nitric oxide. Especially, C. loureirii plant extracts have major metabolites that exhibit cancer cell death associated with cell cycle arrest. These findings support the potential application of Cinnamomum for the development of therapeutic nanoemulsion in future cancer therapy.

The role of a new ALK isoform in the diagnosis and targeted therapy of skin melanoma

Contemporary discoveries of fundamental science in recent decades in the field of oncology have led to the emergence of new highly effective anticancer drugs: targeted drugs and immune checkpoint inhibitors, use of which has made a breakthrough in the treatment of oncological diseases, including skin melanoma. Melanoma is still one of the most cancerous tumors. The number of patients resistant to targeted therapy and immunotherapy increases in the world every year. Oncologists have practically no leverage to influence the disease after the development of resistance to this type of therapy. In this regard, scientists around the world are looking for new application points for targeted drugs. Nowadays, the most common treatment method is BRAF inhibitors, since the BRAF mutation is detected in 40–60 % of patients with skin melanoma. However, the resistance to BRAF inhibitor therapy occur in half cases after 6–8 months. To overcome the resistance to the target therapy is one the most important issue, the studying of new isoform of anaplastic lymphoma kinase (ALK) may help to solve this problem.Purpose of the study – to order the data of the leading researchers of a new isoform of ALK, and reveal the most promising directions for its further progress.In the article, there are comparisons and analyses the 6 of the largest studies over the past 5 years devoted to a new isoform of ALK.The joint inhibition of the new ALK isoform and BRAFV600 showed positive results in several studies with different levels of ALKATI expression (alternative initiation of ALK transcription). The new ALK isoform can stimulate oncogenesis only within a certain “threshold” level of expression. Immunohistochemical examination cannot be the main method for determining the expression of a new ALK isoform due to low sensitivity. In almost all studies, tumors with ALK translocation responded to therapy with ALK inhibitors.Even though that the role of the new ALK isoform has been studied in recent years, the optimal method for evaluating the expression of ALKATI in routine practice has not yet been determined. Additional studies are also needed to understand the effectiveness of the use of ALК inhibitors in combination with BRAF and ERK inhibitors. Of interest is the blockade of extracellular vesicles and the study of the role of interleukin-3 in the inhibition of ALKATI.

Analysis of the Different Lymphatic Drainage Patterns during Sentinel Lymph Node Biopsy for Skin Melanoma

In the last two decades, studies of lymphoscintigraphy imaging in lymphatic mapping reported an extreme heterogeneity of skin lymphatic drainage of some skin area, in contrast with the previous scientific literature. The aim of this study was to investigate the presence of any correlations between the topographical location of cutaneous melanoma and the topographical location of sentinel lymph nodes. Data from 165 patients undergoing sentinel lymph node biopsy between January 2013 and May 2021 were analyzed, demonstrating that melanomas in the Lumbar region presented a significant more heterogeneous drainage by site than those in the Scapular region (p < 0.01) and that melanomas in the Subscapular region were significantly more heterogeneous by laterality (unilateral vs. bilateral) than those in the Scapular region (p < 0.05). Results of this study supported the evidence of multiple lymphatic drainage as regards the sentinel node biopsy performed in skin melanoma located on the dorsal subscapular region and lumbar region. For this reason, the association of preoperative lymphoscintigraphy with another imaging evaluation is needed in these critical cutaneous areas. Recent technical developments enabling fluorescence lymphography together with indocyanine green have significantly improved the visualization of lymphatic drainage patterns at a microscopic level. In the preoperative phase, any doubt can be resolved by associating the SPET-CT scan to lymphoscintigraphy, while during the intraoperative phase, an additional evaluation with indocyanine green can be performed in doubtful cases. The aim of the duplex lymphatic mapping (pre and/or intraoperative) is an accurate search of sentinel nodes, in order to reduce the rate of false negatives.

Pan-Cancer Analysis Reveals the Signature of TMC Family of Genes as a Promising Biomarker for Prognosis and Immunotherapeutic Response

Transmembrane Channel-like (TMC) genes are critical in the carcinogenesis, proliferation, and cell cycle of human cancers. However, the multi-omics features of TMCs and their role in the prognosis and immunotherapeutic response of human cancer have not been explored. We discovered that TMCs 4-8 were commonly deregulated and correlated with patient survival in a variety of cancers. For example, TMC5 and TMC8 were correlated with the relapse and overall survival rates of breast cancer and skin melanoma, respectively. These results were validated by multiple independent cohorts. TMCs were regulated by DNA methylation and somatic alterations, such as TMC5 amplification in breast cancer (523/1062, 49.2%). Six algorithms concordantly uncovered the critical role of TMCs in the tumor microenvironment, potentially regulating immune cell toxicity and lymphocytes infiltration. Moreover, TMCs 4-8 were correlated with tumor mutation burden and expression of PD-1/PD-L1/CTLA4 in 33 cancers. Thus, we established an immunotherapy response prediction (IRP) score based on the signature of TMCs 4-8. Patients with higher IRP scores showed higher immunotherapeutic responses in five cohorts of skin melanoma (area under curve [AUC] = 0.90 in the training cohort, AUCs range from 0.70 to 0.83 in the validation cohorts). Together, our study highlights the great potential of TMCs as biomarkers for prognosis and immunotherapeutic response, which can pave the way for further investigation of the tumor-infiltrating mechanisms and therapeutic potentials of TMCs in cancer.

Relevance of BRAF Subcellular Localization and Its Interaction with KRAS and KIT Mutations in Skin Melanoma

Although skin melanoma (SKM) represents only one-quarter of newly diagnosed skin malignant tumors, it presents a high mortality rate. Hence, new prognostic and therapeutic tools need to be developed. This study focused on investigating the prognostic value of the subcellular expression of BRAF, KRAS, and KIT in SKM in correlation with their gene-encoding interactions. In silico analysis of the abovementioned gene interactions, along with their mRNA expression, was conducted, and the results were validated at the protein level using immunohistochemical (IHC) stains. For IHC expression, the encoded protein expressions were checked on 96 consecutive SKMs and 30 nevi. The UALCAN database showed no prognostic value for the mRNA expression level of KRAS and BRAF and demonstrated a longer survival for patients with low mRNA expression of KIT in SKMs. IHC examinations of SKMs confirmed the UALCAN data and showed that KIT expression was inversely correlated with ulceration, Breslow index, mitotic rate, and pT stage. KRAS expression was also found to be inversely correlated with ulceration and perineural invasion. When the subcellular expression of BRAF protein was recorded (nuclear vs. cytoplasmatic vs. mixed nucleus + cytoplasm), a direct correlation was emphasized between nuclear positivity and lymphovascular or perineural invasion. The independent prognostic value was demonstrated for mixed expression of the BRAF protein in SKM. BRAF cytoplasmic predominance, in association with KIT’s IHC positivity, was more frequently observed in early-stage nonulcerated SKMs, which displayed a low mitotic rate and a late death event. The present study firstly verified the possible prognostic value of BRAF subcellular localization in SKMs. A low mRNA expression or IHC cytoplasmic positivity for KIT and BRAF might be used as a positive prognostic parameter of SKM. SKM’s BRAF nuclear positivity needs to be evaluated in further studies as a possible indicator of perineural and lymphovascular invasion.

A rare case of oculocutaneous melanosis (nevus of Ota) at Ophthalmologist's appointment

A rare clinical case of nevus of Ota in a 6-year-old child is described. The clinical picture and diagnostic methods used in this case are reflected. On the example of the patients presented in this article, differential diagnosis with alkaptonuria is fully described. Given the risk of transition to skin melanoma and ocular melanoma, patients with nevus of Ota should be observed by Dermatologist and Ophthalmologist annually. Such patients should also strictly avoid exposition to any ultraviolet radiation and exclude possible risk factors traumatizing the nevus. Key words: nevus, Ota nevus, alkaptonuria, skin melanoma, eye melanoma.