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MOMP Activity Enhances Immune Modulation: Validated in Melanoma

KEY TAKEAWAYS

  • The study aimed to assess the influence of MOMP activity on immune modulation in cancer therapeutics.
  • The results revealed that the MOMP is correlated to immune modulation ; clinically validated in skin cutaneous melanoma.

Mitochondrial outer membrane permeabilisation (MOMP) has a crucial role to play in cell-death and immune activation. A deeper insights over the impact of tumour MOMP on immunity will assist in guiding more effective immunotherapeutic strategies across various types of cancers, the present study offers validation for the same in Melanoma.

Qingshan Chen and the team investigated the MOMP activity influence on clinical prognosis, immune infiltration, and the effectiveness of immunotherapy.

Researchers conducted a comprehensive pan-cancer analysis using a dataset comprising 30 cancer-type transcriptomic cohorts, 20 immunotherapy transcriptomic cohorts, and 3 immunotherapy scRNA-seq datasets was collected and analyzed.

The study investigated the impact of MOMP activity on immunotherapy outcomes using 65 scRNA-Seq datasets, the study developed a MOMP signature (MOMP.Sig) to accurately measure tumor MOMP activity.

Machine learning models were utilized to invade into the clinical predictive insights and evaluate the value of MOMP.Sig. Further, by integratng the MOMP.Sig model with a pan-cancer immunotherapy CRISPR screen identified potential targets for overcoming immunotherapy resistance, which were then clinically validated.

Results identified that enhanced MOMP activity correlated with reduced mortality risk among patients with cancer, which fostered an anti-tumor immune activity, and amplified responsiveness to immunotherapy. These insights advocated the potential clinical significance of MOMP activity in immunotherapeutic approaches.

The MOMP.Sig demonstrated exceptional predictive accuracy in machine-learning models and leveraging the MOMP.Sig model which revealed FOXO1 as a pivotal regulator that inclined immune resistance. Notably, these findings were validated in clinical cohorts of skin cutaneous melanoma and patients with triple-negative breast cancer undergoing immunotherapy.

The study advanced the understanding of the relevance of MOMP activity in the context of immune modulation, offering valuable insights to optimize immunotherapeutic strategies across various types of cancers.

The study was funded by Natural Science Foundation of China.

Source: https://pubmed.ncbi.nlm.nih.gov/38899748/

Chen Q., Gao F., Wu J., et al. (2024). “Comprehensive pan-cancer analysis of mitochondrial outer membrane permeabilisation activity reveals positive immunomodulation and assists in identifying potential therapeutic targets for immunotherapy resistance.” Clin Transl Med. 2024 Jun;14(6):e1735. doi: 10.1002/ctm2.1735. PMID: 38899748.

IFN-γ/JAK2/STAT1 Pathway in CAD: AIM2 Inflammasome Activation

KEY TAKEAWAYS

  • The study aimed to investigate the mechanism of AIM2 upregulation and its role in inflammasome-induced inflammation in aortic plaques of CAD.
  • Researchers observed that IFN-γ/JAK2/STAT1-induced AIM2 expression promotes monocyte inflammation and pyroptosis, contributing to CAD development.

Numerous studies have demonstrated that Absent in Melanoma 2 (AIM2) is upregulated in aortic plaques, especially in vascular smooth muscle cells in coronary artery disease (CAD), and is related to inflammasome-induced inflammation. However, the underlying mechanism of this phenomenon and the role of AIM2 in atherosclerosis remained unclear.

Yue Zhao and the team aimed to elucidate the mechanism by which AIM2 is upregulated and its specific role in inflammasome-mediated inflammation within aortic plaques associated with CAD.

They performed an inclusive analysis involving 133 patients with CAD and 123 controls. Peripheral Blood Leukocytes (PBLs) were isolated to assess AIM2 inflammasome and downstream gene (ASC, Caspase-1, IL-1β, IL-18) mRNA expression via real-time quantitative PCR (qPCR). Correlations between AIM2 expressions and clinical characteristics were evaluated using multiple linear regression and Spearman’s correlation.

THP-1 cells were cultured under conditions including poly(dA), A151, interferon-gamma (IFN-γ), AG490, or JC2-11. mRNA and protein levels of AIM2, ASC, Caspase-1, IL-1β, IL-18, GSDMD, and STAT1 were analyzed using qPCR and Western blot analysis. Migration and adhesive capacity of THP-1 cells were assessed using inverted and fluorescence microscopes, respectively.

They found that expressions of components of AIM2 inflammasome and its downstream genes (ASC, Caspase-1, IL-1β, and IL-18) were all increased in PBLs of patients with CAD, indicating inflammasome activation. AIM2 inflammasome activation further induced pyroptosis, and stimulated migration and adhesion in monocyte cell lines, which was regulated by IFN-γ probably through JAK2/STAT1 pathway. In addition, AIM2 expressions were positively correlated with systemic inflammatory indicators as an independent risk factor for CAD.

The study concluded that increased AIM2 expression, induced by the IFN-γ/JAK2/STAT1 signal, directs monocytes to an inflammatory status or pyroptosis through AIM2 inflammasome activation, contributing to the development of CAD.

This study was funded by the National Natural Science Foundation of China, Zhongnan Hospital of Wuhan University Joint Fund for Translational Medicine and Interdisciplinary Research International cooperation project of Key Research and Development Program of Hubei Province, and Translation Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University.

Source: https://pubmed.ncbi.nlm.nih.gov/38869352/

Zhao Y, Liang B, Sheng S, et al. (2024). “AIM2 inflammasome regulated by the IFN-γ/JAK2/STAT1 pathway promotes activation and pyroptosis of monocytes in Coronary Artery Disease.” Immun Inflamm Dis. 2024 Jun;12(6):e1317. doi: 10.1002/iid3.1317. PMID: 38869352; PMCID: PMC11170685.

DNN in Imaging and Genomic Profiling for Melanoma Diagnosis

KEY TAKEAWAYS

  • The study aimed to design a multi-modal DNN-based model by multiple imaging and genomic profiling for diagnosis of patients with Melanoma.
  • The designed model showed higher accuracy vs. traditional method further validation and clinical studies were suggested.

Advanced stage Melanoma known for its high mortality rates is particularly an aggressive type of skin cancer. Early and accurate detection of melanoma is crucial for improved patient outlooks. The traditional diagnosis was limited to biopsies and was thus not significantly reliable. This approach is designed to explore new and more effective diagnostic methods is essential for better identification and treatment melanoma.

Ajmeera Kiran and the team attempted to utilize the deep neural networks (DNNs) that integrate multiple types of imaging and genomic data to classify melanoma, potentially offering a more reliable diagnosis vs. currently practiced methods.

Researchers built a dataset comprising dermoscopic images, histopathological slides, gene expression profiles, and whole-exome sequencing data of more than 1,000 patients with melanoma and healthy controls. They used convolutional neural networks (CNNs) for image data analysis and Graph Neural Networks (GNNs) for genomic data analysis, trained and evaluated this framework on datasets retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO).

The results demonstrated that the developed multi-modal DNN achieved higher accuracy than traditional medical approaches, with a mean accuracy of 92.5% and an AUC of 0.96. This further suggested its potential usage in detecting critical features of melanoma beyond traditional methods. AI and machine learning methods could potentially, offer larger datasets and assist dermatologists to make more accurate decisions and refine treatment strategies. However, larger-scale validation and additional clinical trials are needed to establish the effectiveness and feasibility of this novel diagnostic approach.

The study concluded that the combined DNN-based model integrated with multiple imaging and genomic profiling could potentially offer a better diagnostic tool vs. traditional and less reliable methods, subject to larger-scale validation and additional clinical trials.

The funding information was not provided.

Source: https://pubmed.ncbi.nlm.nih.gov/38881051/

Kiran A., Narayanasamy N., Ramesh J.V.N., et al. (2024). “A novel deep learning framework for accurate melanoma diagnosis integrating imaging and genomic data for improved patient outcomes.” Skin Res Technol. 2024 Jun;30(6):e13770. doi: 10.1111/srt.13770. PMID: 38881051; PMCID: PMC11180689.

VATGI: Potential Marker in Melanoma Post-TKI

VATGI: Potential Marker in Melanoma Post-TKI

KEY TAKEAWAYS

  • The study aimed to identify the correlation between BMI and outcomes in pts with melanoma post-TKI treatment.
  • VATGI, a body composition-based marker, shows promising potential in predicting patient outcomes in melanoma.

Tyrosine kinase inhibitors (TKIs) have recently represented a significant advancement in the management of metastatic melanoma. A clinical correlation has been established between body mass index (BMI) and patient outcomes in metastatic melanoma. However, conflicting results have cast doubt on the relevance of this association.

Miriam Menourgoni and the team aimed to analyze and dissect various body composition features among patients with melanoma treated with TKI. The objective was to evaluate these features as potential biomarkers to better understand their predictive value in patient outcomes.

Researchers analyzed the body composition features via CT scans in a retrospective cohort of 57 pts with non-resectable stage III/IV melanoma receiving first-line (1L) treatment with TKI in the department, focusing on the impact of body composition on treatment efficacy and the occurrence of adverse events (AEs).

The results indicated that in both uni- and multivariate analyses, they discovered an association between survival and the visceral adipose tissue gauge index (VATGI). Additionally, they conducted profiling of other body composition features, such as sarcopenia, which also showed a correlation with shorter overall survival. Furthermore, they observed an increased prevalence of fatigue among pts with low VATGI.

The study concluded that body composition could serve as potential biomarkers in TKI-treated melanoma, with VATGI showing promise in predicting patient outcomes.

The study was funded by the Else Kröner-Fresenius-Stiftung and Projekt DEAL.

Source: https://pubmed.ncbi.nlm.nih.gov/38857075/

Mengoni M., Braun A.D., Hinnerichs M.S., et al. (2024) “Comprehensive analysis of body composition features in melanoma patients treated with tyrosine kinase inhibitors.” J Dtsch Dermatol Ges. 2024 Jun;22(6):783-791. doi: 10.1111/ddg.15402. PMID: 38857075.

Rosemary & Carvacrol Nano Emulsions: New Therapy for Melanoma

KEY TAKEAWAYS

  • The study aimed to evaluate the anticancer effects of two plant extract nano emulsions on human melanoma.
  • The results concluded rosemary and carvacrol nano emulsions could revolutionize local human melanoma therapy.

Marwa Mohamed Ahmed Ellithy and the team aimed to evaluate the anticancer effectiveness of 2 plant extract nano emulsions on human melanoma cell lines.

Following synthesis and characterization, carvacrol and rosemary essential oils were skillfully formulated into nano emulsions. These formulations underwent thorough examination using TEM to precisely determine their charge and size distribution. Subsequently, the A375 human melanoma cell line was meticulously cultured and propagated in a controlled environment.

Upon reaching optimal conditions, the IC50 of the prepared nano emulsions was carefully administered to assess their efficacy. Detailed evaluations were conducted to analyze cell cytotoxicity, angiogenesis effects, and apoptosis induction, providing comprehensive insights into their potential therapeutic applications.

The results revealed that both carvacrol nano emulsion (CNE) and rosemary nano emulsion (RNE) inhibited melanoma cell line viability and angiogenesis while enhancing the expression of the caspase-3 proapoptotic marker.

The study concluded that rosemary and carvacrol extract nano emulsions could serve as revolutionary agents in human melanoma therapy, with potential for local application.

No funding information was available.

Source: https://pubmed.ncbi.nlm.nih.gov/38809638/

Ellithy MMA, Abdrabo RAM. (2024). “Plant Based Extract Oil-Based Nano emulsions: Impact on Human Melanoma Cell Line.” Asian Pac J Cancer Prev. 2024 May 1;25(5):1663-1671. doi: 10.31557/APJCP.2024.25.5.1663. PMID: 38809638.

Prognostic Role of SOX2 and KLF4 in Oral SCC

KEY TAKEAWAYS

  • The study aimed to investigate the significance of basal differentiation in patients with oral SCC as a prognostic indicator.
  • Researchers noticed that Basal differentiation and SOX2/KLF4 expression in basal layers are key prognostic factors for oral SCC.

Basal differentiation in oral squamous cell carcinoma (SCC) is typically identified at invasive sites, yet its prognostic value remains underexplored.

Kazuhiro Murakami and the team aimed to investigate the significance of basal differentiation as a prognostic indicator in oral SCC.

They performed an inclusive analysis by subclassifying 65 cases of oral SCC into COL17-high (30 cases) and -low (35 cases) types. Prognostic value was assessed using Cox regression analysis. Additionally, immunohistochemical analysis included stem cell markers such as SOX2, KLF4, MYC, and stem cell-related markers BMI1, EZH2, YAP, and TAZ, investigating their prognostic significance in relation to COL17 status.

About disease-specific survival and recurrence-free survival (RFS) in oral SCC, no significant difference was observed between the COL17-high and -low groups. Combining the COL17-high and -low categories with SOX2, KLF4, EZH2, or YAP/TAZ status in basal layers, alongside gender and age as covariates, resulted in hazard ratios of 3.3, 3.7, 2.8, and 3.1, respectively. Multivariate analysis, including COL17, SOX2, and KLF4, with gender and age as covariates, indicated a significantly poorer prognosis for disease-specific survival.

The study concluded that basal differentiation and the expression status of SOX2 and KLF4 in basal layers are significant prognostic factors for oral SCC, as indicated by their relatively high hazard ratios.

No funding information was given.

Source: https://pubmed.ncbi.nlm.nih.gov/38659289/

Murakami K, Kamiakito T, Kawata H, et al. (2024). “Basal differentiation and expression status of SOX2 and KLF4 in basal layers are prognostic factors for disease-specific survival in oral squamous cell carcinoma.” J Oral Pathol Med. 2024 May;53(5):303-309. doi: 10.1111/jop.13535. Epub 2024 Apr 24. PMID: 38659289.

Enh17: Unveiling its Role in Melanoma Progression

KEY TAKEAWAYS

  • The study aimed to elucidate the function and mechanism of a pivotal enhancer in melanoma pathogenesis.
  • The results indicated enh17’s oncogenic role in melanoma progression, elucidating regulatory mechanisms for potential prevention and treatment.

In the realm of genetics, enhancers serve as vital elements in regulating gene expression during both developmental stages and disease processes. Anomalies within enhancers can influence cancer susceptibility and trigger the activation of oncogenes, contributing to the onset of diverse malignancies. However, the specific mechanisms governing the action of most enhancers in cancer remain elusive.

Junyou Zhang and the team aimed to investigate the function and mechanism of a pivotal enhancer in melanoma.

The study utilized multi-omics data to pinpoint enhancer enh17’s role in melanoma progression. CRISPR/Cas9 technology was employed to knock out enh17 in the A375 melanoma cell line. RNA-seq, ChIP-seq, and Hi-C data analysis, coupled with luciferase reporter assays, were employed to identify enh17’s potential target gene.

Subsequent functional experiments validated the function of the target gene ETV4. Integration of multi-omics data with CUT&Tag sequencing validated the binding profile of the inferred transcription factor STAT3.

The results revealed that the enhancer, referred to as enh17, exhibited abnormal activation and contributed to melanoma progression. Deletion of enh17 using CRISPR/Cas9 technology suppressed melanoma cell proliferation, migration, and tumor growth in both in vitro and in vivo settings.

Mechanistically, ETV4 emerged as a target gene regulated by enh17, with functional experiments supporting its involvement in cancer-associated traits. Moreover, STAT3 was identified as a transcription factor binding to enh17, orchestrating the transcriptional regulation of ETV4.

The study concluded that enh17 exerts an oncogenic influence, driving tumor progression in melanoma. Additionally, the investigation fully elucidated enh17’s transcriptional regulatory mechanisms, potentially paving the way for innovative approaches in melanoma prevention and treatment.

Funding was provided by the National Natural Science Foundation of China and the Fundamental Research Funds for the Central Universities.

Source: https://pubmed.ncbi.nlm.nih.gov/38849954/

Zhang J, Wang Q, Qi S, et al. (2024). “An oncogenic enhancer promotes melanoma progression via regulating ETV4 expression.” J Transl Med. 2024 Jun 7;22(1):547. doi: 10.1186/s12967-024-05356-8. PMID: 38849954; PMCID: PMC11157841.

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