Energy metabolism as the hub of advanced non-small cell lung cancer management: a comprehensive view in the framework of predictive, preventive, and personalized medicine.

Energy metabolism is a hub of governing all processes at cellular and organismal levels such as, on one hand, reparable vs. irreparable cell damage, cell fate (proliferation, survival, apoptosis, malignant transformation etc.), and, on the other hand, carcinogenesis, tumor development, progression and metastazing versus anti-cancer protection and cure. The orchestrator is the mitochondria who produce, store and invest energy, conduct intracellular and systemically relevant signals decisive for internal and environmental stress adaptation, and coordinate corresponding processes at cellular and organismal levels. Consequently, the quality of mitochondrial health and homeostasis is a reliable target for health risk assessment at the stage of reversible damage to the health followed by cost-effective personalized protection against health-to-disease transition as well as for targeted protection against the disease progression (secondary care of cancer patients against growing primary tumors and metastatic disease). The energy reprogramming of non-small cell lung cancer (NSCLC) attracts particular attention as clinically relevant and instrumental for the paradigm change from reactive medical services to predictive, preventive and personalized medicine (3PM). This article provides a detailed overview towards mechanisms and biological pathways involving metabolic reprogramming (MR) with respect to inhibiting the synthesis of biomolecules and blocking common NSCLC metabolic pathways as anti-NSCLC therapeutic strategies. For instance, mitophagy recycles macromolecules to yield mitochondrial substrates for energy homeostasis and nucleotide synthesis. Histone modification and DNA methylation can predict the onset of diseases, and plasma C7 analysis is an efficient medical service potentially resulting in an optimized healthcare economy in corresponding areas. The MEMP scoring provides the guidance for immunotherapy, prognostic assessment, and anti-cancer drug development. Metabolite sensing mechanisms of nutrients and their derivatives are potential MR-related therapy in NSCLC. Moreover, miR-495-3p reprogramming of sphingolipid rheostat by targeting Sphk1, 22/FOXM1 axis regulation, and A2 receptor antagonist are highly promising therapy strategies. TFEB as a biomarker in predicting immune checkpoint blockade and redox-related lncRNA prognostic signature (redox-LPS) are considered reliable predictive approaches. Finally, exemplified in this article metabolic phenotyping is instrumental for innovative population screening, health risk assessment, predictive multi-level diagnostics, targeted prevention, and treatment algorithms tailored to personalized patient profiles-all are essential pillars in the paradigm change from reactive medical services to 3PM approach in overall management of lung cancers. This article highlights the 3PM relevant innovation focused on energy metabolism as the hub to advance NSCLC management benefiting vulnerable subpopulations, affected patients, and healthcare at large. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00357-5.

Immune-related gene methylation prognostic instrument for stratification and targeted treatment of ovarian cancer patients toward advanced 3PM approach.

Background: DNA methylation is an important mechanism in epigenetics, which can change the transcription ability of genes and is closely related to the pathogenesis of ovarian cancer (OC). We hypothesize that DNA methylation is significantly different in OCs compared to controls. Specific DNA methylation status can be used as a biomarker of OC, and targeted drugs targeting these methylation patterns and DNA methyltransferase may have better therapeutic effects. Studying the key DNA methylation sites of immune-related genes (IRGs) in OC patients and studying the effects of these methylation sites on the immune microenvironment may provide a new method for further exploring the pathogenesis of OC, realizing early detection and effective monitoring of OC, identifying effective biomarkers of DNA methylation subtypes and drug targets, improving the efficacy of targeted drugs or overcoming drug resistance, and better applying it to predictive diagnosis, prevention, and personalized medicine (PPPM; 3PM) of OC. Method: Hypermethylated subtypes (cluster 1) and hypomethylated subtypes (cluster 2) were established in OCs based on the abundance of different methylation sites in IRGs. The differences in immune score, immune checkpoints, immune cells, and overall survival were analyzed between different methylation subtypes in OC samples. The significant pathways, gene ontology (GO), and protein-protein interaction (PPI) network of the identified methylation sites in IRGs were enriched. In addition, the immune-related methylation signature was constructed with multiple regression analysis. A methylation site model based on IRGs was constructed and verified. Results: A total of 120 IRGs with 142 differentially methylated sites (DMSs) were identified. The DMSs were clustered into a high-level methylation group (cluster 1) and a low-level methylation group (cluster 2). The significant pathways and GO analysis showed many immune-related and cancer-associated enrichments. A methylation site signature based on IRGs was constructed, including RORC|cg25112191, S100A13|cg14467840, TNF|cg04425624, RLN2|cg03679581, and IL1RL2|cg22797169. The methylation sites of all five genes showed hypomethylation in OC, and there were statistically significant differences among RORC|cg25112191, S100A13|cg14467840, and TNF|cg04425624 (p < 0.05). This prognostic model based on low-level methylation and high-level methylation groups was significantly linked to the immune microenvironment as well as overall survival in OC. Conclusions: This study provided different methylation subtypes for OC patients according to the methylation sites of IRGs. In addition, it helps establish a relationship between methylation and the immune microenvironment, which showed specific differences in biological signaling pathways, genomic changes, and immune mechanisms within the two subgroups. These data provide ones to deeply understand the mechanism of immune-related methylation genes on the occurrence and development of OC. The methylation-site signature is also to establish new possibilities for OC therapy. These data are a precious resource for stratification and targeted treatment of OC patients toward an advanced 3PM approach. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00359-3.

Clinically relevant stratification of lung squamous carcinoma patients based on ubiquitinated proteasome genes for 3P medical approach.

Relevance: The proteasome is a crucial mechanism that regulates protein fate and eliminates misfolded proteins, playing a significant role in cellular processes. In the context of lung cancer, the proteasome's regulatory function is closely associated with the disease's pathophysiology, revealing multiple connections within the cell. Therefore, studying proteasome inhibitors as a means to identify potential pathways in carcinogenesis and metastatic progression is crucial in in-depth insight into its molecular mechanism and discovery of new therapeutic target to improve its therapy, and establishing effective biomarkers for patient stratification, predictive diagnosis, prognostic assessment, and personalized treatment for lung squamous carcinoma in the framework of predictive, preventive, and personalized medicine (PPPM; 3P medicine). Methods: This study identified differentially expressed proteasome genes (DEPGs) in lung squamous carcinoma (LUSC) and developed a gene signature validated through Kaplan-Meier analysis and ROC curves. The study used WGCNA analysis to identify proteasome co-expression gene modules and their interactions with the immune system. NMF analysis delineated distinct LUSC subtypes based on proteasome gene expression patterns, while ssGSEA analysis quantified immune gene-set abundance and classified immune subtypes within LUSC samples. Furthermore, the study examined correlations between clinicopathological attributes, immune checkpoints, immune scores, immune cell composition, and mutation status across different risk score groups, NMF clusters, and immunity clusters. Results: This study utilized DEPGs to develop an eleven-proteasome gene-signature prognostic model for LUSC, which divided samples into high-risk and low-risk groups with significant overall survival differences. NMF analysis identified six distinct LUSC clusters associated with overall survival. Additionally, ssGSEA analysis classified LUSC samples into four immune subtypes based on the abundance of immune cell infiltration with clinical relevance. A total of 145 DEGs were identified between high-risk and low-risk score groups, which had significant biological effects. Moreover, PSMD11 was found to promote LUSC progression by depending on the ubiquitin-proteasome system for degradation. Conclusions: Ubiquitinated proteasome genes were effective in developing a prognostic model for LUSC patients. The study emphasized the critical role of proteasomes in LUSC processes, such as drug sensitivity, immune microenvironment, and mutation status. These data will contribute to the clinically relevant stratification of LUSC patients for personalized 3P medical approach. Further, we also recommend the application of the ubiquitinated proteasome system in multi-level diagnostics including multi-omics, liquid biopsy, prediction and targeted prevention of chronic inflammation and metastatic disease, and mitochondrial health-related biomarkers, for LUSC 3PM practice. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00352-w.

Forensic autosomal and gonosomal short tandem repeat marker reference database for populations in Burkina Faso.

Tandem repeat genetic profiles used in forensic applications varies between populations. Despite the diversity and security issues in the Sahel that require the identification of victims (soldiers and civilians), Burkina Faso (BF) remains understudied. To fill this information gap, 396 unrelated individuals from BF were genotyped using a MICROREADER 21 ID System kit. All 20 short tandem repeat (STR) loci tested passed the Hardy-Weinberg equilibrium (HWE) test. The combined powers of exclusion for duos (CPE duos) and trios (CPE trios) for the 20 tested loci were 0.9999998 and 0.9999307, respectively. The probability that two individuals would share the same DNA profiles among the BF population was 9.80898 × 10-26. For the X-chromosome STR analysis, 292 individuals were included in this study using a MICROREADER 19X Direct ID System kit. Among the 19 loci, no significant deviations from HWE test were observed in female samples after Bonferroni correction (p < 0.05/19 = 0.0026), except for loci GATA165B12 and DXS7423. The results showed that the combined power of exclusion (CPE) and the combined power of discrimination in females (CPDF) and males (CPDM) were 0.999999760893, 0.999999999992, and 1, respectively. Comparison with other African sub-populations showed that geographical proximity is a reliable indicator of genetic relatedness.

Cancer energy reprogramming and the immune responses.

Cancer as an uncontrolled growth of cells due to existing mutation in host cells that may proliferate, induce angiogenesis and sometimes metastasize due to the favorable tumor microenvironment (TME). Since it kills more than any disease, biomedical science does not relent in studying the exact pathogenesis. It was believed to be a problem that lies in the nucleus of the host cells; however, recent oncology findings are shifting attention to the mitochondria as an adjuvant to cancer pathogenesis. The changes in the gene are strongly related to cellular metabolism and metabolic reprogramming. It is now understood that reprogramming the TME will have a direct effect on the immune cells' metabolism. Although there are a number of studies on immune cells' response towards tumor energy reprogramming and cancer progression, there is still no existence with the updated collation of these immune cells' response to distinct energy reprogramming in cancer studies. To this end, this mini review shed some light on cancer energy reprogramming mechanisms and enzyme degradation pathways, the cancer pathogenicity activity series involved with reduced lactate production, the specific immune cell responses due to the energy reprogramming. This study highlighted some prospects and future experiments in harnessing the host immune response towards the altered energy metabolism due to cancer.

BRCA1, BRCA2, TP53, PIK3CA, PTEN and AKT1 genes mutations in Burkina Faso breast cancer patients: prevalence, spectrum and novel variant.

BRCA1 and BRCA2 are the two most commonly mutated tumor suppressor genes associated with hereditary breast cancer (BC). Also, mutations in TP53, PIK3CA, PTEN and AKT1 were observed at a high frequency in BC with their mutation spectrum exhibiting a subgroup particularity with enormous clinical significance in the prevention, classification and treatment of cancers. Unfortunately, the mutation spectrum of these genes is still unknown in most Sub-Saharan African population. Therefore, using samples from 133 unselected BC patients, we aimed to assess the contribution of these mutations by direct Sanger sequencing. The analysis revealed pathogenic germline variants on BRCA1 exon 11 (c.3331C > T, 0.75%) and BRCA2 exon 11 (c.5635G > T, c.6211delA; 1.5%). Five other pathogenic variants were identified in 61 of the 133 subjects (45.86%), with 39.09% for PIK3CA, 12.78% for TP53. Interestingly, a variant in PIK3CA found in high frequency in our population was different from the one usually found in other populations (c.1634A > C, 38.34%), and four patients carried mutations linked to Cowen Syndrome 5 c.[1634A > C;1658_1659delGTinsC]. A novel variant (c.312G > T) was found in TP53 gene at 12.78%. Overall, mutation carriers were found more in Her2 negative and in patients that underwent surgery and chemotherapy. No pathogenic variant was found in PTEN and AKT1. Our population displayed a high frequency of PIK3CA mutations with an unusual distribution and spectrum as well as a relatively low prevalence of BRCA mutations. Our results provided novel data on an unstudied population and may help in prevention, and the establishment of suitable therapeutic approaches for our population.

Population data and genetic structure analysis based on 29 Y-STR loci among the ethnolinguistic groups in Burkina Faso.

Burkina Faso (BF) is a landlocked Sahelian country located in the middle of West Africa. Sixty-three local languages are spoken in BF. Despite this high diversity, the BF population remains poorly investigated, and updated forensic parameters with a large number of Y chromosome short tandem repeats (Y-STRs) are still missing. Herein, 447 DNA samples were typed for a cocktail of 29 Y-STR loci. None of these 447 individuals in total shared a common haplotype. The overall Y-STR haplotypes were successfully uploaded online on the Y-STR Haplotype Reference Database (YHRD) with the accession numbers YA004690 and YA004691. The main haplotype diversity was 0.9999999965, which is much higher than that obtained with 12 Y-STRs in a previous study. Haploid Match Probability for the whole dataset was 0.002237. The phylogenetic analysis of 24 ethnic groups of BF shows that the ethnic group named BISSA is closer to Gur speakers than Mande speakers, where they belong. In addition, genetic structure analysis of 49 African subpopulations sheds light on the fact that geographic proximity turns out to be one of the best predictors of genetic affinity between populations.

No correlation between the variants of exostosin 2 gene and type 2 diabetes in Burkina Faso population.

Recent genome-wide association studies and replication analyses have reported the association of variants of the exostosin- 2 gene (EXT2) and risk of type 2 diabetes (T2D) in some populations, but not in others. This study aimed to characterize the variants rs1113132, rs3740878 and rs11037909 of EXT2 and to determine the existence of a possible correlation with T2D in Burkina Faso. It is a case-control study undertaken in Burkina Faso in the city of Ouagadougou at the Hospital of Saint Camille of Ouagadougou from December 2014 to June 2015. It relates to 121 type 2 diabetes cases and 134 controls. The genotyping of these polymorphisms was done by real-time PCR using the allelic exclusion method with TaqMan probes. The minor allele frequencies (MAFs) was almost identical in diabetic and control subjects for the all three Single Nucleotide Polymorphisms (SNPs) with no statistical significance, p>0.05: rs1113132 (OR=0.89; p=0.82); rs11037909 (OR=0.89; p=0.74) and rs3740878 (OR=1.52; p=0.42). None of the three polymorphisms studied was associated with the risk of DT2. However, an association between the BMI, age and type 2 diabetes was noted. The variants of EXT2 would not be associated to the risk of T2D in the African black population of Burkina Faso.

Positive association between ATP2B1 rs17249754 and essential hypertension: a case-control study in Burkina Faso, West Africa.

BACKGROUND: Genetic and environment play a significant role in the etiology of essential hypertension (EH). Recently STK39 rs3754777, ATP2B1 rs2681472 and rs17249754 have been associated with BP variation and hypertension. In this study we aimed to determine firstly whether index variants were associated with the risk of developing EH in Burkina Faso and secondly to characterize cardiovascular risk markers. METHODS: We conducted a case-control study with 380 participants including 180 case subjects with EH and 200 control subjects with normal BP. We used TaqMan genotyping assays with probes from Applied Biosystems to genotype polymorphisms using the 7500 Real-Time PCR System. Biochemical parameters were measured using chemistry analyzer COBAS C311. RESULTS: T-test showed that cardiovascular risk markers such as body mass index, waist circumference, blood sugar, total cholesterol and triglycerides were significantly higher in hypertensive compared to normotensive (all p <  0.05). Binary logistic regression analysis revealed in decreasing order that overweight, family history of hypertension, central obesity and alcohol intake increased the risk of developing EH (all OR > 3.8; all p <  0.001). In genetic level we observed that individuals carrying the AA+AG genotype of ATP2B1 rs17249754 had a low risk of developing EH than those carrying the GG genotype (OR = 0.48 [95% CI: 0.31-0.75] p = 0.001) and the A allele frequency in the cases was significantly lower than that of the controls (OR = 0.56 [95% CI: 0.38-0.82] p = 0.003). We also observed that ATP2B1 rs17249754 was significantly associated with higher SBP and DPB in case and control groups (GG versus AG + AA; p <  0.05), ATP2B1 rs2681472 was significantly associated with higher SBP only in case and control group (AA versus AG + GG; p <  0.05), STK39 rs3754777 was not significantly associated with any of the BP traits (CC versus CT + TT; p > 0.05). CONCLUSION: Our results confirmed the significant association of ATP2B1 rs17249754 with the risk of developing EH in Burkinabe and showed an increase of cardiovascular risk markers levels in subjects with EH.