BACKGROUND: The growing understanding of cancer biology and the establishment of new treatment modalities has not yielded the expected results in terms of survival for Laryngeal Squamous Cell Cancer (LSCC). Early diagnosis, as well as prompt identification of patients with high risk of relapse would ensure greater chance of therapeutic success. However, this goal remains a challenge due to the absence of specific biomarkers for this neoplasm.
METHODS: Serum samples from 45 LSCC patients and 23 healthy donors were collected for miRNA expression profiling by TaqMan Array analysis. Additional 20 patients and 42 healthy volunteers were included for the validation set, reaching an equal number of clinical samples for each group. The potential diagnostic ability of the such identified three-miRNA signature was confirmed by ROC analysis. Moreover, each miRNA was analyzed for the possible correlation with HNSCC patients\' survival and TNM status by online databases Kaplan-Meier (KM) plotter and OncomiR. In silico analysis of common candidate targets and their network relevance to predict shared biological functions was finally performed by PANTHER and GeneMANIA software.
RESULTS: We characterized serum miRNA profile of LSCC patients identifying a novel molecular signature, including miR-223, miR-93 and miR-532, as circulating marker endowed with high selectivity and specificity. The oncogenic effect and the prognostic significance of each miRNA was investigated by bioinformatic analysis, denoting significant correlation with OS. To analyse the molecular basis underlying the pro-tumorigenic role of the signature, we focused on the simultaneously regulated gene targets-IL6ST, GTDC1, MAP1B, CPEB3, PRKACB, NFIB, PURB, ATP2B1, ZNF148, PSD3, TBC1D15, PURA, KLF12-found by prediction tools and deepened for their functional role by pathway enrichment analysis. The results showed the involvement of 7 different biological processes, among which inflammation, proliferation, migration, apoptosis and angiogenesis.
CONCLUSIONS: In conclusion, we have identified a possible miRNA signature for early LSCC diagnosis and we assumed that miR-93, miR-223 and miR-532 could orchestrate the regulation of multiple cancer-related processes. These findings encourage the possibility to deepen the molecular mechanisms underlying their oncogenic role, for the desirable development of novel therapeutic opportunities based on the use of short single-stranded oligonucleotides acting as non-coding RNA antagonists in cancer.

Whiteflies (Bemisia tabaci sensu lato) have a wide host range and are globally important agricultural pests. In Sub-Saharan Africa, they vector viruses that cause two ongoing disease epidemics: cassava brown streak disease and cassava mosaic virus disease. These two diseases threaten food security for more than 800 million people in Sub-Saharan Africa. Efforts are ongoing to identify target genes for the development of novel management options against the whitefly populations that vector these devastating viral diseases affecting cassava production in Sub-Saharan Africa. This study aimed to identify genes that mediate osmoregulation and symbiosis functions within cassava whitefly gut and bacteriocytes and evaluate their potential as key gene targets for novel whitefly control strategies. The gene expression profiles of dissected guts, bacteriocytes and whole bodies were compared by RNAseq analysis to identify genes with significantly enriched expression in the gut and bacteriocytes. Phylogenetic analyses identified three candidate osmoregulation gene targets: two α-glucosidases, SUC 1 and SUC 2 with predicted function in sugar transformations that reduce osmotic pressure in the gut; and a water-specific aquaporin (AQP1) mediating water cycling from the distal to the proximal end of the gut. Expression of the genes in the gut was enriched 23.67-, 26.54- and 22.30-fold, respectively. Genome-wide metabolic reconstruction coupled with constraint-based modeling revealed four genes (argH, lysA, BCAT & dapB) within the bacteriocytes as potential targets for the management of cassava whiteflies. These genes were selected based on their role and essentiality within the different essential amino acid biosynthesis pathways. A demonstration of candidate osmoregulation and symbiosis gene targets in other species of the Bemisia tabaci species complex that are orthologs of the empirically validated osmoregulation genes highlights the latter as promising gene targets for the control of cassava whitefly pests by in planta RNA interference.

The incidence and mortality of hepatocellular carcinoma (HCC) in Sub-Saharan Africa is projected to increase sharply by 2040 against a backdrop of limited diagnostic and therapeutic options. Two large South African-based case control studies have developed a serum-based miRNome for Hepatitis B-associated hepatocellular carcinoma (HBV-HCC), as well as identifying their gene targets and pathways. Using a combination of RNA sequencing, differential analysis and filters including a unique molecular index count (UMI) ≥ 10 and log fold change (LFC) range > 2: <-0.5 (p < 0.05), 91 dysregulated miRNAs were characterized including 30 that were upregulated and 61 were downregulated. KEGG analysis, a literature review and other bioinformatic tools identified the targeted genes and HBV-HCC pathways of the top 10 most dysregulated miRNAs. The results, which are based on differentiating miRNA expression of cases versus controls, also develop a serum-based miRNA diagnostic panel that indicates 95.9% sensitivity, 91.0% specificity and a Youden Index of 0.869. In conclusion, the results develop a comprehensive African HBV-HCC miRNome that potentially can contribute to RNA-based diagnostic and therapeutic options.

Carotenoids are naturally occurring pigments that are abundant in the natural world. Due to their excellent antioxidant attributes, carotenoids are widely utilized in various industries, including the food, pharmaceutical, cosmetic industries, and others. Plants, algae, and microorganisms are presently the main sources for acquiring natural carotenoids. However, due to the swift progress in metabolic engineering and synthetic biology, along with the continuous and thorough investigation of carotenoid biosynthetic pathways, recombinant strains have emerged as promising candidates to produce carotenoids. The identification and manipulation of gene targets that influence the accumulation of the desired products is a crucial challenge in the construction and metabolic regulation of recombinant strains. In this review, we provide an overview of the carotenoid biosynthetic pathway, followed by a summary of the methodologies employed in the discovery of gene targets associated with carotenoid production. Furthermore, we focus on discussing the gene targets that have shown potential to enhance carotenoid production. To facilitate future research, we categorize these gene targets based on their capacity to attain elevated levels of carotenoid production.

Across the globe, cardiovascular disease (CVD) is the leading cause of mortality. According to reports, around 6.2 million people in the United states have heart failure. Current standards of care for heart failure can delay but not prevent progression of disease. Gene therapy is one of the novel treatment modalities that promises to fill this limitation in the current standard of care for Heart Failure. In this paper we performed an extensive search of the literature on various advances made in gene therapy for heart failure till date. We review the delivery methods, targets, current applications, trials, limitations and feasibility of gene therapy for heart failure. Various methods have been employed till date for administering gene therapies including but not limited to arterial and venous infusion, direct myocardial injection and pericardial injection. Various strategies such as AC6 expression, S100A1 protein upregulation, VEGF-B and SDF-1 gene therapy have shown promise in recent preclinical trials. Furthermore, few studies even show that stimulation of cardiomyocyte proliferation such as through cyclin A2 overexpression is a realistic avenue. However, a considerable number of obstacles need to be overcome for gene therapy to be part of standard treatment of care such as definitive choice of gene, gene delivery systems and a suitable method for preclinical trials and clinical trials on patients. Considering the challenges and taking into account the recent advances in gene therapy research, there are encouraging signs to indicate gene therapy for heart failure to be a promising treatment modality for the future. However, the time and feasibility of this option remains in a situation of balance.

The mycotoxin citrinin, which can contaminate food, is a major global concern. Citrinin is regarded as an inevitable pollutant in foods and feed since fungi are widely present in the environment. To identify contentious toxicity and lessen its severity by understanding the targets of citrinin in the human body and the impacted biosynthetic pathways, we analyzed the production of citrinin from Aspergillus flavus and Penicillium notatum and used a thorough bioinformatics analysis to characterize the toxicity and predict genes and protein targets for it. The predicted median fatal dosage (LD50) for citrinin was 105 mg/kg weight, and it belonged to toxicity class 3 (toxic if swallowed). Citrinin was found to be well absorbed by human intestinal epithelium and was a Pgp nonsubstrate (permeability glycoprotein), which means that once it is absorbed, it cannot be pumped out, hence leading to bioconcentration or biomagnification in the human body. The main targets of toxicity were casp3, TNF, IL10, IL1B, BAG3, CCNB1, CCNE1, and CDC25A, and the biological pathways implicated were signal transduction involved in DNA damage checkpoints, cellular and chemical responses to oxidative stress, DNA damage response signal transduction by P53, stress-activated protein kinase signaling cascade, netrin-UNC5B signaling, PTEN gene regulation, and immune response. Citrinin was linked to neutrophilia, squamous cell carcinoma, Fanconi anemia, leukemia, hepatoblastoma, and fatty liver diseases. The transcription factors E2F1, HSF1, SIRT1, RELA, NFKB, JUN, and MYC were found to be responsible. When data mining was performed on citrinin targets, the top five functional descriptions were a cell\'s response to an organic cyclic compound, the netrin-UNC5B signaling pathway, lipids and atherosclerosis, thyroid cancer, and controlling the transcription of the PTEN gene.

UNASSIGNED: Idiopathic sudden hearing loss (ISHL) is characterized by sudden unexplainable and unilateral hearing loss as a clinically emergent symptom. The use of the herb Erlongjiaonang (ELJN) in traditional Chinese medicine is known to effectively control and cure ISHL. This study explored the underlying molecular mechanisms using network pharmacology and molecular docking analyses.
UNASSIGNED: The Traditional Chinese Medicine System Pharmacological database and the Swiss Target Prediction database were searched for the identification of ELJN constituents and potential gene targets, respectively, while ISHL-related gene abnormality was assessed using the Online Mendelian Inheritance in Man and Gene Card databases. The interaction of ELJN gene targets with ISHL genes was obtained after these databases were cross-screened, and a drug component-intersecting target network was constructed, and the gene ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction networks were analyzed. Cytoscape software tools were used to map the active components-crossover target-signaling pathway network and screened targets were then validated by establishing molecular docking with the corresponding components.
UNASSIGNED: Erlongjiaonang contains 85 components and 250 corresponding gene targets, while ISHL has 714 disease-related targets, resulting in 66 cross-targets. The bioinformatical analyses revealed these 66 cross-targets, including isorhamnetin and formononetin on NOS3 expression, baicalein on AKT1 activity, and kaempferol and quercetin on NOS3 and AKT1 activity, as potential ELJN-induced anti-ISHL targets.
UNASSIGNED: This study uncovered potential ELJN gene targets and molecular signaling pathways in the control of ISHL, providing a molecular basis for further investigation of the anti-ISHL activity of ELJN.

In the United States, over 100,000 women are diagnosed with a gynecologic malignancy every year, with ovarian cancer being the most lethal. One of the hallmark characteristics of ovarian cancer is the development of resistance to chemotherapeutics. While the exact mechanisms of chemoresistance are poorly understood, it is known that changes at the cellular and molecular level make chemoresistance challenging to treat. Improved therapeutic options are needed to target these changes at the molecular level. Using a precision medicine approach, such as gene therapy, genes can be specifically exploited to resensitize tumors to therapeutics. This review highlights traditional and novel gene targets that can be used to develop new and improved targeted therapies, from drug efflux proteins to ovarian cancer stem cells. The review also addresses the clinical relevance and landscape of the discussed gene targets.

Interest in gene-based therapies for neurodevelopmental disorders is increasing exponentially, driven by the rise in recognition of underlying genetic etiology, progress in genomic technology, and recent proof of concept in several disorders. The current prioritization of one genetic disorder over another for development of therapies is driven by competing interests of pharmaceutical companies, advocacy groups, and academic scientists. Although these are all valid perspectives, a consolidated framework will facilitate more efficient and rational gene therapy development. Here we outline features of Mendelian neurodevelopmental disorders that warrant consideration when determining suitability for gene therapy. These features fit into four broad domains: genetics, preclinical validation, clinical considerations, and ethics. We propose a simple mnemonic, GENE TARGET, to remember these features and illustrate how they could be scored using a preliminary scoring rubric. In this suggested rubric, for a given disorder, scores for each feature may be added up to a composite GENE TARGET suitability (GTS) score. In addition to proposing a systematic method to evaluate and compare disorders, our framework helps identify gaps in the translational pipeline for a given disorder, which can inform prioritization of future research efforts.

Microbial tolerance to organic solvents such as ionic liquids (ILs) is a robust phenotype beneficial for novel biotransformation. While most microbes become inhibited in 1% to 5% (vol/vol) IL (e.g., 1-ethyl-3-methylimidazolium acetate), we engineered a robust Yarrowia lipolytica strain (YlCW001) that tolerates a record high of 18% (vol/vol) IL via adaptive laboratory evolution. Yet, genotypes conferring high IL tolerance in YlCW001 remain to be discovered. In this study, we shed light on the underlying cellular processes that enable robust Y. lipolytica to thrive in inhibitory ILs. By using dynamic transcriptome sequencing (RNA-Seq) data, we introduced Gene Coexpression Connectivity (GeCCo) as a metric to discover genotypes conferring desirable phenotypes that might not be found by the conventional differential expression (DE) approaches. GeCCo selects genes based on their number of coexpressed genes in a subnetwork of upregulated genes by the target phenotype. We experimentally validated GeCCo by reverse engineering a high-IL-tolerance phenotype in wild-type Y. lipolytica. We found that gene targets selected by both DE and GeCCo exhibited the best statistical chance at increasing IL tolerance when individually overexpressed. Remarkably, the best combination of dual-overexpression genes was genes selected by GeCCo alone. This nonintuitive combination of genes, BRN1 and OYE2, is involved in guiding/regulating mitotic cell division, chromatin segregation/condensation, microtubule and cytoskeletal organization, and Golgi vesicle transport. IMPORTANCE Cellular robustness to cope with stressors is an important phenotype. Y. lipolytica is an industrial robust oleaginous yeast that has recently been discovered to tolerate record high concentrations of ILs, beneficial for novel biotransformation in organic solvents. However, genotypes that link to IL tolerance in Y. lipolytica are largely unknown. Due to the complex IL-tolerant phenotype, conventional gene discovery and validation based on differential gene expression approaches are time-consuming due to a large search space and might encounter a high false-discovery rate. Here, using the developed Gene Coexpression Connectivity (GeCCo) method, we identified and validated a subset of most promising gene targets conferring the IL-tolerant phenotypes and shed light on their potential mechanisms. We anticipate GeCCo being a useful method to discover the genotype-to-phenotype link.