Therapeutic Opportunities Research Articles

A Brief Review on the Emerging Role of Bacterial Pigments: From Industrial Uses to Novel Therapeutic Applications

Pigments produced by microorganisms are in high demand due to their safe, non-toxic, and biodegradable characteristics in both industrial and pharmaceutical fields. Using bacteria for pigment production offers several advantages, such as a short life cycle and ease of genetic modification. Numerous studies have highlighted that soil bacteria significantly contribute to the production of coloured pigments as secondary metabolites. Bacterial pigments are well-known for their antimicrobial, antioxidant, and anticancer properties, offering new therapeutic opportunities for the development of novel drugs. However, compared to fungal pigments, most bacterial pigments are still in the research and development stage. Hence, efforts to intensify bacterial pigment production are essential to make them readily available on the market at a low cost for various applications. This review article sheds light on bacterial pigments and their various applications based on the data available in the literature.

Intratumoral heterogeneity of oncogenic drivers in mixed histology lung adenocarcinomas: How tissue selection impacts molecular testing?

Majority of the lung adenocarcinomas show a mixture of different histological patterns. The possibility of histologically heterogeneous areas of the adenocarcinoma showing genetic heterogeneity and harboring different driver mutations, with potentially significant clinical impact, has not been adequately addressed. Currently, there are no guidelines to suggest how to submit tumor tissue in adenocarcinomas with mixed histological features for molecular testing.The objective of this study is to assess intra-tumoral heterogeneity in prominent driver mutations among different morphological patterns of lung adenocarcinoma, its implications on the future of molecular testing as well as its potential impact on patient management.Twenty-three cases of mixed histology lung adenocarcinoma resected between 2018 and 2023 were retrieved from the archives. H&E slides were reviewed to identify the predominant and second most predominant histological patterns. The morphologically different tumor areas were manually macro-dissected for DNA extraction. Next-Generation Sequencing with Ion AmpliSeq™ Cancer Hotspot Panel v2 (Thermo Fisher Scientific, USA).Thirteen cases showed the same pathological variant in both histological components tested. Three cases (13 %) exhibited disparities in the variants detected across the different histological patterns tested (p=0.025). The discrepant findings had a direct therapeutic impact in 4.3 % cases. Seven cases showed no pathogenic variants detected on either of the histological components tested.This study elucidates the presence of infrequent yet significant intra-tumoral heterogeneity in the molecular profiles of mixed histology adenocarcinomas, highlighting the need for guidelines directing tissue selection for molecular testing to avoid missed therapeutic opportunities and mitigate disease relapse.

Prospects and Current Challenges of Extracellular Vesicle-Based Biomarkers in Cancer.

Cancer continues to impose a substantial global health burden, particularly among the elderly, where the ongoing global demographic shift towards an ageing population underscores the growing need for early cancer detection. This is essential for enabling personalised cancer care and optimised treatment throughout the disease course to effectively mitigate the increasing societal impact of cancer. Liquid biopsy has emerged as a promising strategy for cancer diagnosis and treatment monitoring, offering a minimally invasive method for the isolation and molecular profiling of circulating tumour-derived components. The expansion of the liquid biopsy approach to include the detection of tumour-derived extracellular vesicles (tdEVs) holds significant therapeutic opportunity. Evidence suggests that tdEVs carry cargo reflecting the contents of their cell-of-origin and are abundant within the blood, exhibiting superior stability compared to non-encapsulated tumour-derived material, such as circulating tumour nucleic acids and proteins. However, despite theoretical promise, several obstacles hinder the translation of extracellular vesicle-based cancer biomarkers into clinical practice. This critical review assesses the current prospects and challenges facing the adoption of tdEV biomarkers in clinical practice, offering insights into future directions and proposing strategies to overcome translational barriers. By addressing these issues, EV-based liquid biopsy approaches could revolutionise cancer diagnostics and management.

Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models.

Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.

Beyond the Beat: Understanding Inherited Risk and Therapeutic Opportunities in Cardiovascular Diseases with Emphasis on Inherited Cardiomyopathies and Inherited Arrhythmic Syndromes

Over the past three decades, significant progress has been made in elucidating the intricate connection between genetic predispositions and cardiovascular diseases (CVDs). Through extensive investigation, numerous genetic variants linked to various cardiovascular conditions have been discovered, shedding crucial light on the underlying biological mechanisms and pathways. These discoveries have not only revolutionized risk assessment for patients but have also paved the way for personalized treatment strategies, allowing healthcare providers to tailor interventions according to individual genetic profiles. Furthermore, genetic testing has facilitated cascade screening, enabling the early identification and intervention of potential cardiovascular issues among at-risk biological family members. This review aims to comprehensively summarize the current state of knowledge regarding inherited risk and novel insights from human genome and epigenome research, as well as therapeutic opportunities in CVDs with special emphasis on inherited cardiomyopathies and inherited arrhythmic syndromes. The newest translational trials for CVDs and pharmaceutical approaches are discussed, including gene therapy options for heart failure and cardiomyopathies.

NUP98 oncofusions in myeloid malignancies: An update on molecular mechanisms and therapeutic opportunities.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a heterogeneous molecular landscape. In the pediatric context, the NUP98 gene is a frequent target of chromosomal rearrangements that are linked to poor prognosis and unfavorable treatment outcomes in different AML subtypes. The translocations fuse NUP98 to a diverse array of partner genes, resulting in fusion proteins with novel functions. NUP98 fusion oncoproteins induce aberrant biomolecular condensation, abnormal gene expression programs, and re-wired protein interactions which ultimately cause alterations in the cell cycle and changes in cellular structures, all of which contribute to leukemia development. The extent of these effects is steered by the functional domains of the fusion partners and the influence of concomitant somatic mutations. In this review, we discuss the complex characteristics of NUP98 fusion proteins and potential novel therapeutic approaches for NUP98 fusion-driven AML.

Circadian Rhythms and Sleep Disorders Associated to Major Depressive Disorder: Pathophysiology and Therapeutic Opportunities.

Major depressive disorder (MDD) is a complex mood disorder. While much progress has been made in understanding the pathophysiology of MDD, no single mechanism can explain all facets of this disorder. Several studies show that disturbances in biological rhythms can lead to the development of MDD. Indeed, insomnia or hypersomnia are symptoms included in the MDD diagnostic criteria. Clinical studies and meta-analyses showed a strong relationship between MDD and sleep disorders. Sleep disorder and MDD are associated with activation in the hypothalamicpituitary- adrenal (HPA) axis and inflammation. The increase in inflammatory response can activate the kynurenine pathway, decrease serotonin synthesis, and affect other factors involved in the pathophysiology of neuropsychiatric conditions. Moreover, sleep disorders and MDD can change the gut microbiota and alter the microbiota-gut-brain axis. Thus, this review discusses the relationship between MDD, circadian rhythms, and sleep disorders, describing the potential pathophysiological mechanism shared in these conditions. In addition, therapeutic opportunities based on antiinflammatory, antioxidant, HPA axis regulatory, and synapse-modulating actions are raised. For the article search, we used the PubMed database. Both sleep disorders and changes in biological rhythms have a bidirectional relationship with MDD. Although some pathophysiological mechanisms, including inflammation, changes in the gut microbiota, and decreased neuroplasticity, may be involved in the relationship between sleep, circadian rhythms, and MDD, other mechanisms are not yet well understood. Therapeutic opportunities based on anti-inflammatory, antioxidant, HPA regulatory axis, and synapse modulating actions appear to be promising targets in preventing MDD, circadian rhythm disturbances, and sleep disorders.

The role of SRC-3 in prostate cancer progression and implications for therapeutic targeting: A systematic review

Context: Prostate cancer remains a significant global health concern, and understanding the molecular drivers of this disease is crucial for developing effective diagnostic and therapeutic strategies. Steroid receptor coactivator-3 (SRC-3), a member of the SRC family, has emerged as a key player in prostate cancer pathogenesis. Aims: To examine the role of SRC-3 in prostate cancer, encompassing molecular mechanisms, clinical implications, and therapeutic opportunities. Methods: A systematic literature search following PRISMA guidelines was conducted in PubMed, PMC, and other relevant databases to identify studies that investigate SRC-3 in prostate cancer. Results: 785 articles were retrieved from databases using specific keywords and MeSH terms related to SRC-3 and Prostate Cancer. After removing 461 duplicates, 260 articles were excluded based on title and abstract review. Subsequently, a comprehensive screening by three researchers resulted in 47 relevant articles for this systematic review. Evidence suggests that SRC-3 expression correlates with prostate cancer aggressiveness, disease recurrence, and poor patient outcomes. Its potential as a diagnostic biomarker and therapeutic target if explored, offers insights into personalized medicine approaches. Conclusions: SRC-3 plays a pivotal role in prostate cancer, influencing disease progression and clinical outcomes. Understanding the molecular intricacies of SRC-3 in prostate cancer offers new opportunities for precision medicine and innovative therapeutic approaches. This review provides a comprehensive overview of SRC-3's involvement in prostate cancer, emphasizing its clinical relevance and potential as a therapeutic target, ultimately contributing to improved patient care in the era of personalized oncology.

Sex-Specific Effects of Anxiety on Cognition and Activity-Dependent Neural Networks: Insights from (Female) Mice and (Wo)Men

Neuropsychiatric symptoms (NPS), such as depression and anxiety, are observed in 90% of Alzheimer's disease (AD) patients, two-thirds of whom are women. NPS usually manifest long before AD onset creating a therapeutic opportunity. Here, we examined the impact of anxiety on AD progression and the underlying brain-wide neuronal mechanisms. To gain mechanistic insight into how anxiety impacts AD progression, we performed a cross-sectional analysis on mood, cognition, and neural activity utilizing the ArcCreERT2 x enhanced yellow fluorescent protein (eYFP) x APP/PS1 (AD) mice. The ADNI dataset was used to determine the impact of anxiety on AD progression in human subjects. Female APP/PS1 mice exhibited anxiety-like behavior and cognitive decline at an earlier age than control (Ctrl) mice and male mice. Brain-wide analysis of c-Fos+ revealed changes in regional correlations and overall network connectivity in APP/PS1 mice. Sex-specific eYFP+/c-Fos+ changes were observed; female APP/PS1 mice exhibited less eYFP+/c-Fos+ cells in dorsal CA3 (dCA3), while male APP/PS1 mice exhibited less eYFP+/c-Fos+ cells in the dorsal dentate gyrus (dDG). In the ADNI dataset, anxiety predicted transition to dementia. Female subjects positive for anxiety and amyloid transitioned more quickly to dementia than male subjects. While future studies are needed to understand whether anxiety is a predictor, a neuropsychiatric biomarker, or a comorbid symptom that occurs during disease onset, these results suggest that there are sex differences in AD network dysfunction, and that personalized medicine may benefit male and female AD patients rather than a one size fits all approach.

Analyzing the role of TM4SF1 expression in pancreatic adenocarcinoma: understanding prognostic implications and therapeutic opportunities.

Pancreatic adenocarcinoma (PAAD) is a highly lethal malignancy characterized by aggressive growth and poor prognosis. Understanding the molecular mechanisms underlying PAAD is crucial for developing effective therapies. This study aimed to explore the role of TM4SF1 and other key genes in PAAD progression, their prognostic implications, and therapeutic opportunities. Differential gene expression analysis was performed using PAAD and normal tissue samples to identify upregulated genes, with TM4SF1 emerging as significantly elevated in PAAD. Functional enrichment analysis elucidated associated signaling pathways. A prognostic model comprising BPIFB4, PLEKHN1, CPTP, DVL1, and DDR1 was developed using least absolute shrinkage and selection operator (LASSO) regression and validated in an independent cohort. Genetic mutation analysis provided insights into the functional significance of identified genes. Pharmacogenomic analysis examined associations between gene expression and drug sensitivity. Experimental validation included quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analyses to confirm gene expression patterns and protein levels. Lower TM4SF1 expression correlated with enhanced anti-tumor immune activity in PAAD, suggesting a complex interplay between genetic expression and immune response. The prognostic model showed robust associations with patient survival outcomes, validated across diverse patient cohorts. Genetic mutation analysis highlighted potential therapeutic targets. Pharmacogenomic analysis revealed correlations between gene expression profiles and drug responsiveness, suggesting personalized treatment strategies. Experimental validation confirmed elevated TM4SF1 levels in tumor tissues and demonstrated its role in promoting cancer cell proliferation and colony formation. This study advances understanding of the molecular landscape of PAAD, emphasizing TM4SF1 as a key regulator and potential therapeutic target. The integration of genetic expression, immune response dynamics, and pharmacogenomics offers a multifaceted approach to personalized treatment strategies for PAAD, paving the way for improved patient outcomes and novel therapeutic interventions. Further research is warranted to elucidate the clinical utility of targeting TM4SF1 and other identified genes in PAAD management.

A common druggable signature of oncogenic c-Myc, mutant KRAS and mutant p53 reveals functional redundancy and competition among oncogenes in cancer

The major driver oncogenes MYC, mutant KRAS, and mutant TP53 often coexist and cooperate to promote human neoplasia, which results in anticancer therapeutic opportunities within their downstream molecular programs. However, little research has been conducted on whether redundancy and competition among oncogenes affect their programs and ability to drive neoplasia. By CRISPR‒Cas9-mediated downregulation we evaluated the downstream proteomics and transcriptomics programs of MYC, mutant KRAS, and mutant TP53 in a panel of cell lines with either one or three of these oncogenes activated, in cancers of the lung, colon and pancreas. Using RNAi screening of the commonly activated molecular programs, we found a signature of three proteins - RUVBL1, HSPA9, and XPO1, which could be efficiently targeted by novel drug combinations in the studied cancer types. Interestingly, the signature was controlled by the oncoproteins in a redundant or competitive manner rather than by cooperation. Each oncoprotein individually upregulated the target genes, while upon oncogene co-expression each target was controlled preferably by a dominant oncoprotein which reduced the influence of the others. This interplay was mediated by redundant routes of target gene activation - as in the case of mutant KRAS signaling to c-Jun/GLI2 transcription factors bypassing c-Myc activation, and by competition - as in the case of mutant p53 and c-Myc competing for binding to target promoters. The global transcriptomics data from the cell lines and patient samples indicate that the redundancy and competition of oncogenic programs are broad phenomena, that may constitute even a majority of the genes dependent on oncoproteins, as shown for mutant p53 in colon and lung cancer cell lines. Nevertheless, we demonstrated that redundant oncogene programs harbor targets for efficient anticancer drug combinations, bypassing the limitations for direct oncoprotein inhibition.

Ventilator-induced diaphragm dysfunction: phenomenology and mechanism(s) of pathogenesis.

Mechanical ventilation (MV) is used to support ventilation and pulmonary gas exchange in patients during critical illness and surgery. Although MV is a life-saving intervention for patients in respiratory failure, an unintended side-effect of MV is the rapid development of diaphragmatic atrophy and contractile dysfunction. This MV-induced diaphragmatic weakness is labelled as 'ventilator-induced diaphragm dysfunction' (VIDD). VIDD is an important clinical problem because diaphragmatic weakness is a risk factor for the failure to wean patients from MV. Indeed, the inability to remove patients from ventilator support results in prolonged hospitalization and increased morbidity and mortality. The pathogenesis of VIDD has been extensively investigated, revealing that increased mitochondrial production of reactive oxygen species within diaphragm muscle fibres promotes a cascade of redox-regulated signalling events leading to both accelerated proteolysis and depressed protein synthesis. Together, these events promote the rapid development of diaphragmatic atrophy and contractile dysfunction. This review highlights the MV-induced changes in the structure/function of diaphragm muscle and discusses the cell-signalling mechanisms responsible for the pathogenesis of VIDD. This report concludes with a discussion of potential therapeutic opportunities to prevent VIDD and suggestions for future research in this exciting field.

Universal Screening for hsCRP in Patients with Atherosclerotic Disease: A Major Therapeutic Opportunity.

Universal Screening for hsCRP in Patients with Atherosclerotic Disease: A Major Therapeutic Opportunity.

MicroRNAs in Hepatocellular Carcinoma Pathogenesis: Insights into Mechanisms and Therapeutic Opportunities.

Hepatocellular carcinoma (HCC) presents a significant global health burden, with alarming statistics revealing its rising incidence and high mortality rates. Despite advances in medical care, HCC treatment remains challenging due to late-stage diagnosis, limited effective therapeutic options, tumor heterogeneity, and drug resistance. MicroRNAs (miRNAs) have attracted substantial attention as key regulators of HCC pathogenesis. These small non-coding RNA molecules play pivotal roles in modulating gene expression, implicated in various cellular processes relevant to cancer development. Understanding the intricate network of miRNA-mediated molecular pathways in HCC is essential for unraveling the complex mechanisms underlying hepatocarcinogenesis and developing novel therapeutic approaches. This manuscript aims to provide a comprehensive review of recent experimental and clinical discoveries regarding the complex role of miRNAs in influencing the key hallmarks of HCC, as well as their promising clinical utility as potential therapeutic targets.

V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities.

Vacuolar-type ATPase (v-ATPase) is a multimeric protein complex that regulates H+ transport across membranes and intra-cellular organelle acidification. Catabolic processes, such as endocytic degradation and autophagy, strictly rely on v-ATPase-dependent luminal acidification in lysosomes. The v-ATPase complex is expressed at high levels in the brain and its impairment triggers neuronal dysfunction and neurodegeneration. Due to their post-mitotic nature and highly specialized function and morphology, neurons display a unique vulnerability to lysosomal dyshomeostasis. Alterations in genes encoding subunits composing v-ATPase or v-ATPase-related proteins impair brain development and synaptic function in animal models and underlie genetic diseases in humans, such as encephalopathies, epilepsy, as well as neurodevelopmental, and degenerative disorders. This review presents the genetic and functional evidence linking v-ATPase subunits and accessory proteins to various brain disorders, from early-onset developmental epileptic encephalopathy to neurodegenerative diseases. We highlight the latest emerging therapeutic strategies aimed at mitigating lysosomal defects associated with v-ATPase dysfunction.

Kinases Inhibitors as New Therapeutic Opportunities in Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of T-cell lymphomas characterised by high relapse rates and no curative treatments unless the allogeneic stem cell transplantation. The main complication in the management of this kind of malignancy is the variability that characterises the genetic and clinical features among the CTCL subtypes. JAK/STAT, MAPK/ERK, PI3K/Akt, and NF-kB are those signalling pathways that are found altered in CTCL and that are responsible for promoting both T-cell malignancy and the pro-tumorigenic microenvironment. Thus, targeting key players of these pathways can be an advantageous therapeutic option for CTCL. In this review, we aim to summarise the different approaches that precisely inhibit the kinases of each cited signalling. JAK inhibitors seem to be the most promising kinase inhibitors for CTCL. However, adverse events have been reported especially in patients with immunosuppression or an underlying autoimmune disease. More studies are needed, especially clinical trials, to investigate the benefits of these drugs for the treatment of cutaneous T-cell lymphomas.

Fallopian tube rheology regulates epithelial cell differentiation and function to enhance cilia formation and coordination

The rheological properties of the extracellular fluid in the female reproductive tract vary spatiotemporally, however, the effect on the behaviour of epithelial cells that line the tract is unexplored. Here, we reveal that epithelial cells respond to the elevated viscosity of culture media by modulating their development and functionality to enhance cilia formation and coordination. Specifically, ciliation increases by 4-fold and cilia beating frequency decreases by 30% when cells are cultured at 100 mPa·s. Further, cilia manifest a coordinated beating pattern that can facilitate the formation of metachronal waves. At the cellular level, viscous loading activates the TRPV4 channel in the epithelial cells to increase intracellular Ca2+, subsequently decreasing the mitochondrial membrane potential level for ATP production to maintain cell viability and function. Our findings provide additional insights into the role of elevated tubal fluid viscosity in promoting ciliation and coordinating their beating—a potential mechanism to facilitate the transport of egg and embryo, suggesting possible therapeutic opportunities for infertility treatment.

Osteoclasts control endochondral ossification via regulating acetyl-CoA availability

Osteoclast is critical in skeletal development and fracture healing, yet the impact and underlying mechanisms of their metabolic state on these processes remain unclear. Here, by using osteoclast-specific small GTPase Rheb1-knockout mice, we reveal that mitochondrial respiration, rather than glycolysis, is essential for cathepsin K (CTSK) production in osteoclasts and is regulated by Rheb1 in a mechanistic target of rapamycin complex 1 (mTORC1)-independent manner. Mechanistically, we find that Rheb1 coordinates with mitochondrial acetyl-CoA generation to fuel CTSK, and acetyl-CoA availability in osteoclasts is the central to elevating CTSK. Importantly, our findings demonstrate that the regulation of CTSK by acetyl-CoA availability is critical and may confer a risk for abnormal endochondral ossification, which may be the main cause of poor fracture healing on alcohol consumption, targeting Rheb1 could successfully against the process. These findings uncover a pivotal role of mitochondria in osteoclasts and provide a potent therapeutic opportunity in bone disorders.

Next-generation DC vaccines with an immunogenic trajectory against cancer: therapeutic opportunities vs. resistance mechanisms.

Next-generation DC vaccines with an immunogenic trajectory against cancer: therapeutic opportunities vs. resistance mechanisms.

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer.

Ferroptosis is a non-apoptotic form of cell death resulting from the iron-dependent accumulation of lipid peroxides. Colorectal cancer (CRC) cells accumulate high levels of intracellular iron and reactive oxygen species (ROS) and are thus particularly sensitive to ferroptosis. The compound (S)-RSL3 ([1S,3R]-RSL3) is a commonly used ferroptosis inducing compound that is currently characterized as a selective inhibitor of the selenocysteine containing enzyme (selenoprotein) Gluathione Peroxidase 4 (GPx4), an enzyme that utilizes glutathione to directly detoxify lipid peroxides. However, through chemical controls utilizing the (R) stereoisomer of RSL3 ([1R,3R]-RSL3) that does not bind GPx4, combined with inducible genetic knockdowns of GPx4 in CRC cell lines, we revealed that GPx4 dependency does not always align with (S)-RSL3 sensitivity, questioning the current characterization of GPx4 as the central regulator of ferroptosis. Utilizing affinity pull-down mass spectrometry with chemically modified (S)-RSL3 probes we discovered that the effects of (S)-RSL3 extend far beyond GPx4 inhibition, revealing that (S)-RSL3 is a broad and non-selective inhibitor of selenoproteins. To further investigate the therapeutic potential of broadly disrupting the selenoproteome as a therapeutic strategy in CRC, we employed additional chemical and genetic approaches. We found that the selenoprotein inhibitor auranofin, an FDA approved gold-salt, chemically induced oxidative cell death and ferroptosis in both in-vitro and in-vivo models of CRC. Consistent with these data, we found that AlkBH8, a tRNA-selenocysteine methyltransferase required for the translation of selenoproteins, is essential for the in-vitro growth and xenograft survival of CRC cell lines. In summary, these findings recharacterize the mechanism of action of the most commonly used ferroptosis inducing molecule, (S)-RSL3, and reveal that broad inhibition of selenoproteins is a promising novel therapeutic angle for the treatment of CRC.