PBX1 as a novel master regulator in cancer: Its regulation, molecular biology, and therapeutic applications.

PBX1 is a critical transcription factor at the top of various cell fate-determining pathways. In cancer, PBX1 stands at the crossroads of multiple oncogenic signaling pathways and mediates responses by recruiting a broad repertoire of downstream targets. Research thus far has corroborated the involvement of PBX1 in cancer proliferation, resisting apoptosis, tumor-associated neoangiogenesis, epithelial-mesenchymal transition (EMT) and metastasis, immune evasion, genome instability, and dysregulating cellular metabolism. Recently, our understanding of the functional regulation of the PBX1 protein has advanced, as increasing evidence has depicted a regulatory network consisting of transcriptional, post-transcriptional, and post-translational levels of control mechanisms. Furthermore, accumulating studies have supported the clinical utilization of PBX1 as a prognostic or therapeutic target in cancer. Preliminary results showed that PBX1 entails vast potential as a targetable master regulator in the treatment of cancer, particularly in those with high-risk features and resistance to other therapeutic strategies. In this review, we will explore the regulation, protein-protein interactions, molecular pathways, clinical application, and future challenges of PBX1.

Novel cancer treatment paradigm targeting hypoxia-induced factor in conjunction with current therapies to overcome resistance.

Chemotherapy, radiotherapy, targeted therapy, and immunotherapy are established cancer treatment modalities that are widely used due to their demonstrated efficacy against tumors and favorable safety profiles or tolerability. Nevertheless, treatment resistance continues to be one of the most pressing unsolved conundrums in cancer treatment. Hypoxia-inducible factors (HIFs) are a family of transcription factors that regulate cellular responses to hypoxia by activating genes involved in various adaptations, including erythropoiesis, glucose metabolism, angiogenesis, cell proliferation, and apoptosis. Despite this critical function, overexpression of HIFs has been observed in numerous cancers, leading to resistance to therapy and disease progression. In recent years, much effort has been poured into developing innovative cancer treatments that target the HIF pathway. Combining HIF inhibitors with current cancer therapies to increase anti-tumor activity and diminish treatment resistance is one strategy for combating therapeutic resistance. This review focuses on how HIF inhibitors could be applied in conjunction with current cancer treatments, including those now being evaluated in clinical trials, to usher in a new era of cancer therapy.

Frontier Review of the Molecular Mechanisms and Current Approaches of Stem Cell-Derived Exosomes.

Exosomes are effective therapeutic vehicles that may transport their substances across cells. They are shown to possess the capacity to affect cell proliferation, migration, anti-apoptosis, anti-scarring, and angiogenesis, via the action of transporting molecular components. Possessing immense potential in regenerative medicine, exosomes, especially stem cell-derived exosomes, have the advantages of low immunogenicity, minimal invasiveness, and broad clinical applicability. Exosome biodistribution and pharmacokinetics may be altered, in response to recent advancements in technology, for the purpose of treating particular illnesses. Yet, prior to clinical application, it is crucial to ascertain the ideal dose and any potential negative consequences of an exosome. This review focuses on the therapeutic potential of stem cell-derived exosomes and further illustrates the molecular mechanisms that underpin their potential in musculoskeletal regeneration, wound healing, female infertility, cardiac recovery, immunomodulation, neurological disease, and metabolic regulation. In addition, we provide a summary of the currently effective techniques for isolating exosomes, and describe the innovations in biomaterials that improve the efficacy of exosome-based treatments. Overall, this paper provides an updated overview of the biological factors found in stem cell-derived exosomes, as well as potential targets for future cell-free therapeutic applications.

Therapeutic Targeting of Glutaminolysis as a Novel Strategy to Combat Cancer Stem Cells.

Rare subpopulations of cancer stem cells (CSCs) have the ability to self-renew and are the primary driving force behind cancer metastatic dissemination and the preeminent hurdle to cancer treatment. As opposed to differentiated, non-malignant tumor offspring, CSCs have sophisticated metabolic patterns that, depending on the kind of cancer, rely mostly on the oxidation of major fuel substrates such as glucose, glutamine, and fatty acids for survival. Glutaminolysis is a series of metabolic reactions that convert glutamine to glutamate and, eventually, α-ketoglutarate, an intermediate in the tricarboxylic acid (TCA) cycle that provides biosynthetic building blocks. These building blocks are mostly utilized in the synthesis of macromolecules and antioxidants for redox homeostasis. A recent study revealed the cellular and molecular interconnections between glutamine and cancer stemness in the cell. Researchers have increasingly focused on glutamine catabolism in their attempt to discover an effective therapy for cancer stem cells. Targeting catalytic enzymes in glutaminolysis, such as glutaminase (GLS), is achievable with small molecule inhibitors, some of which are in early-phase clinical trials and have promising safety profiles. This review summarizes the current findings in glutaminolysis of CSCs and focuses on novel cancer therapies that target glutaminolysis in CSCs.

Dehydroepiandrosterone status and efficacy of dehydroepiandrosterone supplementation for bone health in anorexia nervosa: A systematic review and meta-analysis.

OBJECTIVE: This study was designed to determine the status of dehydroepiandrosterone (DHEA) in women with anorexia nervosa (AN) and to assess the efficacy of DHEA supplementation as a treatment for bone health in women with AN. METHOD: Studies were retrieved from the PubMed, Embase, Cochrane Library, MEDLINE, and Scopus databases from inception to February 14, 2022. Observational studies that compared serum DHEA levels between women with AN and healthy controls were included for meta-analysis, and randomized controlled trials (RCTs) that evaluated the effects of DHEA supplementation on bone mass were reviewed. RESULTS: Meta-analysis of 15 cross-sectional studies revealed that patients with AN had significantly elevated serum DHEA levels (mean difference (MD) = 311.63 ng/dl; 95% confidence interval (CI), 78.01-545.25) and reduced DHEAS levels (MD = -24.90 µg/dl; 95% CI, -41.72 to -8.07) compared with healthy controls. A systematic review of seven RCTs found that DHEA monotherapy does not improve bone mineral density (BMD) compared with placebo after adjusting for weight gain. While the combination of DHEA and conjugated oral contraceptives has led to increased bone strength and decreased bone loss, the beneficial effect appears to be limited to older adolescents and adults with closed physes. Potential detrimental effects on BMD were identified in younger adolescents with open physes in one study. DISCUSSION: Due to the lack of apparent benefit of DHEA in women with AN and its potential detrimental effect on BMD in young patients with AN, current evidence does not support the use of DHEA. PUBLIC SIGNIFICANCE: This study demonstrates that women with anorexia nervosa have abnormal levels of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS), which have been suggested by previous studies to play a role in the development of low bone density in this condition. However, current evidence does not support the use of DHEA as a treatment to preserve bone health in patients with anorexia nervosa given the lack of clear benefit following its use and also because of a potential detrimental effect on bone mineral density in young patients with anorexia nervosa.

OBJETIVO: Este estudio fue diseñado para determinar el estado de la dehidroepiandrosterona (DHEA) en mujeres con anorexia nerviosa (AN) y para evaluar la eficacia de la suplementación con DHEA como tratamiento para la salud ósea en mujeres con AN. MÉTODO: Los estudios se obtuvieron de las bases de datos PubMed, Embase, Cochrane library, MEDLINE y Scopus desde su inicio hasta el 14 de febrero de 2022. Se incluyeron estudios observacionales que compararon los niveles séricos de DHEA entre mujeres que padecen AN y controles sanos para el metanálisis, y se revisaron los ensayos controlados aleatorios (ECA) que evaluaron los efectos de la suplementación con DHEA sobre la masa ósea. RESULTADOS: El metanálisis de 15 estudios transversales reveló que los pacientes que padecen AN tenían niveles séricos significativamente elevados de DHEA (diferencia de medias [DM] = 311,63 ng/dL; intervalo de confianza [IC] del 95%, 78,01-545,25) y niveles reducidos de DHEAS (DM = -24,90 µg/dL; IC del 95%, -41,72 a -8,07) en comparación con los controles sanos. La revisión sistemática de siete ECA encontró que la monoterapia con DHEA no mejora la densidad mineral ósea (DMO) en comparación con placebo después de ajustar el aumento de peso. Si bien la combinación de DHEA y anticonceptivos orales conjugados ha llevado a un aumento de la fuerza ósea y una disminución de la pérdida ósea, el efecto beneficioso parece limitarse a adolescentes mayores y adultos con placas de crecimiento cerradas. En un estudio se identificaron posibles efectos perjudiciales sobre la DMO en adolescentes más jóvenes con placas de crecimiento abiertas. DISCUSIÓN: Debido a la falta de beneficio aparente de la DHEA en mujeres que padecen AN y su posible efecto perjudicial sobre la DMO en pacientes jóvenes que padecen AN, la evidencia actual no apoya el uso de la DHEA.

Continuous use of metformin in patients receiving contrast medium: what is the evidence? A systematic review and meta-analysis.

OBJECTIVES: Substantial inconsistencies exist in current guidelines regarding recommendations of metformin usage with the administration of a contrast medium. We aimed to perform a meta-analysis to determine whether the risks of contrast-induced acute kidney injury (CI-AKI) and lactic acidosis increase with metformin use in diabetic patients receiving a contrast medium. METHODS: Studies were retrieved from databases from inception to May 15, 2021. Studies that compared the outcomes of using metformin with not using metformin during contrast medium administration were included. The primary outcomes were incidence of CI-AKI and lactic acidosis. The secondary outcomes were renal function changes from baseline. Data analysis was using risk ratio (RR) for dichotomous outcomes and mean differences (MD) with 95% confidence intervals (CI) for continuous outcomes. RESULTS: Analyses of two randomized controlled trials and four retrospective cohorts examining a total of 1459 patients revealed no significant differences in the incidence of CI-AKI (RR = 1.08; 95% CI, 0.72 to 1.63) and in changes in renal function measurements (serum creatinine: MD = 0.00 mg/dL, 95% CI, - 0.05 to 0.05; estimated glomerular filtration rate: MD = 0.22, 95% CI, - 2.47 to 2.91) after contrast medium administration between patients using and not using metformin. CONCLUSIONS: There is no evidence that continuing metformin during contrast medium administration is associated with a higher risk of CI-AKI, lactic acidosis, or renal function deterioration compared to patients who discontinued metformin or who were not metformin users. The limited quality of the included studies may compromise the strength of evidence provided in this meta-analysis. KEY POINTS: There is no need to discontinue metformin either before or after intravenous contrast medium exposure in patients with eGFR > 30 mL/min/1.73 m2. In patients receiving intra-arterial contrast medium with first-pass renal exposure, there is no need to withhold metformin if eGFR is above 60 mL/min/1.73 m2. For patients who have an eGFR level between 30 and 60 mL/min/1.73 m2 and are receiving intra-arterial contrast medium with first-pass renal exposure, no case of lactic acidosis was observed based on present data, but further evidence is needed to make a strong suggestion regarding its safety.