Translational medicine is crucial for addressing health issues and translating research findings to improve population health. This Science and Society article highlights the potential of translational medicine in Mexico. It discusses the obstacles and challenges encountered in the translation process, instilling a sense of optimism for the future of healthcare in Mexico.

Alzheimer's disease (AD) poses a significant health challenge worldwide, and the development of effective treatments necessitates a comprehensive understanding of its pathophysiology. Mouse models have been instrumental in offering insights into the crucial pathogenesis of AD. However, current models rarely recapitulate all aspects of AD pathology in patients; thus, translating the findings from mouse to human clinical trials has proved to be complex. In this review, we outline the development of some prevalently used AD mice, with a particular emphasis on the latest advances in newly generated models. In addition, we discuss the advantages and limitations in mouse models of AD and their applications in blood-based biomarkers. Finally, we speculate on potential future research directions.

Dry eye, a prevalent ocular surface disease, is significantly influenced by modern lifestyle factors such as night-shift work and extended screen time. Emerging evidence suggests a strong correlation between disturbances in circadian rhythm, sleep disorders, and dry eye. However, the precise underlying mechanisms remain unclear. Recent studies have underscored the crucial role of circadian rhythms and neuroendocrine regulation in maintaining ocular surface health. Advances in treatment strategies targeting neuroendocrine pathways have shown promising developments. This review explores the interplay between circadian rhythms, neuroendocrine regulation, and the ocular surface, examines the impact of circadian disruption on the pathophysiology of dry eye, and proposes intervention strategies to alleviate dry eye associated with disturbances in circadian rhythms.

Functional precision medicine (FPM), combining ex vivo drug sensitivity testing with genomic profiling to identify treatment options for recurrent/refractory cancer, is feasible and poised to accelerate. This forum explores the history of FPM, recent clinical advancements, and barriers to expanding the clinical utility and accessibility for pediatric/adolescent and adult cancers.

Multiciliated ependymal cells regulate cerebrospinal fluid (CSF) microcirculation and form a dynamic CSF-brain interface. Emerging evidence suggests that ependymal cells enter reactive states in response to pathology that are associated with ciliary and junctional protein alterations. The drivers of these alterations, likely from both acquired and inherited mechanisms, remain elusive.

The development of checkpoint antibodies for cancer therapy has been guided by the principle of blocking T cell inhibitory signals. Recognition of the role of the Fc domain in therapeutic activities, through the depletion of immunosuppressive populations and myeloid cell activation, prompts a shift toward the development of optimized Fc-engineered checkpoint antibodies.

Primarily perceived as an anti-inflammatory and antimicrobial mediator in mucosa and skin, interleukin-22 (IL-22) has emerged as a pivotal metabolic regulator. Central to IL-22 signaling is its receptor, IL-22RA1. Through IL-22RA1, IL-22 orchestrates glucose homeostasis by modulating insulin secretion, reducing cellular stress in pancreatic islets, promoting beta-cell regeneration, and influencing hepatic glucose and lipid metabolism. These actions suggest its potential as a therapeutic for metabolic dysfunctions like diabetes, obesity, and steatohepatitis. However, clinical applications of IL-22 face challenges related to off-target effects and safety concerns. This review explores IL-22's physiological roles, regulatory mechanisms, and profound influence on metabolic tissues. It also underscores IL-22's dual role in metabolic health and disease, advocating further research to harness its therapeutic potential.

Tertiary lymphoid structures (TLSs) frequently occur at sites of chronic inflammation. A more advanced stage of multiple sclerosis (MS) has been associated with certain TLSs. However, tumor-associated TLSs have been shown to correlate with a greater treatment response rate and a better prognosis in glioma mouse models. In this review, we evaluate the clinical significances of TLSs in prognosis and treatment response, as well as the status of TLS-directed therapies targeting alternative biochemical pathways in various central nervous system (CNS) disorders. Potential molecular mechanisms underlying the development of TLSs are also discussed. Exploring these areas may provide an essential understanding of the processes behind disease advancement, uncover new therapeutic objectives, and detect biomarkers that forecast disease progression and treatment efficacy.

The tuberous sclerosis complex (TSC1/TSC2/TBC1D7) primarily functions to inhibit the mechanistic target of rapamycin complex 1 (mTORC1), a crucial regulator of cell growth. Mutations in TSC1 or TSC2 cause tuberous sclerosis complex (TSC), a rare autosomal dominant genetic disorder marked by benign tumors in multiple organs that rarely progress to malignancy. Traditionally, TSC proteins are considered tumor suppressive due to their inhibition of mTORC1 and other mechanisms. However, more recent studies have shown that TSC proteins can also promote tumorigenesis in certain cancer types. In this review, we explore the composition and function of the TSC protein complex, the roles of its individual components in cancer biology, and potential future therapeutic targeting strategies.

Glucose-6-phosphatase catalytic subunit (G6PC)1 and G6PC2 are crucial for glucose metabolism, regulating processes like glycolysis, gluconeogenesis, and glycogenolysis. Despite their structural and functional similarities, G6PC1 and G6PC2 exhibit distinct tissue-specific expression patterns, G6P hydrolysis kinetics, and physiological functions. This review provides a comprehensive overview of their enzymology and distinct roles in glucose homeostasis. We examine how inactivating mutations in G6PC1 lead to glycogen storage disease, and how elevated G6PC1 and G6PC2 expression can affect the incidence of diabetic complications, risk for type 2 diabetes mellitus (T2DM) and various cancers. We also discuss the potential of inhibiting G6PC1 and G6PC2 to protect against complications from elevated blood glucose levels, and highlight drug development efforts targeting G6PC1 and G6PC2, and the therapeutic potential of inhibitors for disease prevention.

Osteoarthritis (OA) is a prevalent articular disorder characterized by joint degeneration and persistent pain; it imposes a significant burden on both individuals and society. While OA has traditionally been viewed as a localized peripheral disorder, recent preclinical and clinical studies have revealed the crucial interconnections between the bone and the brain, highlighting the systemic nature of OA. The neuronal pathway, molecular signaling, circadian rhythms, and genetic underpinnings within the bone-brain axis play vital roles in the complex interplay that contributes to OA initiation and progression. This review explores emerging evidence of the crosstalk between the bone and brain in OA progression, and discusses the potential contributions of the bone-brain axis to the development of effective interventions for managing OA.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating condition with no cure that shares commonality with long-COVID. This review examines current understanding of long-COVID symptoms, characteristics of the affected population, the connection with ME/CFS, and the potential for salubrinal, an agent known for its influence on cellular stress pathways, to mitigate these disorders It also describes the historical development and mechanism of action of salubrinal, to mitigate endoplasmic reticulum (ER)/cellular stress responses, that could potentially contribute to symptom improvement in both ME/CFS and long-COVID patients. Further research and clinical trials are warranted to advance our understanding of the potential role of salubrinal in improving the quality of life for individuals with long-COVID-related ME/CFS symptoms as well as ME/CFS patients.

Monoamine oxidases (MAOs) are a crucial pair of isoenzymes responsible for degrading monoamine neurotransmitters and dietary amines. In addition to extensive studies of their roles in the context of brain functions and disorders over decades, emerging evidence indicates that MAOs are also often dysregulated and associated with clinical outcomes in diverse cancers, with the ability to differentially regulate cancer growth, invasion, metastasis, progression, and therapy response depending on the cancer type. In this review, we summarize recent advances in understanding the clinical relevance, functional importance, and mechanisms of MAOs in a broad range of cancers, and discuss the application and therapeutic benefit of MAO inhibitors (MAOIs) for cancer treatment, highlighting the roles of MAOs as novel regulators, prognostic biomarkers, and therapeutic targets in cancer.

Hodgkin lymphoma (HL) has been and still is the most enigmatic lymphoid malignancy in humans. Since the first molecular analysis of isolated Hodgkin and Reed-Sternberg (HRS) tumor cells of classic HL 30 years ago, substantial advances in our understanding of HL have been made. This review describes the cellular origin of HL, summarizes the current knowledge about the genetic lesions in HRS cells, and highlights the role of Epstein-Barr virus (EBV) in HL pathogenesis. Moreover, the pathobiological roles of altered gene expression and deregulated signaling pathways are discussed and key aspects of the HL microenvironment are presented.

Coeliac disease (CeD) is an immune-mediated disorder characterised by gluten-triggered inflammation and damage in the small intestine, with lifelong gluten-free diet (GFD) as the only treatment. It is a multifactorial disease, involving genetic and environmental susceptibility factors, and its complexity and lack of comprehensive human model systems have hindered understanding of its pathogenesis and development of new treatments. Therefore, it is crucial to establish systems that recapitulate patient genetic background and the interactions between the small intestinal epithelial barrier, immune cells, and environment that contribute to CeD. In this review, we discuss disease complexity, recent advances in stem cell biology, organoids, tissue co-cultures, and organ-on-chip (OoC) systems that facilitate the development of comprehensive human model systems, and model applications in preclinical studies of potential treatments.

Inflammatory bowel diseases (IBD) are chronic, incurable pathologies with unknown causes, affecting millions of people. Pediatric-onset IBD, starting before the age of 18 years, are increasing, with more aggressive and extensive features than adult-onset IBD. These differences remain largely unexplained. Intestinal mucosal damage, cell death, DNA release from nuclear, mitochondrial, or microbiota sources, and DNA-sensing activating the cGAS-STING pathway may contribute to disease evolution. Increased colonic cGAS and STING are increasingly reported in experimental and human IBD. However, limited knowledge of the mechanisms involved hinders the development of new therapeutic options. Here, we discuss recent advances and unresolved questions regarding DNA release, DNA sensor activation, and the role and therapeutic potential of the cGAS-STING pathway in inflammatory colitis.

Immune checkpoint inhibitors (ICIs) have led to improved outcome in patients with various types of cancer. Due to inhibition of physiological anti-inflammatory mechanisms, patients treated with ICIs may develop autoimmune inflammation of the colon, associated with morbidity, decreased quality of life (QoL), and mortality. In this review, we summarize clinical and pathophysiological aspects of immune-mediated colitis (ImC), highlighting novel treatment options. In the colon, ICIs trigger resident and circulating T cell activation and infiltration of myeloid cells. In addition, the gut microbiota critically contribute to intestinal immune dysregulation and loss of barrier function, thereby propagating local and systemic inflammation. Currently available therapies for ImC include corticosteroids, antitumor necrosis factor-α (TNF-α)- and anti-integrin αβ antibodies. Given that systemic immunosuppression might impair antitumor immune responses, novel therapeutic approaches are urgently needed.

The increasing prevalence and poor prognosis of central nervous system (CNS) metastases pose a significant challenge in oncology, necessitating improved therapeutic strategies. Recent research has shed light on the complex genomic landscape of brain metastases, identifying unique and potentially actionable genetic alterations. These insights offer new avenues for targeted therapy, highlighting the potential of precision medicine approaches in treating CNS metastases. However, translating these discoveries into clinical practice requires overcoming challenges such as availability of tissue for characterization, access to molecular testing, drug delivery across the blood-brain barrier (BBB) and addressing intra- and intertumoral genetic heterogeneity. This review explores novel insights into the evolution of CNS metastases, the molecular mechanisms underlying their development, and implications for therapeutic interventions.

Clonal hematopoiesis (CH) of indeterminate potential (CHIP), characterized by propagation of blood cell clones carrying somatic mutations in specific driver genes, is increasingly recognized as a critical factor in the development of hematological malignancies. This phenomenon, which often emerges with age, underscores the complex interplay between genetic predisposition and environmental influences in cancer initiation and progression. Recent years have witnessed significant advances in our understanding of the link between CHIP and hematological diseases. In this review, we provide a comprehensive overview of the features of CHIP and explore its role in promoting tumorigenesis and influencing treatment outcomes for blood cancers. Finally, we summarize current available tools for risk stratification and discuss management strategies for patients with CHIP.

Cyclin-dependent kinase 7 (CDK7) regulates cell cycle and transcription, which are central for cancer progression. CDK7 inhibitors exhibit substantial anticancer activities in preclinical studies and are currently being evaluated in clinical trials. CDK7 is widely expressed in the body. However, the impact of CDK7 inhibition on normal tissues has received little attention. Here, we review the biological functions of CDK7, followed by its emerging roles in development, homeostasis and diseases. We discuss the regulatory mechanisms of CDK7 kinase activation and provide an overview of CDK7 substrates identified to date. Moreover, we highlight unanswered questions and propose key areas for future investigation. An advanced understanding of CDK7 will facilitate the pharmaceutical development of CDK7 inhibitors and help minimize undesirable adverse effects.

Proteasome functional insufficiency (PFI) is implicated in neurodegeneration and heart failure, where aberrant protein aggregation is common and impairs the ubiquitin (Ub)-proteasome system (UPS), exacerbating increased proteotoxic stress (IPTS) and creating a vicious circle. Breaking this circle represents a key to treating these diseases. Protein kinase (PK)-A and PKG can activate the proteasome and promote proteasomal degradation of misfolded proteins. PKA does so by phosphorylating Ser14-RPN6/PSMD11, but how PKG activates the proteasome remains unknown. Emerging evidence supports a strategy to treat diseases with IPTS by augmenting cAMP/PKA and cGMP/PKG. Conceivably, targeted activation of PKA and PKG at proteasome nanodomains would minimize the undesired effects from their actions on other targets. In this review, we discuss PKA and PKG regulation of proteostasis via the UPS.