International review of cell and molecular biology最新文献

The temporal organization of biological processes is critical for an organism's fitness and survival. An internal circadian clock network coordinates the alignment between the external and internal milieus via an array of systemic factors carrying temporal information such as core body temperature, autonomic activity, hormonal secretion, and behavioral functions. Collectively, these so called zeitgebers are characterized by strong temporal variations (i.e., high amplitudes). At the same time, target tissues show time windows of highest and lowest sensitivity to specific zeitgebers and, in this way, tissues can further modulate the effect of zeitgeber input in a process known as circadian gating. Such interplay between systemic signals and local circadian gating, however, suggests an additional level of temporal control-the resetting of target tissue rhythms in response to altered levels of tonic (i.e., non-rhythmic) signals. The recently identified tuning of liver transcriptome rhythms by thyroid hormones (THs) is one example of such regulation. THs show low-amplitude rhythms in the serum levels that are easily disrupted by altered thyroid states. At the same time, circadian rhythms in TH target tissues, such as liver, are markedly affected by alterations in TH state. Temporal regulation of TH target genes in other tissues suggests similar effects across the body. This chapter describes the rationale, experimental evidence, and potential consequences of this new level of circadian regulators.

The sampling of circulating biomarkers provides an opportunity for non-invasive evaluation and monitoring of cancer activity. In modern day practice, this has typically been in the form of circulating tumor DNA (ctDNA) detected in plasma. The field of ctDNA has been a burgeoning technology, with prominent applications for blood-based cancer screening and in disease status assessment, especially after curative-intent surgery to evaluate for minimal residual disease (MRD). Clinical applications for the latter show an incredibly high sensitivity in certain cancer types with a need for additional studies to determine how much clinical decision-making should be adapted based on ctDNA results and which cancer types, stages, and treatments are best informed by ctDNA results. This chapter provides an overview of ctDNA detection as tool for cancer screening, detecting MRD, and/or molecularly characterizing a cancer, highlighting the rapidly amassing research as a prognostic biomarker and emerging data on ctDNA as a predictive biomarker.

More than four decades have passed since the discovery of Transforming Growth Factor beta (TGF-β) in 1981, a pivotal cytokine with profound implications in cell biology and potential clinical interventions for physio-pathological processes including fibrosis, immune-related disorders, chronic infections, vascular alterations, and the progression of tumour growth through invasiveness and metastasis. However, the introduction of a specific inhibitor targeting this cytokine into the pharmaceutical market remains elusive. Various molecular entities and therapeutic strategies, including small molecules, peptides, recombinant proteins (such as specific antibodies), oligonucleotides, and cellular-based therapies have been devised and subjected to clinical trials. These target the specific TGF-β molecular pathway, either directly or indirectly. The combination of different drug types, routes of administration, and clinical indications has generated substantial data, emphasizing significant variability in patient outcomes. Efforts to enhance the effectiveness of cancer immunotherapy by combining TGF-β inhibitors with other drugs and modulating complementary molecular targets have been explored over the past few decades. This approach aims to translate the promising preclinical efficacy of TGF-β blockade into commercially available drugs that are suitable for a broad spectrum of clinical indications. However, a clear path to address the lack of discernible efficacy and overcome the associated marketing challenges has not yet emerged. This review provides a comprehensive overview of the clinical development and emerging trends in TGF-β inhibitors and modulatory strategies, offering novel perspectives for addressing this persistent challenge.

IL-27, a cytokine with pleiotropic immunomodulatory functions, has garnered increasing attention in the context of tumor immunity, and its role in the tumor microenvironment (TME) is complex and just beginning to unravel. IL-27 is pivotal in polarizing immune responses toward an antitumor phenotype, promoting T-cell differentiation, enhancing cytotoxicity, and reducing the number of immunosuppressive elements within the tumor microenvironment. It also directly affects cancer cells, inducing apoptosis and inhibiting angiogenesis. However, IL-27 is a double-edged sword that can also promote mechanisms of action, inducing the expression of inhibitory molecules such as PD-L1 or IL-10 and inhibiting the maturation of dendritic cells. Here, we recapitulate the intricate mechanisms of IL-27, providing a comprehensive understanding of its immune-stimulating and immune-suppressing functions in the TME. This challenge is crucial for designing immunotherapies based on IL-27 in cancer.

The human microbiome is a complex ecological system of commensal, symbiotic, and pathogenic microorganisms that plays a crucial role in human health and disease. The microbiome includes both the living microorganisms also called microbiota and their synthesized metabolites and structural components. It is distributed to the gastrointestinal tract, skin, respiratory system, and oral cavity, each with a distinct microbial composition. Dysbiosis, or imbalance in the microbiome is linked to numerous diseases such as eczema, gastric ulcers, cardiovascular diseases, and cancer. The axes of microbial activity and their connections to disease, including the gut-skin, gut-lung, gut-brain, and gut-kidney play a crucial role in health and disease conditions. Also, the role of the microbiome in cancer development and response to therapy is examined. This book chapter underscores the importance of maintaining a balanced microbiome for overall health and the potential for microbiome-based interventions in disease prevention and treatment.

The human microbiota is a complex ecosystem that dynamically interacts with the host systemically. Perturbations in the delicate balance of this ecological niche, termed dysbiosis, can make individuals susceptible to a multitude of diseases, including cancer. Specific microbes have been implicated in carcinogenesis through direct effects, modulation of the host immune system, and by promoting inflammation. Furthermore, the microbiota alters the response to and efficacy of anti-cancer therapeutics. Here, we highlight mechanisms by which dysbiosis contributes to cancer development, progression, and therapy as well as how the microbiota can be targeted to enhance cancer outcomes.

Microbes are major drivers of many important physiological pathways in the human body. A well-adapted and established microbial community at key body sites performs a wide range of functions, including digestive and immunological roles. However, the structure of these microbial communities depends on numerous factors, both genetic and external. Diet and lifestyle are the most common external factors influencing microbiome composition. A healthy diet and lifestyle promote the growth of beneficial microbes, while disturbances in these factors can alter the entire microbial dynamics, potentially leading to pathogenesis. These perturbations can occur at any stage of life, from birth to old age, and may result in serious clinical conditions such as obesity, diabetes, cancers, metabolic syndromes, and many others. Therefore, it is essential to identify the dietary and lifestyle factors that support a healthy microbiome and prevent dysbiosis. This chapter aims to discuss the role of various component of diet and life style that can ultimately shape the human microbiome.

A growing number of pediatric and adult subjects worldwide suffer from impaired immune response to pathogens, due to both disease and medical treatments. Different types of immunodeficiency or immunosuppressive drugs may affect different aspects of the immune system and therefore predispose to different risks of infections (aetiology and severity) that can seriously compromise the survival of patients. In this context, the identification of immune-therapeutic strategies aimed at enhancing innate and adaptive antimicrobial immunity is desirable. Vγ9Vδ2 T cells constitute a small fraction of T cells in peripheral blood, but exhibit potent, broad, and pleiotropic antiviral activities ranging from direct cytotoxicity of infected cells to the ability to enhance both innate and adaptive immunity of virus-specific αβ T cells. These activities are not virus-specific and can potentially act against virtually any infection. For this reason, Vγ9Vδ2 T cells represent an incredible opportunity in the management of immunocompromised patients who would greatly benefit from improved antimicrobial immunity. The lack of MHC restriction and the easily ex vivo expansion protocols allow to open their possible use in allogeneic context, thus overcoming the obstacle of possible reduced immune function in immunocompromised patients, and offering an "off-the shelves" effective cell therapy. Moreover, the ability of Vγ9Vδ2 T cells to recognize and kill cells expressing stress antigens may be exploited to optimize strategies based on universal Chimeric Antigen Receptor γδ T cells and/or bispecific γδ T-cell engagers. Finally, the recent data on the use of Vγ9Vδ2-derived-vesicles as therapeutic vectors and effective delivery systems further broaden their possible applications.

Gamma delta (γδ) T cells are a unique subset of T lymphocytes capable of bridging innate and adaptive immunity. Unlike αβ T lymphocytes, γδ T cells bypass the need for Major Histocompatibility Complex (MHC)-restricted antigen presentation, allowing them to rapidly respond to stress signals in contexts such as infections and cancer. In breast cancer (BC), γδ T cells play a dual role, exhibiting both anti-tumoral and pro-tumoral activities. Their capacity for direct cytotoxicity, cytokine production, and antigen presentation highlights their versatility within the tumor microenvironment (TME). The prognostic impact of γδ T cells in BC is complex and varies depending on their density, subset, and functional state. While Vδ1 + γδ T cells have been associated with improved survival, particularly in triple-negative BC, other subsets, such as IL-17-producing γδ T cells, contribute to tumor progression, promoting angiogenesis and immune suppression. The emerging therapeutic potential of γδ T cells resides in their MHC-independent activity and stress antigen recognition, highlighting their potential value in cancer immunotherapy, including adoptive cell therapies (e.g., chimeric antigen receptor-T approaches). Additionally, the combination of γδ T cells with immune checkpoint inhibitors or tumor-targeting antibodies has shown promise in overcoming the immunosuppressive challenges of the TME.

Liquid biopsy, which includes both circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) has become a valuable tool for cancer diagnosis and monitoring. It offers a less invasive approach than traditional tissue biopsy and recent technological advancements have enabled their use in comprehensive analysis of tumor molecular characteristics. By capturing the dynamic nature of tumors through repeated sampling, liquid biopsy addresses the limitations of tissue biopsy and provides insights into tumor heterogeneity over time. It is being extensively studied in patients with advanced colorectal cancer because it can aid in diagnosis, predict disease course, and guide treatment selection. Furthermore, as personalized medicine becomes more common, identifying genetic changes that cause cancer cells to become resistant to treatment is crucial. This chapter explores the emerging field of liquid biopsy, with a particular focus on the role and potential of circulating tumor cells (CTCs) in the context of colorectal cancer.