Hussainebbesen6649

In this chapter, we provide an evolutionary rationale for limiting continuous treatment(s) with the same agent or combination of agents to avoid selection of resistant cancer subpopulation phenotypes, allowing "evolutionary rescue." We draw upon evidence from nature demonstrating species extinction rarely occurring as a single event phenomenon, but rather a series of events in the slide to extinction. We posit that eradicating small cancer populations, similar to small populations in natural extinctions, will usually require a sequence of different external perturbations that produce negative, synergistic dynamics termed the "extinction vortex." By exploiting these unique extinction vulnerabilities of small cancer populations, the optimal therapeutic sequences may be informed by evolution-informed strategies for patients with LARC.Colorectal cancer, along with most other cancer types, is driven by somatic mutations. Characteristic patterns of somatic mutations, known as mutational signatures, arise as a result of the activities of different mutational processes. Mutational signatures have diverse origins, including exogenous and endogenous sources. In the case of colorectal cancer, the analysis of mutational signatures has elucidated specific signatures for classically associated DNA repair deficiencies, namely mismatch repair (leading to microsatellite instability), base excision repair (due to MUTYH or NTHL1 mutations), and polymerase proofreading (due to POLE and POLD1 exonuclease domain mutations). Additional signatures also play a role in colorectal cancer, including those related to normal aging and those associated with gut microbiota, as well as a number of signatures with unknown etiologies. This chapter provides an overview of the current knowledge of mutational signatures, with a focus on colorectal cancer and on the recently reported signatures in physiologically normal and inflammatory bowel disease-affected somatic colon tissues.Organoids have revolutionized cancer research as highly adaptable models that enable an array of experimental techniques to interrogate tissue morphology and function. Because they preserve the genetic, phenotypic, and behavioral traits of their source tissue, organoids have gained traction as the most relevant models for drug discovery, tracking therapeutic response and for personalized medicine. As organoids are indisputably becoming a mainstay of cancer research, this review specifically addresses how colon-derived organoids can be perfected as multidimensional, scalable, reproducible models of healthy, pre-neoplastic and neoplastic conditions of the colon and for use in high-throughput "Phase-0" human clinical trials-in-a-dish.Colorectal cancer (CRC) is characterized by genetic-environmental interplay leading to diffuse changes in the entire colonic mucosa (field carcinogenesis or field of injury) and to a pro-neoplastic genetic/epigenetic/physiological milieu. The clinical consequences are increased risk of synchronous and metachronous neoplasia. Factors such as genetics, race, ethnicity, age, and socioeconomic status are thought to influence neoplasia development. Here, we explore the potential improvement to CRC screening through exploiting field carcinogenesis, with particular focus on racial disparities and chemoprevention strategies. Also, we discuss future directions for field carcinogenesis/risk stratification using molecular and novel biophotonic techniques for personalized CRC screening.Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Despite ongoing efforts aimed at increasing screening for CRC and early detection, and development of more effective therapeutic regimens, the overall morbidity and mortality from this malignancy remains a clinical challenge. Therefore, identifying and developing genomic and epigenomic biomarkers that can improve CRC diagnosis and help predict response to current therapies are of paramount importance for improving survival outcomes in CRC patients, sparing patients from toxicity associated with current regimens, and reducing the economic burden associated with these treatments. Although efforts to develop biomarkers over the past decades have achieved some success, the recent availability of high-throughput analytical tools, together with the use of machine learning algorithms, will likely hasten the development of more robust diagnostic biomarkers and improved guidance for clinical decision-making in the coming years. ALK signaling pathway In this chapter, we provide a systematic and comprehensive overview on the current status of genomic and epigenomic biomarkers in CRC, and comment on their potential clinical significance in the management of patients with this fatal malignancy, including in the context of precision medicine.The occurrence of colorectal cancer (CRC) shows a large disparity among recognized races and ethnicities in the U.S., with Black Americans demonstrating the highest incidence and mortality from this disease. Contributors for the observed CRC disparity appear to be multifactorial and consequential that may be initiated by structured societal issues (e.g., low socioeconomic status and lack of adequate health insurance) that facilitate abnormal environmental factors (through use of tobacco and alcohol, and poor diet composition that modifies one's metabolism, microbiome and local immune microenvironment) and trigger cancer-specific immune and genetic changes (e.g., localized inflammation and somatic driver gene mutations). Mitigating the disparity by prevention through CRC screening has been demonstrated; this has not been adequately shown once CRC has developed. Acquiring additional knowledge into the science behind the observed disparity will inform approaches towards abating both the incidence and mortality of CRC between U.S. racial and ethnic groups.The immune tumor microenvironment (TME) of colorectal cancer (CRC) is a crucial contributor to disease biology, making it an important target for therapeutic intervention. The diversity of immune cell populations within various subsets of CRC has led to the discovery that immune characterization of the TME has both prognostic and predictive value for patients. The convergence of improved molecular and cellular characterization of CRC along with the widespread use of immunotherapy in solid tumors has led to a revolution in the approach to clinical care. Monoclonal antibodies (mAbs) which target key immune checkpoints, such as programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), have demonstrated remarkable clinical activity in microsatellite instability-high (MSI-H) CRCs and are now used in routine practice. The observation that MSI-H cancers are highly infiltrated with immune cells and carry a high neoantigen load led to the successful targeting of these cancers with immunotherapy. More recently, the Food and Drug Administration (FDA) approved a PD-1 inhibitor for microsatellite stable (MSS) cancers with high tumor mutation burden. However, the anti-tumor activity of immunotherapy is rare in the majority of CRC. While immune cell characterization does provide prognostic value in these patients, these observations have not yet led to therapeutic interventions. By delineating factors that predict efficacy, resistance, and therapeutic targets, ongoing research will inform the development of effective combination strategies for the vast majority of MSS CRC and immunotherapy-resistant MSI-H cancers.The substantial burden of colorectal cancer and its increasing trend in young adults highlight the importance of dietary and lifestyle modifications for improved cancer prevention and survivorship. In this chapter, we review the cutting-edge evidence for the interplay between diet/lifestyle and the gut microbiota in the incidence and prognosis of colorectal cancer. We focus on factors for which there are data supporting their importance for the gut microbiota and colorectal cancer, including excess body weight, fiber, red and processed meat, and coffee. We discuss the potential precision nutrition approaches for modifying and exploiting the gut microbiota for improved cancer prevention and survivorship.The incidence and mortality associated with colorectal cancer (CRC) diagnosed in patients under the age of 50 have been steadily increasing. The exact etiology of these epidemiologic trends is unclear. This chapter will provide a comprehensive review on the topic of early age onset colorectal cancer (EAO-CRC), defined as colorectal cancer (CRC) diagnosed in patients under the age of 50. Topics reviewed will include the epidemiology of EAO-CRC around the world, clinical and pathological features of EAO-CRC in contrast to later age onset CRC (CRC diagnosed on those over the age of 50) and the observed molecular and somatic characteristics. This chapter will review the etiologies to EAO-CRC and the established, as well as proposed risk factors for disease. Evidence-based approaches to prevention, early detection, treatment and survivorship will be presented.Bronchomalacia (BM) is an inconsistently defined term in dogs, impairing understanding of clinical presentation, therapeutic response and prognosis. Herein the authors propose to clarify the definition of canine bronchomalacia (CBM) as regional to diffuse dynamic airway collapse of segmental and/or subsegmental bronchi with associated clinical signs due to airflow limitation. In contrast to tracheal collapse, mainstem bronchial collapse, and in some cases lobar collapse, CBM requires advanced imaging. Common co-morbid conditions (e.g., chronic bronchitis, mitral valve degenerative disease, etc.) should be identified during a comprehensive diagnostic evaluation. Current empiric treatments advocated in absence of clinical trials documenting efficacy in the dog warrant evaluation, as some (e.g., bronchodilators) may have detrimental effects in certain types of airway collapse in humans. There is no direct treatment for CBM, as defined above, but non-specific therapies and targeted treatment of co-morbid disease may improve clinical signs and quality of life. In this manuscript, the authors provide a review of the different types of airway collapse focusing on CBM, reviewing their definition and etiology, proposing a classification scheme, and discussing clinical signs, diagnostic testing, and treatment. Future studies should focus on both improving understanding of the etiology and natural disease progression of CBM and treatment trials.Electrical impedance tomography (EIT) provides clinically useful lung images; however, it would be an advantage to extract additional cardiovascular information from the data. The aim of this study was to evaluate if cardiac-related changes measured by EIT can be used to measure pulse rate (PR) under physiological as well as high and low blood pressure states in anaesthetised horses. Electrical impedance tomography data and PR from seven horses anaesthetised in dorsal recumbency were recorded over 1 min during mechanical ventilation and 1 min of apnoea. Data were collected at four measurement time points; before and during intravenous administration of nitroprusside and phenylephrine, respectively. Nine pixels, estimated to represent the heart, were chosen from the EIT image. A novel algorithm detected peaks of impedance change for these pixels over 10 s intervals. Concurrent PR measured using an invasive blood pressure trace, was recorded every 10 s. EIT- and pulse-rate data were compared using Bland-Altman assessment for multiple measurements on each horse.