Advances in cancer research最新文献

Cancer remains a complex and multifaceted disease, characterized by a myriad of molecular and cellular alterations that collectively drive tumorigenesis and progression. Hanahan and Weinberg's concept of cancer hallmarks has offered a framework for comprehending the various but related aspects of cancer biology. Initially defined as a set of six hallmarks, further investigation has added more characteristics to this list that also contribute to the malignant phenotype. Changes in cellular energetics, proliferative signaling, and resistance to cell death are three of these hallmarks that have been thoroughly investigated and described. But new discoveries in the field of cancer biology have brought attention to the importance of another aspect of the biology of cancer: the dysregulation of membrane potential.

The integration of computer vision into pathology through slide digitalization represents a transformative leap in the field's evolution. Traditional pathology methods, while reliable, are often time-consuming and susceptible to intra- and interobserver variability. In contrast, computer vision, empowered by artificial intelligence (AI) and machine learning (ML), promises revolutionary changes, offering consistent, reproducible, and objective results with ever-increasing speed and scalability. The applications of advanced algorithms and deep learning architectures like CNNs and U-Nets augment pathologists' diagnostic capabilities, opening new frontiers in automated image analysis. As these technologies mature and integrate into digital pathology workflows, they are poised to provide deeper insights into disease processes, quantify and standardize biomarkers, enhance patient outcomes, and automate routine tasks, reducing pathologists' workload. However, this transformative force calls for cross-disciplinary collaboration between pathologists, computer scientists, and industry innovators to drive research and development. While acknowledging its potential, this chapter addresses the limitations of AI in pathology, encompassing technical, practical, and ethical considerations during development and implementation.

Reactive oxygen species (ROS) work as a second messenger, modulating cell response and establishing homeostasis. Abrupt changes in ROS are used to modulate transient cell response to different stimuli, from viral infection to inflammation. Chronic exposure to high ROS concentration can cause cellular damage and promote the development of diseases. Leukemogenesis is adapted to high concentrations of ROS, hijacking the ROS system, and uses kinase cascades to promote survival advantages. The oxidation-reduction (redox) machinery is composed of enzymes that orchestrate all classes of protein and use available Cys as transmitters and sensors, to disseminate stress signals through cells via kinase cascades. Myeloid leukemias (MLs) are known for being a heterogeneous disease, and clonal diversity is remarkably characterized by differences in the activation of kinase-regulated signaling cascades to provide survival advantage. Stress-activated kinase cascades and other cascades are regulated by the ROS system. Several studies present nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and the ER-resident NOX4 as key elements of ROS activity in healthy myeloid cells and myeloid leukemia. Targeting ROS presents an attractive therapeutic strategy for (MLs) patients, but the boundaries between pro-apoptotic and anti-apoptotic ROS concentrations are not well established. Detailed understanding of the signaling switches that determine cell fate needs to be well understood. This work explores several aspects of the redox system and thiol-mediated reactions with focus on kinase signaling in myeloid cancers and highlights some of the challenges.

Older adults with cancer are at risk of over-treatment or under-treatment, and treatment decision-making is difficult due to both the complexity of adverse aging and under-representation in clinical trials. It is recommended to perform a frailty assessment before treatment decision-making. Although the importance of radiotherapy increases in geriatric oncology, there is less evidence base information on frailty assessment in radiation oncology than in medical/surgical oncology. The present literature review analyzed the available data regarding frailty assessment tools in geriatric radiation oncology. The predictive value of geriatric assessment on survival outcomes has been shown in many cancer subtypes treated with radiotherapy. Additionally, the Geriatric-8 score is the most evidenced screening tool in frailty assessment. However, researches are ongoing on the cut-off points of geriatric screening tools and which one is the best. Prospective randomized controlled trials are required for the integration of geriatric screening tools and geriatric assessment-driven interventions into geriatric radiation oncology practice.

Protein Tyrosine Phosphatases (PTPs) help to maintain the balance of protein phosphorylation signals that drive cell division, proliferation, and differentiation. These enzymes are also well-suited to redox-dependent signaling and oxidative stress response due to their cysteine-based catalytic mechanism, which requires a deprotonated thiol group at the active site. This review focuses on PTP structural characteristics, active site chemical properties, and vulnerability to change by reactive oxygen species (ROS). PTPs can be oxidized and inactivated by H₂O₂ through three non-exclusive mechanisms. These pathways are dependent on the coordinated actions of other H₂O₂-sensitive proteins, such as peroxidases like Peroxiredoxins (Prx) and Thioredoxins (Trx). PTPs undergo reversible oxidation by converting their active site cysteine from thiol to sulfenic acid. This sulfenic acid can then react with adjacent cysteines to form disulfide bonds or with nearby amides to form sulfenyl-amide linkages. Further oxidation of the sulfenic acid form to the sulfonic or sulfinic acid forms causes irreversible deactivation. Understanding the structural changes involved in both reversible and irreversible PTP oxidation can help with their chemical manipulation for therapeutic intervention. Nonetheless, more information remains unidentified than is presently known about the precise dynamics of proteins participating in oxidation events, as well as the specific oxidation states that can be targeted for PTPs. This review summarizes current information on PTP-specific oxidation patterns and explains how ROS-mediated signal transmission interacts with phosphorylation-based signaling machinery controlled by growth factor receptors and PTPs.

At the intersection of genetics, biochemistry and behavioral sciences, there is a largely untapped opportunity to consider how ethnic and racial disparities contribute to individual sensitivity to reactive oxygen species and how these might influence susceptibility to various cancers and/or response to classical cancer treatment regimens that pervasively result in the formation of such chemical species. This chapter begins to explore these connections and builds a platform from which to consider how the disciplines can be strengthened further.

Cutaneous malignant melanoma is one of the few major cancers that continue to exhibit a positive rate of increase in the developed world. A wealth of epidemiological data has undisputedly implicated ultraviolet radiation (UVR) from sunlight and artificial sources as the major risk factor for melanomagenesis. However, the molecular mechanisms of this cause-and-effect relationship remain murky and understudied. Recent efforts on multiple fronts have brought unprecedented expansion of our knowledge base on this subject and it is now clear that melanoma is caused by a complex interaction between genetic predisposition and environmental exposure, primarily to UVR. Here we provide an overview of the effects of the macroenvironment (UVR) on the skin microenvironment and melanocyte-specific intrinsic (mostly genetic) landscape, which conspire to produce one of the deadliest malignancies.

The significantly higher breast cancer (BCa) mortality rates of African-American (AA) women compared to non-Hispanic (NHW) white women constitute a major US health disparity. Investigations have primarily focused on biological differences in tumors to explain more aggressive forms of BCa in AA women. The biology of tumors cannot be modified, yet lifestyle changes can mitigate their progression and recurrence. AA communities have higher percentages of obesity than NHWs and exhibit inefficient access to care, low socioeconomic status, and reduced education levels. Such factors are associated with limited healthy food options and sedentary activity. AA women have the highest prevalence of obesity than any other racial/ethnic/gender group in the United States. The social ecological model (SEM) is a conceptual framework on which interventions could be developed to reduce obesity. The SEM includes intrapersonal factors, interpersonal factors, organizational relationships, and community/institutional policies that are more effective in behavior modification than isolation from the participants' environmental context. Implementation of SEM-based interventions in AA communities could positively modify lifestyle behaviors, which could also serve as a powerful tool in reducing risk of BCa, BCa progression, and BCa recurrence in populations of AA women.

The underrepresentation of ethnically diverse populations in cancer clinical trials results in the inequitable distribution of the risks and benefits of this research. Using a case study approach, we apply a conceptual framework of factors associated with the participation of diverse population groups in cancer clinical trials developed by Dr. Jean Ford and colleagues to increase understanding of the specific strategies, and barriers and promoters addressed by these strategies, that resulted in marked success in accrual of racially and ethnically diverse populations in cancer clinical research. Results indicate that the studies presented were able to successfully engage minority participants due to the creation and implementation of multilevel, multifaceted strategies that included: culturally and linguistically appropriate outreach, education, and research studies that were accessible in local communities; infrastructure to support engagement of key stakeholders, clinicians, and organizations serving minority communities; testimonials by ethnically diverse cancer survivors; availability of medical interpretation services; and providing infrastructure that facilitated the engagement in clinical research of clinicians who care for minority patient populations. These strategic efforts were effective in addressing limited awareness of trials, lack of opportunities to participate, and acceptance of engagement in cancer clinical trials. Careful attention to the context and population characteristics in which cancer clinical trials are conducted will be necessary to address disparities in research participation and cancer outcomes. These studies illustrate that progress on minority accrual into clinical research requires intentional efforts to overcome barriers at all three stages of the accrual process: awareness, opportunity, and acceptance of participation.

The molecular chaperone Hsp90 has attracted a lot of interest in cancer research ever since cancer cells were found to be more sensitive to Hsp90 inhibition than normal cells. Why that is has remained a matter of debate and is still unclear. In addition to increased Hsp90 dependence for some mutant cancer proteins and modifications of the Hsp90 machinery itself, a number of other characteristics of cancer cells probably contribute to this phenomenon; these include aneuploidy and overall increased numbers and levels of defective and mutant proteins, which all contribute to perturbed proteostasis. Work over the last two decades has demonstrated that many cancer-related proteins are Hsp90 clients, and yet only few of them have been extensively investigated, selected either on the basis of their obvious function as cancer drivers or because they proved to be convenient biomarkers for monitoring the effects of Hsp90 inhibitors. The purpose of our review is to go beyond these "usual suspects." We established a workflow to select poorly studied proteins that are related to cancer processes and qualify as Hsp90 clients. By discussing and taking a fresh look at these "unusual suspects," we hope to stimulate others to revisit them as novel therapeutic targets or diagnostic markers.