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Nature Reviews. Clinical Oncology Sep 2021The treatment goal for patients with early-stage lung cancer is cure. Multidisciplinary discussions of surgical resectability and medical operability determine the... (Review)
Review
The treatment goal for patients with early-stage lung cancer is cure. Multidisciplinary discussions of surgical resectability and medical operability determine the modality of definitive local treatment (surgery or radiotherapy) and the associated systemic therapies to further improve the likelihood of cure. Trial evidence supports cisplatin-based adjuvant therapy either after surgical resection or concurrently with radiotherapy. Consensus guidelines support neoadjuvant chemotherapy in lieu of adjuvant chemotherapy and carboplatin-based regimens for patients who are ineligible for cisplatin. The incorporation of newer agents, now standard for patients with stage IV lung cancer, into the curative therapy paradigm has lagged owing to inefficient trial designs, the lengthy follow-up needed to assess survival end points and a developmental focus on the advanced-stage disease setting. Surrogate end points, such as pathological response, are being studied and might shorten trial durations. In 2018, the anti-PD-L1 antibody durvalumab was approved for patients with stage III lung cancer after concurrent chemoradiotherapy. Since then, the study of targeted therapies and immunotherapies in patients with early-stage lung cancer has rapidly expanded. In this Review, we present the current considerations in the treatment of patients with early-stage lung cancer and explore the current and future state of clinical research to develop systemic therapies for non-metastatic lung cancer.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Combined Modality Therapy; Humans; Lung Neoplasms; Neoadjuvant Therapy; Neoplasm Staging; Therapies, Investigational
PubMed: 33911215
DOI: 10.1038/s41571-021-00501-4 -
Developmental Cell May 2023Cardiomyocyte differentiation continues throughout murine gestation and into the postnatal period, driven by temporally regulated expression changes in the...
Cardiomyocyte differentiation continues throughout murine gestation and into the postnatal period, driven by temporally regulated expression changes in the transcriptome. The mechanisms that regulate these developmental changes remain incompletely defined. Here, we used cardiomyocyte-specific ChIP-seq of the activate enhancer marker P300 to identify 54,920 cardiomyocyte enhancers at seven stages of murine heart development. These data were matched to cardiomyocyte gene expression profiles at the same stages and to Hi-C and H3K27ac HiChIP chromatin conformation data at fetal, neonatal, and adult stages. Regions with dynamic P300 occupancy exhibited developmentally regulated enhancer activity, as measured by massively parallel reporter assays in cardiomyocytes in vivo, and identified key transcription factor-binding motifs. These dynamic enhancers interacted with temporal changes of the 3D genome architecture to specify developmentally regulated cardiomyocyte gene expressions. Our work provides a 3D genome-mediated enhancer activity landscape of murine cardiomyocyte development.
Topics: Animals; Mice; Chromatin; Enhancer Elements, Genetic; Myocytes, Cardiac; Promoter Regions, Genetic; Transcriptome
PubMed: 37071996
DOI: 10.1016/j.devcel.2023.03.020 -
Journal of the American Academy of... Jan 2024As children age, there are set milestones that we follow clinically to help track fine motor, gross motor, social, and language development. Because we know what a...
As children age, there are set milestones that we follow clinically to help track fine motor, gross motor, social, and language development. Because we know what a 2-month-old vs 4-month-old vs 1-year-old child should be able to do, we are able to assess whether a given child is on track developmentally. In pediatrics, three developmental stages are assessed and, if, behind there is a clear next step, often to involve early intervention. In child psychiatry, work has been done to establish stages of development as well, seen through the work of Piaget, Erickson, and others. These stages help to define the thoughts and behaviors expected for different-aged children, and thus can help with putting together our diagnostic formulation. The difficulty is that these stages are much broader temporally then the early motor, social, and language developmental milestones. Students may also be participating in the same experiences, such as the same grade level, even though they are at different developmental levels based on their age when they started school, as there could be as much as a year difference between those in a given grade. This has led to concerns about being able to distinguish a child struggling with attention-deficit/hyperactivity disorder (ADHD) relative to a child who is younger than his peers, as teachers may compare a young child to their older peers when filling out assessment forms. These are the developmental questions that we often must ponder as child psychiatrists, inasmuch as mental health and behavioral development are complex and influenced by many factors. In this month's Book Forum, Rishab Chawla looks more into these questions in the review of Nasty, Brutish and Short by Scott Hershovitz, pointing out that there is an overlap between the skills of a child psychiatrist to assess the behavioral impact of these developmental questions and the philosophical questions that younger children start to ponder. The child's developmental understanding of right and wrong will better help us to assess the behaviors that present to us in the office. As Rishab points out in the review, we must ask more about these children whom we see regarding these philosophical questions to better understand some of the behaviors present. Looking more deeply into a student's understanding of these questions may better help us to distinguish developmentally appropriate or inappropriate behaviors.
Topics: Child; Humans; Aged; Infant; Attention Deficit Disorder with Hyperactivity; Schools; Mental Health; Peer Group
PubMed: 37805068
DOI: 10.1016/j.jaac.2023.09.542 -
Children (Basel, Switzerland) Sep 2021Children with End Stage Lung Disease (ESLD) are part of the growing population of individuals with life-limiting conditions of childhood. These patients present with a... (Review)
Review
Children with End Stage Lung Disease (ESLD) are part of the growing population of individuals with life-limiting conditions of childhood. These patients present with a diverse set of pulmonary, cardiovascular, neuromuscular, and developmental conditions. This paper first examines five cases of children with cystic fibrosis, bronchopulmonary dysplasia, neuromuscular disease, pulmonary hypertension, and lung transplantation from Texas Children's Hospital. We discuss the expected clinical course of each condition, then review the integration of primary and specialized palliative care into the management of each diagnosis. This paper then reviews the management of two children with end staged lung disease at Hospital Civil de Guadalajara, providing an additional perspective for approaching palliative care in low-income countries.
PubMed: 34572234
DOI: 10.3390/children8090802 -
Advances in Experimental Medicine and... 2024Many aspects of heart development are topographically complex and require three-dimensional (3D) reconstruction to understand the pertinent morphology. We have recently...
Many aspects of heart development are topographically complex and require three-dimensional (3D) reconstruction to understand the pertinent morphology. We have recently completed a comprehensive primer of human cardiac development that is based on firsthand segmentation of structures of interest in histological sections. We visualized the hearts of 12 human embryos between their first appearance at 3.5 weeks and the end of the embryonic period at 8 weeks. The models were presented as calibrated, interactive, 3D portable document format (PDF) files. We used them to describe the appearance and the subsequent remodeling of around 70 different structures incrementally for each of the reconstructed stages. In this chapter, we begin our account by describing the formation of the single heart tube, which occurs at the end of the fourth week subsequent to conception. We describe its looping in the fifth week, the formation of the cardiac compartments in the sixth week, and, finally, the septation of these compartments into the physically separated left- and right-sided circulations in the seventh and eighth weeks. The phases are successive, albeit partially overlapping. Thus, the basic cardiac layout is established between 26 and 32 days after fertilization and is described as Carnegie stages (CSs) 9 through 14, with development in the outlet component trailing that in the inlet parts. Septation at the venous pole is completed at CS17, equivalent to almost 6 weeks of development. During Carnegie stages 17 and 18, in the seventh week, the outflow tract and arterial pole undergo major remodeling, including incorporation of the proximal portion of the outflow tract into the ventricles and transfer of the spiraling course of the subaortic and subpulmonary channels to the intrapericardial arterial trunks. Remodeling of the interventricular foramen, with its eventual closure, is complete at CS20, which occurs at the end of the seventh week. We provide quantitative correlations between the age of human and mouse embryos as well as the Carnegie stages of development. We have also set our descriptions in the context of variations in the timing of developmental features.
Topics: Humans; Heart; Imaging, Three-Dimensional; Organogenesis
PubMed: 38884703
DOI: 10.1007/978-3-031-44087-8_1 -
EXCLI Journal 2021Animal experimentation helps us to understand human biology. Rodents and, in particular, rats are among the most common animals used in animal experiments. Reporting... (Review)
Review
Animal experimentation helps us to understand human biology. Rodents and, in particular, rats are among the most common animals used in animal experiments. Reporting data on animal age, animal body weight, and animal postnatal developmental stages is not consistent, which can cause the failure to translate animal data to humans. This review summarizes age-related postnatal developmental stages in rats by addressing age-related changes in their body weights. The age and body weight of animals can affect drug metabolism, gene expression, metabolic parameters, and other dependent variables measured in animal studies. In addition, considering the age and the body weight of the animals is of particular importance in animal modeling of human diseases. Appropriate reporting of age, body weight, and the developmental stage of animals used in studies can improve animal to human translation.
PubMed: 34737685
DOI: 10.17179/excli2021-4072 -
The Journal of Animal Ecology Dec 2019The environment experienced early in life often affects the traits that are developed after an individual has transitioned into new life stages and environments. Because... (Review)
Review
The environment experienced early in life often affects the traits that are developed after an individual has transitioned into new life stages and environments. Because the phenotypes induced by earlier environments are then screened by later ones, these 'carry-over effects' influence fitness outcomes across the entire life cycle. While the last two decades have witnessed an explosion of studies documenting the occurrence of carry-over effects, little attention has been given to how they adapt and diversify. To aid future research in this area, we present a framework for the evolution of carry-over effects. Carry-over effects can evolve in two ways. First, the expression of traits later in life may become more or less dependent on the developmental processes of earlier stages (e.g., 'adaptive decoupling'). Genetic correlations between life stages then either strengthen or weaken. Alternatively, those influential developmental processes that begin early in life may become more or less sensitive to that earlier environment. Here, plasticity changes in all the traits that share those developmental pathways across the whole life cycle. Adaptive evolution of a carry-over effect is governed by selection on the induced phenotypes in the later stage, and also by selection on any developmentally linked traits in the earlier life stage. When these selective pressures conflict, the evolution of the carry-over effect will be biased towards maximizing performance in the life stage with stronger selection. Because life stages often contribute unequally to total fitness, the strength of selection in any one stage depends on: (a) the relationship between the traits and the stage-specific fitness components (e.g., juvenile survival, adult mating success), and (b) the reproductive value of the life stage. Considering the evolution of carry-over effects reveals several intriguing features of the evolution of life histories and phenotypic plasticity more generally. For instance, carry-over effects that manifest as maladaptive plasticity in one life stage may represent an adaptive strategy for maximizing fitness in stages with stronger selection. Additionally, adaptation to novel environments encountered early in the life cycle may be faster in the presence of carry-over effects that influence sexually selected traits.
Topics: Adaptation, Physiological; Animals; Biological Evolution; Life Cycle Stages; Phenotype; Reproduction
PubMed: 31402447
DOI: 10.1111/1365-2656.13081 -
The American Naturalist Nov 2022AbstractHosts can defend themselves against parasites either by preventing or limiting infections (resistance) or by limiting parasite-induced damage (tolerance)....
AbstractHosts can defend themselves against parasites either by preventing or limiting infections (resistance) or by limiting parasite-induced damage (tolerance). However, it remains underexplored how these defense types vary over host development with shifting patterns of resource allocation priorities. Here, we studied the role played by developmental stage in resistance and tolerance in Atlantic salmon (). This anadromous fish has distinct life stages related to living in freshwater and seawater. We experimentally exposed 1-year-old salmon, either at the freshwater stage or at the stage transitioning to the marine phase, to the trematode . Using 56 pedigreed families and multivariate animal models, we show that developmental transition is associated with reduced resistance but does not affect tolerance. Furthermore, by comparing tolerance slopes (host fitness against parasite load) based on additive genetic effects among infected and unexposed control relatives, we observed that the slopes can be largely independent of the infection, that is, they may not reflect tolerance. Together, our results suggest that the relative importance of different defense types may vary with host development and emphasize the importance of including control treatments for more confident interpretations of tolerance estimates.
Topics: Animals; Parasites; Fish Diseases; Trematoda; Seawater; Fresh Water
PubMed: 36260846
DOI: 10.1086/721159