In past years, a diagnosis of bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplant (HCT) conferred nearly universal mortality secondary to lack of consensus for ...diagnostic criteria, poorly understood disease pathogenesis, and very few studies of therapeutic or supportive care interventions. Recently, however, progress has been made in these areas: revised consensus diagnostic guidelines are now available, supportive care has improved, there is greater understanding of potential mechanisms of disease, and prospective trials are being conducted. This article describes these advances and provides suggestions to optimize therapy for patients with BOS after HCT.
Noninfectious lung diseases contribute to nonrelapse mortality. They constitute a spectrum of diseases that can affect the parenchyma, airways, or vascular pulmonary components and specifically ...exclude cardiac and renal causes. The differential diagnoses of these entities differ as a function of time after hematopoietic cell transplantation. Specific diagnosis, prognosis, and optimal treatment remain challenging, although progress has been made in recent decades.
Severe acute and chronic graft versus host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Historically, cord blood and matched ...sibling transplantation has been associated with the lowest rates of GVHD. Newer methods have modified the lymphocyte components to minimize alloimmunity, including: anti-thymocyte globulin, post-transplant cyclophosphamide, alpha/beta T cell depletion, and abatacept. These agents have shown promise in reducing severe GVHD, however, can be associated with increased risks of relapse, graft failure, infections, and delayed immune reconstitution. Nonetheless, these GVHD prophylaxis strategies have permitted expansion of donor sources, especially critical for those of non-Caucasian decent who previously lacked transplant options. This review will focus on the biologic mechanisms driving GVHD, the method by which each agent impacts these activated pathways, and the clinical consequences of these modern prophylaxis approaches. In addition, emerging novel targeted strategies will be described. These GVHD prophylaxis approaches have revolutionized our ability to increase access to transplant and have provided important insights into the biology of GVHD and immune reconstitution.
Early allograft dysfunction (EAD) is a functional hepatic insufficiency within a week of orthotopic liver transplantation (OLT) and is associated with morbidity and mortality. The etiology of EAD is ...multifactorial and largely driven by ischemia reperfusion injury (IRI), a phenomenon characterized by oxygen scarcity followed by paradoxical oxidative stress and inflammation. With the expanded use of marginal allografts more susceptible to IRI, the incidence of EAD may be increasing. This necessitates an in-depth understanding of the innate molecular mechanisms underlying EAD and interventions to mitigate its impact. Our central hypothesis is peri-reperfusion hyperoxemia and immune dysregulation exacerbate IRI and increase the risk of EAD. We will perform a pilot prospective single-center observational cohort study of 40 patients. The aims are to determine (1) the association between peri-reperfusion hyperoxemia and EAD and (2) whether peri-reperfusion perturbed cytokine, protein, and hypoxia inducible factor-1 alpha (HIF-1α) levels correlate with EAD after OLT. Inclusion criteria include age ≥ 18 years, liver failure, and donation after brain or circulatory death. Exclusion criteria include living donor donation, repeat OLT within a week of transplantation, multiple organ transplantation, and pregnancy. Partial pressure of arterial oxygen (PaO2) as the study measure allows for the examination of oxygen exposure within the confines of existing variability in anesthesiologist-administered fraction of inspired oxygen (FiO2) and the inclusion of patients with intrapulmonary shunting. The Olthoff et al. definition of EAD is the primary outcome. Secondary outcomes include postoperative acute kidney injury, pulmonary and biliary complications, surgical wound dehiscence and infection, and mortality. The goal of this study protocol is to identify EAD contributors that could be targeted to attenuate its impact and improve OLT outcomes. If validated, peri-reperfusion hyperoxemia and immune perturbations could be targeted via FiO2 titration to a goal PaO2 and/or administration of an immunomodulatory agent by the anesthesiologist intraoperatively.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
With improvements in supportive care, both long-term survival following allogeneic hematopoietic stem cell transplantations (HSCTs) and the indications for this procedure have increased. As a result, ...the number of patients living with long-term toxic effects due to HSCT has increased. A once rare condition of the donor immune cells attacking healthy host tissues, termed chronic graft-vs-host disease, has become a more common phenomenon. When chronic graft-vs-host disease affects the lung tissue, bronchiolitis obliterans syndrome ensues. Recent data suggest that bronchiolitis obliterans syndrome may affect up to 6% of HSCT recipients and dramatically alters survival, with overall survival of only 13% at 5 years. These statistics have not improved since the first presentation of this disease over 20 years ago. Challenges to the progress of medical management of bronchiolitis obliterans syndrome include difficulties and delays in diagnosis and a paucity of data on pathogenesis to direct new therapies. This article critically evaluates the current diagnostic criteria for bronchiolitis obliterans syndrome and reviews the epidemiology, pathogenesis, and available treatments. Improvements in survival will likely require early disease recognition, allowing for therapeutic modulation of disease prior to the development of irreversible airway obliteration.
The companion dog is one of the most phenotypically diverse species. Variability between breeds extends not only to morphology and aspects of behaviour, but also to longevity. Despite this fact, ...little research has been devoted to assessing variation in life expectancy between breeds or evaluating the potential for phylogenetic characterisation of longevity. Using a dataset of 584,734 unique dogs located within the UK, including 284,734 deceased, we present variation in longevity estimates within the following: parental lineage (purebred = 1 breed, crossbred ≥ 2 breeds), breed (n = 155), body size (large, medium, small), sex (male, female) and cephalic index (brachycephalic, mesocephalic, dolichocephalic). Survival estimates were then partitioned amongst phylogenetic clades: providing evidence that canine evolutionary history (via domestication and associated artificial selection) is associated with breed lifespan. This information provides evidence to inform discussions regarding pedigree health, whilst helping current/prospective owners, breeders, policy makers, funding bodies and welfare organisations improve decision making regarding canine welfare.
Despite repeated calls to action, proposals for urban conservation are often met with surprise or scepticism. There remains a pervasive narrative in policy, practice, and the public psyche that urban ...environments, although useful for engaging people with nature or providing ecosystem services, are of little conservation value. We argue that the tendency to overlook the conservation value of urban environments stems from misconceptions about the ability of native species to persist within cities and towns and that this, in turn, hinders effective conservation action. However, recent scientific evidence shows that these assumptions do not always hold. Although it is generally true that increasing the size, quality, and connectivity of habitat patches will improve the probability that a species can persist, the inverse is not that small, degraded, or fragmented habitats found in urban environments are worthless. In light of these findings we propose updated messages that guide and inspire researchers, practitioners, and decision makers to undertake conservation action in urban environments: consider small spaces, recognize unconventional habitats, test creative solutions, and use science to minimize the impacts of future urban development.
Corrección de Ideas Erróneas para Inspirar Acciones de Conservación en Ambientes Urbanos
Resumen
A pesar de las repetidas llamadas a actuar, las propuestas para la conservación urbana con frecuencia se enfrentan a reacciones de sorpresa o escepticismo. Todavía existe una narrativa penetrante en la política, la práctica y el psique del público que dicta que los ambientes urbanos, aunque sean útiles para comprometer a las personas con la naturaleza o para proporcionar servicios ambientales, tienen poco valor para la conservación. Argumentamos que la tendencia de pasar por alto el valor para la conservación de los ambientes urbanos surge de las ideas erróneas sobre la habilidad que tienen las especies nativas para persistir dentro de ciudades y pueblos y que esto, en cambio, impide la acción efectiva de la conservación. A pesar de esto, la evidencia científica reciente muestra que estas suposiciones no siempre se sostienen. Aunque casi siempre es verdad que incrementar el tamaño, la calidad y la conectividad de los fragmentos de hábitat mejorará la probabilidad de que una especie pueda persistir, lo contrario, que los hábitats fragmentados, degradados y pequeños que se encuentran en los ambientes urbanos son inútiles, no lo es. A la luz de estos hallazgos proponemos mensajes actualizados que guíen e inspiren a los investigadores, practicantes y a los tomadores de decisiones a emprender acciones de conservación en ambientes urbanos: considerar espacios pequeños, reconocer hábitats poco convencionales, probar con soluciones creativas, y utilizar la ciencia para minimizar los impactos de desarrollos urbanos futuros.
摘要
尽管人们一再呼吁要采取城市保护行动, 然而却常常对相关提案表示诧异或怀疑。在政策制定、实践行动和公众心理中仍存在一种普遍的认识, 即城市环境虽然有助于人们亲近自然并提供生态系统服务, 但其保护价值微乎其微。我们认为, 这种忽视城市环境保护价值的倾向来源于对本地物种在城市和乡镇间续存能力的误解, 而这反过来又阻碍了有效的保护行动。然而, 最近的科学证据表明这些种种假设并不总是成立。虽然通常情况下增加生境斑块的大小、提高其质量和连接度可以提高物种续存的可能性, 但反过来看, 并不是说退化或碎片化的小面积生境在城市环境中就毫无价值。鉴于以上发现, 我们建议更新这些指导和激励研究者、实践者和决策者采取城市环境保护行动的信息, 应考虑小尺度空间的保护、认识非传统生境、尝试创新性解决方案, 并利用科学知识来减少未来城市发展带来的影响。 【翻译: 胡怡思; 审校: 聂永刚】
Article impact statement: Conserving native biodiversity is both important and achievable in urban environments.
Homologous recombination deficiency (HRD) is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair ...(HRR) pathway. Loss-of-function genes involved in this pathway can sensitize tumors to poly(adenosine diphosphate ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy, which target the destruction of cancer cells by working in concert with HRD through synthetic lethality. However, to identify patients with these tumors, it is vital to understand how to best measure homologous repair (HR) status and to characterize the level of alignment in these measurements across different diagnostic platforms. A key current challenge is that there is no standardized method to define, measure, and report HR status using diagnostics in the clinical setting.
Friends of Cancer Research convened a consortium of project partners from key healthcare sectors to address concerns about the lack of consistency in the way HRD is defined and methods for measuring HR status.
This publication provides findings from the group's discussions that identified opportunities to align the definition of HRD and the parameters that contribute to the determination of HR status. The consortium proposed recommendations and best practices to benefit the broader cancer community.
Overall, this publication provides additional perspectives for scientist, physician, laboratory, and patient communities to contextualize the definition of HRD and various platforms that are used to measure HRD in tumors.
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