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Stem cell regulation by local signals is intensely studied, but less is known about the effects of hormonal signals on stem cells. In Drosophila, the primary steroid twenty-hydroxyecdysone (20E) regulates ovarian germline stem cells (GSCs) but was considered dispensable for testis GSC maintenance. Male GSCs reside in a microenvironment (niche) generated by somatic hub cells and adjacent cyst stem cells (CySCs). Here, we show that depletion of 20E from adult males by overexpressing a dominant negative form of the Ecdysone receptor (EcR) or its heterodimeric partner ultraspiracle (usp) causes GSC and CySC loss that is rescued by 20E feeding, uncovering a requirement for 20E in stem cell maintenance. EcR and USP are expressed, activated and autonomously required in the CySC lineage to promote CySC maintenance, as are downstream genes ftz-f1 and E75. In contrast, GSCs non-autonomously require ecdysone signaling. Global inactivation of EcR increases cell death in the testis that is rescued by expression of EcR-B2 in the CySC lineage, indicating that ecdysone signaling supports stem cell viability primarily through a specific receptor isoform. Finally, EcR genetically interacts with the NURF chromatin-remodeling complex, which we previously showed maintains CySCs. Thus, although 20E levels are lower in males than females, ecdysone signaling acts through distinct cell types and effectors to ensure both ovarian and testis stem cell maintenance.
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Proteínas de Unión al ADN/genética , Proteínas de Drosophila/genética , Ecdisterona/metabolismo , Células Madre Embrionarias/fisiología , Receptores de Esteroides/genética , Factores de Transcripción/genética , Animales , Animales Modificados Genéticamente , Apoptosis/genética , Diferenciación Celular/fisiología , Supervivencia Celular/genética , Proteínas Cromosómicas no Histona/metabolismo , Proteínas de Unión al ADN/biosíntesis , Drosophila , Proteínas de Drosophila/biosíntesis , Proteínas de Drosophila/metabolismo , Ecdisterona/genética , Femenino , Regulación del Desarrollo de la Expresión Génica , Células Germinativas , Masculino , Isoformas de Proteínas , Receptores de Esteroides/biosíntesis , Transducción de Señal , Testículo , Factores de Transcripción/biosíntesisRESUMEN
Plug-in electric vehicles (EVs) in China aim to improve sustainability and reduce environmental health impacts of transport emissions. Urban use of EVs rather than conventional vehicles shifts transportation's air pollutant emissions from urban areas (tailpipes) to predominantly rural areas (power plants), changing the geographic distribution of health impacts. We model PM2.5-related health impacts attributable to urban EV use for 34 major cities. Our investigation focuses on environmental justice (EJ) by comparing pollutant inhalation versus income among impacted counties. We find that EVs could increase EJ challenge in China: most (~77%, range: 41-96%) emission inhalation attributable to urban EVs use is distributed to predominately rural communities whose incomes are on average lower than the cities where EVs are used. Results vary dramatically across cities depending on urban income and geography. Discriminant analysis reveals that counties with low income and high inhalation of urban EV emissions have comparatively higher agricultural employment rates, higher mortality rates, more children in the population, and lower education levels. We find that low-emission electricity sources such as renewable energy can help mitigate EJ issues raised here. Findings here are not unique to EVs, but instead are relevant for nearly all electricity-consuming technologies in urban areas.
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Exposición a Riesgos Ambientales/análisis , Vehículos a Motor , Material Particulado/análisis , Justicia Social , Emisiones de Vehículos/análisis , Administración por Inhalación , China , Ciudades , Electricidad , Humanos , Renta , Material Particulado/toxicidad , Centrales Eléctricas , Salud Pública , Energía Renovable , Población Rural , Emisiones de Vehículos/toxicidadRESUMEN
A novel approach has been developed that enables sterile pharmaceutical products to be freeze-dried in the open laboratory without specialist facilities. The product is filled into vials, semi-stoppered and sealed inside one, followed by a second, sterilization pouch under class 100 conditions. The product is then freeze-dried in the laboratory where the vials are shelf-stoppered before being returned to class 100, unwrapped and crimped. The sterilization pouches increased the resistance to water vapor movement during sublimation, thereby increasing the sublimation time and product temperature. Ovine immunoglobulins were double wrapped and lyophilized (as above) adjusting the primary drying time and shelf temperature for increased product temperature and, therefore, prevention of collapse. Ovine immunoglobulin G formulations freeze-dried to ≤ 1.1% residual moisture with no effect on protein aggregation or biological activity. The process was simulated with tryptone soya broth and no growth of contaminating microbial cells was observed after incubation at 35 °C for 2 weeks. Although increasing lyophilization time, this approach offers significant plant and validation cost savings when sterile freeze-drying small numbers of vials thereby making the manufacture of treatments for neglected and orphan diseases more viable economically.
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Embalaje de Medicamentos/métodos , Liofilización/métodos , Inmunoglobulina G/química , Esterilización/métodos , Animales , Calor , OvinosRESUMEN
Single bicycle crashes, i.e., falls and impacts not involving a collision with another road user, are a significantly underestimated road safety problem. The motions and behaviours of falling people, or fall kinematics, are often investigated in the injury biomechanics research field. Understanding the mechanics of a fall can help researchers develop better protective gear and safety measures to reduce the risk of injury. However, little is known about cyclist fall kinematics or dynamics. Therefore, in this study, a video analysis of cyclist falls is performed to investigate common kinematic forms and impact patterns. Furthermore, a pipeline involving deep learning-based human pose estimation and inverse kinematics optimisation is created for extracting human motion from real-world footage of falls to initialise forward dynamics computational human body models. A bracing active response is then optimised for using a genetic algorithm. This is then applied to a case study of a cyclist fall. The kinematic forms characterised in this study can be used to inform initial conditions for computational modelling and injury estimation in cyclist falls. Findings indicate that protective response is an important consideration in fall kinematics and dynamics, and should be included in computational modelling. Furthermore, the novel reconstruction pipeline proposed here can be applied more broadly for traumatic injury biomechanics tasks. The tool developed in this study is available at https://kevgildea.github.io/KinePose/.
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Accidentes de Tránsito , Aprendizaje Profundo , Humanos , Ciclismo , Simulación por Computador , Movimiento (Física)RESUMEN
Genetic changes in repetitive sequences are a hallmark of cancer and other diseases, but characterizing these has been challenging using standard sequencing approaches. We developed a de novo kmer finding approach, called ARTEMIS (Analysis of RepeaT EleMents in dISease), to identify repeat elements from whole-genome sequencing. Using this method, we analyzed 1.2 billion kmers in 2837 tissue and plasma samples from 1975 patients, including those with lung, breast, colorectal, ovarian, liver, gastric, head and neck, bladder, cervical, thyroid, or prostate cancer. We identified tumor-specific changes in these patients in 1280 repeat element types from the LINE, SINE, LTR, transposable element, and human satellite families. These included changes to known repeats and 820 elements that were not previously known to be altered in human cancer. Repeat elements were enriched in regions of driver genes, and their representation was altered by structural changes and epigenetic states. Machine learning analyses of genome-wide repeat landscapes and fragmentation profiles in cfDNA detected patients with early-stage lung or liver cancer in cross-validated and externally validated cohorts. In addition, these repeat landscapes could be used to noninvasively identify the tissue of origin of tumors. These analyses reveal widespread changes in repeat landscapes of human cancers and provide an approach for their detection and characterization that could benefit early detection and disease monitoring of patients with cancer.
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Ácidos Nucleicos Libres de Células , Neoplasias Hepáticas , Masculino , Humanos , Neoplasias Hepáticas/genética , Elementos Transponibles de ADNRESUMEN
Circulating cell-free DNA (cfDNA) is emerging as an avenue for cancer detection, but the characteristics of cfDNA fragmentation in the blood are poorly understood. We evaluate the effect of DNA methylation and gene expression on genome-wide cfDNA fragmentation through analysis of 969 individuals. cfDNA fragment ends more frequently contained CCs or CGs, and fragments ending with CGs or CCGs are enriched or depleted, respectively, at methylated CpG positions. Higher levels and larger sizes of cfDNA fragments are associated with CpG methylation and reduced gene expression. These effects are validated in mice with isogenic tumors with or without the mutant IDH1, and are associated with genome-wide changes in cfDNA fragmentation in patients with cancer. Tumor-related hypomethylation and increased gene expression are associated with decrease in cfDNA fragment size that may explain smaller cfDNA fragments in human cancers. These results provide a connection between epigenetic changes and cfDNA fragmentation with implications for disease detection.
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Ácidos Nucleicos Libres de Células , Islas de CpG , Fragmentación del ADN , Metilación de ADN , Neoplasias , Humanos , Ácidos Nucleicos Libres de Células/genética , Ácidos Nucleicos Libres de Células/sangre , Animales , Ratones , Islas de CpG/genética , Neoplasias/genética , Epigénesis Genética , Femenino , Isocitrato Deshidrogenasa/genética , Masculino , Regulación Neoplásica de la Expresión GénicaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment enriched with cancer-associated fibroblasts (CAF). This study used a convergence approach to identify tumor cell and CAF interactions through the integration of single-cell data from human tumors with human organoid coculture experiments. Analysis of a comprehensive atlas of PDAC single-cell RNA sequencing data indicated that CAF density is associated with increased inflammation and epithelial-mesenchymal transition (EMT) in epithelial cells. Transfer learning using transcriptional data from patient-derived organoid and CAF cocultures provided in silico validation of CAF induction of inflammatory and EMT epithelial cell states. Further experimental validation in cocultures demonstrated integrin beta 1 (ITGB1) and vascular endothelial factor A (VEGFA) interactions with neuropilin-1 mediating CAF-epithelial cell cross-talk. Together, this study introduces transfer learning from human single-cell data to organoid coculture analyses for experimental validation of discoveries of cell-cell cross-talk and identifies fibroblast-mediated regulation of EMT and inflammation. SIGNIFICANCE: Adaptation of transfer learning to relate human single-cell RNA sequencing data to organoid-CAF cocultures facilitates discovery of human pancreatic cancer intercellular interactions and uncovers cross-talk between CAFs and tumor cells through VEGFA and ITGB1.
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Fibroblastos Asociados al Cáncer , Carcinoma Ductal Pancreático , Técnicas de Cocultivo , Transición Epitelial-Mesenquimal , Inflamación , Integrina beta1 , Neoplasias Pancreáticas , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Inflamación/patología , Inflamación/metabolismo , Integrina beta1/metabolismo , Integrina beta1/genética , Organoides/patología , Organoides/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Neuropilina-1/metabolismo , Neuropilina-1/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Comunicación CelularRESUMEN
Despite China's leaded gasoline phase out in 2000, the continued high rates of lead poisoning found in children's blood lead levels reflect the need for identifying and controlling other sources of lead pollution. From 2001 to 2007, 24% of children in China studied (N = 94,778) were lead poisoned with levels exceeding 100 µg/L. These levels stand well above the global average of 16%. These trends reveal that China still faces significant public health challenges, with millions of children currently at risk of lead poisoning. The unprecedented growth of China's lead-acid battery industry from the electric bike, automotive, and photovoltaic industries may explain these persistently high levels, as China remains the world's leading producer, refiner, and consumer of both lead and lead-acid batteries.This review assesses the role of China's rising lead-acid battery industry on lead pollution and exposure. It starts with a synthesis of biological mechanisms of lead exposure followed by an analysis of the key technologies driving the rapid growth of this industry. It then details the four main stages of lead battery production, explaining how each stage results in significant lead loss and pollution. A province-level accounting of each of these industrial operations is also included. Next, reviews of the literature describe how this industry may have contributed to mass lead poisonings throughout China. Finally, the paper closes with a discussion of new policies that address the lead-acid battery industry and identifies policy frameworks to mitigate exposure.This paper is the first to integrate the market factors, production processes, and health impacts of China's growing lead-acid battery industry to illustrate its vast public health consequences. The implications of this review are two-fold: it validates calls for a nationwide assessment of lead exposure pathways and levels in China as well as for a more comprehensive investigation into the health impacts of the lead-acid battery industry. The continuous growth of this industry signals the urgent need for effective regulatory action to protect the health and lives of China's future generations.
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Suministros de Energía Eléctrica , Contaminantes Ambientales/toxicidad , Sustancias Peligrosas/toxicidad , Política de Salud , Intoxicación por Plomo/etiología , Plomo/toxicidad , China/epidemiología , Regulación Gubernamental , Humanos , Intoxicación por Plomo/epidemiologíaRESUMEN
The transcription factor FOXM1 regulates ß-cell proliferation and insulin secretion. Our previous work demonstrates that expressing an activated form of FOXM1 (FOXM1*) in ß cells increases ß-cell proliferation and mass in aged male mice. Additionally, FOXM1* enhances ß-cell function even in young mice, in which no ß-cell mass elevation occurs. Here, we demonstrate that FOXM1 acts in a sexually dimorphic manner in the ß cell. Expression of FOXM1* in female mouse ß cells does not affect ß-cell proliferation or glucose tolerance. Transduction of male but not female human islets with FOXM1* enhances insulin secretion in response to elevated glucose. Estrogen contributes to diabetes susceptibility differences between males and females, and the estrogen receptor (ER)α is the primary mediator of ß-cell estrogen signaling. We show that FOXM1* can rescue impaired glucose tolerance in female mice with a pancreas-wide ERα deletion. Further, FOXM1 and ERα binding sites overlap with each other and with other ß-cell-enriched transcription factors, including ISL1, PAX6, MAF, and GATA. These data indicate that FOMX1 and ERα cooperate to regulate ß-cell function and suggest a general mechanism contributing to the lower incidence of diabetes observed in women.
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Three-dimensional (3D) in vitro models are essential in cancer research, but they often neglect physical forces. In our study, we combined patient-derived tumor organoids with a microfluidic organ-on-chip system to investigate colorectal cancer (CRC) invasion in the tumor microenvironment (TME). This allowed us to create patient-specific tumor models and assess the impact of physical forces on cancer biology. Our findings showed that the organoid-on-chip models more closely resembled patient tumors at the transcriptional level, surpassing organoids alone. Using 'omics' methods and live-cell imaging, we observed heightened responsiveness of KRAS mutant tumors to TME mechanical forces. These tumors also utilized the γ-aminobutyric acid (GABA) neurotransmitter as an energy source, increasing their invasiveness. This bioengineered model holds promise for advancing our understanding of cancer progression and improving CRC treatments.
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The diversity of genetic programs and cellular plasticity of glioma-associated myeloid cells, and thus their contribution to tumor growth and immune evasion, is poorly understood. We performed single cell RNA-sequencing of immune and tumor cells from 33 glioma patients of varying tumor grades. We identified two populations characteristic of myeloid derived suppressor cells (MDSC), unique to glioblastoma (GBM) and absent in grades II and III tumors: i) an early progenitor population (E-MDSC) characterized by strong upregulation of multiple catabolic, anabolic, oxidative stress, and hypoxia pathways typically observed within tumor cells themselves, and ii) a monocytic MDSC (M-MDSC) population. The E-MDSCs geographically co-localize with a subset of highly metabolic glioma stem-like tumor cells with a mesenchymal program in the pseudopalisading region, a pathognomonic feature of GBMs associated with poor prognosis. Ligand-receptor interaction analysis revealed symbiotic cross-talk between the stemlike tumor cells and E-MDSCs in GBM, whereby glioma stem cells produce chemokines attracting E-MDSCs, which in turn produce growth and survival factors for the tumor cells. Our large-scale single-cell analysis elucidated unique MDSC populations as key facilitators of GBM progression and mediators of tumor immunosuppression, suggesting that targeting these specific myeloid compartments, including their metabolic programs, may be a promising therapeutic intervention in this deadly cancer. One-Sentence Summary: Aggressive glioblastoma harbors two unique myeloid populations capable of promoting stem-like properties of tumor cells and suppressing T cell function in the tumor microenvironment.
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Tumor mutation burden is an imperfect proxy of tumor foreignness and has therefore failed to consistently demonstrate clinical utility in predicting responses in the context of immunotherapy. We evaluated mutations in regions of the genome that are unlikely to undergo loss in a pan-cancer analysis across 31 tumor types (n = 9,242) and eight immunotherapy-treated cohorts of patients with non-small-cell lung cancer, melanoma, mesothelioma, and head and neck cancer (n = 524). We discovered that mutations in single-copy regions and those present in multiple copies per cell constitute a persistent tumor mutation burden (pTMB) which is linked with therapeutic response to immune checkpoint blockade. Persistent mutations were retained in the context of tumor evolution under selective pressure of immunotherapy and tumors with a high pTMB content were characterized by a more inflamed tumor microenvironment. pTMB imposes an evolutionary bottleneck that cancer cells cannot overcome and may thus drive sustained immunologic tumor control in the context of immunotherapy.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Melanoma , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Mutación , Biomarcadores de Tumor/genética , Inmunidad , Inmunoterapia , Microambiente TumoralRESUMEN
Aging is associated with immunological changes that compromise response to infections and vaccines, exacerbate inflammatory diseases and can potentially mitigate tissue repair. Even so, age-related changes to the immune response to tissue damage and regenerative medicine therapies remain unknown. Here, it is characterized how aging induces changes in immunological signatures that inhibit tissue repair and therapeutic response to a clinical regenerative biological scaffold derived from extracellular matrix. Signatures of inflammation and interleukin (IL)-17 signaling increased with injury and treatment both locally and regionally in aged animals, and computational analysis uncovered age-associated senescent-T cell communication that promotes type 3 immunity in T cells. Local inhibition of type 3 immune activation using IL17-neutralizing antibodies improves healing and restores therapeutic response to the regenerative biomaterial, promoting muscle repair in older animals. These results provide insights into tissue immune dysregulation that occurs with aging that can be targeted to rejuvenate repair.
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Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite senescent cells' (SnCs) pathological role and therapeutic interest, their phenotype in vivo remains poorly defined. Here, we developed an in vivo-derived senescence signature (SenSig) using a foreign body response-driven fibrosis model in a p16-CreERT2;Ai14 reporter mouse. We identified pericytes and "cartilage-like" fibroblasts as senescent and defined cell type-specific senescence-associated secretory phenotypes (SASPs). Transfer learning and senescence scoring identified these two SnC populations along with endothelial and epithelial SnCs in new and publicly available murine and human data single-cell RNA sequencing (scRNAseq) datasets from diverse pathologies. Signaling analysis uncovered crosstalk between SnCs and myeloid cells via an IL34-CSF1R-TGFßR signaling axis, contributing to tissue balance of vascularization and matrix production. Overall, our study provides a senescence signature and a computational approach that may be broadly applied to identify SnC transcriptional profiles and SASP factors in wound healing, aging, and other pathologies.
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Envejecimiento , Senescencia Celular , Humanos , Ratones , Animales , Senescencia Celular/genética , Envejecimiento/genética , Fenotipo , Fibroblastos , Aprendizaje AutomáticoRESUMEN
Regulatory T cells (Treg) are conventionally viewed as suppressors of endogenous and therapy-induced antitumor immunity; however, their role in modulating responses to immune checkpoint blockade (ICB) is unclear. In this study, we integrated single-cell RNA-seq/T cell receptor sequencing (TCRseq) of >73,000 tumor-infiltrating Treg (TIL-Treg) from anti-PD-1-treated and treatment-naive non-small cell lung cancers (NSCLC) with single-cell analysis of tumor-associated antigen (TAA)-specific Treg derived from a murine tumor model. We identified 10 subsets of human TIL-Treg, most of which have high concordance with murine TIL-Treg subsets. Only one subset selectively expresses high levels of TNFRSF4 (OX40) and TNFRSF18 (GITR), whose engangement by cognate ligand mediated proliferative programs and NF-κB activation, as well as multiple genes involved in Treg suppression, including LAG3. Functionally, the OX40hiGITRhi subset is the most highly suppressive ex vivo, and its higher representation among total TIL-Treg correlated with resistance to PD-1 blockade. Unexpectedly, in the murine tumor model, we found that virtually all TIL-Treg-expressing T cell receptors that are specific for TAA fully develop a distinct TH1-like signature over a 2-week period after entry into the tumor, down-regulating FoxP3 and up-regulating expression of TBX21 (Tbet), IFNG, and certain proinflammatory granzymes. Transfer learning of a gene score from the murine TAA-specific TH1-like Treg subset to the human single-cell dataset revealed a highly analogous subcluster that was enriched in anti-PD-1-responding tumors. These findings demonstrate that TIL-Treg partition into multiple distinct transcriptionally defined subsets with potentially opposing effects on ICB-induced antitumor immunity and suggest that TAA-specific TIL-Treg may positively contribute to antitumor responses.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Animales , Ratones , Neoplasias Pulmonares/genética , Granzimas , Transducción de Señal , Análisis de la Célula IndividualRESUMEN
E-bikes in China are the single largest adoption of alternative fuel vehicles in history, with more than 100 million e-bikes purchased in the past decade and vehicle ownership about 2× larger for e-bikes as for conventional cars; e-car sales, too, are rapidly growing. We compare emissions (CO(2), PM(2.5), NO(X), HC) and environmental health impacts (primary PM(2.5)) from the use of conventional vehicles (CVs) and electric vehicles (EVs) in 34 major cities in China. CO(2) emissions (g km(-1)) vary and are an order of magnitude greater for e-cars (135-274) and CVs (150-180) than for e-bikes (14-27). PM(2.5) emission factors generally are lower for CVs (gasoline or diesel) than comparable EVs. However, intake fraction is often greater for CVs than for EVs because combustion emissions are generally closer to population centers for CVs (tailpipe emissions) than for EVs (power plant emissions). For most cities, the net result is that primary PM(2.5) environmental health impacts per passenger-km are greater for e-cars than for gasoline cars (3.6× on average), lower than for diesel cars (2.5× on average), and equal to diesel buses. In contrast, e-bikes yield lower environmental health impacts per passenger-km than the three CVs investigated: gasoline cars (2×), diesel cars (10×), and diesel buses (5×). Our findings highlight the importance of considering exposures, and especially the proximity of emissions to people, when evaluating environmental health impacts for EVs.
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Dióxido de Carbono/análisis , Electricidad , Vehículos a Motor , Material Particulado/análisis , Emisiones de Vehículos/análisis , Dióxido de Carbono/toxicidad , China , Carbón Mineral , Ambiente , Gasolina , Humanos , Hidrocarburos/análisis , Hidrocarburos/toxicidad , Óxidos de Nitrógeno/análisis , Óxidos de Nitrógeno/toxicidad , Material Particulado/toxicidad , Centrales Eléctricas , Emisiones de Vehículos/toxicidadRESUMEN
The RAS family of small GTPases represents the most commonly activated oncogenes in human cancers. To better understand the prevalence of somatic RAS mutations and the compendium of genes that are coaltered in RAS-mutant tumors, we analyzed targeted next-generation sequencing data of 607,863 mutations from 66,372 tumors in 51 cancer types in the AACR Project GENIE Registry. Bayesian hierarchical models were implemented to estimate the cancer-specific prevalence of RAS and non-RAS somatic mutations, to evaluate co-occurrence and mutual exclusivity, and to model the effects of tumor mutation burden and mutational signatures on comutation patterns. These analyses revealed differential RAS prevalence and comutations with non-RAS genes in a cancer lineage-dependent and context-dependent manner, with differences across age, sex, and ethnic groups. Allele-specific RAS co-mutational patterns included an enrichment in NTRK3 and chromatin-regulating gene mutations in KRAS G12C-mutant non-small cell lung cancer. Integrated multiomic analyses of 10,217 tumors from The Cancer Genome Atlas (TCGA) revealed distinct genotype-driven gene expression programs pointing to differential recruitment of cancer hallmarks as well as phenotypic differences and immune surveillance states in the tumor microenvironment of RAS-mutant tumors. The distinct genomic tracks discovered in RAS-mutant tumors reflected differential clinical outcomes in TCGA cohort and in an independent cohort of patients with KRAS G12C-mutant non-small cell lung cancer that received immunotherapy-containing regimens. The RAS genetic architecture points to cancer lineage-specific therapeutic vulnerabilities that can be leveraged for rationally combining RAS-mutant allele-directed therapies with targeted therapies and immunotherapy. SIGNIFICANCE: The complex genomic landscape of RAS-mutant tumors is reflective of selection processes in a cancer lineage-specific and context-dependent manner, highlighting differential therapeutic vulnerabilities that can be clinically translated.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Teorema de Bayes , Proteínas Proto-Oncogénicas p21(ras)/genética , Mutación , Genómica , Microambiente TumoralRESUMEN
BACKGROUND: Despite treatment advancements with immunotherapy, our understanding of response relies on tissue-based, static tumor features such as tumor mutation burden (TMB) and programmed death-ligand 1 (PD-L1) expression. These approaches are limited in capturing the plasticity of tumor-immune system interactions under selective pressure of immune checkpoint blockade and predicting therapeutic response and long-term outcomes. Here, we investigate the relationship between serial assessment of peripheral blood cell counts and tumor burden dynamics in the context of an evolving tumor ecosystem during immune checkpoint blockade. METHODS: Using machine learning, we integrated dynamics in peripheral blood immune cell subsets, including neutrophil-lymphocyte ratio (NLR), from 239 patients with metastatic non-small cell lung cancer (NSCLC) and predicted clinical outcome with immune checkpoint blockade. We then sought to interpret NLR dynamics in the context of transcriptomic and T cell repertoire trajectories for 26 patients with early stage NSCLC who received neoadjuvant immune checkpoint blockade. We further determined the relationship between NLR dynamics, pathologic response and circulating tumor DNA (ctDNA) clearance. RESULTS: Integrated dynamics of peripheral blood cell counts, predominantly NLR dynamics and changes in eosinophil levels, predicted clinical outcome, outperforming both TMB and PD-L1 expression. As early changes in NLR were a key predictor of response, we linked NLR dynamics with serial RNA sequencing deconvolution and T cell receptor sequencing to investigate differential tumor microenvironment reshaping during therapy for patients with reduction in peripheral NLR. Reductions in NLR were associated with induction of interferon-γ responses driving the expression of antigen presentation and proinflammatory gene sets coupled with reshaping of the intratumoral T cell repertoire. In addition, NLR dynamics reflected tumor regression assessed by pathological responses and complemented ctDNA kinetics in predicting long-term outcome. Elevated peripheral eosinophil levels during immune checkpoint blockade were correlated with therapeutic response in both metastatic and early stage cohorts. CONCLUSIONS: Our findings suggest that early dynamics in peripheral blood immune cell subsets reflect changes in the tumor microenvironment and capture antitumor immune responses, ultimately reflecting clinical outcomes with immune checkpoint blockade.
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Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Antígeno B7-H1 , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , ADN Tumoral Circulante/genética , Ecosistema , Humanos , Inhibidores de Puntos de Control Inmunológico , Inmunidad , Factores Inmunológicos/uso terapéutico , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Microambiente TumoralRESUMEN
INTRODUCTION: The market share of e-scooters in the United States has proliferated in cities: 86 million trips were made on shared e-scooters in 2019, a more than 100% increase compared to 2018. However, the interaction of e-scooters with other road users and infrastructure remains uncertain. METHOD: This study scrutinized 52 e-scooter and 79 bicycle police-reported crashes in Nashville, Tennessee, from April 2018 to April 2020 from the Tennessee Integrated Traffic Analysis Network (TITAN) database. We used descriptive analysis and a recent prototype version of the Pedestrian and Bicycle Crash Analysis Tool (PBCAT) to classify crashes based on the locations of the crashes relative to roadway segments or intersections, as well as the maneuver of the motor vehicle and e-scooter/bicycle relative to the motor vehicle. RESULTS: Two crash typologies can explain the majority of e-scooter crashes, while bicycle crashes are distributed over several crash typologies. Additionally, 1 in 10 e-scooter- and bicycle-motor vehicle crashes leads to the injury or fatality of the e-scooter rider or bicyclist. Furthermore, we noted statistically significant differences in spatial and temporal distribution, demographics, lighting conditions, and crash distance from home for e-scooter and bicycle crashes. CONCLUSIONS: The police crash report provides a comprehensive picture of e-scooter safety complementing existing literature. We found that e-scooter crash characteristics do not fully overlap with features of bicycle crashes. PRACTICAL IMPLICATIONS: A generalized engineering, education, and enforcement treatment to reduce and prevent e-scooter and bicycle crashes, injuries, and fatalities might not result in equal outcomes for each mode. More rigorous enforcement could be implemented to deter e-scooters riders under the age of 18â¯years and e-scooter safety campaigns could target female riders.
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Accidentes de Tránsito/estadística & datos numéricos , Automóviles/estadística & datos numéricos , Ciclismo/estadística & datos numéricos , Motocicletas/estadística & datos numéricos , Adolescente , Adulto , Distribución por Edad , Anciano , Niño , Preescolar , Bases de Datos Factuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Distribución por Sexo , Factores Socioeconómicos , Análisis Espacial , Tennessee , Estados Unidos , Adulto JovenRESUMEN
As alternative transportation is getting more and more fashionable, and more people worldwide are "shifting" to walking trips, even for their daily commuting, traffic crashes suffered by pedestrians are still a great concern for road safety and public health researchers and practitioners. In this regard, risky or "aberrant" road behaviors have emerged, during the last few years, as a key issue to be considered for crash prevention. Nevertheless, the idea of a "generic pedestrian" is getting re-evaluated, and analyzing key features, such as gender, seems to be crucial for understanding pedestrians' performance and safety outcomes. OBJECTIVE: The objective of this study was to examine the effect of gender on pedestrians' both deliberate (traffic violations) and undeliberate (errors) risky walking behaviors, considering a set of theoretically based demographic and psychosocial variables as their potential predictors. METHOD: For this cross-sectional study, data from 1070 Spanish pedestrians (60 % females and 40 % males, aged between 16 and 79) from the 17 regions of Spain, responding to an electronic questionnaire, were analyzed through a multi-group structural equation modeling (MGSEM) approach. RESULTS: Although age, handheld device-interaction, and sensation-seeking seem to have a similar effect on the errors and violations reported by both genders (similarities), factors such as risk perception, educational level and the misbehaviors observed in other road users are significant predictors only in the case of male pedestrians. On the other hand, road distractions have been shown to play a significant role in females' errors and violations, while males' road distractions seem to only affect their involuntary risky behaviors. CONCLUSION: The findings of this study support the influence of gender in the statistical explanation of both deliberate and undeliberate walking risky road behaviors, also depicting the differential role of certain demographic and psychosocial factors when we compare male and female pedestrians.