The purpose of the study is to genomically characterize the biology and related therapeutic opportunities of prognostically important predominant histologic subtypes in lung adenocarcinoma (LUAD).
We ...identified 604 patients with stage I to III LUAD who underwent complete resection and targeted next-generation sequencing using the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets platform. Tumors were classified according to predominant histologic subtype and grouped by architectural grade (lepidic LEP, acinar or papillary ACI/PAP, and micropapillary or solid MIP/SOL). Associations among clinicopathologic factors, genomic features, mutational signatures, and recurrence were evaluated within subtypes and, when appropriate, quantified using competing-risks regression, with adjustment for pathologic stage and extent of resection.
MIP/SOL tumors had higher tumor mutational burden (p < 0.001), fraction of genome altered (p = 0.001), copy number amplifications (p = 0.021), rate of whole-genome doubling (p = 0.008), and number of oncogenic pathways altered ( p < 0.001) as compared with LEP and ACI/PAP tumors. Across all tumors, mutational signatures attributed to APOBEC activity were associated with the highest risk of postresection recurrence: SBS2 (p = 0.021) and SBS13 (p = 0.005). Three oncogenic pathways (p53, Wnt, Myc) were altered with statistical significance in MIP/SOL tumors. Compared with LEP and ACI/PAP tumors, MIP/SOL tumors had a higher frequency of targetable BRAF-V600E mutations (p = 0.046). Among ACI/PAP tumors, alterations in the cell cycle (p < 0.001) and PI3K (p = 0.002) pathways were associated with recurrence; among MIP/SOL tumors, only PI3K alterations were associated with recurrence (p = 0.049).
These results provide the first in-depth assessment of tumor genomic profiling of predominant LUAD histologic subtypes, their associations with recurrence, and their correlation with targetable driver alterations in patients with surgically resected LUAD.
IMPORTANCE: Recommendations for adjuvant therapy after surgical resection of lung adenocarcinoma (LUAD) are based solely on TNM classification but are agnostic to genomic and high-risk ...clinicopathologic factors. Creation of a prediction model that integrates tumor genomic and clinicopathologic factors may better identify patients at risk for recurrence. OBJECTIVE: To identify tumor genomic factors independently associated with recurrence, even in the presence of aggressive, high-risk clinicopathologic variables, in patients with completely resected stages I to III LUAD, and to develop a computational machine-learning prediction model (PRecur) to determine whether the integration of genomic and clinicopathologic features could better predict risk of recurrence, compared with the TNM system. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 426 patients treated from January 1, 2008, to December 31, 2017, at a single large cancer center and selected in consecutive samples. Eligibility criteria included complete surgical resection of stages I to III LUAD, broad-panel next-generation sequencing data with matched clinicopathologic data, and no neoadjuvant therapy. External validation of the PRecur prediction model was performed using The Cancer Genome Atlas (TCGA). Data were analyzed from 2014 to 2018. MAIN OUTCOMES AND MEASURES: The study end point consisted of relapse-free survival (RFS), estimated using the Kaplan-Meier approach. Associations among clinicopathologic factors, genomic alterations, and RFS were established using Cox proportional hazards regression. The PRecur prediction model integrated genomic and clinicopathologic factors using gradient-boosting survival regression for risk group generation and prediction of RFS. A concordance probability estimate (CPE) was used to assess the predictive ability of the PRecur model. RESULTS: Of the 426 patients included in the analysis (286 women 67%; median age at surgery, 69 interquartile range, 62-75 years), 318 (75%) had stage I cancer. Association analysis showed that alterations in SMARCA4 (clinicopathologic-adjusted hazard ratio HR, 2.44; 95% CI, 1.03-5.77; P = .042) and TP53 (clinicopathologic-adjusted HR, 1.73; 95% CI, 1.09-2.73; P = .02) and the fraction of genome altered (clinicopathologic-adjusted HR, 1.03; 95% CI, 1.10-1.04; P = .005) were independently associated with RFS. The PRecur prediction model outperformed the TNM-based model (CPE, 0.73 vs 0.61; difference, 0.12 95% CI, 0.05-0.19; P < .001) for prediction of RFS. To validate the prediction model, PRecur was applied to the TCGA LUAD data set (n = 360), and a clear separation of risk groups was noted (log-rank statistic, 7.5; P = .02), confirming external validation. CONCLUSIONS AND RELEVANCE: The findings suggest that integration of tumor genomics and clinicopathologic features improves risk stratification and prediction of recurrence after surgical resection of early-stage LUAD. Improved identification of patients at risk for recurrence could enrich and enhance accrual to adjuvant therapy clinical trials.
Modern religious plurality invites religious and non-religious people to navigate four interreligious dialogical problems: (1) the inability to fully articulate faith, (2) the lack of persuasive ...religious language, (3) the reality of violence among the religions, and (4) the liquescent “truth” of modern times. How can plurality be framed for people whose sense of relationality is shaped by their participation in virtual worlds? One answer emerges in this autoethnographic consideration of how video gaming “plays out” fresh understandings of the interreligious encounter and relationality. Adopting a Christian perspective, the first section summarizes the major theologies of religions. These theologies correspond with video-game experiences of interreligious cooperation and contest found in playing out the enrichment and diminishment of (1) Christian spirit in Spiritual Warfare (NES), (2) human connection in Final Fantasy VI (Super NES), (3) sense of salvation in Final Fantasy X (PS2), and (4) symbiotic sacredness in Journey (iOS). These play experiences clarify a concept of expansive relationality among religions that is termed shared contest. The conclusion advances a contestant theology of religions; God removes every obstacle to including all in the company of God’s people, and God provides a playground of cooperation and contest for each religious tradition.
Opioids have been linked to worse oncologic outcomes in surgical patients. Studies in certain cancer types have identified associations between survival and intra-tumoural opioid receptor gene ...alterations, but no study has investigated whether the tumour genome interacts with opioid exposure to affect survival. We sought to determine whether intraoperative opioid exposure is associated with recurrence-specific survival and overall survival in early-stage lung adenocarcinoma, and whether selected tumour genomics are associated with this relationship. Associations between ketamine and dexmedetomidine and outcomes were also studied.
Surgical patients (N=740) with pathological stage I–III lung adenocarcinoma and next-generation sequencing data were retrospectively reviewed from a prospectively maintained database.
On multivariable analysis, ketamine administration was protective for recurrence-specific survival (hazard ratio = 0.44, 95% confidence interval 0.24–0.80; P=0.007), compared with no adjunct. Higher intraoperative oral morphine milligram equivalents were significantly associated with worse overall survival (hazard ratio=1.09/10 morphine milligram equivalents, 95% confidence interval 1.02–1.17; P=0.010). Significant interaction effects were found between morphine milligram equivalents and fraction genome altered and morphine milligram equivalents and CDKN2A, such that higher fraction genome altered or CDKN2A alterations were associated with worse overall survival at higher morphine milligram equivalents (P=0.044 and P=0.052, respectively). In contrast, alterations in the Wnt (P=0.029) and Hippo (P=0.040) oncogenic pathways were associated with improved recurrence-specific survival at higher morphine milligram equivalents, compared with unaltered pathways.
Intraoperative opioid exposure is associated with worse overall survival, whereas ketamine exposure is associated with improved recurrence-specific survival in patients with early-stage lung adenocarcinoma. This is the first study to investigate tumour-specific genomic interactions with intraoperative opioid administration to modify survival associations.
Charge carrier trapping is an important phenomenon in nanocrystal (NC) decay dynamics because it reduces photoluminescence (PL) quantum efficiencies and obscures efforts to understand the interaction ...of NC excitons with their surroundings. Particularly crucial to our understanding of excitation dynamics in, e.g., multiNC assemblies, would be a way of differentiating between processes involving trap states and those that do not. Direct optical measurement of NC trap state processes is not usually possible because they have negligible transition dipole moments; however, they are known to indirectly affect exciton photoluminescence. Here, we develop a framework, based on Marcus electron transfer theory, to determine NC trap state dynamics from time-resolved NC exciton PL measurements. Our results demonstrate the sensitivity of PL to interfacial dynamics, indicating that the technique can be used as an indirect but effective probe of trap distribution changes. We anticipate that this study represents a step toward understanding how excitons in nanocrystals interact with their surroundings: a quality that must be optimized for their efficient application in photovoltaics, photodetectors, or chemical sensors.
The outcome of natural enemy attack in insects is commonly impacted by the presence of defensive microbial symbionts residing within the host. The thermal environment is a factor known to affect ...symbiont‐mediated traits in insects. Lower temperatures, for instance, have been shown to reduce Spiroplasma‐mediated protection in Drosophila. Our understanding of protective symbiosis requires a deeper understanding of environment–symbiont–protection links. Here, we dissect the effect of the thermal environment on Spiroplasma‐mediated protection against Leptopilina boulardi in Drosophila melanogaster by examining the effect of temperature before, during and after wasp attack on fly survival and wasp success. We observed that the developmental temperature of the mothers of attacked larvae, but not the temperature of the attacked larvae themselves during or after wasp attack, strongly determines the protective influence of Spiroplasma. Cooler maternal environments were associated with weaker Spiroplasma protection of their progeny. The effect of developmental temperature on Spiroplasma‐mediated protection is probably mediated by a reduction in Spiroplasma titre. These results indicate that historical thermal environment is a stronger determinant of protection than current environment. Furthermore, protection is a character with transgenerational nongenetic variation probably to produce complex short‐term responses to selection. In addition, the cool sensitivity of the Spiroplasma–Drosophila symbioses contrasts with the more common failure of symbioses at elevated temperatures, indicating a need to understand the mechanistic basis of low temperature sensitivity on this symbiosis.
IMPORTANCE: Surgery is an effective treatment for drug-resistant focal epilepsy. Neuroimaging studies are considered essential in the diagnostic evaluation of individuals with medically refractory ...focal seizures being considered for surgical treatment. OBJECTIVES: To review the evidence for the use of neuroimaging studies in the selection of patients with drug-resistant temporal lobe epilepsy for focal cortical resection and discuss the prognostic importance of selected techniques. EVIDENCE REVIEW: Randomized clinical trials, meta-analyses, and clinical retrospective case studies (≥20 patients with ≥1 year of follow-up) were identified using Medical Subject Headings and indexed text terms in EMBASE (1988-November 29, 2014); MEDLINE (1946-December 2, 2014), Cochrane Central Register of Controlled Trials (1991-October 31, 2014), and Cochrane Database of Systematic Reviews (2005-October 31, 2014). Twenty-seven articles describing 3163 patients were included. Neuroimaging techniques analyzed included magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). Subpopulations and prognostic factors were identified. FINDINGS: Of the 27 studies evaluated (3163 patients), 7 showed the outcome was more favorable in patients with MRI-identified hippocampal atrophy indicating mesial temporal sclerosis. Five additional studies indicated that the outcome was less favorable in patients with unremarkable MRI studies. There are conflicting findings regarding the prognostic importance of PET-identified focal hypometabolism; however, 2 investigations indicated that the presence of a PET imaging study demonstrating abnormalities in individuals with unremarkable MRI results showed an operative outcome similar to that in patients with mesial temporal sclerosis. The studies assessing SPECT use in temporal lobe epilepsy did not reveal a correlation with outcome. CONCLUSIONS AND RELEVANCE: There is strong evidence that preoperative MRI-identified hippocampal atrophy consistent with mesial temporal sclerosis concordant with the seizure origin in the temporal lobe is a significant factor associated with a favorable outcome. PET studies may be valuable in individuals with unremarkable MRI findings. The current evidence does not support the prognostic importance of SPECT in patients undergoing temporal lobe surgery.
OBJECTIVE:We examined management strategies, overall survival (OS), and progression-free survival (PFS) among patients with PMNSGCTs undergoing resection and multidisciplinary management at a ...high-volume institution.
SUMMARY OF BACKGROUND DATA:Outcomes after resection of PMNSGCTs are not well-characterized, with limited data on factors associated with survival.
METHODS:We reviewed patients with PMNSGCT who underwent resection between 1980 and 2019. Median follow-up was 3.4 years. Preoperative therapy (including use of bleomycin), surgical management, recurrence, and survival were examined. Factors associated with survival were analyzed using Cox regression.
RESULTS:In total, 113 patients were included median age, 28 years (range, 16–65). Preoperative serum tumor markers (STMs) normalized/decreased in 74% of patients. Pathology included necrosis only (25%), teratoma +/− necrosis (20%), viable nonteratomatous germ cell tumor +/− teratoma (41%), and secondary somatic-type malignancy +/− teratoma (20%). Bleomycin chemotherapy was not associated with pulmonary complications or 90-day mortality. Patients receiving second-line chemotherapy followed by resection had significantly worse OS and PFS than patients receiving first-line chemotherapy followed by resection. On multivariable analysis, R1/R2 resection (HR, 3.92; P < 0.001) and increasing postoperative STMs (HR, 4.98; P < 0.001) were associated with shorter PFS; necrosis on pathology (HR, 0.42, P = 0.043) was associated with longer PFS.
CONCLUSIONS:In patients with PMNSGCT undergoing resection, completeness of resection, postoperative pathology, and postoperative STMs were associated with PFS. Induction bleomycin was not associated with pulmonary complications or mortality in patients undergoing resection. Patients undergoing second-line chemotherapy followed by resection have a poor prognosis, with long-term survival of 22%.
Although threats to global biodiversity are well known, slowing current rates of biodiversity loss remains a challenge. The Aichi targets set out 20 goals on which the international community should ...act to alleviate biodiversity decline, 1 of which (Target 1) aims to raise public awareness of the importance of biodiversity. Although conventional indicators for Target 1 are of low spatial and temporal coverage, conservation culturomics metrics show how biodiversity awareness can be quantified at the global scale. Following methods used for the Living Planet Index, we devised a species awareness index (SAI) to measure change in species awareness based on Wikipedia views. We calculated this index at the page level for 41,197 species listed by the International Union for Conservation of Nature (IUCN) across 10 Wikipedia languages and >2 billion views from 1 July 2015 to 30 March 2020. Bootstrapped indices for the page‐level SAI showed that overall awareness of biodiversity increased marginally over time, although there were differences among taxonomic classes and languages. Among taxonomic classes, overall awareness increased fastest for reptiles and slowest for amphibians. Among languages, overall species awareness increased fastest for Japanese and slowest for Chinese and German users. Although awareness of species as a whole increased and was significantly higher for traded species, from January 2016 through January 2020, change in awareness appeared not to be strongly related to whether the species is traded or is a pollinator. As a data source for public biodiversity awareness, the SAI could be integrated into the Conservation International Biodiversity Engagement Indicator.
El Índice de Sensibilización de Especie como Medida de Culturomia de la Conservación para la Sensibilización Pública por la Biodiversidad
Resumen
Aunque las amenazas a la biodiversidad mundial son bien conocidas, reducir las tasas actuales de pérdida de la biodiversidad todavía es un desafío. Los objetivos de Aichi establecieron 20 metas para las cuales debe actuar la comunidad internacional para aliviar la declinación de la biodiversidad. Una de estas metas (Objetivo 1) busca sensibilizar al público sobre la importancia de la biodiversidad. Aunque los indicadores convencionales del Objetivo 1 tienen una baja cobertura espacial y temporal, las medidas de culturomia para la conservación muestran cómo la sensibilización por la biodiversidad puede cuantificarse a escala global. Seguimos los métodos utilizados para el Índice del Planeta Viviente para diseñar un índice de sensibilización de especie (ISE) para medir el cambio en la sensibilización por una especie con base en las vistas en Wikipedia. Calculamos este índice a nivel de página para 41,197 especies incluidas en las listas de la Unión Internacional para la Conservación de la Naturaleza (UICN) en diez diferentes idiomas en Wikipedia y más de 2 mil millones de vistas entre el 1 de julio de 2015 y el 30 de marzo de 2020. Los índices de arranque para el ISE a nivel de página mostraron que la sensibilización general por la biodiversidad incrementó ligeramente con el tiempo, aunque hubo diferencia entre las clasificaciones taxonómicas y los idiomas. Entre las clasificaciones taxonómicas, la sensibilización general incrementó más rápido para los reptiles y más lento para los anfibios. Entre los idiomas, la sensibilización general por especie incrementó más rápido para los usuarios del japonés y más lento para los usuarios del chino y el alemán. Aunque la sensibilización por las especies en su totalidad incrementó y fue significativamente más alta para las especies comercializadas, entre enero de 2016 y enero de 2020 el cambio en la sensibilización pareció no estar relacionado fuertemente con si la especie es un polinizador o es comercializada. Como fuente de información para la sensibilización pública por la biodiversidad, el ISE podría ser integrado dentro del Indicador de Participación Internacional para la Conservación de la Biodiversidad.
摘要
尽管全球生物多样性面临的威胁已众所周知, 但要减缓目前生物多样性丧失的速度仍然是一项挑战。 “爱知目标” 提出了 20 个目标来要求国际社会采取行动以缓解生物多样性下降, 其中一个目标 (目标 1) 旨在提高公众对生物多样性重要性的认识。虽然目标 1 的传统指标的时空覆盖度较低, 但保护文化组学指标展示了如何在全球范围内量化生物多样性意识。我们效仿地球生命力指数 (Living Planet Index) 的方法设计了一个物种认知指数, 基于维基百科的浏览量来衡量人们对物种认识的变化。针对国际自然保护联盟 (IUCN) 列出的 41,197 个物种, 我们在 10 种语言的维基百科上基于 2015 年 7 月 1 日到 2020 年 3 月 30 日间超过 20 亿次页面浏览量计算了这个指数。基于网页的物种认知的引导指数显示, 尽管在类群和语言之间存在差异, 但人们对生物多样性的总体意识随时间推移都稍有提高。在不同类群中, 人们对爬行动物的整体认识增长最快, 而两栖动物的增长最慢。在不同语言中, 日语使用者的总体物种认知增长最快, 而中文和德语使用者的则增长最慢。尽管人们对物种的认识整体上有所提高, 且对贸易物种的认识明显更多, 但从 2016 年 1 月到 2020 年 1 月物种认知的变化似乎与该物种是否受贸易或是否为传粉者无关。物种认知指数作为公众生物多样性意识的数据来源, 可以纳入国际生物多样性保护参与指标之中。【翻译 :胡怡思 ;审校 :聂永刚】
Article impact statement: Wikipedia represents a powerful data source for developing indicators of public biodiversity awareness.
The panoply of microorganisms and other species present in our environment influence human health and disease, especially in cities, but have not been profiled with metagenomics at a city-wide scale. ...We sequenced DNA from surfaces across the entire New York City (NYC) subway system, the Gowanus Canal, and public parks. Nearly half of the DNA (48%) does not match any known organism; identified organisms spanned 1,688 bacterial, viral, archaeal, and eukaryotic taxa, which were enriched for genera associated with skin (e.g., Acinetobacter). Predicted ancestry of human DNA left on subway surfaces can recapitulate U.S. Census demographic data, and bacterial signatures can match a station’s history, such as marine-associated bacteria in a hurricane-flooded station. This baseline metagenomic map of NYC could help long-term disease surveillance, bioterrorism threat mitigation, and health management in the built environment of cities.
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•Almost half of all DNA present on the subway’s surfaces matches no known organism.•Hundreds of species of bacteria are in the subway, mostly harmless. More riders bring more diversity.•One station flooded during Hurricane Sandy still resembles a marine environment.•Human allele frequencies in DNA on surfaces can mirror US Census data.
Afshinnekoo et al. describe a city-scale molecular profile of DNA collected from a city's subway system, public surfaces, and one waterway. These data enable a baseline analysis of bacterial, eukaryotic, and aracheal organisms in the built environment of mass transit and urban life.
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