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The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL), particularly the influence off previous InO response and the timing of administration. We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory (r/r) ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO-exposed). InO-exposed patients were more heavily pretreated (p= 0.02) and frequently had active marrow disease pre-apheresis (p= 0.03). Response rate and toxicity profile following brexu-cel were comparable for InO-exposed and InO-naïve; however, consolidation therapy post brexu-cel response was utilized at a higher rate in InO-naïve patients (p= 0.005). With a median follow up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS) (p=0.013) and overall survival (OS) (p=0.006) in univariate analyses; however, prior InO exposure did not influence PFS (HR 1.20, 95%CI, 0.71-2.03) in multivariate models. When InO-exposed patients were stratified according to prior InO response, InO responders had superior PFS (p=0.002) and OS (p<0.0001) relative to InO-refractory. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (p=0.51) and OS (p=0.86) for patients receiving InO as bridging therapy or pre-apheresis. In conclusion, while InO exposure was associated with inferior survival outcomes following brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively impacts brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology.
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More globally diverse perspectives are needed in genomic studies and precision medicine practices on non-Europeans. Here, we illustrate this by discussing the distribution of clinically actionable genetic variants involved in drug response in Andean highlanders and Amazonians, considering their environment, history, genetic structure, and historical biases in the perception of biological diversity of Native Americans.
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Premise: Traditional methods of ploidal-level estimation are tedious; using DNA sequence data for cytotype estimation is an ideal alternative. Multiple statistical approaches to leverage sequence data for ploidy inference based on site-based heterozygosity have been developed. However, these approaches may require high-coverage sequence data, use inappropriate probability distributions, or have additional statistical shortcomings that limit inference abilities. We introduce nQuack, an open-source R package that addresses the main shortcomings of current methods. Methods and Results: nQuack performs model selection for improved ploidy predictions. Here, we implement expectation maximization algorithms with normal, beta, and beta-binomial distributions. Using extensive computer simulations that account for variability in sequencing depth, as well as real data sets, we demonstrate the utility and limitations of nQuack. Conclusions: Inferring ploidy based on site-based heterozygosity alone is difficult. Even though nQuack is more accurate than similar methods, we suggest caution when relying on any site-based heterozygosity method to infer ploidy.
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Motivation: Deep generative models have the potential to overcome difficulties in sharing individual-level genomic data by producing synthetic genomes that preserve the genomic associations specific to a cohort while not violating the privacy of any individual cohort member. However, there is significant room for improvement in the fidelity and usability of existing synthetic genome approaches. Results: We demonstrate that when combined with plentiful data and with population-specific selection criteria, deep generative models can produce synthetic genomes and cohorts that closely model the original populations. Our methods improve fidelity in the site-frequency spectra and linkage disequilibrium decay and yield synthetic genomes that can be substituted in downstream local ancestry inference analysis, recreating results with .91 to .94 accuracy. Availability: The model described in this paper is freely available at github.com/rlaboulaye/clonehort .
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The human alkylation B (AlkB) homologs, ALKBH2 and ALKBH3, respond to methylation damage to maintain genomic integrity and cellular viability. Both ALKBH2 and ALKBH3 are direct reversal repair enzymes that remove 1-methyladenine (1meA) and 3-methylcytosine (3meC) lesions commonly generated by alkylating chemotherapeutic agents. Thus, the existence of deficiencies in ALKBH proteins can be exploited in synergy with chemotherapy. In this study, we investigated possible interactions between ALKBH2 and ALKBH3 with other proteins that could alter damage response and discovered an interaction with the mismatch repair (MMR) system. To test whether the lack of active MMR impacts ALKBH2 and/or ALKBH3 response to methylating agents, we generated cells deficient in ALKBH2, ALKBH3, or both in addition to Mlh homolog 1 (MLH1), another MMR protein. We found that MLH1koALKBH3ko cells showed enhanced resistance toward SN1- and SN2-type methylating agents, whereas MLH1koALKBH2ko cells were only resistant to SN1-type methylating agents. Concomitant loss of ALKBH2 and ALKBH3 (ALKBH2ko3ko) rendered cells sensitive to SN1- and SN2-agents, but the additional loss of MLH1 enhanced resistance to both types of damage. We also showed that ALKBH2ko3ko cells have an ATR-dependent arrest at the G2/M checkpoint, increased apoptotic signaling, and replication fork stress in response to methylation. However, these responses were not observed with the loss of functional MLH1 in MLH1koALKBH2ko3ko cells. Finally, in MLH1koALKBH2ko3ko cells, we observed elevated mutant frequency in untreated and temozolomide treated cells. These results suggest that obtaining a more accurate prognosis of chemotherapeutic outcome requires information on the functionality of ALKBH2, ALKBH3, and MLH1.
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The proper functioning of the nervous system is dependent on the establishment and maintenance of intricate networks of neurons that form functional neural circuits. Once neural circuits are assembled during development, a distinct set of molecular programs is likely required to maintain their connectivity throughout the lifetime of the organism. Here, we demonstrate that Fasciclin 3 (Fas3), an axon guidance cell adhesion protein, is necessary for the maintenance of the olfactory circuit in adult Drosophila. We utilized the TARGET system to spatiotemporally knockdown Fas3 in selected populations of adult neurons. Our findings show that Fas3 knockdown results in the death of olfactory circuit neurons and reduced survival of adults. We also demonstrated that Fas3 knockdown activates caspase-3-mediated cell death in olfactory local interneurons, which can be rescued by overexpressing baculovirus p35, an anti-apoptotic protein. This work adds to the growing set of evidence indicating a crucial role for axon guidance proteins in the maintenance of neuronal circuits in adults.
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Proteínas de Drosophila , Drosophila melanogaster , Interneurônios , Animais , Caspase 3/metabolismo , Caspase 3/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Técnicas de Silenciamento de Genes , Interneurônios/metabolismoRESUMO
Satiation is the physiologic process that regulates meal size and termination, and it is quantified by the calories consumed to reach satiation. Given its role in energy intake, changes in satiation contribute to obesity's pathogenesis. Our study employed a protocolized approach to study the components of food intake regulation including a standardized breakfast, a gastric emptying study, appetite sensation testing, and a satiation measurement by an ad libitummeal test. These studies revealed that satiation is highly variable among individuals, and while baseline characteristics, anthropometrics, body composition and hormones, contribute to this variability, these factors do not fully account for it. To address this gap, we explored the role of a germline polygenic risk score, which demonstrated a robust association with satiation. Furthermore, we developed a machine-learning-assisted gene risk score to predict satiation and leveraged this prediction to anticipate responses to anti-obesity medications. Our findings underscore the significance of satiation, its inherent variability, and the potential of a genetic risk score to forecast it, ultimately allowing us to predict responses to different anti-obesity interventions.
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Anopheles gambiae, Anopheles coluzzii , and Anopheles arabiensis are three of the most widespread vectors of malaria parasites, with geographical ranges stretching across wide swaths of Africa. Understanding the population structure of these closely related species, including the extent to which populations are connected by gene flow, is essential for understanding how vector control implemented in one location might indirectly affect vector populations in other locations. Here, we assessed the population structure of each species based on whole-genome sequences from the third phase of the Anopheles gambiae 1000 Genomes Project. The data set included single nucleotide polymorphisms from whole genomes of 2,242 individual mosquitoes sampled from 119 locations across 19 African countries. We found that A. gambiae sampled from several countries in West and Central Africa showed low genetic differentiation from each other according to principal components analysis (PCA) and ADMIXTURE modeling. Using Estimated Effective Migration Surfaces (EEMS), we showed that this low genetic differentiation indicates high effective migration rates for A. gambiae across this region. Outside of this region, we found six groups of sampling locations from Central, East, and Southern Africa for which A. gambiae showed higher genetic differentiation, and lower effective migration rates, between each other and the West/Central Africa group. These results indicate that the barriers to and corridors for migration between populations of A. gambiae differ across the geographical range of this malaria vector species. Using the same methods, we found higher genetic differentiation and lower migration rates between populations of A. coluzzii in West and Central Africa than for A. gambiae in the same region. On the other hand, we found lower genetic differentiation and higher migration rates between populations of A. arabiensis in Tanzania, compared to A. gambiae in the same region. These differences between A. gambiae, A. coluzzii , and A. arabiensis indicate that migration barriers and corridors may vary between species, even for very closely related species. Overall, our results demonstrate that migration rates vary both between and within species of Anopheles mosquitoes, presumably based on species-specific responses to the ecological or environmental conditions that may impede or facilitate migration, and the geographical patterns of these conditions across the landscape. Together with previous findings, this study provides robust evidence that migration rates between populations of malaria vectors depend on the ecological context, which should be considered when planning surveillance of vector populations, monitoring for insecticide resistance, and evaluating interventions.
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BACKGROUND: Black women are at an increased risk of developing uterine leiomyomas and experiencing worse disease prognosis than White women. Epidemiologic and molecular factors have been identified as underlying these disparities, but there remains a paucity of deep, multiomic analysis investigating molecular differences in uterine leiomyomas from Black and White patients. OBJECTIVE: To identify molecular alterations within uterine leiomyoma tissues correlating with patient race by multiomic analyses of uterine leiomyomas collected from cohorts of Black and White women. STUDY DESIGN: We performed multiomic analysis of uterine leiomyomas from Black (42) and White (47) women undergoing hysterectomy for symptomatic uterine leiomyomata. In addition, our analysis included the application of orthogonal methods to evaluate fibroid biomechanical properties, such as second harmonic generation microscopy, uniaxial compression testing, and shear-wave ultrasonography analyses. RESULTS: We found a greater proportion of MED12 mutant uterine leiomyomas from Black women (>35% increase; Mann-Whitney U, P<.001). MED12 mutant tumors exhibited an elevated abundance of extracellular matrix proteins, including several collagen isoforms, involved in the regulation of the core matrisome. Histologic analysis of tissue fibrosis using trichrome staining and secondary harmonic generation microscopy confirmed that MED12 mutant tumors are more fibrotic than MED12 wild-type tumors. Using shear-wave ultrasonography in a prospectively collected cohort, Black patients had fibroids that were firmer than White patients, even when similar in size. In addition, these analyses uncovered ancestry-linked expression quantitative trait loci with altered allele frequencies in African and European populations correlating with differential abundance of several proteins in uterine leiomyomas independently of MED12 mutation status, including tetratricopeptide repeat protein 38. CONCLUSION: Our study shows that Black women have a higher prevalence of uterine leiomyomas harboring mutations in MED12 and that this mutational status correlates with increased tissue fibrosis compared with wild-type uterine leiomyomas. Our study provides insights into molecular alterations correlating with racial disparities in uterine leiomyomas and improves our understanding of the molecular etiology underlying uterine leiomyoma development within these populations.
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Negro ou Afro-Americano , Leiomioma , Complexo Mediador , Neoplasias Uterinas , Brancos , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Negro ou Afro-Americano/genética , Proteínas da Matriz Extracelular/genética , Disparidades nos Níveis de Saúde , Leiomioma/diagnóstico por imagem , Leiomioma/etnologia , Leiomioma/genética , Complexo Mediador/genética , Mutação , Neoplasias Uterinas/diagnóstico por imagem , Neoplasias Uterinas/etnologia , Neoplasias Uterinas/genética , Brancos/genéticaRESUMO
Genomic surveillance is crucial for identifying at-risk populations for targeted malaria control and elimination. Identity-by-descent (IBD) is increasingly being used in Plasmodium population genomics to estimate genetic relatedness, effective population size (N e ), population structure, and signals of positive selection. Despite its potential, a thorough evaluation of IBD segment detection tools for species with high recombination rates, such as P. falciparum, remains absent. Here, we perform comprehensive benchmarking of IBD callers - probabilistic (hmmIBD, isoRelate), identity-by-state-based (hap-IBD, phased IBD) and others (Refined IBD) - using population genetic simulations tailored for high recombination, and IBD quality metrics at both the IBD segment level and the IBD-based downstream inference level. Our results demonstrate that low marker density per genetic unit, related to high recombination relative to mutation, significantly compromises the accuracy of detected IBD segments. In genomes with high recombination rates resembling P. falciparum, most IBD callers exhibit high false negative rates for shorter IBD segments, which can be partially mitigated through optimization of IBD caller parameters, especially those related to marker density. Notably, IBD detected with optimized parameters allows for more accurate capture of selection signals and population structure; IBD-based N e inference is very sensitive to IBD detection errors, with IBD called from hmmIBD uniquely providing less biased estimates of N e in this context. Validation with empirical data from the MalariaGEN Pf 7 database, representing different transmission settings, corroborates these findings. We conclude that context-specific evaluation and parameter optimization are essential for accurate IBD detection in high-recombining species and recommend hmmIBD for quality-sensitive analysis, such as estimation of N e in these species. Our optimization and high-level benchmarking methods not only improve IBD segment detection in high-recombining genomes but also enhance overall genomic analysis, paving the way for more accurate genomic surveillance and targeted intervention strategies for malaria.
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We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model's performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1 to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8 to 5.1% (SBP) and 4.7 to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs. In summary, non-linear ML models improves BP prediction in models incorporating diverse populations.
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Pressão Sanguínea , Estudo de Associação Genômica Ampla , Aprendizado de Máquina , Herança Multifatorial , Fenótipo , Humanos , Pressão Sanguínea/genética , Herança Multifatorial/genética , Estudo de Associação Genômica Ampla/métodos , Fatores de Risco , Masculino , Feminino , Predisposição Genética para Doença , Modelos Genéticos , Hipertensão/genética , Hipertensão/fisiopatologia , Pessoa de Meia-Idade , Estratificação de Risco GenéticoRESUMO
Genome-wide association studies have been useful in identifying genetic risk factors for various phenotypes. These studies rely on imputation and many existing panels are largely composed of individuals of European ancestry, resulting in lower levels of imputation quality in underrepresented populations. We aim to analyze how the composition of imputation reference panels affects imputation quality in four target Latin American cohorts. We compared imputation quality for chromosomes 7 and X when altering the imputation reference panel by: 1) increasing the number of Latin American individuals; 2) excluding either Latin American, African, or European individuals, or 3) increasing the Indigenous American (IA) admixture proportions of included Latin Americans. We found that increasing the number of Latin Americans in the reference panel improved imputation quality in the four populations; however, there were differences between chromosomes 7 and X in some cohorts. Excluding Latin Americans from analysis resulted in worse imputation quality in every cohort, while differential effects were seen when excluding Europeans and Africans between and within cohorts and between chromosomes 7 and X. Finally, increasing IA-like admixture proportions in the reference panel increased imputation quality at different levels in different populations. The difference in results between populations and chromosomes suggests that existing and future reference panels containing Latin American individuals are likely to perform differently in different Latin American populations.
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Colophospermum mopane (mopane) forms mono-dominant woodlands covering extensive areas of southern Africa. Mopane provides a staple foodstuff for elephants, who hedge woodland by reducing trees to small trees or shrubs, leaving emergent trees which are too large to be pollarded. Emergent trees are important for supporting faunal biodiversity, but they can be killed by ringbarking. This study first examined the influence of elephant density on woodland transformation and the height distribution of canopy volume, and, second, whether canopy volume is maintained, and tall emergent trees too large to be broken can persist, under chronic elephant utilisation. Three regimes of 0.23, 0.59 and 2.75 elephants km-2 differed in vegetation structure and the height structure of trees. Areas under the highest elephant density supported the lowest total canopy volume owing to less canopy for plants >3 m in height, shorter trees, loss of most trees 6-10 m in height, but trees >10 m in height (>45 cm stem diameter) persisted. Under eight years of chronic utilisation by elephants, transformed mopane woodland maintained its plant density and canopy volume. Plant density was greatest for the 0-1 m height class, whereas the 3.1-6 m height class provided the bulk of canopy volume, and the 1.1-3 m height layer contained the most canopy volume. Emergent trees (>10 m in height) suffered a loss of 1.4% per annum as a result of debarking. Canopy dieback of emergent trees increased conspicuously when more than 50% of a stem was debarked, and such trees could be toppled by windthrow before being ringbarked. Thus relict emergent trees will slowly be eliminated but will not be replaced whilst smaller trees are being maintained in a pollarded state. Woodland transformation has not markedly reduced canopy volume available to elephants, but the slow attrition of emergent trees may affect supported biota, especially cavity-dependent vertebrate species, making use of these trees.
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Elefantes , Fabaceae , Animais , Árvores , Florestas , PlantasRESUMO
Malaria genomic surveillance often estimates parasite genetic relatedness using metrics such as Identity-By-Decent (IBD), yet strong positive selection stemming from antimalarial drug resistance or other interventions may bias IBD-based estimates. In this study, we use simulations, a true IBD inference algorithm, and empirical data sets from different malaria transmission settings to investigate the extent of this bias and explore potential correction strategies. We analyze whole genome sequence data generated from 640 new and 3089 publicly available Plasmodium falciparum clinical isolates. We demonstrate that positive selection distorts IBD distributions, leading to underestimated effective population size and blurred population structure. Additionally, we discover that the removal of IBD peak regions partially restores the accuracy of IBD-based inferences, with this effect contingent on the population's background genetic relatedness and extent of inbreeding. Consequently, we advocate for selection correction for parasite populations undergoing strong, recent positive selection, particularly in high malaria transmission settings.
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Antimaláricos , Malária Falciparum , Humanos , Plasmodium falciparum , Malária Falciparum/parasitologia , Viés de Seleção , Antimaláricos/farmacologia , DemografiaRESUMO
PURPOSE: We investigated racial disparities in survival by histology in cervical cancer and examined the factors contributing to these disparities. METHODS: Non-Hispanic Black and non-Hispanic White (hereafter known as Black and White) patients with stage I-IV cervical carcinoma diagnosed between 2004 and 2017 in the National Cancer Database were studied. Survival differences were compared using Cox modeling to estimate hazard ratio (HR) or adjusted HR (AHR) and 95% confidence interval (CI). The contribution of demographic, socioeconomic and clinical factors to the Black vs White differences in survival was estimated after applying propensity score weighting in patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC). RESULTS: This study included 10,111 Black and 43,252 White patients with cervical cancer. Black patients had worse survival than White cervical cancer patients (HR = 1.40, 95% CI = 1.35-1.45). Survival disparities between Black and White patients varied significantly by histology (HR = 1.20, 95% CI = 1.15-1.24 for SCC; HR = 2.32, 95% CI = 2.12-2.54 for AC, interaction p < 0.0001). After balancing the selected demographic, socioeconomic and clinical factors, survival in Black vs. White patients was no longer different in those with SCC (AHR = 1.01, 95% CI 0.97-1.06) or AC (AHR = 1.09, 95% CI = 0.96-1.24). In SCC, the largest contributors to survival disparities were neighborhood income and insurance. In AC, age was the most significant contributor followed by neighborhood income, insurance, and stage. Diagnosis of AC (but not SCC) at ≥65 years old was more common in Black vs. White patients (26% vs. 13%, respectively). CONCLUSIONS: Histology matters in survival disparities and diagnosis at ≥65 years old between Black and White cervical cancer patients. These disparities were largely explained by modifiable factors.
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Negro ou Afro-Americano , Carcinoma de Células Escamosas , Neoplasias do Colo do Útero , População Branca , Humanos , Feminino , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/etnologia , Neoplasias do Colo do Útero/mortalidade , População Branca/estatística & dados numéricos , Pessoa de Meia-Idade , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/etnologia , Carcinoma de Células Escamosas/mortalidade , Adulto , Adenocarcinoma/patologia , Adenocarcinoma/etnologia , Adenocarcinoma/mortalidade , Estados Unidos/epidemiologia , Disparidades em Assistência à Saúde/etnologia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Disparidades nos Níveis de Saúde , Fatores Socioeconômicos , Modelos de Riscos Proporcionais , Estadiamento de NeoplasiasRESUMO
BACKGROUND: COVID-19 can have a particularly detrimental effect on patients with cancer, but no studies to date have examined if the presence, or site, of metastatic cancer is related to COVID-19 outcomes. METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, the authors identified 10,065 patients with COVID-19 and cancer (2325 with and 7740 without metastasis at the time of COVID-19 diagnosis). The primary ordinal outcome was COVID-19 severity: not hospitalized, hospitalized but did not receive supplemental O2, hospitalized and received supplemental O2, admitted to an intensive care unit, received mechanical ventilation, or died from any cause. The authors used ordinal logistic regression models to compare COVID-19 severity by presence and specific site of metastatic cancer. They used logistic regression models to assess 30-day all-cause mortality. RESULTS: Compared to patients without metastasis, patients with metastases have increased hospitalization rates (59% vs. 49%) and higher 30 day mortality (18% vs. 9%). Patients with metastasis to bone, lung, liver, lymph nodes, and brain have significantly higher COVID-19 severity (adjusted odds ratios [ORs], 1.38, 1.59, 1.38, 1.00, and 2.21) compared to patients without metastases at those sites. Patients with metastasis to the lung have significantly higher odds of 30-day mortality (adjusted OR, 1.53; 95% confidence interval, 1.17-2.00) when adjusting for COVID-19 severity. CONCLUSIONS: Patients with metastatic cancer, especially with metastasis to the brain, are more likely to have severe outcomes after COVID-19 whereas patients with metastasis to the lung, compared to patients with cancer metastasis to other sites, have the highest 30-day mortality after COVID-19.
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COVID-19 , Hospitalização , Metástase Neoplásica , Neoplasias , Sistema de Registros , SARS-CoV-2 , Humanos , COVID-19/mortalidade , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Hospitalização/estatística & dados numéricos , Neoplasias/patologia , Neoplasias/mortalidade , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Respiração Artificial/estatística & dados numéricosRESUMO
OBJECTIVE: This study investigated the risk of an aggressive endometrial cancer (EC) diagnosis by race, ethnicity, and country of origin to further elucidate histologic disparities in non-Hispanic Black (NHB), Hispanic, Asian/Pacific Islander (API), American Indian/Alaskan Native (AIAN) vs. non-Hispanic White (NHW) patients, particularly in Hispanic or API subgroups. METHODS: Patient diagnosed between 2004 and 2020 with low grade (LG)-endometrioid endometrial cancer (ECC) or an aggressive EC including grade 3 EEC, serous carcinoma, clear cell carcinoma, mixed epithelial carcinoma, or carcinosarcoma in the National Cancer Database were studied. The odds ratio (OR) and 95% confidence interval (CI) for diagnosis of an aggressive EC histology was estimated using logistic modeling. RESULTS: There were 343,868 NHW, 48,897 NHB, 30,013 Hispanic, 15,015 API and 1646 AIAN patients. The OR (95% CI) for an aggressive EC diagnosis was 3.07 (3.01-3.13) for NHB, 1.08 (1.06-1.11) for Hispanic, 1.17 (1.13-1.21) for API and 1.07 (0.96-1.19) for AIAN, relative to NHW patients. Subset analyses by country of origin illustrated the diversity in the OR for an aggressive EC diagnosis among Hispanic (1.18 for Mexican to 1.87 for Dominican), Asian (1.14 Asian Indian-Pakistani to 1.48 Korean) and Pacific Islander (1.00 for Hawaiian to 1.33 for Samoan) descendants. Hispanic, API and AIAN patients were diagnosed 5-years younger that NHW patients, and the risk for an aggressive EC histology were all significantly higher than NHW patients after correcting for age. Insurance status was another independent risk factor for aggressive histology. CONCLUSIONS: Risk of an aggressive EC diagnosis varied by race, ethnicity, and country of origin. NHB patients had the highest risk, followed by Dominican, South/Central American, Cuban, Korean, Thai, Vietnamese, and Filipino descendants.
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Neoplasias do Endométrio , Humanos , Feminino , Neoplasias do Endométrio/etnologia , Neoplasias do Endométrio/patologia , Pessoa de Meia-Idade , Idoso , Estados Unidos/epidemiologia , Adulto , População Branca/estatística & dados numéricos , Hispânico ou Latino/estatística & dados numéricos , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/etnologia , Adenocarcinoma de Células Claras/epidemiologia , Carcinossarcoma/patologia , Carcinossarcoma/etnologia , Havaiano Nativo ou Outro Ilhéu do Pacífico/estatística & dados numéricos , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/etnologia , Idoso de 80 Anos ou mais , Etnicidade/estatística & dados numéricos , Disparidades nos Níveis de Saúde , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/etnologia , Negro ou Afro-Americano/estatística & dados numéricosRESUMO
There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimer's disease. The role of amyloid beta 42 (Aß42) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases Aß42, which is increased from adipose tissue of male mice with obesity and is associated with higher plasma Aß42. Increasing circulating Aß42 levels in male mice without obesity has no effect on systemic glucose homeostasis but has obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. The closely related Aß40 isoform does not have these same effects on the heart. Administration of an Aß-neutralising antibody prevents obesity-induced cardiac dysfunction and hypertrophy. Furthermore, Aß-neutralising antibody administration in established obesity prevents further deterioration of cardiac function. Multi-contrast transcriptomic analyses reveal that Aß42 impacts pathways of mitochondrial metabolism and exposure of cardiomyocytes to Aß42 inhibits mitochondrial complex I. These data reveal a role for systemic Aß42 in the development of cardiac disease in obesity and suggest that therapeutics designed for Alzheimer's disease could be effective in combating obesity-induced heart failure.
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Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Masculino , Camundongos , Animais , Peptídeos beta-Amiloides , Diabetes Mellitus Tipo 2/complicações , Anticorpos Neutralizantes , Obesidade/complicações , Glucose , Fragmentos de PeptídeosRESUMO
OBJECTIVE: Proximal junctional failure following surgical correction for adult spinal deformity significantly impacts quality of life and increases the economic burden of treating underlying spinal deformity. The objective of this cadaver study was to determine optimal tension parameters in junctional tethers for proximal junctional kyphosis prevention. METHODS: Cadaveric specimens were used to establish the optimal tension range in polyethylene tethering devices, such as the VersaTie (NuVasive) used in this study. Three specimens were instrumented to test tether tensions of 0, 75, and 150 Newtons (N) at L1-L2, T9-T10, and T3-T4. An optical tracking system was used to measure when specimens reached proximal junctional kyphosis, experienced instrumentation or tissue failure, or reached a cap of 2500 cycles. Radiographs were obtained before and after testing. RESULTS: At all levels, use of a tether at tension forces of 75 N and 150 N elicited a protective effect. The only level in which a higher tension on the tether resulted in more protection was at T3-T4. When averaged, the use of a tether at tension forces of 75 N and 150 N showed 1000 cycles of protection at L1-L2, 2000 cycles at T9-T10, and 1426 cycles at T3-T4. Radiographic analysis corroborated these findings. CONCLUSIONS: The use of a tether in a cadaveric model prevents the development of proximal junctional kyphosis across all tested levels and an increased tension force of 150 N is protective at the proximal thoracic spine. These data can be used to develop further models for a tether system that reproducibly applies a fixed tension force above the thoracolumbar rod construct.
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Cifose , Fusão Vertebral , Adulto , Humanos , Qualidade de Vida , Complicações Pós-Operatórias/prevenção & controle , Fusão Vertebral/métodos , Cifose/diagnóstico por imagem , Cifose/cirurgia , Cifose/prevenção & controle , Cadáver , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/cirurgia , Estudos RetrospectivosRESUMO
Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle, resulting in increased non-oxidative glucose metabolism. This metabolic reprogramming was also associated with impaired apoptosis and ferroptosis responses, and preserved muscle cell viability in response to lipotoxicity. Mechanistically, increased HDAC4 and 5 decreased acetylation of p53 at K120, a modification required for transcriptional activation of apoptosis. Redox drivers of ferroptosis derived from oxidative metabolism were also reduced. The relevance of this pathway was demonstrated by overexpression of loss-of-function HDAC4 and HDAC5 mutants in skeletal muscle of obese db/db mice, which enhanced oxidative metabolic capacity, increased apoptosis and ferroptosis and reduced muscle mass. This study identifies HDAC4 and HDAC5 as repressors of skeletal muscle oxidative metabolism, which is linked to inhibition of cell death pathways and preservation of muscle integrity in response to lipotoxicity.