RESUMO
Obesity, defined by body mass index (BMI), is an established risk factor for specific renal cell carcinoma (RCC) subtypes such as clear cell RCC, the most common RCC histology. Many studies have identified an association between obesity and improved survival after diagnosis of RCC, a potential "obesity paradox." Clinically, there is uncertainty whether improved outcomes observed after diagnosis are driven by stage, type of treatment received, or artifacts of longitudinal changes in weight and body composition. The biological mechanisms underlying obesity's influence on RCC are not fully established, but multiomic and mechanistic studies suggest an impact on tumor metabolism, particularly fatty acid metabolism, angiogenesis, and peritumoral inflammation, which are known to be key biological hallmarks of clear cell RCC. Conversely, high-intensity exercise associated with increased muscle mass may be a risk factor for renal medullary carcinoma, a rare RCC subtype that predominantly occurs in individuals with sickle hemoglobinopathies. Herein, we highlight methodologic challenges associated with studying the influence of obesity on RCC and review the clinical evidence and potential underlying mechanisms associating RCC with BMI and body composition.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/etiologia , Neoplasias Renais/etiologia , Neoplasias Renais/patologia , Obesidade/complicações , Fatores de RiscoRESUMO
All placental abruptions begin as partial abruptions, which sometimes manifest as fetal bradycardia. The progression from partial to total abruption was mimicked by a new rabbit model of placental insufficiency, and we compared it, with sufficient statistical power, with the previous model mimicking total placental abruption. The previous model uses total uterine ischemia at E22 or E25 (70% or 79% term, respectively), in pregnant New Zealand white rabbits for 40 min (Full H-I). The new model, Partial+Full H-I, added a 30-min partial ischemia before the 40-min total ischemia. Fetuses were delivered either at E31.5 (full term) vaginally for neurobehavior testing, or by C-section at E25 for ex vivo brain cell viability evaluation. The onset of fetal bradycardia was within the first 2 min of either H-I protocol. There was no difference between Full H-I (n = 442 for E22, 312 for E25) and Partial+Full H-I (n = 154 and 80) groups in death or severely affected kits at E22 (76% vs. 79%) or at E25 (66% vs. 64%), or normal kits at E22 or E25, or any of the individual newborn neurobehavioral tests at any age. No sex differences were found. Partial+Full H-I (n = 6) showed less cell viability than Full H-I (n = 8) at 72-hr ex vivo in the brain regions studied. Partial+Full H-I insult produced similar cerebral palsy phenotype as our previous Full H-I model in a sufficiently powered study and may be more suitable for testing of potential neuroprotectants.
Assuntos
Paralisia Cerebral , Hipóxia-Isquemia Encefálica , Fármacos Neuroprotetores , Insuficiência Placentária , Humanos , Animais , Coelhos , Gravidez , Feminino , Bradicardia , PlacentaRESUMO
BACKGROUND: Androgen signaling is central to prostate cancer and men's health. Prior data indicates that increasing body fat is unfavorable in the localized setting yet associated with favorable outcomes in men with metastatic disease. Understanding the biological links between adiposity and prostate cancer may optimize the therapeutic index with ASI. We hypothesized that host adiposity and androgen synthesis are linked to the efficacy and toxicity of ASI for men with metastatic castration-resistant prostate cancer (mCRPC). METHODS: A post-hoc analysis was done of NCT02703623 where men with mCRPC (n = 186) were treated for 8 weeks with abiraterone acetate, prednisone, and apalutamide (AAPA), and a satisfactory response was defined as a PSA decline >50%. Body composition was measured on baseline CT scans. Germline DNA WES was performed with a focus on variants in steroidogenic genes. Adipokine levels were measured in pre-treatment plasma. RESULTS: Germline polymorphisms in 3 genes involved in androgen synthesis (AKR1C3 rs12529, CYP17A1 rs6162, SRD5A2 rs523349) were associated with differences in body composition at baseline on ADT alone (prior to receipt of AAPA). Elevated subcutaneous adipose tissue index (SATi, p = 0.02), visceral adipose tissue index (VATi, p = 0.03), and BMI (p = 0.04) were associated with satisfactory response to AAPA. Leptin had positive correlation with VATi (r = 0.47) and SATi (r = 0.48). CONCLUSION: Inherited polymorphisms in androgen synthesis correlated with differences in body composition after exposure to ADT and warrant further investigation as candidate markers for body composition toxicity. Elevated subcutaneous and visceral adiposity were associated with improved response to ASI.
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Altered RNA metabolism is a common pathogenic mechanism linked to familial and sporadic Amyotrophic lateral sclerosis (ALS). ALS is characterized by mislocalization and aggregation of TDP-43, an RNA-binding protein (RBP) with multiple roles in post-transcriptional RNA processing. Recent studies have identified genetic interactions between TDP-43 and Ataxin-2, a polyglutamine (polyQ) RBP in which intermediate length polyQ expansions confer increased ALS risk. Here, we used live-cell confocal imaging, photobleaching and translation reporter assays to study the localization, transport dynamics and mRNA regulatory functions of TDP-43/Ataxin-2 in rodent primary cortical neurons. We show that Ataxin-2 polyQ expansions aberrantly sequester TDP-43 within ribonucleoprotein (RNP) condensates, and disrupt both its motility along the axon and liquid-like properties. Our data suggest that Ataxin-2 governs motility and translation of neuronal RNP condensates and that Ataxin-2 polyQ expansions fundamentally perturb spatial localization of mRNA and suppress local translation. Overall, these results indicate Ataxin-2 polyQ expansions have detrimental effects on stability, localization, and translation of transcripts critical for axonal and cytoskeletal integrity, particularly important for motor neurons.
RESUMO
Immune checkpoint blockade (ICB) is a mainstay of treatment for advanced cancer, yet tumor response and host toxicity are heterogenous in those patients who receive ICB. There is growing interest in understanding how host factors interact with tumor intrinsic properties and the tumor microenvironment to influence the therapeutic index with ICB. Obesity, defined by body mass index, is a host factor associated with improved outcomes in select cancers when treated with ICB. While the biological mechanism for this obesity paradox is not fully understood, pre-clinical and translational studies suggest obesity may potentially impact tumor metabolism, inflammation, and angiogenesis. Herein, we summarize clinical studies that support an obesity paradox with ICB, explore potential biological mechanisms that may account for the obesity paradox, and address methodological challenges to consider when studying obesity and treatment outcomes.
Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/patologia , Obesidade/complicações , Obesidade/tratamento farmacológico , Inflamação/tratamento farmacológico , Microambiente TumoralRESUMO
The knowledge of ancestral origin is monumental in conservation of endangered animals since it can aid in preservation of population level genetic integrity and prevent inbreeding among related individuals. Despite maintenance of studbook, the biogeographical affiliation of most captive gorillas is largely unknown, which has constrained management of captive gorillas aiming at maximizing genetic diversity at the population level. In recent years, ancestry informative markers (AIMs) has been successfully employed for the inference of genomic ancestry in a wide range of studies in evolutionary genetics, biomedical research, genetic stock identification, and introgression analysis and forensic analyses. In this study, we sought to derive the AIMs yielding the most cohesive and faithful understanding of biogeographical affiliation of query gorillas. To this end, we compared three commonly used AIMs-determining methods namely, Infocalc, F ST , and Smart Principal Component Analysis (SmartPCA) with ADMIXTURE, using gorilla genome data available through Great Ape Genome Project database. Our findings suggest that the SNPs that were detected by at least three of the four AIMs-determining approaches (N = 1,531), is likely most suitable for delineation of gorilla AIMs. It recapitulated the finer structure within western lowland gorilla genomes with high degree of precision. We further have validated the robustness of our results using a randomized negative control containing the same number of SNPs. To the best of our knowledge, this is the first report of an AIMs panel for gorillas that may aid in developing cost-effective resources for large-scale demographic analyses, and greatly help in conservation of this charismatic mega-fauna.