RESUMO
Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19) has shown extensive lung manifestations in vulnerable individuals, putting lung imaging and monitoring at the forefront of early detection and treatment. Magnetic particle imaging (MPI) is an imaging modality, which can bring excellent contrast, sensitivity, and signal-to-noise ratios to lung imaging for the development of new theranostic approaches for respiratory diseases. Advances in MPI tracers would offer additional improvements and increase the potential for clinical translation of MPI. Here, a high-performance nanotracer based on shape anisotropy of magnetic nanoparticles is developed and its use in MPI imaging of the lung is demonstrated. Shape anisotropy proves to be a critical parameter for increasing signal intensity and resolution and exceeding those properties of conventional spherical nanoparticles. The 0D nanoparticles exhibit a 2-fold increase, while the 1D nanorods have a > 5-fold increase in signal intensity when compared to VivoTrax. Newly designed 1D nanorods displayed high signal intensities and excellent resolution in lung images. A spatiotemporal lung imaging study in mice revealed that this tracer offers new opportunities for monitoring disease and guiding intervention.
Assuntos
Nanopartículas de Magnetita , Nanopartículas , Camundongos , Animais , Anisotropia , Diagnóstico por Imagem/métodos , Magnetismo , Fenômenos Magnéticos , Imageamento por Ressonância MagnéticaRESUMO
Transcription factor AP2 gamma (TFAP2C) is a well-established regulator of the trophoblast lineage in mice and humans, but a handful of studies indicate that TFAP2C may play an important role in pluripotency. Here, we hypothesize and provide new evidence that TFAP2C functions as an activator of trophoblast and pluripotency genes during preimplantation embryo development.
Assuntos
Blastocisto , Fator de Transcrição AP-2 , Animais , Feminino , Humanos , Camundongos , Gravidez , Desenvolvimento Embrionário , Fator de Transcrição AP-2/genética , TrofoblastosRESUMO
PURPOSE: We intended to investigate the risk for second primary malignancy (SPM) development in Laryngeal Cancer (LC) survivors. We conducted a population-based analysis of SPM risk using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Data of selected LC survivors from the SEER database between 2000 and 2020 were examined. Standardized Incidence ratios (SIRs) for SPM development were calculated, followed by detailed stratification according to anatomical site and different latency periods. RESULTS: A total of 8413 SPMs were observed in our extracted cohort. The collective standardized incidence of SPMs was 2.12 (95% CI 2.07-2.17) compared to the US population, with an absolute excess risk (AER) of 201.73 per 10,000 individuals. The highest SPM risks were observed in patients with young age at diagnosis, females, and American Indians/Alaska natives. Increased SPM risks were reported in patients receiving all modalities of treatment including surgery, chemotherapy, and radiotherapy. Most SPMs were detected in solid organs such as the lungs and bronchus, oral cavity and pharynx, and prostate. The highest increased risks of developing SPMs were observed in Trachea, larynx, oral cavity and pharynx, lung and bronchus, and esophagus. CONCLUSIONS: The risk of SPMs in LC survivors was significantly increased compared to the general US population. Accordingly, a more impactful cancer surveillance strategy for LC patients should be implemented.
Assuntos
Sobreviventes de Câncer , Neoplasias Laríngeas , Segunda Neoplasia Primária , Programa de SEER , Humanos , Segunda Neoplasia Primária/epidemiologia , Neoplasias Laríngeas/epidemiologia , Masculino , Feminino , Sobreviventes de Câncer/estatística & dados numéricos , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Idoso , Adulto , Incidência , Fatores de Risco , Medição de RiscoRESUMO
BACKGROUND: Several reports examined the survival of laryngeal cancer (LC) patients, most of these studies only focused on the prognosis of the disease, and just a small number of studies examined non-cancer-related causes of death. The objective of the current study is to investigate and quantify the most common causes of deaths following LC diagnosis. METHODS: The data of 44,028 patient with LC in the United States diagnosed between 2000 and 2018 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) program and analyzed. We stratified LC patients according to various demographic and clinical parameters and calculated standardized mortality ratios (SMRs) for all causes of death. RESULTS: Over the follow-up period, 25,407 (57.7%) deaths were reported. The highest fatalities (11,121; 43.8%) occurred within 1-5 years following LC diagnosis. Non-cancer causes of death is the leading cause of death (8945; 35.2%), followed by deaths due to laryngeal cancer (8,705; 34.3%), then other cancers deaths (7757; 30.5%). The most common non-cancer causes of death were heart diseases (N = 2953; SMR 4.42), followed by other non-cancer causes of death (N = 1512; SMR 3.93), chronic obstructive pulmonary diseases (N = 1420; SMR 4.90), then cerebrovascular diseases (N = 547; SMR 4.28). Compared to the general population, LC patients had a statistically significant higher risk of death from all reported causes. CONCLUSIONS: Non-cancer causes of death is the leading cause of death in LC patients, exceeding deaths attributed to LC itself. These findings provide important insight into how LC survivors should be counselled regarding future health risks.
Assuntos
Transtornos Cerebrovasculares , Neoplasias Laríngeas , Humanos , Estados Unidos/epidemiologia , Causas de Morte , Neoplasias Laríngeas/diagnóstico , Causalidade , PrognósticoRESUMO
Caudal Type Homeobox 2 (CDX2) is a key regulator of trophectoderm formation and maintenance in preimplantation embryos. We previously demonstrated that supplementation of exogenous follistatin, during in vitro culture of bovine IVF embryos, upregulates CDX2 expression, possibly, via alteration of the methylation status of CDX2 gene. Here, we further investigated the effects of exogenous follistatin supplementation on developmental competence and CDX2 methylation in bovine somatic cell nuclear transfer (SCNT) embryos. SCNT embryos were cultured with or without follistatin for 72h, then transferred into follistatin free media until d7 when blastocysts were collected and subjected to CDX2 gene expression and DNA methylation analysis for CDX2 regulatory regions by bisulfite sequencing. Follistatin supplementation significantly increased both blastocyst development as well as blastocyst CDX2 mRNA expression on d7. Three different CpG rich fragments within the CDX2 regulatory elements; proximal promoter (fragment P1, -1644 to -1180; P2, -305 to +126) and intron 1 (fragment I, + 3030 to + 3710) were identified and selected for bisulfite sequencing analysis. This analysis showed that follistatin treatment induced differential methylation (DM) at specific CpG sites within the analyzed fragments. Follistatin treatment elicited hypomethylation at six CpG sites at positions -1374, -279, -163, -23, +122 and +3558 and hypermethylation at two CpG sites at positions -243 and +20 in promoter region and first intron of CDX2 gene. Motif analysis using MatInspector revealed that differentially methylated CpG sites are putative binding sites for key transcription factors (TFs) known to regulate Cdx2 expression in mouse embryos and embryonic stem cells including OCT1, AP2F, KLF and P53, or TFs that have indirect link to CDX2 regulation including HAND and NRSF. Collectively, results of the present study together with our previous findings in IVF embryos support the hypothesis that alteration of CDX2 methylation is one of the epigenetic mechanisms by which follistatin may regulates CDX2 expression in preimplantation bovine embryos.
Assuntos
Blastocisto/efeitos dos fármacos , Fator de Transcrição CDX2/genética , Metilação de DNA/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Folistatina/farmacologia , Animais , Blastocisto/fisiologia , Fator de Transcrição CDX2/efeitos dos fármacos , Bovinos/embriologia , Células Cultivadas , Clonagem de Organismos/veterinária , Ilhas de CpG/efeitos dos fármacos , Ilhas de CpG/genética , Metilação de DNA/genética , Técnicas de Cultura Embrionária/métodos , Técnicas de Cultura Embrionária/veterinária , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Feminino , Fertilização in vitro/veterinária , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Técnicas de Maturação in Vitro de Oócitos/métodos , Técnicas de Maturação in Vitro de Oócitos/veterinária , Técnicas de Transferência Nuclear/veterináriaRESUMO
Characterization of the molecular factors regulating early embryonic development and their functional mechanisms is critical for understanding the causes of early pregnancy loss in monotocous species (cattle, human). We previously characterized a stage specific functional role of follistatin, a TGF-beta superfamily binding protein, in promoting early embryonic development in cattle. The mechanism by which follistatin mediates this embryotropic effect is not precisely known as follistatin actions in cattle embryos are independent of its classically known activin inhibition activity. Apart from activin, follistatin is known to bind and modulate the activity of the bone morphogenetic proteins (BMPs), which signal through SMAD1/5 pathway and regulate several aspects of early embryogenesis in other mammalian species. Present study was designed to characterize the activity and functional requirement of BMP signaling during bovine early embryonic development and to investigate if follistatin involves BMP signaling for its stage specific embryotropic actions. Immunostaining and western blot analysis demonstrated that SMAD1/5 signaling is activated after embryonic genome activation in bovine embryos. However, days 1-3 follistatin treatment reduced the abundance of phosphorylated SMAD1/5 in cultured embryos. Inhibition of active SMAD1/5 signaling (8-16 cell to blastocyst) using pharmacological inhibitors and/or lentiviral-mediated inhibitory SMAD6 overexpression showed that SMAD1/5 signaling is required for blastocyst production, first cell lineage determination as well as mRNA and protein regulation of TE (CDX2) cell markers. SMAD1/5 signaling was also found to be essential for embryotropic actions of follistatin during days 4-7 but not days 1-3 of embryo development suggesting a role for follistatin in regulation of SMAD1/5 signaling in bovine embryos.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Folistatina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Bovinos , Diferenciação Celular/efeitos dos fármacos , Técnicas de Cultura Embrionária , Desenvolvimento Embrionário/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Gravidez , Transdução de Sinais/fisiologia , Proteínas Smad/metabolismoRESUMO
In mammals, the first cell-fate decision occurs during preimplantation embryo development when the inner cell mass (ICM) and trophectoderm (TE) lineages are established. The ICM develops into the embryo proper, while the TE lineage forms the placenta. The underlying molecular mechanisms that govern lineage formation involve cell-to-cell interactions, cell polarization, cell signaling and transcriptional regulation. In this review, we will discuss the current understanding regarding the cellular and molecular events that regulate lineage formation in mouse preimplantation embryos with an emphasis on cell polarity and the Hippo signaling pathway. Moreover, we will provide an overview on some of the molecular tools that are used to manipulate the Hippo pathway and study cell-fate decisions in early embryos. Lastly, we will provide exciting future perspectives on transcriptional regulatory mechanisms that modulate the activity of the Hippo pathway in preimplantation embryos to ensure robust lineage segregation.
Assuntos
Blastocisto , Diferenciação Celular/genética , Linhagem da Célula/genética , Proteínas Serina-Treonina Quinases/fisiologia , Fatores de Transcrição/fisiologia , Animais , Blastocisto/citologia , Blastocisto/metabolismo , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Via de Sinalização Hippo , Camundongos , Gravidez , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição/metabolismoRESUMO
CDX2 plays a crucial role in the formation and maintenance of the trophectoderm epithelium in preimplantation embryos. Follistatin supplementation during the first 72 hr of in vitro culture triggers a significant increase in blastocyst rates, CDX2 expression, and trophectoderm cell numbers. However, the underlying epigenetic mechanisms by which follistatin upregulates CDX2 expression are not known. Here, we investigated whether stimulatory effects of follistatin are linked to alterations in DNA methylation within key regulatory regions of the CDX2 gene. In vitro-fertilized (IVF) zygotes were cultured with or without 10 ng/ml of recombinant human follistatin for 72 hr, then cultured without follistatin until Day 7. The bisulfite-sequencing analysis revealed differential methylation (DM) at specific CpG sites within the CDX2 promoter and intron 1 following follistatin treatment. These DM CpG sites include five hypomethylated sites at positions -1384, -1283, -297, -163, and -23, and four hypermethylated sites at positions -1501, -250, -243, and +20 in the promoter region. There were five hypomethylated sites at positions +3060, +3105, +3219, +3270, and +3545 in intron 1. Analysis of transcription factor binding sites using MatInspector combined with a literature search revealed a potential association between differentially methylated CpG sites and putative binding sites for key transcription factors involved in regulating CDX2 expression. The hypomethylated sites are putative binding sites for FXR, STAF, OCT1, KLF, AP2 family, and P53 protein, whereas the hypermethylated sites are putative binding sites for NRSF. Collectively, our results suggest that follistatin may increase CDX2 expression in early bovine embryos, at least in part, by modulating DNA methylation at key regulatory regions.
Assuntos
Blastocisto/efeitos dos fármacos , Fator de Transcrição CDX2/genética , Bovinos/embriologia , Metilação de DNA/efeitos dos fármacos , Folistatina/farmacologia , Animais , Blastocisto/metabolismo , Fator de Transcrição CDX2/metabolismo , Bovinos/genética , Células Cultivadas , Técnicas de Cultura Embrionária , Embrião de Mamíferos , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Fertilização in vitro/veterinária , Regulação da Expressão Gênica no DesenvolvimentoRESUMO
BACKGROUND: TGF-ß signaling pathways regulate several crucial processes in female reproduction. AKT is a non-SMAD signaling pathway regulated by TGF-ß ligands essential for oocyte maturation and early embryonic development in the mouse, but its regulatory role in bovine early embryonic development is not well established. Previously, we demonstrated a stimulatory role for follistatin (a binding protein for specific members of TGF-ß superfamily) in early bovine embryonic development. The objectives of the present studies were to determine the functional role of AKT signaling in bovine early embryonic development and embryotrophic actions of follistatin. METHODS: We used AKT inhibitors III and IV as pharmacological inhibitors of AKT signaling pathway during the first 72 h of in vitro embryo culture. Effects of AKT inhibition on early embryonic development and AKT phosphorylation were investigated in the presence or absence of exogenous follistatin. RESULTS: Pharmacological inhibition of AKT signaling resulted in a significant reduction in early embryo cleavage, and development to the 8- to 16-cell and blastocyst stages (d7). Treatment with exogenous follistatin increased AKT phosphorylation and rescued the inhibitory effect of AKT inhibitors III and IV on AKT phosphorylation and early embryonic development. CONCLUSIONS: Collectively, results suggest a potential requirement of AKT for bovine early embryonic development, and suggest a potential role for follistatin in regulation of AKT signaling in early bovine embryos.
Assuntos
Bovinos/embriologia , Desenvolvimento Embrionário , Folistatina/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Animais , Bovinos/metabolismo , Feminino , Folistatina/metabolismo , Folistatina/farmacologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismoRESUMO
The objectives of the present studies were to investigate the developmental capacity of dromedary camel oocytes selected by brilliant cresyl blue (BCB) staining and to investigate the expression of select transcripts in germinal vesicle (GV) stage oocytes. These transcripts included BMP15 and GDF9 as important transcripts for folliculogenesis and oocyte development, Zar1 and Mater as maternal transcripts required for embryonic development, Cyclin B1 and CDK1 as cell cycle regulators and Oct4 and STAT3 as transcription factors. Dromedary camel oocytes were retrieved from ovaries collected at a local slaughterhouse. After exposure to BCB staining, cumulus-oocyte complexes (COCs) from BCB+, BCB- and control (selected based on morphological criteria) groups were subjected to in vitro maturation, in vitro fertilization and in vitro culture. For gene expression studies, after BCB staining cumulus cells were stripped off and the completely denuded GV stage oocytes were used for RT-PCR analysis of selected transcripts. BCB+ oocytes showed higher maturation, and fertilization rates compared with BCB- and control groups. Indices of early embryonic development, namely, cleavage at 48 hours post insemination (hpi), and development to morula at day 5 and day 7 blastocyst rates were also significantly higher in the BCB+ group. RT-PCR revealed a higher expression of BMP15, GDF9, Zar1, Mater, Cyclin B1, CDK1, OCT4 and STAT3 in good quality oocytes that stained positively for BCB (BCB+). Collectively, results provide novel information about the use of BCB screening for selecting good quality oocytes to improve in vitro embryo production in the dromedary camel.
Assuntos
Camelus , Técnicas de Maturação in Vitro de Oócitos/métodos , Oócitos/fisiologia , Oxazinas/farmacologia , Coloração e Rotulagem/métodos , Animais , Blastocisto/fisiologia , Proteína Morfogenética Óssea 15/genética , Proteína Quinase CDC2/genética , Ciclina B1/genética , Feminino , Fertilização in vitro , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Oócitos/citologia , Oócitos/efeitos dos fármacos , Fator de Transcrição STAT3/genéticaRESUMO
Brilliant cresyl blue (BCB) is a super-vital stain that has been used to select competent oocytes in different species. One objective of the present study was to assess the relationship between BCB staining, which correlates with an oocyte's developmental potential, and the transcript abundance for select TGFß-superfamily components, SMAD2/3 and SMAD1/5 phosphorylation levels, and oocyte (JY1) and cumulus-cell (CTSB, CTSK, CTSS, and CTSZ) transcript markers in bovine oocytes and/or adjacent cumulus cells. The capacity of exogenous follistatin or JY1 supplementation or cathepsin inhibitor treatment to enhance development of embryos derived from low-quality oocytes, based on BCB staining, was also determined. Cumulus-oocyte complexes (COCs) from abattoir-derived ovaries were subjected to BCB staining, and germinal-vesicle-stage oocytes and cumulus cells were harvested from control, BCB+, and BCB- (low-quality oocyte) groups for real-time PCR or Western-blot analysis. Remaining COCs underwent in vitro maturation, in vitro fertilization, and embryo culture in the presence or absence of the above exogenous supplements. Levels of FST, JY1, BMP15, and SMAD1, 2, 3, and 5 transcripts were higher in BCB+ oocytes whereas CTSB, CTSK, CTSS, and CTSZ mRNA abundance was higher in cumulus cells surrounding BCB- oocytes. Western-blot analysis revealed higher SMAD1/5 and SMAD2/3 phosphorylation in BCB+ than BCB- oocytes. Embryo-culture studies demonstrated that follistatin and cathepsin inhibitor treatment, but not JY-1 treatment, improve the developmental competence of BCB- oocytes. These results contribute to a better understanding of molecular indices of oocyte competence.
Assuntos
Biomarcadores/metabolismo , Células do Cúmulo/fisiologia , Desenvolvimento Embrionário/fisiologia , Oócitos/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Análise de Variância , Animais , Western Blotting , Bovinos , Células do Cúmulo/metabolismo , Primers do DNA/genética , Técnicas de Cultura Embrionária , Fertilização in vitro , Folistatina/farmacologia , Perfilação da Expressão Gênica , Técnicas de Maturação in Vitro de Oócitos , Oócitos/metabolismo , Oxazinas , Fosforilação , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Smad/metabolismoRESUMO
Despite recent progress in antithrombotic therapy, there's still an unmet medical need for safe and orally available anticoagulants. Encouraged by the marked antithrombotic and anticoagulant activities of some coumarin derivatives, twenty-three new N-coumarinyl-4-amidinobenzamides 4a-f and 6-heterocycle substituted coumarin derivatives 5, 6a,b, 10a-e, 12a-e and 14a-d were synthesized and evaluated for their in vivo antithrombotic activity. The most active congeners were the unsubstituted amidine 4a (36.5 s), coumarinyl oxadiazole 5 (42.3 s), bis coumarinyl oxadiazole 6b (37.8 s) and coumarinyl pyrazole 10b (38.5 s) that presented prothrombin time (PT) values comparable to the reference drug warfarin (42.3 s). Furthermore, docking studies were undertaken to gain insight into the possible binding mode of these compounds with the coagulation factor Xa (FXa) binding site.
Assuntos
Anticoagulantes/farmacologia , Cumarínicos/química , Inibidores do Fator Xa , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Animais , Anticoagulantes/síntese química , Anticoagulantes/química , Sítios de Ligação , Fator Xa/química , Fator Xa/metabolismo , Fibrinolíticos/síntese química , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Tempo de Protrombina , Relação Estrutura-Atividade , Varfarina/farmacologiaRESUMO
BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is infrequent. Currently, non-invasive biomarkers for early detection of PDAC are not accessible. Here, we intended to identify a set of urine markers able to discriminate patients with early-stage PDAC from healthy individuals. PATIENTS AND METHODS: Seventy-five urine samples from PDAC patients and 50 healthy controls were assayed using quantitative real-time PCR (qPCR). The chosen biomarkers were lymphatic vessel endothelial HA receptor (LYVE-1), regenerating islet-derived 1 alpha (REG1A), and trefoil factor family (TFF1). RESULTS: LYVE-1, REG1A, and TFF1 expression in PDAC proved to be significantly elevated compared to healthy individuals (p < 0.05). Determination of these markers' expression might be useful for early tumor diagnosis with a sensitivity of 96â¯%, 100â¯%, and 73.33â¯% respectively, and a specificity of 100â¯%, 82â¯%, and 100â¯% respectively. CONCLUSION: We have recognized three diagnostic biomarkers REG1A, TFF1, and LYVE1 that can detect patients with early-stage pancreatic cancer in non-invasive urine specimens with improved sensitivity and specificity. To the best of our knowledge, there have been no prior investigations examining the mRNA expression levels of them in urine within the Egyptian population.
RESUMO
Large language models (LLMs) like ChatGPT have potential applications in medical education such as helping students study for their licensing exams by discussing unclear questions with them. However, they require evaluation on these complex tasks. The purpose of this study was to evaluate how well publicly accessible LLMs performed on simulated UK medical board exam questions. 423 board-style questions from 9 UK exams (MRCS, MRCP, etc.) were answered by seven LLMs (ChatGPT-3.5, ChatGPT-4, Bard, Perplexity, Claude, Bing, Claude Instant). There were 406 multiple-choice, 13 true/false, and 4 "choose N" questions covering topics in surgery, pediatrics, and other disciplines. The accuracy of the output was graded. Statistics were used to analyze differences among LLMs. Leaked questions were excluded from the primary analysis. ChatGPT 4.0 scored (78.2%), Bing (67.2%), Claude (64.4%), and Claude Instant (62.9%). Perplexity scored the lowest (56.1%). Scores differed significantly between LLMs overall (p < 0.001) and in pairwise comparisons. All LLMs scored higher on multiple-choice vs true/false or "choose N" questions. LLMs demonstrated limitations in answering certain questions, indicating refinements needed before primary reliance in medical education. However, their expanding capabilities suggest a potential to improve training if thoughtfully implemented. Further research should explore specialty specific LLMs and optimal integration into medical curricula.
Assuntos
Avaliação Educacional , Humanos , Reino Unido , Avaliação Educacional/métodos , Educação Médica/métodos , Inteligência Artificial , Estudantes de MedicinaRESUMO
Research on mortality outcomes and non-cancer-related causes of death in patients with cutaneous melanoma (CM) remains limited. This study aimed to identify the prevalence of non-cancer-related deaths following CM diagnosis. The data of 224,624 patients diagnosed with malignant CM in the United States between 2000 and 2019 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. We stratified our cohort based on their melanoma stage at diagnosis and further calculated standardized mortality ratios (SMRs) for each cause of death, comparing their relative risk to that of the general US population. The total number of fatalities among melanoma patients was 60,110, representing 26.8% of the total cases. The percentage of deaths is directly proportional to the disease stage, reaching 80% in distant melanoma. The highest fatalities among the localized melanoma group (25,332; 60.5%) occurred from non-cancer causes, followed by melanoma-attributable deaths (10,817; 25.8%). Conversely, melanoma is the leading cause of death in regional and distant melanoma cohorts. Cardiovascular and cerebrovascular diseases were the most prevalent non-cancer causes of death among the three disease-stage cohorts. Compared to the general population, we did not observe an increased risk of death due to non-cancer causes in the localized CM cohort, while patients diagnosed with regional and distant CMs had a statistically significant higher risk of death from all the reported major causes of death.
Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Estados Unidos/epidemiologia , Melanoma/patologia , Neoplasias Cutâneas/patologia , Causas de Morte , Programa de SEER , Melanoma Maligno CutâneoRESUMO
BACKGROUND/AIMS: Effective management of diabetic retinopathy requires multidisciplinary input. We aimed to evaluate the impact of point of care (POC) HbA1c testing as a tool to identify patients most in need of specialist diabetologist input and assess the accuracy and determinants of patients' insight into their glycaemic and blood pressure control. METHODS: Forty-nine patients with diabetic retinopathy were recruited from the eye clinic at Great Western Hospital. Patients completed a questionnaire and POC HbA1c and blood pressure values were measured. Statistical analysis was completed with SPSS v23. RESULTS: Mean age was 64.4 years, median interval since the last formal HbA1c reading was 10.2 months and the mean POC HbA1c was 64.1 mmol/mol. HbA1c significantly correlated with the degree of retinopathy. Of the patients, 81.6% had POC readings above the levels recommended by the National Institute for Health and Care Excellence, with only 16.3% having insight into this. Insight to HbA1c levels was predicted by age but not by duration of disease. Fourteen patients (33.3%) identified with high HbA1c readings were referred to secondary diabetic services and 88.8% of patients felt that the test was useful and likely to improve their diabetic control. CONCLUSION: The majority of patients had poor insight into their diabetes control, with sub-optimal treatment and follow-up. Poor insight is high in younger patients, suggesting that POC HbA1c testing is particularly important in educating younger patients who may be Type 1 diabetics with more severe disease. POC HbA1c represents a cost-effective, reproducible and clinically significant tool for the management of diabetes in an outpatient ophthalmology setting, allowing the rapid recognition of high-risk patients and appropriate referral to secondary diabetic services.
RESUMO
A phase II study was conducted to assess the efficacy and toxicity of combination therapy with capecitabine and cisplatin in patients with de-novo advanced gastric cancer, and in patients with refractory/recurrent gastric cancer after previous nonplatinum-based therapy. Sixty-four patients were enrolled in the study. Of these, 50 patients had untreated gastric cancer, and 14 had received previous therapy with nonplatinum-based therapy. All patients received oral capecitabine 1250 mg/m2 twice daily, days 1-14, and intravenous cisplatin 60 mg/m2 on day 1. This cycle was repeated every 3 weeks. Among the 50 previously untreated patients, three achieved complete response, and 19 had partial response, giving a response rate of 44% in the intention-to-treat population. The median time to progression and median overall survival were 6 months [95% confidence interval (CI): 1.4-10.6] and 9 months (95% CI: 5.7-12.3), respectively. In patients who had received previous therapy, clinical usefulness was evaluated resulting in response rate of 14%, disease control rate of 28.5%, and median overall survival of 4 months (95% CI: 3.1-4.9). The principal grade 3/4 adverse events were neutropenia (20%), anemia (14%). No neutropenic fever or treatment-related deaths. Capecitabine in combination with cisplatin is effective and well tolerated as first-line treatment in patients with advanced gastric cancer. Unfortunately, we could not positively suggest the usefulness of the same combination regimen as salvage therapy in patients with progressive or recurrent disease after nonplatinum-based therapy.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Adulto , Idoso , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Gastrectomia , Gastroenteropatias/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Cuidados Paliativos , Indução de Remissão , Terapia de Salvação , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgiaRESUMO
Using sex-sorted semen to produce offspring of desired sex is associated with reduced developmental competence in vitro and lower fertility rates in vivo. The objectives of the present study were to investigate the effects of exogenous follistatin supplementation on the developmental competence of bovine embryos produced with sex-sorted semen and possible link between TGF-ß regulated pathways and embryotrophic actions of follistatin. Effects of follistatin on expression of cell lineage markers (CDX2 and Nanog) and downstream targets of SMAD signaling (CTGF, ID1, ID2 and ID3) and AKT phosphorylation were investigated. Follistatin was supplemented during the initial 72â¯h of embryo culture. Exogenous follistatin restored the in vitro developmental competence of embryos produced with sex-sorted semen to the levels of control embryos produced with unsorted semen, and comparable results were obtained using sorted semen from three different bulls. The mRNA abundance for SMAD signaling downstream target genes, CTGF (SMAD 2/3 pathway) and ID2 (SMAD 1/5 pathway), was lower in blastocysts produced using sex-sorted versus unsorted semen, but mRNA levels for CDX2, NANOG, ID1 and ID3 were similar in both groups. Follistatin supplementation restored CTGF and ID2 mRNA in blastocysts produced using sex-sorted semen to levels of control embryos. Moreover, levels of phosphorylated (p)AKT (Ser-473 and Thr-308) were similar in embryos derived from sex-sorted and unsorted semen, but follistatin treatment increased pAKT levels in both groups. Taken together, results demonstrated that follistatin improves in vitro development of embryos produced with sex-sorted semen and such effects are associated with enhanced indices of SMAD signaling.
Assuntos
Técnicas de Cultura Embrionária/veterinária , Desenvolvimento Embrionário/efeitos dos fármacos , Fertilização in vitro/veterinária , Folistatina/farmacologia , Sêmen , Animais , Bovinos , Desenvolvimento Embrionário/fisiologia , Feminino , Masculino , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
In the past few years, basic and clinical scientists have witnessed landmark achievements in many research projects, such as those conducted by the US National Institutes of Health Roadmap Epigenomics Mapping Consortium, the International Human Epigenome Consortium, The Cancer Genome Atlas Network and the International Cancer Genome Consortium, which have provided near-complete resolution of epigenetic landscape in different diseases. Furthermore, genome sequencing of tumors has provided compelling evidence related to frequent existence of mutations in readers, erasers and writers of epigenome in different cancers. Histone acetylation is an intricate mechanism modulated by two opposing sets of enzymes and deeply studied as a key biological phenomenon in 1964 by Vincent Allfrey and colleagues. The research group suggested that this protein modification contributed substantially in transcriptional regulation. Subsequently, histone deacetylases (HDACs), histone acetyltransferases and acetyl-Lys-binding proteins were identified as transcriptional mediators, which further deepened our comprehension regarding biochemical modifications. Overwhelmingly increasing high-impact research is improving our understanding of this molecularly controlled mechanism; moreover, quantification and identification of lysine acetylation by mass spectrometry has added new layers of information. We partition this multi-component review into how both activity and expression of HDAC are targeted using natural agents. We also set spotlight on how oncogenic fusion proteins tactfully utilize HDAC-associated nano-machinery to modulate expression of different genes and how HDAC inhibitors regulate TRAIL-induced apoptosis in cancer cells. HDAC inhibitors have been reported to upregulate expression of TRAIL receptors and protect TRAIL from proteasomal degradation. Deeper understanding of HDAC biology will be useful for stratification and selection of patients who are responders, non-responders and poor-responders for HDACi therapy, and for the rational design of combination studies using HDACi.