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Antibiotic responses in bacteria are highly dynamic and heterogeneous, with sudden exposure of bacterial colonies to high drug doses resulting in the coexistence of recovered and arrested cells. The dynamics of the response is determined by regulatory circuits controlling the expression of resistance genes, which are in turn modulated by the drug's action on cell growth and metabolism. Despite advances in understanding gene regulation at the molecular level, we still lack a framework to describe how feedback mechanisms resulting from the interdependence between expression of resistance and cell metabolism can amplify naturally occurring noise and create heterogeneity at the population level. To understand how this interplay affects cell survival upon exposure, we constructed a mathematical model of the dynamics of antibiotic responses that links metabolism and regulation of gene expression, based on the tetracycline resistancetetoperon inE. coli. We use this model to interpret measurements of growth and expression of resistance in microfluidic experiments, both in single cells and in biofilms. We also implemented a stochastic model of the drug response, to show that exposure to high drug levels results in large variations of recovery times and heterogeneity at the population level. We show that stochasticity is important to determine how nutrient quality affects cell survival during exposure to high drug concentrations. A quantitative description of how microbes respond to antibiotics in dynamical environments is crucial to understand population-level behaviors such as biofilms and pathogenesis.
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Antibacterianos , Farmacorresistência Bacteriana , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/genética , Tetraciclina , Bactérias , Modelos TeóricosRESUMO
Natural product ring distortion strategies have enabled rapid access to unique libraries of stereochemically complex compounds to explore new chemical space and increase our understanding of biological processes related to human disease. Herein is described the development of a ring-cleavage strategy using the indole alkaloids yohimbine, apovincamine, vinburnine, and reserpine that were reacted with a diversity of chloroformates paired with various alcohol/thiol nucleophiles to enable the rapid synthesis of 47 novel small molecules. Ring cleavage reactions of yohimbine and reserpine produced two diastereomeric products in moderate to excellent yields, whereas apovincamine and vinburnine produced a single diastereomeric product in significantly lower yields. Free energy calculations indicated that diastereoselectivity regarding select ring cleavage reactions from yohimbine and apovincamine is dictated by the geometry and three-dimensional structure of reactive cationic intermediates. These compounds were screened for antiplasmodial activity due to the need for novel antimalarial agents. Reserpine derivative 41 was found to exhibit interesting antiplasmodial activities against Plasmodium falciparum parasites (EC50 = 0.50 µM against Dd2 cultures), while its diastereomer 40 was found to be three-fold less active (EC50 = 1.78 µM). Overall, these studies demonstrate that the ring distortion of available indole alkaloids can lead to unique compound collections with re-engineered biological activities for exploring and potentially treating human disease.
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Previously described approaches for the alkylation of NH-sulfoximines typically rely either on transition metal catalysis, or the use of traditional alkylation reagents and strong bases. Herein, we report a straightforward alkylation of diverse NH-sulfoximines under simple Mitsunobu-type conditions, despite the unusually high pKa of the NH center.
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Human fungal infections may fail to respond to contemporary antifungal therapies in vivo despite in vitro fungal isolate drug susceptibility. Such a discrepancy between in vitro antimicrobial susceptibility and in vivo treatment outcomes is partially explained by microbes adopting a drug-resistant biofilm mode of growth during infection. The filamentous fungal pathogen Aspergillus fumigatus forms biofilms in vivo, and during biofilm growth it has reduced susceptibility to all three classes of contemporary antifungal drugs. Specific features of filamentous fungal biofilms that drive antifungal drug resistance remain largely unknown. In this study, we applied a fluorescence microscopy approach coupled with transcriptional bioreporters to define spatial and temporal oxygen gradients and single-cell metabolic activity within A. fumigatus biofilms. Oxygen gradients inevitably arise during A. fumigatus biofilm maturation and are both critical for, and the result of, A. fumigatus late-stage biofilm architecture. We observe that these self-induced hypoxic microenvironments not only contribute to filamentous fungal biofilm maturation but also drive resistance to antifungal treatment. Decreasing oxygen levels toward the base of A. fumigatus biofilms increases antifungal drug resistance. Our results define a previously unknown mechanistic link between filamentous fungal biofilm physiology and contemporary antifungal drug resistance. Moreover, we demonstrate that drug resistance mediated by dynamic oxygen gradients, found in many bacterial biofilms, also extends to the fungal kingdom. The conservation of hypoxic drug-resistant niches in bacterial and fungal biofilms is thus a promising target for improving antimicrobial therapy efficacy.
Assuntos
Antifúngicos/farmacologia , Aspergillus fumigatus , Biofilmes/efeitos dos fármacos , Microambiente Celular , Farmacorresistência Fúngica , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/fisiologia , Hipóxia Celular , Microambiente Celular/efeitos dos fármacos , Microambiente Celular/fisiologia , Oxigênio/farmacologiaRESUMO
In the past 25 years, a number of efforts have been made toward the development of small molecule interleukin-6 (IL-6) signaling inhibitors, but none have been approved to date. Monosaccharides are a diverse class of bioactive compounds, but thus far have been unexplored as a scaffold for small molecule IL-6-signaling inhibitor design. Therefore, in this present communication, we combined a structure-based drug design approach with carbohydrate building blocks to design and synthesize novel IL-6-signaling inhibitors targeting glycoprotein 130 (gp130). Of this series of compounds, LS-TG-2P and LS-TF-3P were the top lead compounds, displaying IC50 values of 6.9 and 16 µM against SUM159 cell lines, respectively, while still retaining preferential activity against the IL-6-signaling pathway. The carbohydrate moiety was found to improve activity, as N-unsubstituted triazole analogues of these compounds were found to be less active in vitro compared to the leads themselves. Thus, LS-TG-2P and LS-TF-3P are promising scaffolds for further development and study as IL-6-signaling inhibitors.
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Antineoplásicos , Interleucina-6 , Antineoplásicos/farmacologia , Carboidratos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Interleucina-6/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Transdução de Sinais , Relação Estrutura-Atividade , HumanosRESUMO
Cellular responses to the presence of toxic compounds in their environment require prompt expression of the correct levels of the appropriate enzymes, which are typically regulated by transcription factors that control gene expression for the duration of the response. The characteristics of each response dictate the choice of regulatory parameters such as the affinity of the transcription factor to its binding sites and the strength of the promoters it regulates. Although much is known about the dynamics of cellular responses, we still lack a framework to understand how different regulatory strategies evolved in natural systems relate to the selective pressures acting in each particular case. Here, we analyze a dynamical model of a typical antibiotic response in bacteria, where a transcriptionally repressed enzyme is induced by a sudden exposure to the drug that it processes. We identify strategies of gene regulation that optimize this response for different types of selective pressures, which we define as a set of costs associated with the drug, enzyme, and repressor concentrations during the response. We find that regulation happens in a limited region of the regulatory parameter space. While responses to more costly (toxic) drugs favor the usage of strongly self-regulated repressors, responses where expression of enzyme is more costly favor the usage of constitutively expressed repressors. Only a very narrow range of selective pressures favor weakly self-regulated repressors. We use this framework to determine which costs and benefits are most critical for the evolution of a variety of natural cellular responses that satisfy the approximations in our model and to analyze how regulation is optimized in new environments with different demands.
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Regulação da Expressão Gênica , Fatores de Transcrição , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Sítios de Ligação , Regiões Promotoras Genéticas , Bactérias/genética , Regulação Bacteriana da Expressão GênicaRESUMO
INTRODUCTION: Respiratory tract infections are a worldwide health problem for humans and animals. Different cell types produce lipid mediators in response to infections, which consist of eicosanoids like hydroxyeicosatetraenoic acids (HETEs) or oxylipins like hydroxydocosahexaenoic acids (HDHAs). Both substance classes possess immunomodulatory functions. However, little is known about their role in respiratory infections. OBJECTIVES: Here, we aimed to analyze the lipid mediator imprint of different organs of C57BL/6J mice after intranasal mono-infections with Streptococcus pneumoniae (pneumococcus), Staphylococcus aureus or Influenza A virus (IAV) as wells as pneumococcal-IAV co-infection. METHODS: C57BL/6J mice were infected with different pathogens and lungs, spleen, and plasma were collected. Lipid mediators were analyzed using HPLC-MS/MS. In addition, spatial-distribution of sphingosine 1-phosphate (S1P) and ceramide 1-phosphates (C1P) in tissue samples was examined using MALDI-MS-Imaging. The presence of bacterial pathogens in the lung was confirmed via immunofluorescence staining. RESULTS: We found IAV specific changes for different HDHAs and HETEs in mouse lungs as well as enhanced levels of 20-HETE in severe S. aureus infection. Moreover, MALDI-MS-Imaging analysis showed an accumulation of C1P and a decrease of S1P during co-infection in lung and spleen. Long chain C1P was enriched in the red and not in the white pulp of the spleen. CONCLUSIONS: Lipid mediator analysis showed that host synthesis of bioactive lipids is in part specific for a certain pathogen, in particular for IAV infection. Furthermore, MS-Imaging displayed great potential to study infections and revealed changes of S1P and C1P in lungs and spleen of co-infected animals, which was not described before.
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Coinfecção , Vírus da Influenza A , Infecções Respiratórias , Animais , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Staphylococcus aureus , Streptococcus pneumoniae , Espectrometria de Massas em TandemRESUMO
In experimental evolution, scientists evolve organisms in the lab, typically by challenging them to new environmental conditions. How best to evolve a desired trait? Should the challenge be applied abruptly, gradually, periodically, sporadically? Should one apply chemical mutagenesis, and do strains with high innate mutation rate evolve faster? What are ideal population sizes of evolving populations? There are endless strategies, beyond those that can be exposed by individual labs. We therefore arranged a community challenge, Evolthon, in which students and scientists from different labs were asked to evolve Escherichia coli or Saccharomyces cerevisiae for an abiotic stress-low temperature. About 30 participants from around the world explored diverse environmental and genetic regimes of evolution. After a period of evolution in each lab, all strains of each species were competed with one another. In yeast, the most successful strategies were those that used mating, underscoring the importance of sex in evolution. In bacteria, the fittest strain used a strategy based on exploration of different mutation rates. Different strategies displayed variable levels of performance and stability across additional challenges and conditions. This study therefore uncovers principles of effective experimental evolutionary regimens and might prove useful also for biotechnological developments of new strains and for understanding natural strategies in evolutionary arms races between species. Evolthon constitutes a model for community-based scientific exploration that encourages creativity and cooperation.
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Evolução Biológica , Escherichia coli/metabolismo , Humanos , Modelos Genéticos , Mutação/genética , Saccharomyces cerevisiae/metabolismo , TemperaturaRESUMO
Inhibitors of gamma-glutamyl transpeptidase (GGT1, aka gamma-glutamyl transferase) are needed for the treatment of cancer, cardiovascular illness and other diseases. Compounds that inhibit GGT1 have been evaluated in the clinic, but no inhibitor has successfully demonstrated specific and systemic GGT1 inhibition. All have severe side effects. L-2-amino-4boronobutanoic acid (l-ABBA), a glutamate analog, is the most potent GGT1 inhibitor in vitro. In this study, we have solved the crystal structure of human GGT1 (hGGT1) with ABBA bound in the active site. The structure was interrogated to identify interactions between the enzyme and the inhibitor. Based on these data, a series of novel ABBA analogs were designed and synthesized. Their inhibitory activity against the hydrolysis and transpeptidation activities of hGGT1 were determined. The lead compounds were crystalized with hGGT1 and the structures solved. The kinetic data and structures of the complexes provide new insights into the critical role of protein structure dynamics in developing compounds for inhibition of hGGT1.
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Compostos de Boro , gama-Glutamiltransferase , Domínio Catalítico , Ácido Glutâmico , Humanos , gama-Glutamiltransferase/metabolismoRESUMO
HER2 (ERBB2) gene status serves as a strong predictive marker of response to HER2-targeted agents in invasive breast cancers, albeit with heterogeneous response. Our aim was to determine the distribution and prognosis of HER2 groups by fluorescent in situ hybridization (FISH) using the updated 2018 American Society of Clinical Oncology-College of American Pathologist (ASCO-CAP) guidelines. We identified 226 cases of equivocal or positive HER2 FISH invasive breast cancer (interpreted by ASCO-CAP guidelines at the time of reporting) who received HER2-targeted agents from 2006 to 2017. We subcategorized Group 1 further into three subgroups: low amplified (HER2/CEP17 ratio ≥ 2.0-2.99, mean HER2/cell 4.0-5.9), amplified (HER2/CEP17 ratio ≥ 2.0-2.99, mean HER2/cell ≥ 6), and excessive amplification (HER2/CEP17 ratio ≥ 3.0, mean HER2/cell ≥ 4.0). Outcomes studied were recurrence, metastasis, second breast primary, disease-specific survival (DSS), and overall survival (OS). Univariate analysis showed that the five categories of HER2 FISH were significantly associated with OS (p < 0.01), specifically higher HER2 amplification was associated with fewer deaths. HER2 FISH status also statistically significantly relates to DFS (p < 0.01) and metastasis (p = 0.01) but not with recurrence or second breast primary in our study. Tumor type and HER2 ISH Groups are independent predictors for both OS and DFS in our cohort. The proposed Group 1 subcategories were significantly associated with OS (p < 0.01) and DFS (p < 0.01), excessive HER2 amplification was associated with longer median survival. The Cox regression models showed better survival outcomes for the excessive amplification subgroup than the low amplified subgroup, with OS (hazard ratio = 0.63, 95% CI 0.42-0.93) and DFS (HR = 0.55, 95% CI 0.37-0.83). We demonstrated that in HER2 FISH Group 1 patients, high HER2 amplification was significantly associated with longer OS and DFS; these patients seem to benefit more from HER2-targeted regimens. We recommend reporting these Group 1 subcategories when assessing HER2 FISH.
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Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Hibridização in Situ Fluorescente , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Tomada de Decisão Clínica , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Invasividade Neoplásica , Recidiva Local de Neoplasia , Valor Preditivo dos Testes , Receptor ErbB-2/genética , Estudos Retrospectivos , Fatores de TempoRESUMO
BACKGROUND: Expression profiles of erythroblast transformation-specific (ETS)-related gene fusions and serine protease inhibitor Kazal-type 1 (SPINK1) in early onset prostate cancer have not been thoroughly explored. METHODS: We retrieved 151 radical prostatectomy specimens from young men with prostate cancer (<55 years) and characterized the expression of ETS-related gene (ERG), SPINK1, ETS Variant 1 (ETV1), and ETV4 by dual immunohistochemistry and dual RNA in situ hybridization. Age, race, family history, preoperative prostate-specific antigen, biochemical recurrence, and pathological variables using whole-mount radical prostatectomy tissue were collected. RESULTS: A total of 313 tumor nodules from 151 men including 68 (45%) Caucasians and 61 (40%) African Americans were included in the analysis. Positive family history of prostate cancer was seen in 65 (43%) patients. Preoperative prostate-specific antigen ranged from 0.3 to 52.7 ng/mL (mean = 7.04). The follow-up period ranged from 1 to 123.7 months (mean = 30.3). Biochemical recurrence was encountered in 8 of 151 (5%). ERG overexpression was observed in 85 of 151 (56%) cases, followed by SPINK1 in 61 of 151 (40%), ETV1 in 9 of 149 (6%), and ETV4 in 4 of 141 (3%). There were 25 of 151 (17%) cases showing both ERG and SPINK1 overexpression within different regions of either the same tumor focus or different foci. Higher frequency of ERG overexpression was seen in younger patients (≤45 years old; 76% vs 49%, P = .002), Caucasian men (71% vs 41% P = .0007), organ-confined tumors (64% vs 33%, P = .0008), and tumors of Gleason Grade groups 1 and 2 (62% vs 26%, P = .009). SPINK1 overexpression was more in African American men (68% vs 26%, P = .00008), in tumors with high tumor volume (>20%) and with anterior located tumors. ETV1 and ETV4 demonstrated rare overexpression in these tumors, particularly in the higher-grade tumors. CONCLUSION: This study expands the knowledge of the clonal evolution of multifocal cancer in young patients and support differences in relation to racial background and genetics of prostate cancer.
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Proteínas de Ligação a DNA/genética , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-ets/genética , Fatores de Transcrição/genética , Inibidor da Tripsina Pancreática de Kazal/genética , Adulto , Proteínas de Ligação a DNA/sangue , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Prostatectomia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Proteínas Proto-Oncogênicas c-ets/biossíntese , Fatores de Transcrição/sangue , Regulador Transcricional ERG/biossíntese , Regulador Transcricional ERG/genética , Inibidor da Tripsina Pancreática de Kazal/biossínteseRESUMO
The phosphorelay of Bacillus subtilis, a kinase cascade that activates master regulator Spo0A ~ P in response to starvation signals, is the core of a large network controlling the cell's decision to differentiate into sporulation and other phenotypes. This article reviews recent advances in understanding the origins and purposes of the complex dynamical behavior of the phosphorelay, which pulses with peaks of activity coordinated with the cell cycle. The transient imbalance in the expression of two critical genes caused by their strategic placement at opposing ends of the chromosome proved to be the key for this pulsed behavior. Feedback control loops in the phosphorelay use these pulses to implement a timer mechanism, which creates several windows of opportunity for phenotypic transitions over multiple generations. This strategy allows the cell to coordinate multiple differentiation programs in a decision process that fosters phenotypic diversity and adapts to current conditions.
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Bacillus subtilis/metabolismo , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Proteínas Quinases/metabolismo , Esporos Bacterianos/metabolismo , Fatores de Transcrição/metabolismo , Bacillus subtilis/efeitos dos fármacos , Bacillus subtilis/genética , Proteínas de Bactérias/genética , Cromossomos Bacterianos/química , Cromossomos Bacterianos/metabolismo , Meios de Cultura/química , Meios de Cultura/farmacologia , Retroalimentação Fisiológica , Periodicidade , Fenótipo , Fosforilação , Proteínas Quinases/genética , Transdução de Sinais , Esporos Bacterianos/efeitos dos fármacos , Esporos Bacterianos/genética , Fatores de Transcrição/genéticaRESUMO
Endometrial carcinomas (ECs) are the most common gynecologic cancers in the western world. The impact of androgen receptor (AR) on clinicopathologic parameters of EC is not well studied. The aim of our study is to assess the role of AR expression in ECs and correlate its expression with estrogen (ER) and progesterone (PR). A retrospective review of 261 EC was conducted. H&E slides were reviewed and clinicopathologic parameters were analyzed. Immunohistochemical stains for AR, ER, and PR were performed on a tissue microarray. The hormonal expression was evaluated and the data were analyzed using the Fisher exact test and Kaplan-Meier survival analysis. Patients' age ranged from 31 to 91 (median=65 y). Type I EC included 202 endometrioid and 7 mucinous carcinoma, whereas type II included 34 serous, 16 carcinosarcoma, and 2 clear cell carcinoma. Although not significant, AR expression showed more frequent association with type I EC, early tumor stage (I-II), and low FIGO grade (1-2) EC. AR expression significantly correlated with absence of lymphovascular invasion (P=0.041) and decreased LN involvement (P=0.048). Patients with AR expression showed increased disease-free survival (208 vs. 165 mo, P=0.008) and late disease recurrence (P=0.009). AR expression had a positive significant correlation with PR (P<0.001) and ER (P=0.037) expression. AR might play a role as a prognostic marker for ECs.
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Biomarcadores Tumorais/metabolismo , Neoplasias do Endométrio/metabolismo , Receptores Androgênicos/metabolismo , Intervalo Livre de Doença , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
To analyze the clinical significance of the extent of lymphovascular space invasion (LVI) in patients with uterine serous carcinoma. After IRB approval, 232 patients with uterine serous carcinoma from the pathology databases of 4 large academic institutions were included. Patients were divided into 3 groups based on extent of LVI. Extensive LVI (E-LVI) was defined as ≥3 vessel involvement; low LVI (L-LVI) was defined <3 vessel involvement; and the third group consisted of tumors with no LVI (A-LVI). The association between LVI and myometrial invasion, cervical involvement, lower uterine segment involvement, positive peritoneal washings, lymph node involvement, stage, and survival were analyzed. Of 232 patients, 47 had E-LVI (20.3%), 83 had L-LVI (35.8%), and 102 had A-LVI (44%). A total of 9.8% of the patients with A-LVI had lymph node involvement as compared with 18.1% in the L-LVI group and 55.4% in the E-LVI group (P<0.0001). Fifty-nine percent of the patients in A-LVI, 85% in L-LVI, and 100% in the E-LVI group demonstrated myometrial invasion (P<0.0001). Cervical involvement was noted in 23%, 43%, 66% (P<0.0001) and lower uterine segment involvement involvement in 31%, 43%, and 42% of A-LVI, L-LVI, and E-LVI (P<0.0001), respectively. Stage III and IV disease were seen in 29%, 38%, and 79% of the patients with A-LVI, L-LVI, and E-LVI, respectively (P<0.0001). The median overall survival was 172, 95, and 39 mo for the A-LVI, L-LVI, and E-LVI groups, respectively (P<0.0001). The racial distribution was significant with African American patients demonstrating significantly more L-LVI (27.8%) and E-LVI (40.4%) when compared with A-LVI (19.6%) (P=0.040). In a subgroup analysis including patients with Stage I and II (n=123) revealed median survivals of 172, 169, and 38 mo in the A-LVI, L-LVI, and E-LVI groups, respectively (P<0.0001). Fifty percent of these patients with E-LVI, 20% in L-LVI group, and 15% in A-LVI group had disease recurrence (P=0.040). The extent of LVI was associated with multiple pathologic factors and was found to be a negative prognostic factor for overall survival and disease recurrence.
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Sistema Cardiovascular/patologia , Sistema Linfático/patologia , Neoplasias Císticas, Mucinosas e Serosas/diagnóstico , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/diagnóstico , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Císticas, Mucinosas e Serosas/mortalidade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Neoplasias Uterinas/mortalidade , Útero/patologiaAssuntos
Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/patologia , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/patologia , Ducto Hepático Comum/patologia , Icterícia Obstrutiva/diagnóstico , Icterícia Obstrutiva/patologia , Adulto , Citodiagnóstico/métodos , Feminino , HumanosRESUMO
We assessed the consumer food environment in rural areas by using the Nutrition Environment Measures Survey for Stores (NEMS-S) to measure the availability, price, and quality of fruits and vegetables. We randomly selected 20 grocery stores (17 rural, 3 urban) in 12 Montana counties using the 2013 US Department of Agriculture's rural-urban continuum codes. We found significant differences in NEMS-S scores for quality of fruits and vegetables; of 6 possible points, the mean quality score was 4.5; of rural stores, the least rural stores had the highest mean quality scores (6.0). Intervention strategies should aim to increase fruit and vegetable quality in rural areas.
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Abastecimento de Alimentos/normas , Frutas/normas , População Rural/estatística & dados numéricos , População Urbana/estatística & dados numéricos , Verduras/normas , Adulto , Idoso , Análise de Variância , Doença Crônica/prevenção & controle , Comércio/estatística & dados numéricos , Assistência Alimentar/estatística & dados numéricos , Abastecimento de Alimentos/classificação , Abastecimento de Alimentos/economia , Frutas/economia , Frutas/provisão & distribuição , Humanos , Montana , Inquéritos Nutricionais/métodos , Valor Nutritivo , Pobreza/estatística & dados numéricos , População Rural/classificação , Fatores Socioeconômicos , Estados Unidos , United States Department of Agriculture , População Urbana/classificação , Verduras/economia , Verduras/provisão & distribuiçãoRESUMO
OBJECTIVE: There are known disparities in endometrial cancer survival with black women who experience a greater risk of death compared with white women. The purpose of this investigation was to evaluate the role of comorbid conditions as modifiers of endometrial cancer survival by race. STUDY DESIGN: Two hundred seventy-one black women and 356 white women who had been diagnosed with endometrial cancer from 1990-2005 were identified from a large urban integrated health center. A retrospective chart review was conducted to gather information on comorbid conditions and other known demographic and clinical predictors of survival. RESULTS: Black women experienced a higher hazard of death from any cause (hazard ratio [HR] 1.51; 95% confidence interval [CI], 1.22-1.87) and from endometrial cancer (HR, 2.42; 95% CI, 1.63-3.60). After adjustment for known clinical prognostic factors and comorbid conditions, the hazard of death for black women was elevated but no longer statistically significant for overall survival (HR, 1.22; 95% CI, 0.94-1.57), and the hazard of death from endometrial cancer remained significantly increased (HR, 2.27; 95% CI, 1.39-3.68). Both black and white women with a history of hypertension experienced a lower hazard of death from endometrial cancer (HR, 0.47; 95% CI, 0.23-0.98; and HR, 0.35; 95% CI, 0.19-0.67, respectively). CONCLUSION: The higher prevalence of comorbid conditions among black women does not explain fully the racial disparities that are seen in endometrial cancer survival. The association between hypertension and a lower hazard of death from endometrial cancer is intriguing, and further investigation into the underlying mechanism is needed.
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Adenocarcinoma/mortalidade , Negro ou Afro-Americano/estatística & dados numéricos , Diabetes Mellitus/epidemiologia , Neoplasias do Endométrio/mortalidade , Hipertensão/epidemiologia , Obesidade/epidemiologia , População Branca/estatística & dados numéricos , Adenocarcinoma/epidemiologia , Adenocarcinoma/etnologia , Adenocarcinoma de Células Claras/epidemiologia , Adenocarcinoma de Células Claras/etnologia , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma Mucinoso/epidemiologia , Adenocarcinoma Mucinoso/etnologia , Adenocarcinoma Mucinoso/mortalidade , Idoso , Carcinoma Endometrioide/epidemiologia , Carcinoma Endometrioide/etnologia , Carcinoma Endometrioide/mortalidade , Estudos de Coortes , Comorbidade , Intervalo Livre de Doença , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/etnologia , Feminino , Disparidades nos Níveis de Saúde , Humanos , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Proteção , Estudos Retrospectivos , Fatores de RiscoRESUMO
OBJECTIVES: This study aimed to determine the impact of tumor grade on patterns of recurrence and survival end points in patients with endometrioid carcinoma 2009 International Federation of Gynecology and Obstetrics stages I-II. METHODS: We identified 949 patients who underwent hysterectomy between 1988 and 2011. Patients were divided into 3 groups based on tumor grade. Kaplan-Meier plots were generated for each group for recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS). RESULTS: Median follow-up was 52 months. Median age was 60 years. All patients underwent total abdominal hysterectomy and salpingo-oophorectomy. Eighty percent of patients underwent lymph node dissection, 83% had peritoneal cytology. There were 76 (8%) patients who developed tumor recurrence. Tumor recurrence rates were significantly higher in patients with grade 3 tumors compared to grade 1 (P = 0.006). Additionally, patients with grade 3 tumors developed significantly more frequent distant metastases compared to patients with grade 1 (P = 0.002). Five-year RFS for the patients with grade 1, 2, and 3 were 95%, 82%, and 68%, respectively (P = <0.001). Five-year DSS was 99%, 93%, and 79%, respectively (P = <0.001). Five-year OS was 89%, 84%, and 63%, respectively (P = <0.001). Lymphovascular space involvement and grade were significant independent predictors of RFS and DSS. For OS age, lymphovascular space involvement, grade, and body mass index were significant predictors. CONCLUSIONS: International Federation of Gynecology and Obstetrics grade is a strong predictor of clinical survival end points in women with early-stage endometrioid carcinoma. The pattern of recurrence in patients with grade 3 tumors is mainly distant rather than locoregional. Further studies incorporating systemic therapy in the adjuvant settings in these patients are warranted.
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Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Genitália Feminina/patologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/mortalidade , Neoplasias do Endométrio/mortalidade , Feminino , Humanos , Michigan/epidemiologia , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Recidiva Local de Neoplasia/epidemiologia , Estudos RetrospectivosRESUMO
The lag phase of bacterial growth is important from a medical and food safety perspective, but difficult to study due to the low density and metabolic rate of cells. A new study by Alon and colleagues reveals that the gene expression program during early lag phase prioritizes carbon source utilization enzymes over genes responsible for biomass accumulation. This cellular strategy ultimately maximizes growth, making the best long-term use of the new nutrient-rich environment.