RESUMO
Akt kinase plays a central role in cell growth, metabolism, and tumorigenesis. The TRAF6 E3 ligase orchestrates IGF-1-mediated Akt ubiquitination and activation. Here, we show that Akt ubiquitination is also induced by activation of ErbB receptors; unexpectedly, and in contrast to IGF-1 induced activation, the Skp2 SCF complex, not TRAF6, is a critical E3 ligase for ErbB-receptor-mediated Akt ubiquitination and membrane recruitment in response to EGF. Skp2 deficiency impairs Akt activation, Glut1 expression, glucose uptake and glycolysis, and breast cancer progression in various tumor models. Moreover, Skp2 overexpression correlates with Akt activation and breast cancer metastasis and serves as a marker for poor prognosis in Her2-positive patients. Finally, Skp2 silencing sensitizes Her2-overexpressing tumors to Herceptin treatment. Our study suggests that distinct E3 ligases are utilized by diverse growth factors for Akt activation and that targeting glycolysis sensitizes Her2-positive tumors to Herceptin treatment.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Transformação Celular Neoplásica , Proteínas F-Box/metabolismo , Glicólise , Proteínas Quinases Associadas a Fase S/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Neoplasias da Mama/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Camundongos , Receptor ErbB-2/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Trastuzumab , UbiquitinaçãoRESUMO
OBJECTIVE: To assess if evidence of disparities exists in functional recovery and social health post-lower limb amputation. DESIGN: Race-ethnicity, gender, and income-based group comparisons of functioning and social health in a convenience sample of lower limb prosthetic users. SETTING: Prosthetic clinics in 4 states. PARTICIPANTS: A geographically diverse cohort of 56 English and Spanish speaking community-dwelling individuals with dysvascular lower limb amputation, between 18-80 years old. INTERVENTIONS: None. MAIN OUTCOMES MEASURES: Primary outcomes included 2 physical performance measures, the Timed Up and Go test and 2-minute walk test, and thirdly, the Prosthetic Limb Users Survey of Mobility. The PROMIS Ability to Participate in Social Roles and Activities survey measured social health. RESULTS: Of the study participants, 45% identified as persons of color, and 39% were women (mean ± SD age, 61.6 (9.8) years). People identifying as non-Hispanic White men exhibited better physical performance than men of color, White women, and women of color by -7.86 (95% CI, -16.26 to 0.53, P=.07), -10.34 (95% CI, -19.23 to -1.45, P=.02), and -11.63 (95% CI, -21.61 to -1.66, P=.02) seconds, respectively, on the TUG, and by 22.6 (95% CI, -2.31 to 47.50, P=.09), 38.92 (95% CI, 12.53 to 65.30, P<.01), 47.53 (95% CI, 17.93 to 77.13, P<.01) meters, respectively, on the 2-minute walk test. Income level explained 14% and 11% of the variance in perceived mobility and social health measures, respectively. CONCLUSIONS: Study results suggest that sociodemographic factors of race-ethnicity, gender, and income level are associated with functioning and social health post-lower limb amputation. The clinical effect of this new knowledge lies in what it offers to health care practitioners who treat this patient population, in recognizing potential barriers to optimal recovery and quality of life. More work is required to assess lived experiences after amputation and provide better understanding of amputation-related health disparities.
Assuntos
Amputados , Membros Artificiais , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Adulto , Idoso , Idoso de 80 Anos ou mais , Projetos Piloto , Qualidade de Vida , Equilíbrio Postural , Estudos Transversais , Etnicidade , Estudos de Tempo e Movimento , Amputação Cirúrgica , Extremidade Inferior/cirurgiaRESUMO
OBJECTIVE: To examine participants' experiences with peer-support after lower limb loss (LLL) and the associations between the peer-support experience (perceived benefits and barriers) and mobility outcomes. DESIGN: Quantitative and qualitative descriptive study with a cross-sectional design. SETTING: National survey (distributed to 169 peer-support groups in 44 states in the US). PARTICIPANTS: The survey was completed by 82 individuals with a major lower limb amputation (53% female, 54% over 55 years of age; N=82). MAIN OUTCOME MEASURES: A 32-item survey to examine respondents' experiences in peer-support activities. Prosthetic mobility was measured using the Prosthetic Limb Users Survey of Mobility (PLUS-M). RESULTS: Two out of 3 respondents received some forms of peer-support after amputation. Among them 75% reported peer-support having a positive effect on their outlook on life, and 78% reported that information gained from peer-support was helpful. Companionship, altruistic acts, and gaining information on how to cope with amputation were the top themes of why respondents enjoyed the peer-support experience. Nearly all (94%) respondents would recommend peer-support to other people with LLL. Individuals who received peer-support exhibited a trend of greater mobility (55th vs 36th percentile on PLUS-M; P=.055). CONCLUSION: Individuals with LLL reported generally positive experiences regarding their engagement in peer-support activities. Peer-support groups are viewed as a helpful source for both information and emotional support, potentially benefiting functional and psychological recovery after amputation. Individuals who have received peer-support also exhibited greater mobility.
Assuntos
Membros Artificiais , Extremidade Inferior , Grupo Associado , Apoio Social , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Transversais , Estados Unidos , Membros Artificiais/psicologia , Extremidade Inferior/cirurgia , Idoso , Adulto , Amputação Cirúrgica/reabilitação , Amputação Cirúrgica/psicologia , Amputados/reabilitação , Amputados/psicologia , Limitação da Mobilidade , Grupos de AutoajudaRESUMO
GPI-anchored folate receptor α (FRα) is an attractive anticancer drug target and diagnosis marker in fundamental biology and medical research due to its significant expression on many cancer cells. Currently, analyses of FRα expression levels are usually achieved using immunological methods. Due to the continual FRα synthesis and degradation, immunological methods are not suitable for studying real-time dynamic activities of FRα in living cells. In this paper, we introduce a rapid and specific FRα protein-labeling fluorescent probe, FR1, to facilitate the study of the dynamics of expression and degradation processes of endogenous FRα in living cells. With this labeling probe, insights on FRα protein lifetime and shedding from the cell surface can be obtained using fluorescence live-cell imaging and electrophoresis techniques. We revealed that FRα undergoes soluble domain release and endocytosis degradation simultaneously. Imaging results showed that most of the membrane FRα are transported to the lysosomes after 2 h of incubation. Furthermore, we also showed that the secretion of a FRα soluble domain into the environment is most likely accomplished by phospholipase. We believe that this protein-labeling approach can be an important tool for analyzing various dynamic processes involving FRα.
Assuntos
Antineoplásicos , Receptor 1 de Folato , Receptor 1 de Folato/metabolismo , Corantes FluorescentesRESUMO
Adenosine-to-inosine (A-to-I) RNA editing is the most common posttranscriptional editing to create somatic mutations and increase proteomic diversity. However, the functions of the edited mutations are largely underexplored. To identify novel targets in lung adenocarcinoma (LUAD), we conducted a genome-wide somatic A-to-I RNA editing analysis of 23 paired adjacent normal and LUAD transcriptomes and identified 26,280 events, including known nonsynonymous AZIN1-S367G and novel RHOAiso2 (RHOA isoform 2)-R176G, tubulin gamma complex associated protein 2 (TUBGCP2)-N211S, and RBMXL1-I40 M mutations. We validated the edited mutations in silico in multiple databases and in newly collected LUAD tissue pairs with the SEQUENOM MassARRAY® and TaqMan PCR Systems. We selected RHOAiso2-R176G due to its significant level, isoform-specificity, and being the most common somatic edited nonsynonymous mutation of RHOAiso2 to investigate its roles in LUAD tumorigenesis. RHOAiso2 is a ubiquitous but low-expression alternative spliced isoform received a unique Alu-rich exon at the 3' RHOA mRNA to become an editing RNA target, leading to somatic hypermutation and protein diversity. Interestingly, LUAD patients harboring the RHOAiso2-R176G mutation were associated with aberrant RHOA functions, cancer cell proliferation and migration, and poor clinical outcomes in transcriptome analysis. Mechanistically, RHOAiso2-R176G mutation-expressing LUAD cells potentiate RHOA-guanosine triphosphate (GTP) activity to phosphorylate ROCK1/2 effectors and enhance cell proliferation and migration in vitro and increase tumor growth in xenograft and systemic metastasis models in vivo. Taken together, the RHOAiso2-R176G mutation is a common somatic A-to-I edited mutation of the hypermutated RHOA isoform 2. It is an oncogenic and isoform-specific theranostic target that activates RHOA-GTP/p-ROCK1/2 signaling to promote tumor progression.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , RNA , Proteômica , Adenosina , Adenocarcinoma de Pulmão/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Neoplasias Pulmonares/genética , Guanosina Trifosfato , Inosina , Mutação , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
LKB1 is activated by forming a heterotrimeric complex with STRAD and MO25. Recent studies suggest that LKB1 has pro-oncogenic functions, besides acting as a tumor suppressor. How the LKB1 activity is maintained and how LKB1 regulates cancer development are largely unclear. Here we show that K63-linked LKB1 polyubiquitination by Skp2-SCF ubiquitin ligase is critical for LKB1 activation by maintaining LKB1-STRAD-MO25 complex integrity. We further demonstrate that oncogenic Ras acts upstream of Skp2 to promote LKB1 polyubiquitination by activating Skp2-SCF ubiquitin ligase. Moreover, Skp2-mediated LKB1 polyubiquitination is required for energy-stress-induced cell survival. We also detected overexpression of Skp2 and LKB1 in late-stage hepatocellular carcinoma (HCC), and their overexpression predicts poor survival outcomes. Finally, we show that Skp2-mediated LKB1 polyubiquitination is important for HCC tumor growth in vivo. Our study provides new insights into the upstream regulation of LKB1 activation and suggests a potential target, the Ras/Skp2/LKB1 axis, for cancer therapy.
Assuntos
Neoplasias Hepáticas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Idoso , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Sobrevivência Celular , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/genética , Estudos Retrospectivos , Proteínas Quinases Associadas a Fase S/genética , Estresse Fisiológico , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
The regulation of RagA(GTP) is important for amino-acid-induced mTORC1 activation. Although GATOR1 complex has been identified as a negative regulator for mTORC1 by hydrolyzing RagA(GTP), how GATOR1 is recruited to RagA to attenuate mTORC1 signaling remains unclear. Moreover, how mTORC1 signaling is terminated upon amino acid stimulation is also unknown. We show that the recruitment of GATOR1 to RagA is induced by amino acids in an mTORC1-dependent manner. Skp2 E3 ligase drives K63-linked ubiquitination of RagA, which facilitates GATOR1 recruitment and RagA(GTP) hydrolysis, thereby providing a negative feedback loop to attenuate mTORC1 lysosomal recruitment and prevent mTORC1 hyperactivation. We further demonstrate that Skp2 promotes autophagy but inhibits cell size and cilia growth through RagA ubiquitination and mTORC1 inhibition. We thereby propose a negative feedback whereby Skp2-mediated RagA ubiquitination recruits GATOR1 to restrict mTORC1 signaling upon sustained amino acid stimulation, which serves a critical mechanism to maintain proper cellular functions.
Assuntos
Aminoácidos/farmacologia , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Autofagia/genética , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Retroalimentação Fisiológica/efeitos dos fármacos , Guanosina Trifosfato/metabolismo , Células HEK293 , Humanos , Immunoblotting , Lisina/metabolismo , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Knockout , Microscopia Confocal , Modelos Biológicos , Células NIH 3T3 , Ligação Proteica/efeitos dos fármacos , Interferência de RNA , Proteínas Quinases Associadas a Fase S/genética , Ubiquitinação/efeitos dos fármacosRESUMO
This study aims to describe the relationship between physical activity, suboptimal health status based on traditional Chinese medicine, and psychological health in older people in Taiwan. A total of 4,497 older individuals were selected from the Taiwan Biobank Research Database. Suboptimal health status was assessed using a body constitution questionnaire to measure yang deficiency, yin deficiency, and stasis. The results showed that older adults involved in physical activity had a lower likelihood of yang/yin deficiency and stasis constitutions than physically inactive people. Participants with yang deficiency or stasis constitutions had a higher likelihood of poor psychological health, whereas those with yin deficiency had a greater likelihood of depression. People involved in physical activity had a lower likelihood of depression than physically inactive people. Compared with male older adults, females had a lower percentage of physical activity habits, poorer body constitutions, and poorer psychological health.
Assuntos
Bancos de Espécimes Biológicos , Deficiência da Energia Yin , Feminino , Humanos , Masculino , Idoso , Medicina Tradicional Chinesa/métodos , Deficiência da Energia Yang , Constituição CorporalRESUMO
Vascular calcification (VC) is associated with cardiovascular disease. Baicalein, a natural flavonoid extract of Scutellaria baicalensis rhizome has several biological properties which may inhibit VC. We investigated whether baicalein suppresses Runt-related transcription factor 2 (Runx2) and bone morphogenetic protein 2 (BMP-2) and upregulates smooth muscle 22-alpha (SM22-α) and alpha-smooth muscle actin (α-SMA). In an in vitro experiment, primary rat aortic vascular smooth muscle cells (VSMCs) were pretreated with 0.1, 1, and 5 µM baicalein, followed by ß-glycerophosphate (ß-GP) to induce calcification. In an in vivo experiment, VC was generated by vitamin D3 plus nicotine (VDN) administration to male Sprague Dawley (SD) rats randomly assigned into a control group, a VC group, a VC group pretreated with baicalein, and a baicalein alone group. Each group comprised 10 rats. Left ventricular (LV) morphology, function and performance were assessed by echocardiography. Calcium content was measured by Alizarin red S staining and alkaline phosphatase (ALP) activity assays. Apoptotic VSMCs were detected by flow cytometry. Protein levels and superoxide changes were evaluated using Western blotting and immunofluorescence assays respectively. Plasma malondialdehyde (MDA) was assayed. Baicalein pretreatment significantly reduced calcium content in calcified VSMCs (p < 0.001) as well as in VC rat aortic smooth muscle (p < 0.001). Additionally, ALP activity was decreased in calcified VSMCs and VC rat aortic smooth muscle (p < 0.001). Apoptosis was significantly attenuated by 1 µM baicalein pretreatment in calcified VSMCs. Runx2 and BMP-2 expressions were downregulated by the baicalein in calcified VSMCs. Baicalein pretreatment increased typical VSMCs markers SM22-α and α-SMA in calcified VSMCs. Baicalein pretreatment was associated with adverse changes in LV morphometry. Markers of oxidative stress declined, and endogenous antioxidants increased in VC rats pretreated with baicalein. Baicalein mitigates VC through the inhibition of Runx2/BMP-2 signaling pathways, enhancement of vascular contractile phenotype and oxidative stress reduction. However, our study is of basic experimental design; more advanced investigations to identify other molecular regulators of VC and their mechanisms of action is required.
Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core , Calcificação Vascular , Animais , Cálcio/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Flavanonas , Masculino , Miócitos de Músculo Liso/metabolismo , Ratos , Ratos Sprague-Dawley , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/metabolismo , Calcificação Vascular/prevenção & controleRESUMO
BACKGROUND: Chronic kidney disease (CKD) introduces an increased cardiovascular risk among patients with diabetes mellitus (DM). The risk and tempo of cardiovascular diseases may differ depending upon their type. Whether CKD differentially influences the risk of developing each cardiovascular morbidity in patients with newly diagnosed DM remains unexplored. METHODS: We identified patients with incident DM from the Longitudinal Cohort of Diabetes Patients (LCDP) cohort (n = 429,616), and uncovered those developing CKD after DM and their propensity score-matched counterparts without. After follow-up, we examined the cardiovascular morbidity-free rates of patients with and without CKD after DM, followed by Cox proportional hazard regression analyses. We further evaluated the cumulative risk of developing each outcome consecutively during the study period. RESULTS: From LCDP, we identified 55,961 diabetic patients with CKD and matched controls without CKD. After 4.2 years, patients with incident DM and CKD afterward had a significantly higher risk of mortality (hazard ratio [HR] 1.1, 95% confidence interval [CI] 1.06-1.14), heart failure (HF) (HR 1.282, 95% CI 1.19-1.38), acute myocardial infarction (AMI) (HR 1.16, 95% CI 1.04-1.3), and peripheral vascular disease (PVD) (HR 1.277, 95% CI 1.08-1.52) compared to those without CKD. The CKD-associated risk of mortality, HF and AMI became significant soon after DM occurred and remained significant throughout follow-up, while the risk of PVD conferred by CKD did not emerge until 4 years later. The CKD-associated risk of ischemic, hemorrhagic stroke and atrial fibrillation remained insignificant. CONCLUSIONS: The cardiovascular risk profile among incident DM patients differs depending on disease type. These findings can facilitate the selection of an optimal strategy for early cardiovascular care for newly diagnosed diabetic patients.
Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Adulto , Idoso , Doenças Cardiovasculares/diagnóstico , Comorbidade , Bases de Dados Factuais , Diabetes Mellitus/diagnóstico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Pontuação de Propensão , Insuficiência Renal Crônica/diagnóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taiwan/epidemiologia , Fatores de TempoRESUMO
AIMS: Delirium, a form of acute brain failure, exhibits a high incidence among older adults. Recent studies have implicated frailty as an under-recognized complication of diabetes mellitus. Whether the presence of frailty increases the risk of delirium/cognitive impairment among patients with diabetic kidney disease (DKD) remains unclear. METHODS: From the longitudinal cohort of diabetes patients (LCDP) (n = 840,000) in Taiwan, we identified adults with DKD, dividing them into those without and with different severities of frailty based on a modified FRAIL scale. Cox proportional hazard regression was utilized to examine the frailty-associated risk of delirium/cognitive impairment, identified using approaches validated by others. RESULTS: Totally 149,145 patients with DKD (mean 61.0 years, 44.2% female) were identified, among whom 31.0%, 51.7%, 16.0% and 1.3% did not have or had 1, 2 and >2 FRAIL items at baseline. After 3.68 years, 6613 (4.4%) developed episodes of delirium/cognitive impairment. After accounting for demographic/lifestyle factors, co-morbidities, medications and interventions, patients with DKD and 1, 2 and >2 FRAIL items had a progressively higher risk of developing delirium/cognitive impairment than those without (for those with 1, 2 and >2 items, hazard ratio 1.18, 1.26 and 1.30, 95% confidence interval 1.08-1.28, 1.14-1.39 and 1.10-1.55, respectively). For every FRAIL item increase, the associated risk rose by 9%. CONCLUSIONS: Frailty significantly increased the risk of delirium/cognitive impairment among patients with DKD. Frailty screening in these patients may assist in delirium risk stratification.
Assuntos
Disfunção Cognitiva/epidemiologia , Delírio/epidemiologia , Nefropatias Diabéticas/epidemiologia , Fragilidade/epidemiologia , Idoso , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taiwan/epidemiologiaRESUMO
A series of phenylurea hydroxamic acids incorporating pharmacophores of inhibitors of HDAC inhibitors and VEGFR-2 has been designed. Most of the compounds show antiproliferative activity comparable to that of Vorinostat and Sorafenib, and better EPC inhibitory activity. Enzymatic assays and Western blotting results indicated that compound 14 not only inhibits HDAC but also has slight VEGFR-2 inhibitory activity. A docking study revealed that the polar hydroxamic acid retains the interaction with HDAC through a zinc ion and also interacts with some residues of the active site of VEGFR-2. Despite 14 displaying a weaker VEGFR-2 activity, a possible route to develop potent HDAC/VEGFR-2 inhibitors is suggested.
Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Estrutura Molecular , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Patients with diabetic mellitus (DM) and chronic kidney disease (CKD) are at an increased risk of urinary tract infection (UTI) due to their altered immunological integrity. These patients are similarly prone to developing frailty, a state of cumulative health deficits involving multiple domains and leading to adverse outcomes. Whether frailty predisposes affected individuals to UTI among patients with DM and CKD remains unclear. METHODS: A population-based cohort of patients with DM and CKD (n = 79,887) were assembled from the Longitudinal Cohort of Diabetes Patients, with their baseline frailty status measured by a modified FRAIL scale. We analyzed their risk of developing UTI depending on their severity of frailty, after accounting demographic profiles, lifestyle factors, comorbidities, concurrent medications, and major interventions. A secondary analysis focused on the risk of urosepsis related to frailty. RESULTS: Among all participants, 36.1 %, 50.3 %, 12.8 %, and 0.8 % did not have or had 1, 2, and ≥ 3 FRAIL items, respectively, at baseline. After 3.51 years, 11,175 UTI events occurred. Kaplan-Meier analysis showed that participants with DM, CKD and an increasing number of FRAIL items had successively higher incidence of UTI than those without any FRAIL items (log rank p < 0.001). Cox proportional hazard modeling revealed that after accounting for all confounders, those with more severe frailty exhibited a significantly higher risk of incident UTI (for groups of 1, 2, and ≥ 3 FRAIL items, hazard ratio 1.19, 1.24, and 1.43, respectively; all p < 0.001) than those without. An 11 % risk elevation for UTI could be observed for every FRAIL item increase. Participants with more severe frailty exhibited a trend of having higher risk of urosepsis as well. CONCLUSIONS: Having frailty predicted a higher risk of developing UTI in the future in patients with DM and CKD. It would be prudent to screen for frailty in these patients and provide optimal frailty-directed management to attenuate their risk of UTI and improve their outcomes.
Assuntos
Diabetes Mellitus , Fragilidade , Insuficiência Renal Crônica , Infecções Urinárias , Idoso , Estudos de Coortes , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Idoso Fragilizado , Fragilidade/diagnóstico , Fragilidade/epidemiologia , Humanos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Fatores de Risco , Infecções Urinárias/diagnóstico , Infecções Urinárias/epidemiologiaRESUMO
Nutrient stress driven by glutamine deficiency activates EGFR signaling in a subset of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cells. EGFR signaling in the context of glutamine starvation is thought to be instigated by the transcriptional upregulation of EGFR ligands and functions as an adaptation mechanism to allow PDAC cells to maintain metabolic fitness. Having a clear view of the intricate signaling cascades potentiated by the metabolic induction of EGFR is important in understanding how these effector pathways influence cancer progression. In this study, we examined the complex signaling that occurs in PDAC cells when EGFR is activated by glutamine deprivation. We elucidate that the metabolic activation of EGFR is principally mediated by HB-EGF, and that other members of the ErbB receptor tyrosine kinase family are not activated by glutamine starvation. Additionally, we determine that glutamine depletion-driven EGFR signaling is associated with a specific receptor phosphorylation known to participate in a feedback loop, a process that is dependent on Erk. Lastly, we determine that K-Ras is required for glutamine depletion-induced Erk activation, as well as EGFR feedback phosphorylation, but is dispensable for Akt activation. These data provide important insights into the regulation of EGFR signaling in the context of metabolic stresses.
Assuntos
Carcinoma Ductal Pancreático/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Carcinoma Ductal Pancreático/enzimologia , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Retroalimentação Fisiológica , Glutamina/fisiologia , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/fisiologia , Humanos , Sistema de Sinalização das MAP Quinases , Neoplasias Pancreáticas/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
The interplay between nutrient scarcity and signal transduction circuits is an important aspect of tumorigenesis that regulates many aspects of cancer progression. Glutamine is a critical nutrient for cancer cells, as it contributes to biosynthetic reactions that sustain cancer proliferation and growth. In tumors, because nutrient utilization can often outpace supply, glutamine levels can become limiting and oncogene-mediated metabolic rewiring triggers signaling cascades that support nutrient stress survival. Recently, we identified that in pancreatic ductal adenocarcinoma (PDAC) cells, glutamine depletion can trigger p21-activated kinase (Pak) activation through EGFR signaling as a means to circumvent metabolic stress. Here, we elucidate that glutamine starvation, as well EGF stimulation, can enhance the presence of many different Pak phosphoforms, and that this activation only occurs in a subset of PDAC cells. Pak is a well-established effector of Rac1, and while Rac1 mutant variants can modulate the metabolic induction of Pak phosphorylation, Rac1 inhibition only partially attenuates Pak activation upon glutamine depletion. We decipher that in order to efficiently suppress metabolic activation of Pak, both EGFR and Rac1 signaling must be inhibited. These results provide a mechanistic understanding of how glutamine-regulated signal transduction can control Pak activation in PDAC cells.
Assuntos
Carcinoma Ductal Pancreático/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais , Estresse Fisiológico , Quinases Ativadas por p21/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Carcinoma Ductal Pancreático/enzimologia , Ativação Enzimática , Glutamina/fisiologia , Humanos , Isoenzimas/metabolismo , Nutrientes , Neoplasias Pancreáticas/enzimologia , Fosforilação , Células Tumorais CultivadasRESUMO
Computational imaging with random encoding patterns obtained by scattering of light in complex media has enabled simple imaging systems with compelling performance. Here, we extend this concept to axial reflectivity profiling using spatio-temporal coupling of broadband light in a multimode fiber (MMF) to generate the encoding functions. Interference of light transmitted through the MMF with a sample beam results in path-length-specific patterns that enable computational reconstruction of the axial sample reflectivity profile from a single camera snapshot. Leveraging the versatile nature of MMFs, we demonstrate depth profiling with bandwidth-limited axial resolution of 13.4â µm over a scalable sensing range reaching well beyond one centimeter.
RESUMO
X-ray photoelectron spectroscopy, reflection-absorption infrared spectroscopy, and temperature-programmed reaction/desorption have been employed to investigate the adsorption and reaction pathways of CH2=CHCOOH and CH3CHFCOOH on Cu(100) and oxygen-precovered Cu(100) [O/Cu(100)]. In the case of CH2=CHCOOH on O/Cu(100), CH2=CHCOO is the surface intermediate detected between 110 K and 400 K. CH2=CHCOO is adsorbed vertically and can change adsorption sites at a higher temperature. The propenoate (acrylate) decomposes at higher temperatures (>500 K), with formation of >C=C=O (ketenylidene) surface species and gaseous products. On Cu(100), CH2=CHCOOH is adsorbed in dimer form and can dissociate to generate CH2=CHCOO and CH3CHCOO intermediates on the surface. The CH3CHCOO continuously recombines with the H from deprotonation of CH2=CHCOOH, resulting in the formation CH3CH2COO. The co-existing CH2=CHCOO and CH3CH2COO further decompose at â¼550 K to evolve reaction products, but without >C=C=O being detected. On O/Cu(100), CH3CHFCOOH readily deprotonates to form CH3CHFCOO at 120 K. This intermediate reacts on the surface at â¼460 K to evolve gaseous products, also producing CH2=CHCOO. In the case of Cu(100), deprotonation of CH3CHFCOOH occurs at â¼250 K, forming CH3CHFCOO. Without oxygen on the surface, this intermediate decomposes into HF and CH2=CHCOO at â¼455 K.
RESUMO
Lee, S-P, Gillis, CB, Ibarra, JJ, Oldroyd, DF, and Zane, RS. Heel-raised foot posture does not affect trunk and lower extremity biomechanics during a barbell back squat in recreational weight lifters. J Strength Cond Res 33(3): 606-614, 2019-It is claimed that weightlifting shoes with a raised heel may lead to a more upright trunk posture, and thus reduce the risk of back injuries during a barbell back squat. These proclaimed biomechanical effects have not been thoroughly investigated. The purpose of this study was to compare trunk and lower extremity biomechanics during barbell back squats in three foot postures. Fourteen recreational weight lifters (7 men and 7 women) between the ages of 18 and 50 years performed barbell back squats in three conditions (barefoot on a flat surface, barefoot on a heel-raised platform, and wearing heel-raised weightlifting shoes) at 80% of their 1 repetition maximum. Surface electromyography was used to assess the activation of the knee extensors and paraspinal muscles at L3 and T12 spinal levels. A 3D motion capture system and an electrogoniometer recorded the kinematics of the thoracic spine, lumbar spine, and knee during the back squat to a depth where the hip was at least at the same level to the knee. Results indicated that none of the heel-raised foot postures significantly affected trunk and lower extremity muscle activation (thoracolumbar paraspinal [p = 0.52], lumbar paraspinal [p = 0.179], knee extensor [p = 0.507]) or the trunk angles (thoracolumbar spine [p = 0.348], lumbar spine [p = 0.283]) during the squat. Our results demonstrated that during barbell back squats, heel-raised foot postures do not significantly affect spinal and knee extensor muscle activations, and trunk and knee kinematics. Heel-raised weightlifting shoes are unlikely to provide significant protection against back injuries for recreational weight lifters during the barbell back squat.
Assuntos
Calcanhar/fisiologia , Músculos Paraespinais/fisiologia , Postura/fisiologia , Músculo Quadríceps/fisiologia , Sapatos , Levantamento de Peso/fisiologia , Adolescente , Adulto , Fenômenos Biomecânicos , Eletromiografia , Feminino , Humanos , Joelho/fisiologia , Vértebras Lombares , Masculino , Pessoa de Meia-Idade , Tronco/fisiologia , Adulto JovemRESUMO
The baby boom after World War II, coupled with the rapid advances in medical technology and public health, has led to the current rapid aging in the world's population. Countries in Asia are experiencing a faster rate of aging than most other countries around the world. Taiwan is expected to advance from an aged society to a super-aged society in the next 7~10 years. Consequently, the demand for long-term care is increasing. The focus of healthcare has changed from acute to chronic, from disease-oriented to function-oriented and from cure to care. Families, once the cornerstone of care, have become overwhelmed by the effects of the declining birthrate and aging. Encountering the public demand for a balance between healthcare and quality of life has led to the increasing role of home-based care in the medical system. The elderly-care profession is diverse and growing. The trend of transdisciplinary team which integrating care professions, nursing professions, family medicine, geriatric medicine, rehabilitation medicine, telemedicine, and medical aids with the resource of social welfare enables home health care services to better provide well-rounded medical care. Before end of life, hospice home care services increase the likelihood of dying at home in accordance with the patient's preference, easing the symptoms of terminal illness and reducing the sorrow experienced by family members. The single insurer model used by the National Health Insurance system will inevitably replace some hospital and institutional services with home health care services that more effectively and flexibly use medical resources and attenuate the increase in medical costs.