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1.
Mol Ther Methods Clin Dev ; 32(2): 101252, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38774583

RESUMO

Virus particle (VP) quantification plays a pivotal role in the development of production processes of VPs for virus-based therapies. The yield based on total VP count serves as a process performance indicator for evaluating process efficiency and consistency. Here, a label-free particle quantification method for enveloped VPs was developed, with potential applications in oncolytic virotherapy, vaccine development, and gene therapy. The method comprises size-exclusion chromatography (SEC) separation using high-performance liquid chromatography (HPLC) instruments. Ultraviolet (UV) was used for particle quantification and multi-angle light scattering (MALS) for particle characterization. Consistent recoveries of over 97% in the SEC were achieved upon mobile phase screenings and addition of bovine serum albumin (BSA) as sample stabilizer. A calibration curve was generated, and the method's performance and applicability to in-process samples were characterized. The assay's repeatability variation was <1% and its intermediate precision variation was <3%. The linear range of the method spans from 7.08 × 108 to 1.72 × 1011 VP/mL, with a limit of detection (LOD) of 7.72 × 107 VP/mL and a lower limit of quantification (LLOQ) of 4.20 × 108 VP/mL. The method, characterized by its high precision, requires minimal hands-on time and provides same-day results, making it efficient for process development.

2.
Mol Biol Cell ; 35(6): ar75, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38598298

RESUMO

To cause vision-disrupting fibrotic secondary cataract (PCO), lens epithelial cells that survive cataract surgery must migrate to the posterior of the lens capsule and differentiate into myofibroblasts. During this process, the cells become exposed to the FGF that diffuses out of the vitreous body. In normal development, such relatively high levels of FGF induce lens epithelial cells to differentiate into lens fiber cells. It has been a mystery as to how lens cells could instead undergo a mutually exclusive cell fate, namely epithelial to myofibroblast transition, in the FGF-rich environment of the posterior capsule. We and others have reported that the ability of TGFß to induce lens cell fibrosis requires the activity of endogenous ErbBs. We show here that lens fiber-promoting levels of FGF induce desensitization of ErbB1 (EGFR) that involves its phosphorylation on threonine 669 mediated by both ERK and p38 activity. Transinhibition of ErbB1 by FGF is overcome by a time-dependent increase in ErbB1 levels induced by TGFß, the activation of which is increased after cataract surgery. Our studies provide a rationale for why TGFß upregulates ErbB1 in lens cells and further support the receptor as a therapeutic target for PCO.


Assuntos
Catarata , Células Epiteliais , Receptores ErbB , Fibrose , Cristalino , Fator de Crescimento Transformador beta , Humanos , Catarata/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Receptores ErbB/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Cristalino/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Fosforilação , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
3.
Mol Biol Cell ; 35(3): ar35, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38170570

RESUMO

Fibrosis is a major, but incompletely understood, component of many diseases. The most common vision-disrupting complication of cataract surgery involves differentiation of residual lens cells into myofibroblasts. In serum-free primary cultures of lens epithelial cells (DCDMLs), inhibitors of either ERK or of ErbB signaling prevent TGFß from upregulating both early (fibronectin) and late (αSMA) markers of myofibroblast differentiation. TGFß stimulates ERK in DCDMLs within 1.5 h. Kinase inhibitors of ErbBs, but not of several other growth factor receptors in lens cells, reduce phospho ERK to below basal levels in the absence or presence of TGFß. This effect is attributable to constitutive ErbB activity playing a major role in regulating the basal levels pERK. Additional studies support a model in which TGFß-generated reactive oxygen species serve to indirectly amplify ERK signaling downstream of tonically active ErbBs to mediate myofibroblast differentiation. ERK activity is in turn essential for expression of ErbB1 and ErbB2, major inducers of ERK signaling. By mechanistically linking TGFß, ErbB, and ERK signaling to myofibroblast differentiation, our data elucidate a new role for ErbBs in fibrosis and reveal a novel mode by which TGFß directs lens cell fate.


Assuntos
Miofibroblastos , Transdução de Sinais , Humanos , Células Epiteliais/metabolismo , Fibrose , Miofibroblastos/metabolismo , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Receptores ErbB
4.
J Pediatr Rehabil Med ; 16(4): 581-582, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38160377

RESUMO

Whether it is for collaboration on folic acid fortification or the standardization of care efforts concerning neurogenic bowel dysfunction, a global forum on neural tube defects related issues is needed. Propitiously, the 2023 Spina Bifida World Congress sponsored by the Spina Bifida Association (SBA) was a catalyst for transnational dialog in the field of spina bifida (SB) research. Concurrently, the Journal of Pediatric Rehabilitation Medicine (JPRM) provides a platform for both international research as well as numerous clinical and educational projects, such as The Lifespan Bowel Management Protocol, and social interventions taught through the American Academy of Pediatrics' Spina Bifida Transition ECHO. Through this open access issue, work by colleagues in Ethiopia, the Nordic countries, and Switzerland, as well as among other transnational populations is highlighted. The development of the Spina Bifida Global Learning Collaborative is also showcased, representing a training initiative across four continents. Correspondingly in this issue, JPRM published an update to the Transition Guidelines for the Care of People with Spina Bifida. The clinical guidelines are a product of the SBA Collaborative Care Network cooperative agreement with the National Center on Birth Defects and Developmental Disabilities in the Centers for Disease Control and Prevention. While colleagues across the globe remain committed to native, immigrant, and displaced populations of individuals affected by SB, JPRM will continue to distribute premier research in multidisciplinary care, education, and advocacy.


Assuntos
Emigrantes e Imigrantes , Defeitos do Tubo Neural , Disrafismo Espinal , Gravidez , Feminino , Humanos , Criança , Estados Unidos , Cuidado Pré-Natal , Longevidade , Disrafismo Espinal/complicações , Disrafismo Espinal/prevenção & controle
5.
Invest Ophthalmol Vis Sci ; 64(10): 6, 2023 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-37418274

RESUMO

Purpose: TGFß-induced epithelial-to-myofibroblast transition (EMyT) of lens cells has been linked to the most common vision-disrupting complication of cataract surgery-namely, posterior capsule opacification (PCO; secondary cataract). Although inhibitors of the ErbB family of receptor tyrosine kinases have been shown to block some PCO-associated processes in model systems, our knowledge of ErbB signaling in the lens is very limited. Here, we investigate the expression of ErbBs and their ligands in primary cultures of chick lens epithelial cells (dissociated cell-derived monolayer cultures [DCDMLs]) and how TGFß affects ErbB function. Methods: DCDMLs were analyzed by immunofluorescence microscopy and Western blotting under basal and profibrotic conditions. Results: Small-molecule ErbB kinase blockers, including the human therapeutic lapatinib, selectively inhibit TGFß-induced EMyT of DCDMLs. Lens cells constitutively express ErbB1 (EGFR), ErbB2, and ErbB4 protein on the plasma membrane and release into the medium ErbB-activating ligand. Culturing DCDMLs with TGFß increases soluble bioactive ErbB ligand and markedly alters ErbBs, reducing total and cell surface ErbB2 and ErbB4 while increasing ErbB1 expression and homodimer formation. Similar, TGFß-dependent changes in relative ErbB expression are induced when lens cells are exposed to the profibrotic substrate fibronectin. A single, 1-hour treatment with lapatinib inhibits EMyT in DCDMLs assessed 6 days later. Short-term exposure to lower doses of lapatinib is also capable of eliciting a durable response when combined with suboptimal levels of a mechanistically distinct multikinase inhibitor. Conclusions: Our findings support ErbB1 as a therapeutic target for fibrotic PCO, which could be leveraged to pharmaceutically preserve the vision of millions of patients with cataracts.


Assuntos
Opacificação da Cápsula , Catarata , Humanos , Opacificação da Cápsula/metabolismo , Lapatinib/metabolismo , Ligantes , Catarata/etiologia , Catarata/metabolismo , Células Epiteliais/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fibrose
6.
J Pediatr Rehabil Med ; 16(s1): S1-S2, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37270821

RESUMO

As with the wide range in spina bifida (SB) incidence rates across nations, there is also wide variance in topics encountered by clinicians today. Both the wide variance in SB incidence rates and the wide diversity of topics to be addressed provide the backdrop for any dialogue among professionals serving this population. On the international stage, the World Congress on Spina Bifida Research and Care has been the only conference dedicated solely to research, practical challenges, and real-life solutions for those living with SB, their families, and caregivers. As a conference with a clear sense of the growing global village, the 2023 congress showcased innovative research from junior to preeminent investigators. Topical areas included urology, neurosurgery, global health, prenatal surgery, and transition to adult care amid others. Ultimately, through the dissemination of a compendium of conference abstracts, we hope that professionals will be aided and inspired to continue to improve the education, advocacy, and care among the many communities of individuals affected by SB globally.


Assuntos
Neurocirurgia , Disrafismo Espinal , Adulto , Gravidez , Feminino , Humanos , Disrafismo Espinal/epidemiologia
7.
Am J Prev Med ; 64(3): 305-314, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36460525

RESUMO

INTRODUCTION: Experiences of discrimination and bias in healthcare contribute to health disparities for lesbian, gay, bisexual, transgender, and queer populations. To avoid discrimination, many go to great lengths to find healthcare providers who they trust and who are knowledgeable about their health needs. This study examines whether access to an affirming provider improves health outcomes for lesbian, gay, bisexual, transgender, and queer populations across a range of preventive health and chronic disease management outcomes. METHODS: This cross-sectional study uses Poisson regression models to examine original survey data (n=1,120) from Wave 1 of the Vanderbilt University Social Networks, Aging, and Policy Study, a panel study examining older (aged 50-76 years) lesbian, gay, bisexual, transgender, and queer adults' health and aging, collected between April 2020 and September 2021. RESULTS: Overall, access to an affirming provider is associated with greater uptake of preventive health screenings and improved management of mental health conditions. Participants with an affirming provider are more likely to have ever and recently received several types of preventive care than participants reporting a usual source of care that is not affirming, including past year provider visit, influenza vaccination, colorectal cancer screening, and HIV test. Access to an affirming provider is also associated with better management of mental health conditions. CONCLUSIONS: Inclusive care is essential for reducing health disparities among lesbian, gay, bisexual, transgender, and queer populations. Health systems can reduce disparities by expanding continuing education opportunities; adopting nondiscrimination policies for patients and employees; and ensuring that necessary care is covered by health insurance.


Assuntos
Minorias Sexuais e de Gênero , Pessoas Transgênero , Feminino , Humanos , Idoso , Estudos Transversais , Bissexualidade , Doença Crônica
8.
Thyroid ; 33(2): 192-202, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36074932

RESUMO

Introduction: Long-term cardiovascular (CV) risk is a concern for differentiated thyroid cancer (DTC) survivors. Methods: We performed a systematic review and meta-analysis evaluating the risks of CV mortality and morbidity in DTC survivors compared with the general population. Respective meta-analyses were conducted for data that were adjusted for relevant confounders and crude data. We searched five electronic databases from inception to October 2021, supplemented with a hand search. Two reviewers independently screened citations, reviewed full text articles, extracted data, and critically appraised the studies, with discrepancies resolved by a third reviewer. The primary outcome was CV mortality. Secondary outcomes included atrial fibrillation, ischemic heart disease, stroke, and heart failure. We estimated the relative risk (RR) and confidence intervals [CI] of outcomes using random-effects models (adjusted for age and gender), compared with the general population. Results: We reviewed 3409 unique citations, 65 full text articles, and included 7 studies. CV mortality risk was significantly increased in DTC survivors in one study adjusted for confounders-adjusted RR (aRR) 3.35 ([CI 1.66-6.67]; 524 DTC, 1572 controls). The risk of CV morbidity in DTC survivors, adjusted for risk factors, was estimated as follows: atrial fibrillation-aRR 1.66 [CI 1.22-2.27] (3 studies, 4428 DTC, I2 = 75%), ischemic heart disease-aRR 0.97 [CI 0.84-1.13] (2 studies, 3910 DTC, I2 = 0%), stroke-aRR 1.14 [CI 0.84-1.55] (2 studies, 3910 DTC, I2 = 69%), and heart failure-aRR 0.98 [CI 0.60-1.59] (2 studies, 3910 DTC, I2 = 79%). In meta-analyses of unadjusted data, the risks of CV mortality were not significantly increased but the CV morbidity risks were similar to adjusted data. Conclusions: There is limited evidence suggesting that DTC survivors may be at an increased risk of CV death and atrial fibrillation (after adjustment for confounders). We did not observe a significantly increased risk of ischemic heart disease, stroke, or heart failure. Most analyses were subject to significant heterogeneity and further research, with careful attention to CV risk factors, is needed to clarify CV risk in DTC survivors. Registration: PROSPERO CRD42021244743.


Assuntos
Fibrilação Atrial , Sobreviventes de Câncer , Insuficiência Cardíaca , Isquemia Miocárdica , Acidente Vascular Cerebral , Neoplasias da Glândula Tireoide , Humanos , Fibrilação Atrial/complicações , Neoplasias da Glândula Tireoide/complicações , Insuficiência Cardíaca/epidemiologia , Fatores de Risco , Isquemia Miocárdica/complicações
9.
J Pediatr Rehabil Med ; 15(4): 545-547, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36565077

RESUMO

Whereas legislation mandates for folic acid fortification have been implemented throughout many nations, divergent neural tube defects (NTDs) prevalence rates still remain among the world's populations. In North America, the prevalence estimate is 39 infants per 100,000 live births. Open spina bifida (SB), also known as myelomeningocele, remains the most complex congenital abnormality of the central nervous system compatible with long term survival; this recognized complexity gives rise to emerging comorbidities and interventions. For example, increasing autism spectrum disorder rates have been reported among individuals with SB utilizing a 31,220 subject population-based birth cohort. Along with new clinical observations, telecommunication platforms such as Zoom® have evolved as clinical and investigational tools. Historically, society meetings, research conferences, and journals have provided opportunities for professional development and dissemination of up-to-date materials. The Journal of Pediatric Rehabilitation Medicine (JPRM) has arisen as an open-access global platform for the dissemination of SB-related inquiry. The journal has also highlighted the research presented at the Spina Bifida Association's previous Spina Bifida World Congresses. At the last congress, which was held in 2017, twenty-three countries were represented; this number is expected to grow by the next convocation in 2023. This congress will provide an opportunity for health care professionals from around the globe to present a broad array of research topics and build collaborations. Concurrently, the JPRM will continue as an open-access platform for SB advocacy, care, education, and investigation, across our fast changing world for the international SB community well into the future.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Defeitos do Tubo Neural , Disrafismo Espinal , Lactente , Criança , Humanos , Disrafismo Espinal/terapia , Disrafismo Espinal/epidemiologia , Defeitos do Tubo Neural/epidemiologia , Ácido Fólico , Prevalência
10.
J Pediatr Rehabil Med ; 14(4): 569-570, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34864704

RESUMO

Worldwide neural tube defects, such as encephalocele and spina bifida (SB), remain a substantial cause of the global burden of disease; and in the US, Latinos consistently have a higher birth prevalence of SB compared with other ethnic groups. From limited access and fragmented care, to scarcely available adult services, many are the challenges that besiege those living with SB. Thus, to provide inclusion and active involvement of parents of children and adults with SB from all communities, innovative approaches will be required, such as community-based participatory research and culturally competent learning collaboratives. Promisingly, the Spina Bifida Community-Centered Research Agenda was developed by the community of people living with SB through the Spina Bifida Association (SBA). Additionally, the SBA will host the Fourth World Congress on Spina Bifida Research and Care in March of 2023. Just as the SBA is clearly committed to this population, the Journal of Pediatric Rehabilitation Medicine will continue to serve as a catalyst for SB care, education, and research across the SB population in a global context.


Assuntos
Defeitos do Tubo Neural , Disrafismo Espinal , Adulto , Criança , Hispânico ou Latino , Humanos , Prevalência , Disrafismo Espinal/reabilitação
11.
Indian J Orthop ; 55(1): 158-168, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33569110

RESUMO

BACKGROUND: We evaluated screening, referral and treatment practices for developmental dysplasia of the hip (DDH) in India by surveying Orthopaedic surgeons who treat patients with DDH. The survey assessed the timing of DDH presentation, resource availability, and current state of screening and diagnosis, which would help in the development of a DDH care pathway for India. METHODS: An online survey was distributed to Orthopaedic surgeons practicing in India via email and administered onsite to those attending the annual conference of the Pediatric Orthopaedic Society of India in 2019. RESULTS: 173 completed surveys were received from surgeons practicing in a predominantly urban setting. 68.8% of respondents had performed initial evaluations on children with DDH aged over 1 year in the past 12 months, and 49.1% had assessed children with DDH aged > 2 years on initial presentation. There was no consistent use of established guidelines, with only 30% of respondents stating that a care pathway was in place at their institution. However, 91.9% would support the implementation of a care pathway developed in India, to decrease the incidence of delayed diagnosis and facilitate earlier intervention. 85% of respondents had ready access to ultrasound scans and 95.4% had access to X-rays. CONCLUSIONS: In India, there is still a large number of late-presenting cases of DDH, which could be improved with effective screening. The development of a care pathway for DDH in India is well-supported by Orthopaedic surgeons and may help decrease the incidence of late presenting cases; potentially improving outcomes, decreasing morbidity, and upskilling local practitioners.

12.
Diabetologia ; 63(5): 944-953, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31993714

RESUMO

AIMS/HYPOTHESIS: Diabetes is associated with an increased incidence of colorectal cancer (CRC). There exists conflicting evidence regarding the impact of diabetes on CRC-specific mortality (herein also referred to as cancer-specific mortality). The objectives of this study were to determine whether diabetes is associated with a more advanced CRC stage at diagnosis and with higher all-cause and cancer-specific mortality. METHODS: This retrospective cohort study used linked, population-based health databases from Ontario, Canada. Among individuals diagnosed with CRC from 2007 to 2015, we compared the likelihood of presenting with later- (III or IV) vs early- (I or II) stage CRC between patients with and without diabetes adjusting for relevant covariates. We then determined the association between diabetes and all-cause and CRC-specific mortality, after adjusting for CRC stage at diagnosis and other covariates. RESULTS: Of the 44,178 individuals with CRC, 11,822 (26.7%) had diabetes. After adjustment for CRC screening and other covariates, individuals with diabetes were not more likely to present with later-stage CRC (adjusted OR 0.97, 95% CI 0.93, 1.01). Over a median follow-up of 2.63 (interquartile range [IQR] 0.97-5.10) years, diabetes was associated with higher all-cause mortality (adjusted HR 1.08, 95% CI 1.04, 1.12) but similar cancer-specific survival (adjusted HR 1.0, 95% CI 0.95, 1.06). CONCLUSIONS/INTERPRETATION: Individuals with diabetes who develop CRC are not more likely to present with a later stage of CRC and have similar cancer-specific mortality compared with those without diabetes. Diabetes was associated with higher all-cause mortality in CRC patients, indicating that greater attention to non-cancer care is needed for CRC survivors with diabetes.


Assuntos
Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/mortalidade , Diabetes Mellitus/epidemiologia , Estudos de Coortes , Diabetes Mellitus/mortalidade , Humanos , Incidência , Modelos Logísticos , Ontário , Estudos Retrospectivos
13.
Transl Cancer Res ; 9(9): 5743-5759, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35117936

RESUMO

Rates of obesity and diabetes have risen significantly in recent years and are projected to increase even further in the coming decades. Obesity and diabetes are associated with increased risk of certain tumours, with the strongest relationships demonstrated for colorectal, post-menopausal breast, and endometrial cancer. Another important risk factor for cancer development is aging. Aging is characterized by chronic inflammation and immunosenescence, and accelerated by obesity, which may further stimulate the development of cancer. In this review, we summarize recent literature on the complex interactions between obesity, diabetes, aging, and cancer risk and mortality. We will also provide an overview of both epidemiological as well as pathophysiologic data and their clinical implications. In the context of an aging population and anticipated rise in rates of obesity and diabetes, a better understanding of how these factors interact and impact on cancer risk and prognosis will be important in helping to guide therapeutic interventions.

14.
Transfusion ; 59(2): 545-554, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30488956

RESUMO

BACKGROUND: Recent province-wide audits of frozen plasma (FP) and RBC use in Ontario showed a high rate of inappropriate transfusions. STUDY DESIGN AND METHODS: This was a retrospective, ecological study to determine variations in RBC and FP utilization rates across Ontario community hospitals between 2012 and 2017. Annual utilization rates were reported using descriptive statistics. Rates of blood component use were correlated with size of hospital, presence of specialized programs, and quality improvement (QI) initiatives, using Poisson regression. RESULTS: RBC and FP utilization rates decreased from 2012 to 2017 (p = 0.03 for FP; p < 0.01 for RBC). There was a 10-fold difference in RBC and FP transfusion rates between the highest and lowest users. Smaller hospitals (p < 0.05) and sites with any QI initiative (p = 0.006) were associated with lower FP utilization rates. Hospitals without cancer programs (p = 0.02) and sites with RBC guidelines (p = 0.05) or with technologists who prospectively screened transfusion orders (p = 0.01) had lower RBC transfusion rates. RBC utilization rates decreased further after the implementation of RBC guidelines (p = 0.02) and order sets (p = 0.005). There was a positive correlation between FP and RBC transfusion rates for each fiscal year (p < 0.005 for all years). CONCLUSION: RBC and FP utilization showed wide variation across community hospitals in Ontario. Overall, transfusion rates decreased over time. A further decrease was observed at sites with QI initiatives, supporting their implementation in reducing utilization. These data will serve as a baseline to highlight sites and practices where QI initiatives may be most beneficial and replicated in other jurisdictions.


Assuntos
Transfusão de Eritrócitos , Hospitais Comunitários , Plasma , Transfusão de Plaquetas , Feminino , Humanos , Masculino , Ontário , Estudos Retrospectivos
15.
Oncogene ; 38(8): 1200-1210, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30242244

RESUMO

Certain cancers, including gastrointestinal stromal tumor (GIST) and subsets of melanoma, are caused by somatic KIT mutations that result in KIT receptor tyrosine kinase constitutive activity, which drives proliferation. The treatment of KIT-mutant GIST has been revolutionized with the advent of KIT-directed cancer therapies. KIT tyrosine kinase inhibitors (TKI) are superior to conventional chemotherapy in their ability to control advanced KIT-mutant disease. However, these therapies have a limited duration of activity due to drug-resistant secondary KIT mutations that arise (or that are selected for) during KIT TKI treatment. To overcome the problem of KIT TKI resistance, we sought to identify novel therapeutic targets in KIT-mutant GIST and melanoma cells using a human tyrosine kinome siRNA screen. From this screen, we identified lemur tyrosine kinase 3 (LMTK3) and herein describe its role as a novel KIT regulator in KIT-mutant GIST and melanoma cells. We find that LMTK3 regulated the translation rate of KIT, such that loss of LMTK3 reduced total KIT, and thus KIT downstream signaling in cancer cells. Silencing of LMTK3 decreased cell viability and increased cell death in KIT-dependent, but not KIT-independent GIST and melanoma cell lines. Notably, LMTK3 silencing reduced viability of all KIT-mutant cell lines tested, even those with drug-resistant KIT secondary mutations. Furthermore, targeting of LMTK3 with siRNA delayed KIT-dependent GIST growth in a xenograft model. Our data suggest the potential of LMTK3 as a target for treatment of patients with KIT-mutant cancer, particularly after failure of KIT TKIs.


Assuntos
Tumores do Estroma Gastrointestinal/tratamento farmacológico , Melanoma/tratamento farmacológico , Proteínas de Membrana/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-kit/genética , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/administração & dosagem , Melanoma/genética , Melanoma/patologia , Camundongos , Mutação/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , RNA Interferente Pequeno/genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Psychoneuroendocrinology ; 102: 114-120, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30544002

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with disturbed sleep and elevated levels of pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Studies in animals and healthy humans have also shown that disrupted sleep elevates pro-inflammatory cytokines, including IL-6 and TNF-α. A better understanding of overnight cytokine levels and sleep might shed light on possible mechanisms for elevated inflammation in PTSD. Thus, we investigated overnight levels of IL-6 and TNF-α in individuals with and without PTSD while recording sleep polysomnography (PSG). METHOD: Serum samples were collected from otherwise healthy, medication-free participants with chronic PTSD (n = 44; 50% female; M age = 30.34 ± 8.11) and matched controls (n = 49; 53% female; M age = 30.53 ± 6.57) during laboratory PSG. Levels of IL-6 and TNF-α were measured at hours 0, 2, 4, 6, and 8 after typical sleep onset time using serial serum samples. Plasma IL-6 and TNF-α levels were quantified using enzyme-linked immunosorbent assays. RESULTS: Growth model analysis indicated a significantgroup by time interaction for IL-6 (t[247] = -2.92, p = .005) and a significant group by sex by time interaction for TNF-α (t[275] = 2.02, p = .04). PTSD positive men and women initially had higher IL-6 and TNF-α at sleep onset, but not at the end of their sleep cycle. Men with PTSD showed a peak of TNF-α at the end of the sleep cycle, whereas male control subjects demonstrated an inverted U-shaped profile. There were no significant differences in TNF-α levels overnight between women with and without PTSD. CONCLUSION: To our knowledge, this is the largest study to examine IL-6 overnight in a PTSD sample and the first study to examine overnight TNF-α in PTSD. Overnight IL-6 and TNF-α levels may be altered in individuals with PTSD compared to those without PTSD, and TNF-α trajectories also differed by sex. The current findings highlight the need to consider sex, sleep, time of day, and circadian variation when examining inflammation in PTSD. Additional research in broader study samples will be necessary to clarify associations between disrupted sleep, cytokines, and increased risk for disease in PTSD.


Assuntos
Citocinas/análise , Transtornos de Estresse Pós-Traumáticos/metabolismo , Adulto , Citocinas/sangue , Feminino , Humanos , Hidrocortisona/análise , Hidrocortisona/sangue , Inflamação/sangue , Inflamação/metabolismo , Interleucina-6/análise , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Polissonografia , Sono , Transtornos do Sono-Vigília , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/sangue
17.
J Cell Sci ; 131(22)2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30404825

RESUMO

Lens epithelial cells are bound to the lens extracellular matrix capsule, of which laminin is a major component. After cataract surgery, surviving lens epithelial cells are exposed to increased levels of fibronectin, and so we addressed whether fibronectin influences lens cell fate, using DCDML cells as a serum-free primary lens epithelial cell culture system. We found that culturing DCDMLs with plasma-derived fibronectin upregulated canonical TGFß signaling relative to cells plated on laminin. Fibronectin-exposed cultures also showed increased TGFß signaling-dependent differentiation into the two cell types responsible for posterior capsule opacification after cataract surgery, namely myofibroblasts and lens fiber cells. Increased TGFß activity could be identified in the conditioned medium recovered from cells grown on fibronectin. Other experiments showed that plating DCDMLs on fibronectin overcomes the need for BMP in fibroblast growth factor (FGF)-induced lens fiber cell differentiation, a requirement that is restored when endogenous TGFß signaling is inhibited. These results demonstrate how the TGFß-fibronectin axis can profoundly affect lens cell fate. This axis represents a novel target for prevention of late-onset posterior capsule opacification, a common but currently intractable complication of cataract surgery.


Assuntos
Proteínas do Olho/metabolismo , Fibronectinas/metabolismo , Cristalino/metabolismo , Diferenciação Celular , Humanos , Transdução de Sinais
18.
Nutrients ; 10(10)2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30287766

RESUMO

The potential for nutrition labels to impact on population health is dependent on consumer ability to understand and use this information. Consumer understanding of this information varies across sociodemographic groups and with different label design formats. Labeling legislation requires consumer education on how to use nutrition labels, and recent mandatory changes to the Nutrition Facts Panel (NFP) are underway to improve comprehensibility. This review aimed to evaluate if educational programs can improve understanding and use of nutrition labels. Database searches were performed to identify interventions which delivered education on nutrition labels with outcomes measuring aspects of comprehension or use. A total of 17 studies were selected for review, including nine randomized and eight cohort studies. The majority of studies were conducted in the United States Study participants included school aged children, older adults, and those with diabetes within a range of intervention types involving taught sessions or web-based education. Whilst outcome measures were heterogenous, all studies reported a statistically significant improvement in one or more outcomes of participant understanding or use of nutrition labels. Aspects such as general nutrition knowledge, health literacy, and program delivery format warrant attention in future research. Education which optimizes comprehension and use of nutrition labels may have the potential to improve the impact of this information on dietary health.


Assuntos
Compreensão , Comportamento do Consumidor , Dieta , Rotulagem de Alimentos , Comportamentos Relacionados com a Saúde , Educação em Saúde , Letramento em Saúde , Comportamento Alimentar , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Avaliação de Programas e Projetos de Saúde , Estados Unidos
19.
Oncol Nurs Forum ; 45(4): 457-462, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29947353

RESUMO

OBJECTIVES: To describe the clinical characteristics of children and adolescents undergoing hematopoietic cell transplantation (HCT) who develop oral mucositis. SAMPLE & SETTING: 45 patients who underwent HCT from July 2015 to May 2016 at St. Jude Children's Research Hospital in Memphis, Tennessee. METHODS & VARIABLES: Clinical factors were described as transplantation type, mucositis severity or grade, mucositis duration, days to engraftment, total parenteral nutrition (TPN) support, IV opioid pain management use during mucositis, positive blood or oral cultures, and length of hospitalization, then compared across mucositis grade. RESULTS: 24 patients had grade 3 or greater mucositis onset from day -3 to day 9 of transplantation; of these, 23 required IV opioid medication to treat mucosal pain. Patients with mucositis grade 3 or greater were more likely to have undergone an allogeneic transplantation, receive TPN, have documented positive blood or oral cultures, and have longer hospitalizations than those with low-grade mucositis. IMPLICATIONS FOR NURSING: Nurses are in a unique position to propose and administer interventions to prevent and alleviate symptoms of mucositis.


Assuntos
Analgésicos Opioides/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Manejo da Dor/métodos , Dor/tratamento farmacológico , Estomatite/tratamento farmacológico , Estomatite/etiologia , Transplante Homólogo/efeitos adversos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Tennessee , Adulto Jovem
20.
J Urol ; 200(1): 187-194, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29588216

RESUMO

PURPOSE: Most children with spina bifida now survive into adulthood, although most have neuropathic bladder with potential complications of incontinence, infection, renal damage and diminished quality of life. In this study we sought to 1) describe contemporary bladder management and continence outcomes of adults with spina bifida, 2) describe differences from younger individuals and 3) assess for association with socioeconomic factors. MATERIALS AND METHODS: We analyzed data on bladder management and outcomes in adults with spina bifida from the National Spina Bifida Patient Registry. A strict definition of continence was used. Results were compared to young children (age 5 to 11 years) and adolescents (12 to 19). Statistical analysis compared cohorts by gender, ethnicity, spina bifida type, lesion level, insurance status, educational attainment, employment status and continence. RESULTS: A total of 5,250 patients with spina bifida were included, of whom 1,372 (26.1%) were adults. Of the adult patients 45.8% did not take medication, but 76.8% performed clean intermittent catheterization. Continence was decreased in adults with myelomeningocele (45.8%) vs those with nonmyelomeningocele spina bifida (63.1%, p <0.0001). Continence rates were higher in the older cohorts with myelomeningocele (p <0.0001) but not in those with nonmyelomeningocele spina bifida (p = 0.1192). Bladder management and history of urological surgery varied among age groups. On univariate analysis with spina bifida related or socioeconomic variables continence was significantly associated with educational level but on multivariable logistic regression analysis bladder continence was significantly associated with employment status only. CONCLUSIONS: Bladder management techniques differ between adults and children with spina bifida. Bladder continence outcomes were better in adults, with nearly half reporting continence. Continence was significantly associated with employment status in patients age 25 years or older.


Assuntos
Disrafismo Espinal/complicações , Bexiga Urinaria Neurogênica/terapia , Incontinência Urinária/terapia , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Humanos , Cateterismo Uretral Intermitente , Sistema de Registros , Autocuidado , Fatores Socioeconômicos , Estados Unidos , Bexiga Urinaria Neurogênica/etiologia , Incontinência Urinária/etiologia , Adulto Jovem
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