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"Hershey, Milton Snavely"
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Who was Milton Hershey?
\"Discover the man behind the chocolate bar! Milton Hershey's life was filled with invention and innovation. As a young man, he was not afraid to dream big and work hard. Eventually, he learned the secret to mass-producing milk chocolate and the recipe that gave it a longer, more stable shelf life. He founded a school for those who didn't have access to a good education and an entire town for his employees. Both his chocolate empire and his great personal legacy live on today.\"--Provided by publisher.
Book
Matrix Metalloproteinase-9 (MMP-9) induced disruption of intestinal epithelial tight junction barrier is mediated by NF-κB activation
Matrix Metalloproteinase-9 (MMP-9) has been shown to play a key role in mediating inflammation and tissue damage in inflammatory bowel disease (IBD). In patients with IBD, the intestinal tight junction (TJ) barrier is compromised as characterized by an increase in intestinal permeability. MMP-9 is elevated in intestinal tissue, serum and stool of patients with IBD. Previous studies from our laboratory showed that MMP-9 causes an increase in intestinal epithelial TJ permeability and that the MMP-9 induced increase in intestinal permeability is an important pathogenic factor contributing to the development of intestinal inflammation in IBD. However, the intracellular mechanisms that mediate the MMP-9 modulation of intestinal barrier function remain unclear.
The main aim of this study was to further elucidate the molecular mechanisms involved in MMP-9 induced increase in intestinal epithelial TJ permeability using Caco-2 monolayers as an in-vitro model system.
MMP-9 induced increase in Caco-2 TJ permeability was associated with activation and cytoplasmic-to-nuclear translocation of NF-κB p65. Knocking-down NF-κB p65 by siRNA transfection prevented the MMP-9 induced expression of the NF-κB target gene IL-8, myosin light chain kinase (MLCK) protein expression, and subsequently prevented the increase in Caco-2 TJ permeability. In addition, the effect of MMP-9 on Caco-2 intestinal epithelial TJ barrier function was not mediated by apoptosis or necrosis.
Our data show that the MMP-9 induced disruption of Caco-2 intestinal epithelial TJ barrier function is regulated by NF-κB pathway activation of MLCK.
Journal Article
MicroRNA-146a is induced by inflammatory stimuli in airway epithelial cells and augments the anti-inflammatory effects of glucocorticoids
MicroRNAs (miRNAs) are emerging as central regulators of inflammation, but their role in asthma and airway epithelial cells is not well studied. Glucocorticoids are the cornerstone of therapy in asthma and other inflammatory disease, yet their mechanisms of action are not completely elucidated, and it is not clear whether miRNAs modulate their effects.
We aimed to identify miRNAs that regulate cytokine and chemokine expression in airway epithelial cells and whether these miRNAs are subject to the effects of glucocorticoids.
MicroRNAomic analyses of immortalized, normal human bronchial epithelial cells identified 7 miRNAs that were altered by inflammatory cytokine treatment and 22 that were regulated by glucocorticoids (n = 3 for each treatment condition). MiR-146a emerged as a central candidate, whose expression was induced by TNF-α and repressed by glucocorticoids. Its role as a candidate in asthmatic inflammation was supported by expression profiling in human asthmatics, which showed that plasma miR-146a expression was elevated in asthma and associated with measures related to worse asthma outcomes, including elevated blood eosinophil counts, higher asthma control questionnaire scores, and need for higher doses of inhaled glucocorticoids. However, transfection of miR-146a in A549 cells treated with TNF-α +/- glucocorticoids produced an anti-inflammatory effect and increased efficacy of glucocorticoids.
We propose a model whereby miR-146a is induced by inflammatory conditions as a feedback mechanism to limit inflammation. Exogenous administration of miR-146a augmented the effects of glucocorticoids and could be a novel therapeutic strategy to enhance efficacy of these medications.
Journal Article
Placental pathology reports: A qualitative study in a US university hospital setting on perceived clinical utility and areas for improvement
To explore how placental pathology is currently used by clinicians and what placental information would be most useful in the immediate hours after delivery.
We used a qualitative study design to conduct in-depth, semi-structured interviews with obstetric and neonatal clinicians who provide delivery or postpartum care at an academic medical center in the US (n = 19). Interviews were transcribed and analyzed using descriptive content analysis.
Clinicians valued placental pathology information yet cited multiple barriers that prevent the consistent use of pathology. Four main themes were identified. First, the placenta is sent to pathology for consistent reasons, however, the pathology report is accessed by clinicians inconsistently due to key barriers: difficult to find in the electronic medical record, understand, and get quickly. Second, clinicians value placental pathology for explanatory capability as well as for contributions to current and future care, particularly when there is fetal growth restriction, stillbirth, or antibiotic use. Third, a rapid placental exam (specifically including placental weight, infection, infarction, and overall assessment) would be helpful in providing clinical care. Fourth, placental pathology reports that connect clinically relevant findings (similar to radiology) and that are written with plain, standardized language and that non-pathologists can more readily understand are preferred.
Placental pathology is important to clinicians that care for mothers and newborns (particularly those that are critically ill) after birth, yet many problems stand in the way of its usefulness. Hospital administrators, perinatal pathologists, and clinicians should work together to improve access to and contents of reports. Support for new methods to provide quick placenta information is warranted.
Journal Article
Outcomes in 1096 patients with severe thrombotic thrombocytopenic purpura before the Caplacizumab era
Thrombotic thrombocytopenic purpura (TTP) is a diagnostic and therapeutic emergency. Therapeutic plasma exchange (TPE) combined with immunosuppression has been the cornerstone of the initial management. To produce optimal benefits, emerging treatments must be used against a background of best standard of care. Clarifying current uncertainties is therefore crucial.
The objective of this study was to analyze a large high-quality database (Marketscan) of TTP patients managed between 2005 and 2014, in the pre-caplacizumab era, in order to assess the impact of time to first TPE and use of first-line rituximab on mortality, and whether mortality declines over time.
Among the 1096 included patients (median age 46 [IQR 35-55], 70% female), 28.8% received TPE before day 2 in the ICU. Hospital mortality was 7.6% (83 deaths). Mortality was independently associated with older age (hazard ratio [HR], 1.024/year; 95% confidence interval [95%CI], [1.009-1.040]), diagnosis of sepsis (HR, 2.360; 95%CI [1.552-3.588]), and the need for mechanical ventilation (HR, 4.103; 95%CI, [2.749-6.126]). Factors independently associated with lower mortality were TPE at ICU admission (HR, 0.284; 95%CI, [0.112-0.717]), TPE within one day after ICU admission (HR, 0.449; 95%CI, [0.275-0.907]), and early rituximab therapy (HR, 0.229; 95% CI, [0.111-0.471]). Delayed TPE was associated with significantly higher costs.
Immediate TPE and early rituximab are associated with improved survival in TTP patients. Improved treatments have led to a decline in mortality over time, and alternate outcome variables such as the use of hospital resources or longer term outcomes therefore need to be considered.
Journal Article
Hospital-Based Community Gardens as a Strategic Partner in Addressing Community Health Needs
As part of community health needs assessments, US nonprofit hospitals are identifying a high prevalence of chronic diseases associated with poor diets. Institutions have responded by establishing nutrition-related initiatives such as farmers’ markets and community gardens. There is public health value in demonstrating how these partnerships can help hospitals address identified community health needs. Here we describe diverse strategies undertaken by a hospital-based community garden at Penn State Milton S. Hershey Medical Center, explore implications for US hospitals, and provide implementation guidance. (Am J Public Health. 2023;113(9):939–942. https://doi.org/10.2105/AJPH.2023.307336 )
Journal Article
Regional, racial, gender, and tumor biology disparities in breast cancer survival rates in Africa: A systematic review and meta-analysis
The survival rates from breast cancer in Africa are poor and yet the incidence rates are on the rise. In this study, we hypothesized that, in Africa, a continent with great disparities in socio-economic status, race, tumor biology, and cultural characteristics, the survival rates from breast cancer vary greatly based on region, tumor biology (hormone receptor), gender, and race. We aimed to conduct the first comprehensive systematic review and meta-analysis on region, gender, tumor-biology and race-specific 5-year breast cancer survival rates in Africa and compared them to 20-year survival trends in the United States.
We searched MEDLINE, EMBASE, and Cochrane Library to identify studies on breast cancer survival in African published before October 17, 2018. Pooled 5-year survival rates of breast cancer were estimated by random-effects models. We explored sources of heterogeneity through subgroup meta-analyses and meta-regression. Results were reported as absolute difference (AD) in percentages. We compared the survival rates of breast cancer in Africa and the United States.
There were 54 studies included, consisting of 18,970 breast cancer cases. There was substantial heterogeneity in the survival rates (mean 52.9%, range 7-91%, I2 = 99.1%; p for heterogeneity <0.0001). Meta-regression analyses suggested that age and gender-adjusted 5-year survival rates were lower in sub-Saharan Africa compared to north Africa (AD: -25.4%; 95% CI: -34.9 - -15.82%), and in predominantly black populations compared to predominantly non-black populations (AD: -25.9%; 95% CI: 35.40 - -16.43%). Survival rates were 10 percentage points higher in the female population compared to male, but the difference was not significant. Progesterone and estrogen receptor-positive breast cancer subtypes were positively associated with survival (r = 0.39, p = 0.08 and r = 0.24, p = 0.29 respectively), but triple-negative breast cancer was negatively associated with survival. Survival rates are increasing over time more in non-black Africans (55% in 2000 versus 65% in 2018) compared to black Africans (33% in 2000 versus 40% in 2018); but, the survival rates for Africans are still significantly lower when compared to black (76% in 2015) and white (90% in 2015) populations in the United States.
Regional, sub-regional, gender, and racial disparities exist, influencing the survival rates of breast cancer in Africa. Therefore, region and race-specific public health interventions coupled with prospective genetic studies are urgently needed to improve breast cancer survival in this region.
Journal Article
The receptor tyrosine kinase Ror is required for dendrite regeneration in Drosophila neurons
While many regulators of axon regeneration have been identified, very little is known about mechanisms that allow dendrites to regenerate after injury. Using a Drosophila model of dendrite regeneration, we performed a candidate screen of receptor tyrosine kinases (RTKs) and found a requirement for RTK-like orphan receptor (Ror). We confirmed that Ror was required for regeneration in two different neuron types using RNA interference (RNAi) and mutants. Ror was not required for axon regeneration or normal dendrite development, suggesting a specific role in dendrite regeneration. Ror can act as a Wnt coreceptor with frizzleds (fzs) in other contexts, so we tested the involvement of Wnt signaling proteins in dendrite regeneration. We found that knockdown of fz, dishevelled (dsh), Axin, and gilgamesh (gish) also reduced dendrite regeneration. Moreover, Ror was required to position dsh and Axin in dendrites. We recently found that Wnt signaling proteins, including dsh and Axin, localize microtubule nucleation machinery in dendrites. We therefore hypothesized that Ror may act by regulating microtubule nucleation at baseline and during dendrite regeneration. Consistent with this hypothesis, localization of the core nucleation protein γTubulin was reduced in Ror RNAi neurons, and this effect was strongest during dendrite regeneration. In addition, dendrite regeneration was sensitive to partial reduction of γTubulin. We conclude that Ror promotes dendrite regeneration as part of a Wnt signaling pathway that regulates dendritic microtubule nucleation.
Journal Article