Showing papers by "East Carolina University published in 2018"
TL;DR: The epidemiological features of cutaneous melanoma along with the biological mechanisms involved in its development and progression are summarized and the current state-of-the-art of advanced stage melanoma treatment strategies and the currently available evidence of the use of predictive and prognostic biomarkers are discussed.
Abstract: In less than 10 years, melanoma treatment has been revolutionized with the approval of tyrosine kinase inhibitors and immune checkpoint inhibitors, which have been shown to have a significant impact on the prognosis of patients with melanoma. The early steps of this transformation have taken place in research laboratories. The mitogen‑activated protein kinase (MAPK) pathway, phosphoinositol‑3‑kinase (PI3K) pathway promote the development of melanoma through numerous genomic alterations on different components of these pathways. Moreover, melanoma cells deeply interact with the tumor microenvironment and the immune system. This knowledge has led to the identification of novel therapeutic targets and treatment strategies. In this review, the epidemiological features of cutaneous melanoma along with the biological mechanisms involved in its development and progression are summarized. The current state‑of‑the‑art of advanced stage melanoma treatment strategies and the currently available evidence of the use of predictive and prognostic biomarkers are also discussed.
361 citations
TL;DR: These transcriptome datasets provide an information-rich resource for studies of SSCs, male meiosis, testicular cancer, male infertility, or contraceptive development, as well as a gene expression roadmap to be emulated in efforts to achieve spermatogenesis in vitro.
350 citations
TL;DR: The role of ET to promote clinically significant weight loss and promote weight maintenance is evaluated and the likelihood of weight loss from ET programs composed of aerobic training only, resistance training only and programs that combine diet and ET are evaluated.
246 citations
TL;DR: This study provides a holistic understanding of microbiome structure within a bioenergy relevant plant host, one of the most complete niche-level analyses of any plant and constitutes a detailed atlas or map for further hypothesis testing on the significance of individual microbial taxa within specific niches and habitats of Populus.
Abstract: Microorganisms serve important functions within numerous eukaryotic host organisms. An understanding of the variation in the plant niche-level microbiome, from rhizosphere soils to plant canopies, is imperative to gain a better understanding of how both the structural and functional processes of microbiomes impact the health of the overall plant holobiome. Using Populus trees as a model ecosystem, we characterized the archaeal/bacterial and fungal microbiome across 30 different tissue-level niches within replicated Populus deltoides and hybrid Populus trichocarpa × deltoides individuals using 16S and ITS2 rRNA gene analyses. Our analyses indicate that archaeal/bacterial and fungal microbiomes varied primarily across broader plant habitat classes (leaves, stems, roots, soils) regardless of plant genotype, except for fungal communities within leaf niches, which were greatly impacted by the host genotype. Differences between tree genotypes are evident in the elevated presence of two potential fungal pathogens, Marssonina brunnea and Septoria sp., on hybrid P. trichocarpa × deltoides trees which may in turn be contributing to divergence in overall microbiome composition. Archaeal/bacterial diversity increased from leaves, to stem, to root, and to soil habitats, whereas fungal diversity was the greatest in stems and soils. This study provides a holistic understanding of microbiome structure within a bioenergy relevant plant host, one of the most complete niche-level analyses of any plant. As such, it constitutes a detailed atlas or map for further hypothesis testing on the significance of individual microbial taxa within specific niches and habitats of Populus and a baseline for comparisons to other plant species.
241 citations
TL;DR: It is shown that nurses, as frontline patient care providers, are the foundation for patient safety and care quality, and healthier work environments lead to more satisfied nurses who will result in better job performance and higher quality of patient care, which will subsequently improve healthcare organizations' financial viability.
234 citations
TL;DR: The costs of transplantation and dialysis were compared with the use of discrete event simulation over a 10‐year period, and kidney transplantation is cost‐effective across all donor types despite higher costs for marginal organs and innovative living donor practices.
225 citations
TL;DR: The ISCHEMIA trial will provide new scientific evidence regarding whether an invasive management strategy improves clinical outcomes when added to optimal medical therapy in patients with SIHD and moderate or severe ischemia.
216 citations
TL;DR: This article defines guidelines for the measurement of cardiac physiology in mice, as the most commonly used animal model in cardiovascular research, and provides best-practice information regarding how to measure accurately heart physiology in animal models.
Abstract: Cardiovascular disease is a leading cause of death, and translational research is needed to understand better mechanisms whereby the left ventricle responds to injury. Mouse models of heart disease...
202 citations
TL;DR: The examined studies suggest that ES, SGs, and SEGs do not differ in a statistically significant way when compared to traditional instruction but do differ from each other, and are more effective in increasing outcomes than SGs and simulations.
190 citations
Boston Children's Hospital1, University of Pennsylvania2, Children's Hospital of Wisconsin3, East Carolina University4, Wake Forest University5, Duke University6, Emory University7, Columbia University8, Medical University of South Carolina9, National Institutes of Health10, Cincinnati Children's Hospital Medical Center11, University of Michigan12, Children's Hospital Los Angeles13, Wilmington University14, Primary Children's Hospital15
TL;DR: Transplant-free survival for the RVPAS versus modified Blalock–Taussig shunt groups did not differ at 6 years or with all available follow-up, and the hazards of death or transplant and catheter interventions were not different.
Abstract: Background: In the SVR trial (Single Ventricle Reconstruction), 1-year transplant-free survival was better for the Norwood procedure with right ventricle-to-pulmonary artery shunt (RVPAS) compared with a modified Blalock–Taussig shunt in patients with hypoplastic left heart and related syndromes. At 6 years, we compared transplant-free survival and other outcomes between the groups. Methods: Medical history was collected annually using medical record review, telephone interviews, and the death index. The cohort included 549 patients randomized and treated in the SVR trial. Results: Transplant-free survival for the RVPAS versus modified Blalock–Taussig shunt groups did not differ at 6 years (64% versus 59%, P =0.25) or with all available follow-up of 7.1±1.6 years (log-rank P =0.13). The RVPAS versus modified Blalock–Taussig shunt treatment effect had nonproportional hazards ( P =0.009); the hazard ratio (HR) for death or transplant favored the RVPAS before stage II surgery (HR, 0.66; 95% confidence interval, 0.48–0.92). The effect of shunt type on death or transplant was not statistically significant between stage II to Fontan surgery (HR, 1.36; 95% confidence interval, 0.86–2.17; P =0.17) or after the Fontan procedure (HR, 0.76; 95% confidence interval, 0.33–1.74; P =0.52). By 6 years, patients with RVPAS had a higher incidence of catheter interventions (0.38 versus 0.23/patient-year, P Conclusions: By 6 years, the hazards of death or transplant and catheter interventions were not different between the RVPAS versus modified Blalock–Taussig shunt groups. Children assigned to the RVPAS group had 5% higher transplant-free survival, but the difference did not reach statistical significance, and they required more catheter interventions. Both treatment groups have accrued important complications. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00115934.
165 citations
TL;DR: Among recreational runners, women sustain injuries at a higher rate than men and greater knee stiffness, more common in runners with higher body weights, significantly increases the odds of sustaining an overuse running injury.
Abstract: Background:The National Center for Injury Prevention and Control, noting flaws in previous running injury research, called for more rigorous prospective designs and comprehensive analyses to define...
TL;DR: The discovery of high concentrations of GenX and related perfluoroalkyl ether acids (PFEAs) in the Cape Fear River and in finished drinking water of more than 200,000 North Carolina residents required quick action by researchers, regulators, public health officials, commercial laboratories, drinking water providers, and consulting engineers.
Abstract: For several decades, a common processing aid in the production of fluoropolymers was the ammonium salt of perfluorooctanoic acid (PFOA). Because PFOA is persistent, bioaccumulative, and toxic, its production and use are being phased out in the United States. In 2009, the US Environmental Protection Agency stipulated conditions for the manufacture and commercial use of GenX, a PFOA replacement. While GenX is produced for commercial purposes, the acid form of GenX is also generated as a byproduct during the production of fluoromonomers. The discovery of high concentrations of GenX and related perfluoroalkyl ether acids (PFEAs) in the Cape Fear River and in finished drinking water of more than 200,000 North Carolina residents required quick action by researchers, regulators, public health officials, commercial laboratories, drinking water providers, and consulting engineers. Information about sources and toxicity of GenX as well as an analytical method for the detection of GenX and eight related PFEAs is presented. GenX/PFEA occurrence in water and GenX/PFEA removal by different drinking water treatment processes are also discussed.
TL;DR: By providing a clear framework for mating rules and how these rules affect speciation through maintaining or eroding barriers to gene flow among closely related species or populations, this work hopes to inspire greater alignment in the ways that both theoreticians and empiricists study mating rules.
Abstract: The large body of theory on speciation with gene flow has brought to light fundamental differences in the effects of two types of mating rules on speciation: preference/trait rules, in which divergence in both (female) preferences and (male) mating traits is necessary for assortment, and matching rules, in which individuals mate with like individuals on the basis of the presence of traits or alleles that they have in common. These rules can emerge from a variety of behavioral or other mechanisms in ways that are not always obvious. We discuss the theoretical properties of both types of rules and explain why speciation is generally thought to be more likely under matching rather than preference/trait rules. We furthermore discuss whether specific assortative mating mechanisms fall under a preference/trait or matching rule, present empirical evidence for these mechanisms, and propose empirical tests that could distinguish between them. The synthesis of the theoretical literature on these assortative mating rules with empirical studies of the mechanisms by which they act can provide important insights into the occurrence of speciation with gene flow. Finally, by providing a clear framework we hope to inspire greater alignment in the ways that both theoreticians and empiricists study mating rules and how these rules affect speciation through maintaining or eroding barriers to gene flow among closely related species or populations.
TL;DR: No evidence that laws designed to increase layperson engagement in opioid-overdose reversal were associated with increased non-medical opioid use and there was no evidence that these measures wereassociated with increasedNon- medical opioid use.
TL;DR: Clinical studies on pregabalin, gabapentin enacarbil, oxycodone-naloxone, and iron preparations have provided new treatment options, but most patients still report inadequate long-term management of symptoms.
Abstract: Restless legs syndrome, also known as Willis-Ekbom disease, is a common neurological condition whose manifestation is affected by complex environmental and genetic interactions Restless legs syndrome can occur on its own, mostly at a young age, or with comorbidities such as cardiovascular disease, diabetes, and arterial hypertension, making it a difficult condition to properly diagnose However, the concept of restless legs syndrome as being two entities, primary or secondary to another condition, has been challenged with genetic data providing further insight into the pathophysiology of the condition Although dopaminergic treatment was formerly the first-line therapy, prolonged use can result in a serious worsening of symptoms known as augmentation Clinical studies on pregabalin, gabapentin enacarbil, oxycodone-naloxone, and iron preparations have provided new treatment options, but most patients still report inadequate long-term management of symptoms Studies of the hypoxic pathway activation and iron deficiency have provided valuable information about the pathophysiology of restless legs syndrome that should now be translated into new, more effective treatments for restless legs syndrome
TL;DR: The NIAS subscales demonstrated high internal consistency, test-retest reliability, invariant item loadings between two samples, and convergent/discriminant validity with other measures of picky eating, appetite, fear of negative consequences, and psychopathology, and are a brief, reliable instrument that may be used to further investigate ARFID-related eating behaviors.
TL;DR: Zhang et al. as mentioned in this paper investigated the impact of environmental regulations on green technological innovative behavior via the mediation of Green technological innovative intention, and found that both command-and-control environmental regulation and market-based incentive environmental regulation have positive impact on green technology innovative intention and also have different positive effects on end-of-pipe technological innovative behaviour.
TL;DR: Successful TR reduction by TTVR serves as a predictor for reduced mortality and heart failure hospitalization and may assist in decision making whether a patient is anatomically suited for TTVr.
Abstract: Objectives This study sought to investigate predictors of procedural success and clinical outcomes in patients with tricuspid regurgitation (TR) at increased surgical risk undergoing transcatheter tricuspid valve edge-to-edge repair (TTVR). Background Recent data suggest TTVR using the edge-to-edge repair technique in patients at high surgical risk is feasible and improves functional status at short-term follow-up. Methods TTVR was carried out in 117 patients with symptomatic TR (median age 79.0 years [interquartile range (IQR): 75.5 to 83.0 years], EuroSCORE II 6.3% [IQR: 4.1% to 10.8%], STS mortality score 5.3% [IQR: 2.9% to 7.1%]) at 2 centers in Germany between March 2016 and November 2017. Seventy-four patients had concomitant severe mitral regurgitation and underwent transcatheter edge-to-edge repair of both valves. Results During TTVR, 185 and 34 clips were implanted at the anteroseptal and posteroseptal commissures, respectively. Procedural success (TR reduction ≥1) was achieved in 81% of patients. Median TR effective regurgitant orifice area was reduced from 0.5 to 0.2 cm2. After a median follow-up of 184 days (IQR: 106 to 363 days), 24 patients died and 21 patients were readmitted for heart failure. TTVR procedural success independently predicted the time free of death and admission for heart failure (hazard ratio: 0.20 [95% confidence interval: 0.08 to 0.48]; p Conclusions Successful TR reduction by TTVR serves as a predictor for reduced mortality and heart failure hospitalization. TR coaptation gap and jet location may assist in decision making whether a patient is anatomically suited for TTVR.
TL;DR: A high-quality draft genome sequence for Gnetum montanum is reported, the first for any gnetophyte, enabling a better resolution of ancestral genomic features within seed plants, and the identification of genomic characters that distinguish gnetum from other gymnosperms.
Abstract: Gnetophytes are an enigmatic gymnosperm lineage comprising three genera, Gnetum, Welwitschia and Ephedra, which are morphologically distinct from all other seed plants. Their distinctiveness has triggered much debate as to their origin, evolution and phylogenetic placement among seed plants. To increase our understanding of the evolution of gnetophytes, and their relation to other seed plants, we report here a high-quality draft genome sequence for Gnetum montanum, the first for any gnetophyte. By using a novel genome assembly strategy to deal with high levels of heterozygosity, we assembled >4 Gb of sequence encoding 27,491 protein-coding genes. Comparative analysis of the G. montanum genome with other gymnosperm genomes unveiled some remarkable and distinctive genomic features, such as a diverse assemblage of retrotransposons with evidence for elevated frequencies of elimination rather than accumulation, considerable differences in intron architecture, including both length distribution and proportions of (retro) transposon elements, and distinctive patterns of proliferation of functional protein domains. Furthermore, a few gene families showed Gnetum-specific copy number expansions (for example, cellulose synthase) or contractions (for example, Late Embryogenesis Abundant protein), which could be connected with Gnetum's distinctive morphological innovations associated with their adaptation to warm, mesic environments. Overall, the G. montanum genome enables a better resolution of ancestral genomic features within seed plants, and the identification of genomic characters that distinguish Gnetum from other gymnosperms.
TL;DR: In this paper, the authors examined the role of innovativeness in the intellectual capital and organizational performance relationship using a sample of small firms and found a positive relationship between two components of intellectual capital, human capital, and organizational capital.
TL;DR: The results indicate that comment quantity, comment score, reply length, and reply speed are positively associated with the fundraising success and comment sentiment positively moderates the effect of comment quantity on crowdfunding success.
01 Nov 2018
TL;DR: The interaction between land degradation and the livelihoods of the poor is complex and conditioned by important economic, social and environmental factors as discussed by the authors, and these factors are also in part responsible for the limited success of economic growth policies to reduce poverty.
Abstract: Land is one of the few productive assets owned by the rural poor, and almost all such households engage in some form of agriculture. Over 2000–2010 the rural poor on degrading agricultural land increased in low-income countries and in sub-Saharan Africa and South Asia. Although degradation threatens the livelihoods of the poor, this interaction is complex and conditioned by key economic, social and environmental factors. These factors also limit the poverty-reducing impacts of economic growth and economy-wide reforms. A comprehensive development strategy requires investments that improve the livelihoods of affected populations and regions, and facilitates outmigration in severely impacted areas. The interaction between land degradation and the livelihoods of the poor is complex and conditioned by important economic, social and environmental factors. These factors are also in part responsible for the limited success of economic growth policies to reduce poverty.
TL;DR: Identifying patterns in microbial diversity and ecosystem function relationships can provide insight into microbiome management, which will require manipulating soil nutrients and resources mediated through plant diversity.
Abstract: Agricultural management can have lasting impacts on microbial community structure and function through changes in biotic (i.e., plant inputs) and abiotic (i.e., soil fertility) soil properties. Enhancing biodiversity is expected to increase ecosystem functions, and in an agricultural context, such functions include enhanced plant production and pest suppression. For example, disease suppressive soils are characterized by the biocontrol properties provided by resident soil microorganisms capable of producing antifungal or antibacterial compounds known to suppress the growth of soil-borne pathogens. In this study, we investigated the impact of long-term crop diversity on microbial communities and disease suppressive functional potential in soils. In 2012, we collected soil samples from the Biodiversity Gradient Experiment (established in 2000) at the Kellogg Biological Station Long-Term Ecological Research (KBS-LTER) site. We sampled 7 treatments along the crop diversity gradient (monoculture to 5 crop species) and a spring fallow treatment to examine the influence of crop diversity on total bacterial community composition (16S rRNA amplicon sequencing) and a subset of microorganisms capable of producing antifungal compounds (2,4-diacetylphloroglucinol: phlD gene fingerprint analysis; pyrrolnitrin: prnD gene quantitative PCR). Our study revealed that crop diversity significantly influenced bacterial community composition and abundance of disease suppressive functional groups. Variation in plant inputs to soil organic matter pools may be a possible mechanism driving shifts in microbial community patterns and disease suppressive functional potential.
TL;DR: In this paper, the authors used social network analysis to examine a theoretical model exploring why, and under what circumstances, the perpetrators' ostracizing behaviors are accurately perceived by the target employees.
Abstract: We used social network analysis to examine a theoretical model exploring why, and under what circumstances, the perpetrators’ ostracizing behaviors are accurately perceived by the target employees. In turn, these perceptions of ostracism lead to the target employees’ counterproductive work behaviors. Adopting perspectives from both perpetrators and targets, we directly measured the ostracizing behaviors by all potential perpetrators (coworkers) and perceived workplace ostracism by target employees. We integrate Social information processing theory and conservation of resource theory to propose a moderated mediation model, and found that employees who have a high level of need to belong are more likely to capture coworkers’ ostracizing behaviors, and those with low political skill are more likely to engage in counterproductive work behavior as their reaction to perceived workplace ostracism. Theoretical and practical implications are discussed.
TL;DR: It is demonstrated that E2 directly modulates membrane biophysical properties and bioenergetic function in mitochondria, offering a direct mechanism by which E2 status broadly influences energy homeostasis.
Boston Children's Hospital1, University of Florida2, Merck & Co.3, Mayo Clinic4, Stanford University5, University of Texas MD Anderson Cancer Center6, University of Southern California7, City of Hope National Medical Center8, University of Sydney9, Johns Hopkins University10, East Carolina University11, University of Texas Southwestern Medical Center12, Harvard University13, Memorial Sloan Kettering Cancer Center14, University of Oklahoma15
TL;DR: The addition of VI to VAC did not improve EFS or OS for patients with intermediate- risk RMS, making VAC/VI an alternative standard therapy for intermediate-risk RMS.
Abstract: PurposeIntermediate-risk rhabdomyosarcoma (RMS) includes patients with either nonmetastatic, unresected embryonal RMS (ERMS) with an unfavorable primary site or nonmetastatic alveolar RMS (ARMS). The primary aim of this study was to improve the outcome of patients with intermediate-risk RMS by substituting vincristine and irinotecan (VI) for half of vincristine, dactinomycin, and cyclophosphamide (VAC) courses. All patients received a lower dose of cyclophosphamide and earlier radiation therapy than in previous trials.Patients and MethodsPatients were randomly assigned at study entry to either VAC (cumulative cyclophosphamide dose, 16.8 g/m2) or VAC/VI (cumulative cyclophosphamide dose, 8.4 g/m2) for 42 weeks of therapy. Radiation therapy started at week 4, with individualized local control plans permitted for patients younger than 24 months. The primary study end point was event-free survival (EFS). The study design had an 80% power (5% one-sided α-level) to detect an improved long-term EFS from 65% (wit...
TL;DR: Successful site-directed mutagenesis in carrot with CRISPR/Cas9 is demonstrated and the usefulness of a model callus culture to validate genome editing systems is demonstrated.
Abstract: The first report presenting successful and efficient carrot genome editing using CRISPR/Cas9 system. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas9) is a powerful genome editing tool that has been widely adopted in model organisms recently, but has not been used in carrot-a model species for in vitro culture studies and an important health-promoting crop grown worldwide. In this study, for the first time, we report application of the CRISPR/Cas9 system for efficient targeted mutagenesis of the carrot genome. Multiplexing CRISPR/Cas9 vectors expressing two single-guide RNA (gRNAs) targeting the carrot flavanone-3-hydroxylase (F3H) gene were tested for blockage of the anthocyanin biosynthesis in a model purple-colored callus using Agrobacterium-mediated genetic transformation. This approach allowed fast and visual comparison of three codon-optimized Cas9 genes and revealed that the most efficient one in generating F3H mutants was the Arabidopsis codon-optimized AteCas9 gene with up to 90% efficiency. Knockout of F3H gene resulted in the discoloration of calli, validating the functional role of this gene in the anthocyanin biosynthesis in carrot as well as providing a visual marker for screening successfully edited events. Most resulting mutations were small Indels, but long chromosome fragment deletions of 116-119 nt were also generated with simultaneous cleavage mediated by two gRNAs. The results demonstrate successful site-directed mutagenesis in carrot with CRISPR/Cas9 and the usefulness of a model callus culture to validate genome editing systems. Given that the carrot genome has been sequenced recently, our timely study sheds light on the promising application of genome editing tools for boosting basic and translational research in this important vegetable crop.
TL;DR: Fitness level and body mass index were identified as significant predictive variables for post‐exercise irisin concentration, however, a multiple meta‐regression model identified fitness level as the single best predictor, with being fit associated with a nearly twofold increase in post-exerciseirisin concentration.
Abstract: Irisin is a recently discovered myokine that increases adipocyte metabolism, induces further "browning" of white adipose tissue, and enhances glucose metabolism. No study has ever determined how an acute bout of exercise impacts immediate post-exercise irisin concentration using a meta-analytic approach. The purpose of this study is to determine the impact of an acute bout of exercise on the magnitude of post-exercise irisin concentration in adults using meta-analytic procedures. Searches were performed on PubMed, EMBASE, CINAHL, PEDro, SCOPUS, and SPORTDiscus databases. Effect summaries were obtained using random-effects models. Random-effects single and multiple meta-regressions were performed to determine relationships between, and potential confounding effects of, variables of interest. Ten articles were retained for the final meta-analysis, producing 21 study estimates. An acute bout of exercise was accompanied by a post-exercise average increase in irisin concentration of 15.0 (95% CI: 10.8%-19.3%). There was no significant relationship between post-exercise irisin concentration and age, intensity of aerobic exercise, or type of exercise training session (resistance vs aerobic training). Fitness level and body mass index were identified as significant predictive variables for post-exercise irisin concentration. However, a multiple meta-regression model identified fitness level as the single best predictor, with being fit (21.1%±2.2%) associated with a nearly twofold increase in post-exercise irisin concentration, compared with being unfit (11.8%±2.1%). Immediately following an acute bout of exercise, irisin concentration increases substantially in adults, with fitness level as an important modifier for the effect.
TL;DR: The current study identifies the setting for improved short-term survival in MPN-BP, but also highlights the limited value of current therapy, including AlloSCT, in securing long- term survival.
Abstract: A total of 410 patients with blast phase myeloproliferative neoplasm (MPN-BP) were retrospectively reviewed: 248 from the Mayo Clinic and 162 from Italy. Median survival was 3.6 months, with no improvement over the last 15 years. Multivariable analysis performed on the Mayo cohort identified high risk karyotype, platelet count 65 years and transfusion need as independent risk factors for survival. Also in the Mayo cohort, intensive chemotherapy resulted in complete remission (CR) or CR with incomplete count recovery (CRi) rates of 35 and 24%, respectively; treatment-specified 3-year/5-year survival rates were 32/10% for patients receiving allogeneic stem cell transplant (AlloSCT) (n = 24), 19/13% for patients achieving CR/CRi but were not transplanted (n = 24), and 1/1% in the absence of both AlloSCT and CR/CRi (n = 200) (p < 0.01). The survival impact of AlloSCT (HR 0.2, 95% CI 0.1–0.3), CR/CRi without AlloSCT (HR 0.3, 95% CI 0.2–0.5), high risk karyotype (HR 1.6, 95% CI 1.1–2.2) and platelet count < 100 × 109/L (HR 1.6, 95% CI 1.1–2.2) were confirmed to be inter-independent. Similar observations were made in the Italian cohort. The current study identifies the setting for improved short-term survival in MPN-BP, but also highlights the limited value of current therapy, including AlloSCT, in securing long-term survival.
TL;DR: It is hypothesized that intramuscular injection of miR‐23a/27a would counteract both muscle wasting and renal fibrosis lesions in a streptozotocin‐induced diabetic model.
Abstract: Background The treatment of muscle wasting is accompanied by benefits in other organs, possibly resulting from muscle-organ crosstalk. However, how the muscle communicates with these organs is less understood. Two microRNAs (miRs), miR-23a and miR-27a, are located together in a gene cluster and regulate proteins that are involved in the atrophy process. MiR-23a/27a has been shown to reduce muscle wasting and act as an anti-fibrotic agent. We hypothesized that intramuscular injection of miR-23a/27a would counteract both muscle wasting and renal fibrosis lesions in a streptozotocin-induced diabetic model. Methods We generated an adeno-associated virus (AAV) that overexpresses the miR-23a∼27a∼24-2 precursor RNA and injected it into the tibialis anterior muscle of streptozotocin-induced diabetic mice. Muscle cross-section area (immunohistology plus software measurement) and muscle function (grip strength) were used to evaluate muscle atrophy. Fibrosis-related proteins were measured by western blot to monitor renal damage. In some cases, AAV-GFP was used to mimic the miR movement in vivo, allowing us to track organ redistribution by using the Xtreme Imaging System. Results The injection of AAV-miR-23a/27a increased the levels of miR-23a and miR-27a as well as increased phosphorylated Akt, attenuated the levels of FoxO1 and PTEN proteins, and reduced the abundance of TRIM63/MuRF1 and FBXO32/atrogin-1 in skeletal muscles. It also decreased myostatin mRNA and protein levels as well as the levels of phosphorylated pSMAD2/3. Provision of miR-23a/27a attenuates the diabetes-induced reduction of muscle cross-sectional area and muscle function. Curiously, the serum BUN of diabetic animals was reduced in mice undergoing the miR-23a/27a intervention. Renal fibrosis, evaluated by Masson trichromatic staining, was also decreased as were kidney levels of phosphorylated SMAD2/3, alpha smooth muscle actin, fibronectin, and collagen. In diabetic mice injected intramuscularly with AAV-GFP, GFP fluorescence levels in the kidneys showed linear correlation with the levels in injected muscle when examined by linear regression. Following intramuscular injection of AAV-miR-23a∼27a∼24-2, the levels of miR-23a and miR-27a in serum exosomes and kidney were significantly increased compared with samples from control virus-injected mice; however, no viral DNA was detected in the kidney. Conclusions We conclude that overexpression of miR-23a/27a in muscle prevents diabetes-induced muscle cachexia and attenuates renal fibrosis lesions via muscle-kidney crosstalk. Further, this crosstalk involves movement of miR potentially through muscle originated exosomes and serum distribution without movement of AAV. These results could provide new approaches for developing therapeutic strategies for diabetic nephropathy with muscle wasting.