Extensor carpi ulnaris muscle shows unexpected slow-to-fast fiber-type switch in Duchenne muscular dystrophy dogs.

Aged dystrophin-null canines are excellent models for studying experimental therapies for Duchenne muscular dystrophy, a lethal muscle disease caused by dystrophin deficiency. To establish the baseline, we studied the extensor carpi ulnaris (ECU) muscle in 15 terminal age (3-year-old) male affected dogs and 15 age/sex-matched normal dogs. Affected dogs showed histological and anatomical hallmarks of dystrophy, including muscle inflammation and fibrosis, myofiber size variation and centralized myonuclei, as well as a significant reduction of muscle weight, muscle-to-body weight ratio and muscle cross-sectional area. To rigorously characterize the contractile properties of the ECU muscle, we developed a novel in situ assay. Twitch and tetanic force, contraction and relaxation rate, and resistance to eccentric contraction-induced force loss were significantly decreased in affected dogs. Intriguingly, the time-to-peak tension and half-relaxation time were significantly shortened in affected dogs. Contractile kinetics predicted an unforeseen slow-to-fast myofiber-type switch, which we confirmed at the protein and transcript level. Our study establishes a foundation for studying long-term and late-stage therapeutic interventions in dystrophic canines. The unexpected myofiber-type switch highlights the complexity of muscle remodeling in dystrophic large mammals. This article has an associated First Person interview with the first author of the paper.

Home healthcare patient, caregiver and provider perspectives on use of unscheduled acute care and the usability and acceptability of on-demand telehealth solutions.

BACKGROUND/OBJECTIVES: Home health care (HHC) agencies provide an important role in helping to transition patients from acute care to independent residential living. Telehealth has the potential to transform care delivery in HHC, however the majority of studies in HHC have focused on the use of telemonitoring for patients with specific chronic conditions. The objective of this study was to examine reasons HHC patients use acute care services and assess the acceptability of on-demand telehealth services among HHC patients, caregivers and personnel to help alleviate the need for seeking in-person acute care. Design/Setting/Participants/Measures: This study was a secondary analysis of qualitative data from in-depth interviews of 30 HHC personnel, patients and caregivers from a Medicare-certified HHC agency affiliated with a large healthcare system from January through May 2020. A conventional content analysis approach was used to identify themes. RESULTS: Themes associated with reasons for seeking acute care included: sense of urgency, behavioral and psychosocial factors, and access to care. Participants described their perceptions of the benefits, usability and acceptability and barriers to using telehealth. Patients and HHC personnel agreed that on-demand telehealth should not replace in-person visits but all identified roles that on-demand telehealth services could play in improving communication and access to care. The biggest barriers to use of telehealth identified by HHC personnel were cost, access and ability to use technology by HHC patients. CONCLUSION: This study identified reasons HHC patients seek unscheduled acute care and the usability and acceptability of on-demand telehealth services to increase access to care among HHC patients. These findings underscore the need to improve communication and coordination between patients, HHC personnel, and primary care providers and the role that on-demand telehealth services can have in transforming HHC.

Micro-dystrophin AAV Vectors Made by Transient Transfection and Herpesvirus System Are Equally Potent in Treating mdx Mouse Muscle Disease.

Vector production scale-up is a major barrier in systemic adeno-associated virus (AAV) gene therapy. Many scalable manufacturing methods have been developed. However, the potency of the vectors generated by these methods has rarely been compared with vectors made by transient transfection (TT), the most commonly used method in preclinical studies. In this study, we blindly compared therapeutic efficacy of an AAV9 micro-dystrophin vector generated by the TT method and scalable herpes simplex virus (HSV) system in a Duchenne muscular dystrophy mouse model. AAV was injected intravenously at 5 × 1014 (high), 5 × 1013 (medium), or 5 × 1012 (low) viral genomes (vg)/kg. Comparable levels of micro-dystrophin expression were observed at each dose in a dose-dependent manner irrespective of the manufacturing method. Vector biodistribution was similar in mice injected with either the TT or the HSV method AAV. Evaluation of muscle degeneration/regeneration showed equivalent protection by vectors made by either method in a dose-dependent manner. Muscle function was similarly improved in a dose-dependent manner irrespective of the vector production method. No apparent toxicity was observed in any mouse. Collectively, our results suggest that the biological potency of the AAV micro-dystrophin vector made by the scalable HSV method is comparable to that made by the TT method.

A goal programming approach for balancing diet costs and feed water use under different environmental conditions.

Water is essential in livestock production systems. In typical dairy production systems, 90% of the total water used by a dairy farm is attributed to feed production. Theoretically, ration manipulation is a method to potentially reduce the irrigation water needed for feed crops without dramatically increasing diet costs. However, published quantitative studies on the relationship between feed production and water use that are integrated with linear programming models are scarce. The overall objective of this study was to develop an optimization framework that could achieve a balance between minimization of dietary costs and dietary irrigation water usage, and that could be used as a framework for future research and models for various livestock production systems. Weighted goal programming models were developed to minimize the dietary costs and irrigation water usage for a hypothetical cow under 8 different environmental scenarios. The environmental conditions used a 2 × 2 × 2 factorial design, including 2 atmospheric CO2 concentrations (400 and 550 ppm), 2 water years (dry and wet), and 2 irrigation methods (furrow and drip). A systematic weighting scheme was used to model the trade-off between minimizing diet cost and minimizing irrigation water use for feedstuffs. Each environmental condition generated a set of distinct diets, which each met the same nutrient requirements of the hypothetical cow but had a different water usage when the weighting scheme was changed from weighting minimum diet costs to minimum irrigation water usage. For water resource planning in areas of dairy production, this set of unique solutions provides the decision maker with different feeding options according to diet cost, water usage, and available feeds. As water was more constrained, dietary dry matter intake increased, concentrations of neutral detergent fiber, ether extract, and energy decreased, and the concentration of lignin increased because less nutritive but more water-saving feedstuffs were included in the diet. Mitigation costs of water usage were calculated from goal programming results and indicated that the potential value of water under water-limited conditions (e.g., in a drought region) was higher than that under water-sufficient conditions. However, a smaller increase in feed costs can initially significantly reduce water usage compared with that of a least-cost diet, which implies that the reduction of water usage through ration manipulation might be possible. This model serves as a framework for the study of irrigation water usage in dairy production and other livestock production systems and for decision-making processes involved in water resources planning in the broader area of animal production.

Fast skeletal muscle troponin activator CK-2066260 increases fatigue resistance by reducing the energetic cost of muscle contraction.

KEY POINTS: Skeletal muscle fatigue limits performance in various physical activities, with exercise intolerance being a key symptom in a broad spectrum of diseases. We investigated whether a small molecule fast skeletal troponin activator (FSTA), CK-2066260, can mitigate muscle fatigue by reducing the cytosolic free [Ca2+ ] required to produce a given submaximal force and hence decreasing the energy requirement. Isolated intact single mouse muscle fibres and rat muscles in-situ treated with CK-2066260 showed improved muscle endurance., which was accompanied by decreased ATP demand and reduced glycogen usage. CK-2066260 treatment improved in-vivo exercise capacity in healthy rats and in a rat model of peripheral artery insufficiency. In conclusion, we show that the FSTA CK-2066260 effectively counteracts muscle fatigue in rodent skeletal muscle in vitro, in situ, and in vivo. This may translate to humans and provide a promising pharmacological treatment to patients suffering from severe muscle weakness and exercise intolerance. ABSTRACT: Skeletal muscle fatigue limits performance during physical exercise and exacerbated muscle fatigue is a prominent symptom among a broad spectrum of diseases. The present study investigated whether skeletal muscle fatigue is affected by the fast skeletal muscle troponin activator (FSTA) CK-2066260, which increases myofibrillar Ca2+ sensitivity and amplifies the submaximal force response. Because more force is produced for a given Ca2+ , we hypothesized that CK-2066260 could mitigate muscle fatigue by reducing the energetic cost of muscle activation. Isolated single mouse muscle fibres were fatigued by 100 repeated 350 ms contractions while measuring force and the cytosolic free [Ca2+ ] or [Mg2+ ] ([Mg2+ ]i ). When starting fatiguing stimulation at matching forces (i.e. lower stimulation frequency with CK-2066260): force was decreased by ∼50% with and by ∼75% without CK-2066260; [Mg2+ ]i was increased by ∼10% with and ∼32% without CK-2066260, reflecting a larger decrease in [ATP] in the latter. The glycogen content in in situ stimulated rat muscles fatigued by repeated contractions at matching forces was about two times higher with than without CK-2066260. Voluntary exercise capacity, assessed by rats performing rotarod exercise and treadmill running, was improved in the presence of CK-2066260. CK-2066260 treatment also increased skeletal muscle fatigue resistance and exercise performance in a rat model of peripheral artery insufficiency. In conclusion, we demonstrate that the FSTA CK-2066260 mitigates skeletal muscle fatigue by reducing the metabolic cost of force generation.

Nitric oxide-dependent attenuation of noradrenaline-induced vasoconstriction is impaired in the canine model of Duchenne muscular dystrophy.

KEY POINTS: We developed a novel method to study sympatholysis in dogs. We showed abolishment of sarcolemmal nNOS, and reduction of total nNOS and total eNOS in the canine Duchenne muscular dystrophy (DMD) model. We showed sympatholysis in dogs involving both nNOS-derived NO-dependent and NO-independent mechanisms. We showed that the loss of sarcolemmal nNOS compromised sympatholysis in the canine DMD model. We showed that NO-independent sympatholysis was not affected in the canine DMD model. ABSTRACT: The absence of dystrophin in Duchenne muscular dystrophy (DMD) leads to the delocalization of neuronal nitric oxide synthase (nNOS) from the sarcolemma. Sarcolemmal nNOS plays an important role in sympatholysis, a process of attenuating reflex sympathetic vasoconstriction during exercise to ensure blood perfusion in working muscle. Delocalization of nNOS compromises sympatholysis resulting in functional ischaemia and muscle damage in DMD patients and mouse models. Little is known about the contribution of membrane-associated nNOS to blood flow regulation in dystrophin-deficient DMD dogs. We tested the hypothesis that the loss of sarcolemmal nNOS abolishes protective sympatholysis in contracting muscle of affected dogs. Haemodynamic responses to noradrenaline in the brachial artery were evaluated at rest and during contraction in the absence and presence of NOS inhibitors. We found sympatholysis was significantly compromised in DMD dogs, as well as in normal dogs treated with a selective nNOS inhibitor, suggesting that the absence of sarcolemmal nNOS underlies defective sympatholysis in the canine DMD model. Surprisingly, inhibition of all NOS isoforms did not completely abolish sympatholysis in normal dogs, suggesting sympatholysis in canine muscle also involves NO-independent mechanism(s). Our study established a foundation for using the dog model to test therapies aimed at restoring nNOS homeostasis in DMD.

Revisits after adenotonsillectomy in children with sleep-disordered breathing: A retrospective single-institution study.

OBJECTIVE: To investigate emergency room (ER) revisits and hospital readmissions following adenotonsillectomy (T&A) in children with sleep-disordered breathing (SDB), and correlations between SDB severity and ER revisits. DESIGN: Retrospective chart review study. SETTING: Tertiary referral centre. PARTICIPANT: 610 consecutive children underwent T&A for treating SDB. MAIN OUTCOME MEASURES: Sleep-disordered breathing severity was defined according to the apnoea-hypopnoea index (AHI) (primary snoring = AHI < 1; mild = AHI 1-5; moderate = AHI 5-10; and severe = AHI > 10). Revisit and readmission patterns within 30 days of the surgery were extracted and analysed. RESULTS: Of these children (mean age = 7.2 years; males = 72%), 49 (8.0%) had first ER revisit, nine (1.5%) had second ER revisits, and one (0.2%) had third ER revisits. Reasons for ER revisits were bleeding related (46%) or non-bleeding related (54%). The timing for revisits was 6.9±1.9 postoperative days for bleeding-related revisits and 9.3±10.0 days for non-bleeding-related revisits. Treatment strategies during these revisits were treat and release in 44 children (74.6%), admission for observation in eight children (13.5%), and admission for surgery in seven children (11.9%). The incidence of ER revisit and hospital readmission was similar among children with all levels of SDB severity. Multivariable logistic regression analysis showed that young children (<3 years) experienced an increased risk of non-bleeding-related revisits (odds ratio [OR] = 4.1). CONCLUSIONS: Children with severe SDB do not experience increased risks of revisit or readmission; however, young children are at increased risk of non-bleeding-related revisits.

Dual AAV Gene Therapy for Duchenne Muscular Dystrophy with a 7-kb Mini-Dystrophin Gene in the Canine Model.

Dual adeno-associated virus (AAV) technology was developed in 2000 to double the packaging capacity of the AAV vector. The proof of principle has been demonstrated in various mouse models. Yet, pivotal evidence is lacking in large animal models of human diseases. Here we report expression of a 7-kb canine ΔH2-R15 mini-dystrophin gene using a pair of dual AAV vectors in the canine model of Duchenne muscular dystrophy (DMD). The ΔH2-R15 minigene is by far the most potent synthetic dystrophin gene engineered for DMD gene therapy. We packaged minigene dual vectors in Y731F tyrosine-modified AAV-9 and delivered to the extensor carpi ulnaris muscle of a 12-month-old affected dog at the dose of 2 × 1013 viral genome particles/vector/muscle. Widespread mini-dystrophin expression was observed 2 months after gene transfer. The missing dystrophin-associated glycoprotein complex was restored. Treatment also reduced muscle degeneration and fibrosis and improved myofiber size distribution. Importantly, dual AAV therapy greatly protected the muscle from eccentric contraction-induced force loss. Our data provide the first clear evidence that dual AAV therapy can be translated to a diseased large mammal. Further development of dual AAV technology may lead to effective therapies for DMD and many other diseases in human patients.

A chronic physical activity treatment in obese rats normalizes the contributions of ET-1 and NO to insulin-mediated posterior cerebral artery vasodilation.

This study tested the hypotheses that obesity-induced decrements in insulin-stimulated cerebrovascular vasodilation would be normalized with acute endothelin-1a receptor antagonism and that treatment with a physical activity intervention restores vasoreactivity to insulin through augmented nitric oxide synthase (NOS)-dependent dilation. Otsuka Long-Evans Tokushima Fatty rats were divided into the following groups: 20 wk old food controlled (CON-20); 20 wk old free food access (model of obesity, OB-20); 40 wk old food controlled (CON-40); 40 wk old free food access (OB-40); and 40 wk old free food access+RUN (RUN-40; wheel-running access from 20 to 40 wk). Rats underwent Barnes maze testing and a euglycemic hyperinsulinemic clamp (EHC). In the 40-wk cohort, cerebellum and hippocampus blood flow (BF) were examined (microsphere infusion). Vasomotor responses (pressurized myography) to insulin were assessed in untreated, endothelin-1a receptor antagonism, and NOS inhibition conditions in posterior cerebral arteries. Insulin-stimulated vasodilation was attenuated in the OB vs. CON and RUN groups (P ≤ 0.04). Dilation to insulin was normalized with endothelin-1a receptor antagonism in the OB groups (between groups, P ≥ 0.56), and insulin-stimulated NOS-mediated dilation was greater in the RUN-40 vs. OB-40 group (P < 0.01). At 40 wk of age, cerebellum BF decreased during EHC in the OB-40 group (P = 0.02) but not CON or RUN groups (P ≥ 0.36). Barnes maze testing revealed increased entry errors and latencies in the RUN-40 vs. CON and OB groups (P < 0.01). These findings indicate that obesity-induced impairments in vasoreactivity to insulin involve increased endothelin-1 and decreased nitric oxide signaling. Chronic spontaneous physical activity, initiated after disease onset, reversed impaired vasodilation to insulin and decreased Barnes maze performance, possibly because of increased exploratory behavior.NEW & NOTEWORTHY The new and noteworthy findings are that 1) in rodents, obesity-related deficits in insulin-mediated vasodilation are associated with increased influence of insulin-stimulated ET-1 and depressed influence of insulin-stimulated NOS and 2) a physical activity intervention, initiated after the onset of disease, restores insulin-mediated vasodilation, likely by normalizing insulin-stimulated ET-1 and NOS balance. These data demonstrate that the treatment effects of chronic exercise on insulin-mediated vasodilation extend beyond active skeletal muscle vasculature and include the cerebrovasculature.

Vascular cell transcriptomic changes to exercise training differ directionally along and between skeletal muscle arteriolar trees.

EXT-induced arteriolar adaptations in skeletal muscle are heterogeneous because of spatial variations in muscle fiber type composition and fiber recruitment patterns during exercise. The purpose of this report is to summarize a series of experiments conducted to test the hypothesis that changes in vascular gene expression are signaled by alterations in shear stress resulting from increases in blood flow, muscle fiber type composition, and fiber recruitment patterns. We also report results from a follow-up study of Ankrd23, one gene whose expression was changed by EXT. We expected to see differences in magnitude of changes in gene expression along arteriolar trees and between/among arteriolar trees but similar directional changes. However, transcriptional profiles of arterioles/arteries from OLETF rats exposed to END or SIT reveal that EXT does not lead to similar directional changes in the transcriptome among arteriolar trees of different skeletal muscles or along arteriolar trees within a particular muscle. END caused the most changes in gene expression in 2A arterioles of soleus and white gastrocnemius with little to no changes in the FAs. Ingenuity Pathway Analysis across vessels revealed significant changes in gene expression in 18 pathways. EXT increased expression of some genes (Shc1, desert hedgehog protein (Dhh), adenylate cyclase 4 (Adcy4), G protein-binding protein, alpha (Gnat1), and Bcl2l1) in all arterioles examined, but decreased expression of ubiquitin D (Ubd) and cAMP response element modulator (Crem). Many contractile and/or structural protein genes were increased by SIT in the gastrocnemius FA, but the same genes exhibited decreased expression in red gastrocnemius arterioles. Ankrd23 mRNA levels increased with increasing branch order in the gastrocnemius arteriolar tree and were increased 19-fold in gastrocnemius muscle FA by SIT. Follow-up experiments indicate that Ankrd23 mRNA level was increased 14-fold in cannulated gastrocnemius FA when intraluminal pressure was increased from 90 and 180 cm H2O for 4 hours. Also, Ankrd23-/- mice exhibit limited ability to form collateral arteries following femoral artery occlusion compared to WT mice (angioscore WT=0.18±0.03; Ankrd23-/- =0.04±0.01). Further research will be required to determine whether Ankrd23 plays an important role in mechanically induced vascular remodeling of the arterial tree in skeletal muscle.

Spatiotemporal control of estrogen-responsive transcription in ERα-positive breast cancer cells.

Recruitment of transcription machinery to target promoters for aberrant gene expression has been well studied, but underlying control directed by distant-acting enhancers remains unclear in cancer development. Our previous study demonstrated that distant estrogen response elements (DEREs) located on chromosome 20q13 are frequently amplified and translocated to other chromosomes in ERα-positive breast cancer cells. In this study, we used three-dimensional interphase fluorescence in situ hybridization to decipher spatiotemporal gathering of multiple DEREs in the nucleus. Upon estrogen stimulation, scattered 20q13 DEREs were mobilized to form regulatory depots for synchronized gene expression of target loci. A chromosome conformation capture assay coupled with chromatin immunoprecipitation further uncovered that ERα-bound regulatory depots are tethered to heterochromatin protein 1 (HP1) for coordinated chromatin movement and histone modifications of target loci, resulting in transcription repression. Neutralizing HP1 function dysregulated the formation of DERE-involved regulatory depots and transcription inactivation of candidate tumor-suppressor genes. Deletion of amplified DEREs using the CRISPR/Cas9 genomic-editing system profoundly altered transcriptional profiles of proliferation-associated signaling networks, resulting in reduction of cancer cell growth. These findings reveal a formerly uncharacterized feature wherein multiple copies of the amplicon congregate as transcriptional units in the nucleus for synchronous regulation of function-related loci in tumorigenesis. Disruption of their assembly can be a new strategy for treating breast cancers and other malignancies.

NKX6.1 functions as a metastatic suppressor through epigenetic regulation of the epithelial-mesenchymal transition.

The transcription factor NKX6.1 (NK6 homeobox 1) is important in the development of pancreatic ß-cells and neurons. Although recent publications show that NKX6.1 is hypermethylated and downregulated during tumorigenesis, the function of NKX6.1 in carcinogenesis remains elusive. Here, we address the metastasis suppressor function of human NKX6.1 using cell, animal and clinical analyses. Our data show that NKX6.1 represses tumor formation and metastatic ability both in vitro and in vivo. Mechanistically, NKX6.1 suppresses cell invasion by inhibiting the epithelial-to-mesenchymal transition (EMT). NKX6.1 directly enhances the mRNA level of E-cadherin by recruiting BAF155 coactivator and represses that of vimentin and N-cadherin by recruiting RBBP7 (retinoblastoma binding protein 7) corepressor. Clinical cancer tumors with metastasis show low NKX6.1 protein expression coinciding with low E-cadherin and high vimentin expression. Our results demonstrate that NKX6.1 functions as an EMT suppressor by interacting with different epigenetic modifiers, making it a potential novel therapeutic option.

Safe and bodywide muscle transduction in young adult Duchenne muscular dystrophy dogs with adeno-associated virus.

The ultimate goal of muscular dystrophy gene therapy is to treat all muscles in the body. Global gene delivery was demonstrated in dystrophic mice more than a decade ago using adeno-associated virus (AAV). However, translation to affected large mammals has been challenging. The only reported attempt was performed in newborn Duchenne muscular dystrophy (DMD) dogs. Unfortunately, AAV injection resulted in growth delay, muscle atrophy and contracture. Here we report safe and bodywide AAV delivery in juvenile DMD dogs. Three ∼2-m-old affected dogs received intravenous injection of a tyrosine-engineered AAV-9 reporter or micro-dystrophin (µDys) vector at the doses of 1.92-6.24 × 10(14) viral genome particles/kg under transient or sustained immune suppression. DMD dogs tolerated injection well and their growth was not altered. Hematology and blood biochemistry were unremarkable. No adverse reactions were observed. Widespread muscle transduction was seen in skeletal muscle, the diaphragm and heart for at least 4 months (the end of the study). Nominal expression was detected in internal organs. Improvement in muscle histology was observed in µDys-treated dogs. In summary, systemic AAV gene transfer is safe and efficient in young adult dystrophic large mammals. This may translate to bodywide gene therapy in pediatric patients in the future.

Slug is temporally regulated by cyclin E in cell cycle and controls genome stability.

The transcriptional repressor Slug is best known to control epithelial-mesenchymal transition (EMT) and promote cancer invasion/metastasis. In this study, we demonstrate that Slug is temporally regulated during cell cycle progression. At G1/S transition, cyclin E-cyclin-dependent kinase 2 mediates the phosphorylation of Slug at Ser-54 and Ser-104, resulting in its ubiquitylation and degradation. Non-phosphorylatable Slug is markedly stabilized at G1/S transition compared with wild-type Slug and greatly leads to downregulation of DNA synthesis and checkpoint-related proteins, including TOP1, DNA Ligase IV and Rad17, reduces cell proliferation, delays S-phase progression and contributes to genome instability. Our results indicate that Slug has multifaceted roles in cancer progression by controlling both EMT and genome stability.

Assessment of autonomic nervous system by using empirical mode decomposition-based reflection wave analysis during non-stationary conditions.

Arterial blood pressure (ABP) is an important indicator of cardiovascular circulation and presents various intrinsic regulations. It has been found that the intrinsic characteristics of blood vessels can be assessed quantitatively by ABP analysis (called reflection wave analysis (RWA)), but conventional RWA is insufficient for assessment during non-stationary conditions, such as the Valsalva maneuver. Recently, a novel adaptive method called empirical mode decomposition (EMD) was proposed for non-stationary data analysis. This study proposed a RWA algorithm based on EMD (EMD-RWA). A total of 51 subjects participated in this study, including 39 healthy subjects and 12 patients with autonomic nervous system (ANS) dysfunction. The results showed that EMD-RWA provided a reliable estimation of reflection time in baseline and head-up tilt (HUT). Moreover, the estimated reflection time is able to assess the ANS function non-invasively, both in normal, healthy subjects and in the patients with ANS dysfunction. EMD-RWA provides a new approach for reflection time estimation in non-stationary conditions, and also helps with non-invasive ANS assessment.

miR-93-directed downregulation of DAB2 defines a novel oncogenic pathway in lung cancer.

The disabled homolog 2 (DAB2) gene was recently identified as a tumor suppressor gene with its expression downregulated in multiple cancer types. The role of DAB2 in lung tumorigenesis, however, is not fully characterized, and the mechanisms of DAB2 dysregulation in lung cancer are not defined. Here we show that low DAB2 levels in lung tumor specimens are significantly correlated with poor patient survival, and that DAB2 overexpression significantly inhibits cell growth in cultured lung cancer cells, indicating its potent tumor suppressor function. We next identify that microRNA miR-93 functions as a potent repressor of DAB2 expression by directly targeting the 3'UTR of the DAB2 mRNA. Using in vitro and in vivo approaches, we demonstrate that miR-93 overexpression has an important role in promoting lung cancer cell growth, and that its oncogenic function is primarily mediated by downregulating DAB2 expression. Our clinical investigations further indicate that high tumor levels of miR-93 are correlated with poor survival of lung cancer patients. The correlations of both low DAB2 and high miR-93 expression levels with poor patient survival strongly support the critical role of the miR-93/DAB2 pathway in determining lung cancer progression.

Dolor y medicina complementaria y acupuntura / Pain and complementary medicine and acupuncture

El objetivo de este artículo es entregar información documentada sobre la situación actual de la Medicina Complementaria y la Acupuntura en Chile, su definición, reglamentación, mecanismos de acción y evidencia. Busca orientar sobre el uso de estas herramientas terapéuticas que son cada vez más solicitadas en el país.