Intramyocardial Injection of Hypoxia-Conditioned Extracellular Vesicles Modulates Response to Oxidative Stress in the Chronically Ischemic Myocardium.

INTRODUCTION: Patients with advanced coronary artery disease (CAD) who are not eligible for stenting or surgical bypass procedures have limited treatment options. Extracellular vesicles (EVs) have emerged as a potential therapeutic target for the treatment of advanced CAD. These EVs can be conditioned to modify their contents. In our previous research, we demonstrated increased perfusion, decreased inflammation, and reduced apoptosis with intramyocardial injection of hypoxia-conditioned EVs (HEVs). The goal of this study is to further understand the function of HEVs by examining their impact on oxidative stress using our clinically relevant and extensively validated swine model of chronic myocardial ischemia. METHODS: Fourteen Yorkshire swine underwent a left thoracotomy for the placement of an ameroid constrictor on the left circumflex coronary artery to model chronic myocardial ischemia. After two weeks of recovery, the swine underwent a redo thoracotomy with injection of either HEVs (n = 7) or a saline control (CON, n = 7) into the ischemic myocardium. Five weeks after injection, the swine were subjected to terminal harvest. Protein expression was measured using immunoblotting. OxyBlot analysis and 3-nitrotyrosine staining were used to quantify total oxidative stress. RESULTS: There was a significant increase in myocardial expression of the antioxidants SOD 2, GPX-1, HSF-1, UCP-2, catalase, and HO-1 (all p ≤ 0.05) in the HEV group when compared to control animals. The HEVs also exhibited a significant increase in pro-oxidant NADPH oxidase (NOX) 1, NOX 3, p47phox, and p67phox (all p ≤ 0.05). However, no change was observed in the expression of NFkB, KEAP 1, and PRDX1 (all p > 0.05) between the HEV and CON groups. There were no significant differences in total oxidative stress as determined by OxyBlot and 3-nitrotyrosine staining (p = 0.64, p = 0.32) between the groups. CONCLUSIONS: Administration of HEVs in ischemic myocardium induces a significant increase in pro- and antioxidant proteins without a net change in total oxidative stress. These findings suggest that HEV-induced changes in redox signaling pathways may play a role in increased perfusion, decreased inflammation, and reduced apoptosis in ischemic myocardium. Further studies are required to determine if HEVs alter the net oxidative stress in ischemic myocardium at an earlier time point of HEV administration.

Proteomic Analysis and Sex-Specific Changes in Chronically Ischemic Swine Myocardium Treated with Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin.

BACKGROUND: Although sodium-glucose cotransporter-2 inhibitors have been shown to improve cardiovascular outcomes in general, little is presently known about any sex-specific changes that may result from this therapy. We sought to investigate and quantify potential sex-specific changes seen with the sodium-glucose cotransporter-2 inhibitor canagliflozin (CAN) in a swine model of chronic myocardial ischemia. STUDY DESIGN: Eighteen Yorkshire swine underwent left thoracotomy with placement of an ameroid constrictor. Two weeks postop, swine were assigned to receive either control (F = 5 and M = 5) or CAN 300 mg daily (F = 4 and M = 4). After 5 weeks of therapy, swine underwent myocardial functional measurements, and myocardial tissue was sent for proteomic analysis. RESULTS: Functional measurements showed increased cardiac output, stroke volume, ejection fraction, and ischemic myocardial flow at rest in male swine treated with CAN compared with control male swine (all p < 0.05). The female swine treated with CAN had no change in cardiac function as compared with control female swine. Proteomic analysis demonstrated 6 upregulated and 97 downregulated proteins in the CAN female group compared with the control female group. Pathway analysis showed decreases in proteins in the tricarboxylic acidic cycle. The CAN male group had 639 upregulated and 172 downregulated proteins compared with control male group. Pathway analysis showed increases in pathways related to cellular metabolism and decreases in pathways relevant to the development of cardiomyopathy and to oxidative phosphorylation. CONCLUSIONS: Male swine treated with CAN had significant improvements in cardiac function that were not observed in female swine treated with CAN. Moreover, CAN treatment in male swine was associated with significantly more changes in protein expression than in female swine treated with CAN. The increased proteomic changes seen in the CAN male group likely contributed to the more robust changes in cardiac function seen in male swine treated with CAN.

Sodium-glucose co-transporter 2 inhibitor canagliflozin modulates myocardial metabolism and inflammation in a swine model for chronic myocardial ischemia.

BACKGROUND: Inflammation and disruption of cardiac metabolism are prevalent in the setting of myocardial ischemia. Canagliflozin, a sodium-glucose costransporter-2 inhibitor, has beneficial effects on the heart, though the precise mechanisms are unknown. This study investigated the effects of canagliflozin therapy on metabolic pathways and inflammation in ischemic myocardial tissue using a swine model of chronic myocardial ischemia. METHODS: Sixteen Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic ischemia. Two weeks later, pigs received either no drug (n = 8) or 300 mg canagliflozin (n = 8) daily. Five weeks later, pigs underwent terminal harvest and tissue collection. RESULTS: Canagliflozin treatment was associated with a trend toward decreased expression of fatty acid oxidation inhibitor acetyl-CoA carboxylase and decreased phosphorylated/inactivated acetyl-CoA carboxylase, a promotor of fatty acid oxidation, compared with control ischemic myocardium (P = .08, P = .03). There was also a significant modulation in insulin resistance markers p-IRS1, p-PKCα, and phosphoinositide 3-kinase in ischemic myocardium of the canagliflozin group compared with the control group (all P < .05). Canagliflozin treatment was associated with a significant increase in inflammatory markers interleukin 6, interleukin 17, interferon-gamma, and inducible nitric oxide synthase (all P < .05). There was a trend toward decreased expression of the anti-inflammatory cytokines interleukin 10 (P = .16) and interleukin 4 (P = .31) with canagliflozin treatment. CONCLUSION: The beneficial effects of canagliflozin therapy appear to be associated with inhibition of fatty acid oxidation and enhancement of insulin signaling in ischemic myocardium. Interestingly, canagliflozin appears to increase the levels of several inflammatory markers, but further studies are required to better understand how canagliflozin modulates inflammatory signaling pathways.

Intramyocardial injection of hypoxia-conditioned extracellular vesicles modulates apoptotic signaling in chronically ischemic myocardium.

Objective: Limited treatments exist for nonoperative chronic coronary artery disease. Previously, our laboratory has investigated extracellular vesicle (EV) therapy as a potential treatment for chronic coronary artery disease using a swine model and demonstrated improved cardiac function in swine treated with intramyocardial EV injection. Here, we seek to investigate the potential cardiac benefits of EVs by using hypoxia-conditioned EVs (HEV). Specifically, this study aims to investigate the effect of HEV on apoptosis in chronically ischemic myocardium in swine. Methods: Fourteen Yorkshire swine underwent placement of an ameroid constrictor on the left circumflex artery. Two weeks later, swine underwent redo left thoracotomy with injection of either saline (control, n = 7) or HEVs (n = 7). After 5 weeks, swine were euthanized for tissue collection. Terminal deoxynucleotidyl transferase dUTP nick end labeling was used to quantify apoptosis. Immunoblotting was used for protein quantification. Results: Terminal deoxynucleotidyl transferase dUTP nick end labeling staining showed a decrease in apoptosis in the HEV group compared with the control (P = .049). The HEV group exhibited a significant increase in the anti-apoptotic signaling molecule phospho-BAD (P = .005), a significant decrease in B-cell lymphoma 2 (P = .006) and an increase in the phospho-B-cell lymphoma to B-cell lymphoma 2 ratio (P < .001). Furthermore, the HEV group exhibited increased levels of prosurvival signaling markers including phosphoinositide 3-kinase, phosphor-extracellular signal-regulated kinase 1/2, phospho-forkhead box protein O1, and phospho-protein kinase B to protein kinase B ratio (all P < .05). Conclusions: In chronic myocardial ischemia, treatment with HEV results in a decrease in overall apoptosis, possibly through the activation of both pro-survival and anti-apoptotic signaling pathways.

Seamless Coupling of Chemical Glycan Release and Labeling for an Accelerated Protein N-Glycan Sample Preparation Workflow.

Analytical methods fr direct quantitative N-glycan analysis require a sequence of sample preparation and clean-up steps that result in reduced glycan recovery. Therefore, we aimed to combine glycan release and labeling steps. Based on the hypothesis that the reaction mechanism for oxidative chemical glycan release comprises a stable glycan isocyanate intermediate, we investigated whether this could be exploited for the in-situ preparation of fluorescent glycan conjugates. ANTS-labeled N-glycans were derived from chicken ovalbumin via an in-situ chemical release/coupling approach and by standard Peptide-N-Glycosidase F (PNGase F) digestion/reductive amination. Synoptic fluorescence-assisted carbohydrate electrophoresis with UV detection (FACE-UV) analysis yielded matching patterns of fluorescent N-glycan bands in the expected electrophoretic mobility range between hexose units GU-5 and GU-11 of the standard. Anthranilamide (2-AB)-glycan conjugates prepared from a test glycoprotein carrying a predominant Core-F glycan gave single predominant peaks in hydrophilic interaction chromatography with fluorescence detection (HILIC-FLD) and electrospray ionization mass spectrometry (ESI-MS) spectra in agreement with sodiated triply charged Core-F-AB conjugates for both the standard and the in-situ coupling methods. The Core-F-AB conjugate prepared by the in-situ coupling approach had a slightly elevated retention time on HILIC-FLD and an ESI-MS m/z peak in line with a urea-bonded glycan-AB conjugate, with closed pyran ring structures on the glycan moiety. Glycan isocyanates intermittently formed during chemical glycan release, which could be utilized to prepare labeled glycan samples directly from glycoproteins and fluorescent dyes bearing a primary amine functional group.

Comparative Analysis of Normoxia- and Hypoxia-Modified Extracellular Vesicle Therapy in Function, Perfusion, and Collateralization in Chronically Ischemic Myocardium.

We have previously shown that normoxia serum-starved extracellular vesicle (EV) therapy improves myocardial function, perfusion, and angiogenesis in a swine model of chronic myocardial ischemia. Hypoxia-modified EVs have increased abundance of anti-oxidant, pro-angiogenic, and pro-survival proteins. The purpose of this study is to investigate the differential effects of normoxia serum-starved EVs and hypoxia-modified EVs on myocardial function, perfusion, and microvascular density in chronically ischemic myocardium. Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, the pigs underwent intramyocardial injection of either normoxia serum-starved EVs (NOR, n = 10) or hypoxia-modified EVs (HYP, n = 7). Five weeks later, pigs were euthanized, and ischemic myocardium was harvested. Hypoxia EV treatment was associated with improved contractility compared to NOR, as well as improved capillary density, without changes in arteriolar density. There were trends towards improved perfusion at rest and during pacing in the HYP group compared to NOR. Ischemic myocardium in the HYP group had increased pro-angiogenic Akt and ERK signaling and decreased expression of anti-angiogenic markers compared to the NOR group. In the setting of chronic myocardial ischemia, hypoxia-modified EVs may enhance contractility, capillary density, and angiogenic signaling pathways compared to normoxia serum-starved EVs.

Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial Ischemia.

Background Sodium-glucose cotransporter-2 inhibitors are cardioprotective independent of glucose control, as demonstrated in animal models of acute myocardial ischemia and clinical trials. The functional and molecular mechanisms of these benefits in the setting of chronic myocardial ischemia are poorly defined. The purpose of this study is to determine the effects of canagliflozin therapy on myocardial perfusion, fibrosis, and function in a large animal model of chronic myocardial ischemia. Methods and Results Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received either no drug (n=8) or 300 mg sodium-glucose cotransporter-2 inhibitor canagliflozin orally, daily (n=8). Treatment continued for 5 weeks, followed by hemodynamic measurements, harvest, and tissue analysis. Canagliflozin therapy was associated with increased stroke volume and stroke work and decreased left ventricular stiffness compared with controls. The canagliflozin group had improved perfusion to ischemic myocardium compared with controls, without differences in arteriolar or capillary density. Canagliflozin was associated with decreased interstitial and perivascular fibrosis in chronically ischemic tissue, with reduced Jak/STAT (Janus kinase/signal transducer and activator of transcription) signaling compared with controls. In ischemic myocardium of the canagliflozin group, there was increased expression and activation of adenosine monophosphate-activated protein kinase, decreased activation of endothelial nitric oxide synthase, and unchanged total endothelial nitric oxide synthase. Canagliflozin therapy reduced total protein oxidation and increased expression of mitochondrial antioxidant superoxide dismutase 2 compared with controls. Conclusions In the setting of chronic myocardial ischemia, canagliflozin therapy improves myocardial function and perfusion to ischemic territory, without changes in collateralization. Attenuation of fibrosis via reduced Jak/STAT signaling, activation of adenosine monophosphate-activated protein kinase, and antioxidant signaling may contribute to these effects.

Release of protein N-glycans by effectors of a Hofmann carboxamide rearrangement.

Background: Chemical methods for glycan release have gained traction because of their cost efficiency, accelerated reaction time and ability to release glycans not amenable to enzymatic cleavage. Oxidative chemical glycan release via hypochlorite treatment has been shown to be a convenient and efficient method that yields N-glycans similar to classical PNGase F digestion. We observed that the initial steps of the suggested mechanism for the oxidative release of glycans from glycoproteins by hypohalites showed similarities to the initiating steps of the classical Hofmann rearrangement of carboxamides. Therefore, we investigated the ability of different stable effectors of a Hofmann-type carboxamide rearrangement to efficiently and selectively release N-glycans from glycoproteins. Methods: Released glycans obtained from different experimental chemical release approaches were analyzed by HILIC-FLD, BHZ-FACE and ESI-MS and evaluated with respect to electrophoretic mobility, retention time and integrated peak area for resolved glycans. Results: We show that the known Hoffmann catalysts 1,3-dichloro-5,5-dimethylhydantoin, the hypervalent organoiodine (III) compound diacetoxy-iodobenzene as well as in-situ hypobromite generation using Oxone® and potassium bromide are all capable of releasing protein-bound N-glycans in good yield. Among the compounds investigated, diacetoxy-iodobenzene was capable of releasing glycans in the absence of alkali. Detailed investigations of the bromide/Oxone® method revealed a dependence of N-glycan release efficiency from the temporal order of bromide addition to the reaction mix as well as from a molar excess of bromide over Oxone®. Conclusions. These findings suggest that the oxidative release of N-glycans occurs via the initiating steps of a Hofmann carboxamide rearrangement. Hypervalent organoiodine compounds hold the promise of releasing glycans in the absence of alkali. The in-situ generation of hypobromite by bromide/Oxone® produces a consistent defined amount of reagent for rapid N-glycan release for both analytical and preparative purposes.

In-hospital and Readmission Outcomes With Percutaneous Balloon Mitral Valvuloplasty.

Percutaneous balloon mitral valvuloplasty (PBMV) is primarily performed for rheumatic mitral stenosis (MS). Therefore, limited data exist on PBMV in countries with a low incidence of rheumatic disease. Using the Nationwide Readmission Database, we examined trends in in-hospital mortality and 30-day readmission among patients who received PBMV for rheumatic and non-rheumatic MS. We also examined the change in 90-day hospitalization rate before vs after PBMV. Between 2016 and 2019, there were 1109 hospitalizations in which patients received PBMV for rheumatic (n = 955, 86.1%) vs non-rheumatic MS (n = 154, 13.9%). The all-cause in-hospital mortality for rheumatic and non-rheumatic MS did not change over time (0.9% → 2.0%, P = 0.94, and 5.9% → 9.5%, P = 0.09 respectively). Similarly, the 30-day readmission for patients with rheumatic and non-rheumatic MS did not change over time (12.4% → 9.9%, P = 0.26, and 4.4% → 10.5%, P = 0.30, respectively). The 90-day all-cause hospitalization rate remained the same before vs after PBMV for rheumatic and non-rheumatic MS (25.5% → 21.8%; P = 0.14, and 24.0% → 33.7%; P = 0.19, respectively). Although no statistically significant change was noted over time for trends in in-hospital mortality, 30-day readmission, or even in the change in 90-day all-cause hospitalizations before and after PBMV for both types of MS, among those with non-rheumatic MS, there was a signal of an increase in the in-hospital mortality, and 30-day readmission, even more, there was 29% relative increase in 90-day hospitalizations after PBMV. Future studies are needed to examine the role of PBMV in patients with non-rheumatic MS.

Biosynthesis of Zinc Oxide Nanoparticles Using Catharanthus Roseus Leaves and Their Therapeutic Response in Breast Cancer (MDA-MB-231) Cells.

As the current study reports the utilization of the leaf extract of Catharanthus roseus (C.roseus) for the biological synthesis of zinc oxide nanoparticles (ZnO NPs) because of the importance of the importance of health and environment. Bioinspired synthesis were characterized using Fourier Transform Infrared Spectroscopy (FT-IR), Field Emission-Scanning Electron Microscopy (FE-SEM), Transmission Electron Microscopy (TEM), Energy-Dispersive X-ray Spectroscopy (EDX) and X-Ray diffraction (XRD). XRD and TEM micrograph analysis revealed that the synthesized nanostructures were well-dispersed and spherical with the average particle size in the 18-30 nm range were produced. The FT-IR spectra confirmed presence of phenolic compounds that act as reducing and capping agents. Further, it suggested the possible utilization of hydroxyl groups and amides in the reduction of Zn ions and stablization of ZnO NPs. Zinc oxide nanomaterials are effective in cancer treatments, including the destruction of tumor cells with minimal damage to healthy cells. The toxicity of zinc oxide nanomaterials was checked in vitro in the human breast cancer line MDA-MB-231. Inverse relation of the percentage of viable cells to the concentration of zinc oxide nanomaterials at increasing molar levels was assessed. The cytotoxicity analysis used in the MTT test shows the substantial viable MDA-MB-231-cells despite the increased concentration of exposure to zinc oxide nanomaterials. Reduction in the ratio of viable MDA-MB-231 cells after being exposed to zinc oxide nanomaterials was compared to untreated cancerous cells. The present approach to biosynthesis is quick, inexpensive, eco-friendly, and high-rise stable nanomaterials of zinc oxide with substantial cancer potential. This is the first study that reports molar concentrations (with the lowest concentration of 10 mM) as an anticancer agent for breast cancer and potential clinical uses for synthesized zinc oxide nanomaterials. Thus, C. roseus based synthesized ZnO NPs could be explored not only as environmentally benign method but also as a potential anti-carcinogenic agent.

LncRNA ZFAS1 inhibits triple-negative breast cancer by targeting STAT3.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with fewer treatment options than other types of invasive breast cancer due to the loss of the estrogen, progesterone receptors and low levels of the HER2 protein, resulting in a poor prognosis for these patients. Here, we found that the expression of the lncRNA, ZFAS1, was significantly downregulated (∼3.0-fold) in blood samples of TNBC patients (n=40) compared to matched healthy controls (n=40). Functionally, silencing of ZFAS1 promoted cell proliferation and colonization of human MDA-MB-231 TNBC cells by inhibiting the expression levels of the cyclin-dependent kinase (CDK) inhibitors p21 (CDKN1A) and p27 (CDKN1B) compared to the scrambled siRNA control cells. Further, we found that downregulation of ZFAS1 led to decreased protein levels of the epithelial markers, E-cadherin, Claudin-1, and Zo-1, with increased protein levels of the mesenchymal markers, Slug and ZEB1. In addition, by utilizing the bioinformatic tools such as RAID v2.0 (RNA Interactome Database Version 2.0), AnnoLnc (Annotate human lncRNA database), and GEPIA (Gene Expression Profiling Interactive Analysis), we identified a strong negative correlation between ZFAS1 and signal transducer and activator of transcription 3 (STAT3) gene expression (R = -0.11, p-value = 0.0002). Further, we observed that decreased ZFAS1 expression significantly (p < 0.05) increased STAT3 and phosphorylated STAT3 (at Ser727 residue) protein levels in TNBC cells. The composite data indicate that ZFAS1 may function as a tumor-suppressor lncRNA with potential as a diagnostic/prognostic marker and may offer a new target for the treatment of TNBC patients.

Long non-coding RNA TINCR as potential biomarker and therapeutic target for cancer.

Despite the recent scientific advances made in cancer diagnostics and therapeutics, cancer still remains the second leading cause of death worldwide. Thus, there is a need to identify new potential biomarkers/molecular targets to improve the diagnosis and treatment of cancer patients. In this regard, long non-coding RNAs (lncRNAs), a type of non-coding RNA molecule, have been found to play important roles in diverse biological processes, including tumorigenesis, and may provide new biomarkers and/or molecular targets for the improved detection of treatment of cancer. For example, one lncRNA, tissue differentiation-inducing non-protein coding RNA (TINCR) has been found to be significantly dysregulated in many cancers, and has an impact on tumor development and progression through targeting pivotal molecules in cancer-associated signaling pathways. Hence, based on recent discoveries, herein, we discuss the regulatory functions and the underlying mechanisms of how TINCR regulates signaling pathways attributed to cancer hallmarks associated with the pathogenesis of various human cancers. We also highlight studies assessing its potential clinical utility as a biomarker/target for early detection, cancer risk stratification, and personalized cancer therapies.

Stabilization of miRNAs in esophageal cancer contributes to radioresistance and limits efficacy of therapy.

The five-year survival rate of esophageal cancer patients is less than 20%. This may be due to increased resistance (acquired or intrinsic) of tumor cells to chemo/radiotherapies, often caused by aberrant cell cycle, deregulated apoptosis, increases in growth factor signaling pathways, and/or changes in the proteome network. In addition, deregulation in non-coding RNA-mediated signaling pathways may contribute to resistance to therapies. At the molecular level, these resistance factors have now been linked to various microRNA (miRNAs), which have recently been shown to control cell development, differentiation and neoplasia. The increased stability and dysregulated expression of miRNAs have been associated with increased resistance to various therapies in several cancers, including esophageal cancer. Therefore, miRNAs represent the next generation of molecules with tremendous potential as biomarkers and therapeutic targets. However, detailed studies on miRNA-based therapeutic interventions are still in their infancy. Hence, in this review, we have summarized the current status of microRNAs in dictating the resistance/sensitivity of tumor cells to chemotherapy and radiotherapy. In addition, we have discussed various strategies to increase radiosensitivity, including targeted therapy, and the use of miRNAs as radiosensitive/radioresistance biomarkers for esophageal cancer in the clinical setting.

The regulatory roles of long non-coding RNAs in the development of chemoresistance in breast cancer.

Chemoresistance is one of the major hurdles in the treatment of breast cancer, which limits the effect of both targeted and conventional therapies in clinical settings. Therefore, understanding the mechanisms underpinning resistance is paramount for developing strategies to circumvent resistance in breast cancer patients. Several published reports have indicated that lncRNAs play a dynamic role in the regulation of both intrinsic and acquired chemoresistance through a variety of mechanisms that endow cells with a drug-resistant phenotype. Although a number of lncRNAs have been implicated in chemoresistance of breast cancer, their mechanistic roles have not been systematically reviewed. Thus, here we present a detailed review on the latest research findings and discoveries on the mechanisms of acquisition of chemoresistance in breast cancer related to lncRNAs, and how lncRNAs take part in various cancer signalling pathways involved in breast cancer cells. Knowledge obtained from this review could assist in the development of new strategies to avoid or reverse drug resistance in breast cancer chemotherapy.

The emerging role of long non-coding RNA in gallbladder cancer pathogenesis.

Gallbladder cancer (GBC) is the most common and aggressive form of biliary tract carcinoma with an alarmingly low 5-year survival rate. Despite its high mortality rate, the underlying mechanisms of GBC pathogenesis are not completely understood. Recently, from a growing volume of literature, long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression and appear to play vital roles in many human cancers. To date, a number of lncRNAs have been implicated in GBC, but their potential roles in GBC have not been systematically examined. Thus, in this review, we critically discuss the emerging roles of lncRNAs in GBC, and the pathways involved. Specifically, we note that some lncRNAs show greater expression in T1 and T2 tumor stages compared to T3 and T4 tumor stages and that their dysregulation leads to alterations in cell cycle progression and can cause an increase in GBC cell proliferation or apoptosis. In addition, some lncRNAs control the epithelial-mesenchymal transition process, while others take part in the regulation of ERK/MAPK and Ras cancer-associated signaling pathways. We also present their potential utility in diagnosis, prognosis, and/or treatment of GBC. The overall goal of this review is to stimulate interest in the role of lncRNAs in GBC, which may open new avenues in the determination of GBC pathogenesis and may lead to the development of new preventive and therapeutic strategies for GBC.

Unusual lesions mimicking impingement syndrome in the shoulder joint - Think medially.

Impingement syndrome is usually caused by irritation of the rotator cuff within the sub acromial space and this includes the coraco-acromial arch (Acromion and Coraco-acromial ligament), the acromio-clavicular joint and occasionally the coracoid. Iatrogenic causes such as sutures, pins, plates or wires left from previous surgery can cause similar symptoms. We present a series of four cases mimicking "classical" impingement symptoms/signs in which the causal pathology was identified outside the sub-acromial space. Magnetic Resonance Imaging (MRI) showed lesions that were present in the supra-spinatus fossa but were causing pressure effects on the sub-acromial space, namely - a ganglion cyst in one case, lipomata in two other cases, and a glomus tumour. A ganglion cyst and glomus tumour mimicking impingement syndrome is a rare reported case to our knowledge. These are unusual causes that should be considered when investigating classical impingement syndrome and particularly those who may have failed to respond to decompression surgery. They highlight the potential value of looking beyond the sub-acromial space for causal lesions and in these cases, at a time when limited ultrasound investigation has become increasingly popular; MRI has clearly played an important and was essential in planning surgery as these lesions would not have been identified on USS. Even though the symptoms were classical.

An epidemiological study of paediatric motocross injuries in the United Kingdom.

PURPOSE: Although off-road motorcycling is one of the most popular sports activities practised by millions of people worldwide, little has been written on motocross injuries and their prevention. In the UK alone, motocross has grown into a phenomenally ambitious and popular franchise. There are >200 motocross clubs across the country holding >900 events annually. The aim of this study is to categorise and quantify the magnitude of motocross paediatric injuries and associated morbidity. METHODS: Data were collected prospectively over 4 years (2010-2014) at our unit. All injuries caused by motocross biking that were referred to our trauma and orthopaedic department were included in this study, regardless of whether the rider was performing the sport competitively or recreationally. RESULTS: During the study period, 130 patients (aged 4-17 years) were identified with a total of 142 injuries, ranging from one to six injuries per patient. Most of the injuries were sustained within the early spring and summer months, representing the start of the motocross season; 76 patients required hospital admission, with 60 (42 %) requiring surgical intervention. CONCLUSION: We present the first epidemiological study of motocross paediatric injuries in the UK. The results from this study highlight the frequency and severity of motocross-related injuries in the paediatric population in the UK. This may assist in providing recommendations and guidelines to governing bodies and to parents. The injuries sustained during motocross have significant resource implications, especially for smaller rural hospitals, as shown by the number of injuries doubling over the past 4 years.

Management of traumatic anterior shoulder dislocation in the 17- to 25-year age group: a dramatic evolution of practice.

BACKGROUND: Anterior shoulder dislocation in the young patient is a common problem, yet there is no universal agreement on its management. METHODS: In this study, we comprehensively surveyed all members of the British Elbow and Shoulder Society (BESS) to ascertain their preferred methods of treating young patients with traumatic, anterior shoulder dislocation. We then repeated exactly the same survey 7 years later to find out whether practices had changed and if any consensus of opinion had been reached. RESULTS: The number of surgeons indicating their preferred stabilization procedure was arthroscopic more than quadrupled from only 16% in 2002 to 71% in 2009, while the numbers of those preferring an open technique fell in a correspondingly dramatic manner. The numbers who now potentially offer stabilization surgery to first-time dislocators virtually doubled from 35% to 68%. There was also a big rise in the use of magnetic resonance imaging (MRI) arthrograms as an investigation prior to surgery and in the use of bio-absorbable anchors during surgical stabilization. There remain, however, aspects of treatment and rehabilitation where little consensus exists. CONCLUSION: Rarely in the history of orthopaedic surgery has such a dramatic and widespread change in operative technique occurred in such a short space of time. Rarer still has such a change been prospectively documented.