Design and functional validation of a mutant variant of the lncRNA HOTAIR to counteract Snail function in Epithelial-to-Mesenchymal Transition

alwin shared this article with you from Inoreader Design and functional validation of a mutant variant of the lncRNA HOTAIR to counteract Snail function in Epithelial-to-Mesenchymal Transition Via Cancer Research Online First Articles HOTAIR is a lncRNA overexpressed in several epithelial cancers and strongly correlated with invasion. This lncRNA was proven a pivotal element of the epithelial-mesenchymal transition (EMT), a trans-differentiation process triggering metastasis. Snail, master inducer of EMT, requires HOTAIR to recruit EZH2 on specific epithelial target genes (i.e., HNF4α, E-cadherin and HNF1α) and cause their repression. Here we designed a HOTAIR deletion mutant form, named HOTAIR-sbid, including the putative Snail-binding domain but depleted of the EZH2 binding domain. HOTAIR-sbid acted as a dominant negative of the endogenous HOTAIR. In both murine and human tumor cells, HOTAIR-sbid impaired the ability of HOTAIR to bind Snail and, in turn, trigger H3K27me3/EZH2-mediated repression of Snail epithelial target genes. Notably, HOTAIR-sbid expression was proven to reduce cellular motility, invasiveness, anchorage-independent growth, and responsiveness to TGFß-induced EMT. These data provide ev idence on a lncRNA-based strategy to effectively impair the function of a master EMT-transcriptional factor. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Enhanced efficacy of simultaneous PD-1 and PD-L1 immune checkpoint blockade in high grade serous ovarian cancer

alwin shared this article with you from Inoreader Enhanced efficacy of simultaneous PD-1 and PD-L1 immune checkpoint blockade in high grade serous ovarian cancer Via Cancer Research Online First Articles Immune therapies have had limited efficacy in high grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single cell RNA-seq transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-PD-1/PD-L1 antibody compared to monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and NK cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small molecule inhibition of BRD1 induced similar state changes in vitro and demonstrated efficacy in vivo, validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Hypoxic glioma stem cell-derived exosomes containing Linc01060 promote progression of glioma by regulating the MZF1/c-Myc/HIF-1{alpha}

alwin shared this article with you from Inoreader Hypoxic glioma stem cell-derived exosomes containing Linc01060 promote progression of glioma by regulating the MZF1/c-Myc/HIF-1{alpha} Via Cancer Research Online First Articles Glioma stem cells (GSC) are a subpopulation of tumor cells with special abilities to proliferate and differentiate in gliomas. They are one of the main causes of tumor recurrence, especially under hypoxic conditions. Although long noncoding RNAs (lncRNA) are known to be involved in numerous biological processes and are implied in the occurrence of certain diseases, their role in tumor development and progression remains poorly understood. Here we explored the mechanisms by which lncRNA derived from hypoxic glioma stem cells (H-GSC) cause glioma progression. Isolation and identification of the Linc01060 gene, the exosomes containing them, and the proteins from tumor cells regulating the gene allowed for studying the effects of Linc01060 on proliferation and glycometabolism. H-GSC exerted their effects by transferring exosomes to glioma cells, resulting in a significant increase in Linc01060 levels. Mechanistically, Linc01060 directly interacted with the transcription factor myel oid zinc finger 1 (MZF1) and enhanced its stability. Linc01060 facilitated nuclear translocation of MZF1 and promoted MZF1-mediated c-Myc transcriptional activities. In addition, c-Myc enhanced the accumulation of the hypoxia-inducible factor-1 alpha (HIF-1α) at the post-transcriptional level. HIF-1α bound the hormone response elements (HRE) of the Linc01060 promoter, upregulating the transcription of Linc01060 gene. Clinically, Linc01060 was upregulated in glioma and was significantly correlated with tumor grade and poor clinical prognosis. Overall, these data show that secretion of Linc01060-containing exosomes from hypoxic glioma stem cells activates pro-oncogenic signaling pathways in glioma cells to promote disease progression. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Is the plantaris muscle the most undefined human skeletal muscle?

alwin shared this article with you from Inoreader Is the plantaris muscle the most undefined human skeletal muscle? Via Anatomical Science International Abstract The plantaris muscle is located in the posterior aspect of the superficial compartment of the lower leg, running from the lateral condyle of the femur to the calcaneal tuberosity. Classically, it is characterized by a small and fusiform muscle belly, which then changes into a long slender tendon. From the evolutionary point of view, the muscle is considered vestigial. However, it has recently been suspected of being a highly specialized sensory muscle because of its high density of muscle spindles. It has a noticeable tendency to vary in respect of both origin and insertion. Researchers have published many reports on the potential clinical significance of the muscle belly and tendon, including mid-portion Achilles tendinopathy, 'tennis leg syndrome', and popliteal artery entrapment syndrome. The right knee joint area was subjected to classical anatomical dissection, during which an atypical plantaris muscle was found and examined in detail. Accurate morphomet ric measurements were made. The muscle belly was assessed as bifurcated. Morphologically, superior and inferior parts were presented. There was a tendinous connection (named band A) with the iliotibial tract and an additional insertion (named band B) to the semimembranosus tendon. Both bands A and B presented very broad fan-shaped attachments. The human plantaris muscle is of considerable interest and has frequent morphological variations in its proximal part. Its specific characteristics can cause clinical problems and lead to confusion in diagnosis. More studies are needed to define its actual features and functions. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Tracheal stenosis after tracheostomy

alwin shared this article with you from Inoreader Tracheal stenosis after tracheostomy Via The British Journal of Oral and Maxillofacial Surgery Tracheal stenosis is a late and usually non-life-threatening complication of surgical and percutaneous tracheostomies (PDT) as well as delayed endotracheal extubation. We undertook a retrospective review of all patients who had a surgical tracheostomy over a 10-year period. Patients were included if they had computed tomography (CT) or magnetic resonance imaging (MRI) of the tracheostomy site both preoperatively and six or more weeks postoperatively. Patients whose imaging was not available were excluded (n=3), as were those who still had a tracheostomy in situ (n=8). (Source: The British Journal of Oral and Maxillofacial Surgery) View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Low-cost model using a digital microscope for learning, practicing, and maintaining microvascular surgical skills

alwin shared this article with you from Inoreader Low-cost model using a digital microscope for learning, practicing, and maintaining microvascular surgical skills Via The British Journal of Oral and Maxillofacial Surgery The recent COVID-19 outbreak has seen the majority of courses cancelled due to government policies during the acute pandemic.1 This unfortunately has had a knock on effect on the progression of training, especially with respect to microvascular surgery, as it is thought that a trainee should be fully trained outside the operating room · The practice of microvascular surgery is extremely complex and a trainee should be taken through a number of validated steps prior to progression.2 The first author has sourced a cheap and portable model for developing key skills for microsurgery. (Source: The British Journal of Oral and Maxillofacial Surgery) View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Quality of life, chronic pain, insomnia, and jaw malfunction in patients after alloplastic temporomandibular joint replacement: a questionnaire-based pilot study

alwin shared this article with you from Inoreader Quality of life, chronic pain, insomnia, and jaw malfunction in patients after alloplastic temporomandibular joint replacement: a questionnaire-based pilot study Via International Journal of Oral and Maxillofacial Surgery Studies of patients undergoing alloplastic total temporomandibular joint replacement seldom report on quality of life (QoL) and sleep. The aim of this pilot study was to assess these factors in such a patient cohort using validated psychometric questionnaires. Data were collected via online surveys comprising the following six questionnaires: Short Form-12 Health Survey (SF-12), Patient Health Questionnaire-15, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, Insomnia Severity Index, Graded Chronic Pain Scale, and Jaw Disability List. (Source: International Journal of Oral and Maxillofacial Surgery) View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Antibiotics in orthognathic surgery: a retrospective analysis and identification of risk factors for postoperative infection

alwin shared this article with you from Inoreader Antibiotics in orthognathic surgery: a retrospective analysis and identification of risk factors for postoperative infection Via International Journal of Oral and Maxillofacial Surgery This study was undertaken to evaluate the infection rate following orthognathic surgery and to identify possible risk factors. A retrospective study was conducted. Patients undergoing orthognathic surgery from August 1, 2017 to July 31, 2018 were included. The outcome variable was surgical site infection (SSI). All data were analysed with respect to demographics and procedure specifications. A total of 137 patients (mean age 28.5 ±12.69 years) were included in this study, of whom 20 (14.6%) developed a SSI. (Source: International Journal of Oral and Maxillofacial Surgery) View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Neuromuscular Specializations of the Human Hypopharyngeal Muscles

alwin shared this article with you from Inoreader Neuromuscular Specializations of the Human Hypopharyngeal Muscles Via Latest Results for Dysphagia Abstract The hypopharyngeal muscles in humans play a vital role in swallowing, speech, and respiration. Increasing evidence indicates that these muscles are specialized to perform life-sustaining upper aerodigestive functions. This review aims to provide current knowledge regarding the key structural, physiological, and biochemical features of the hypopharyngeal muscles, including innervation, contractile properties, histochemistry, biochemical properties, myosin heavy chain (MyHC) expression and regulation, and age-related alterations. These would clarify the unique neuromuscular specializations of the human hypopharyngeal muscles for a better understanding of the functions and pathological conditions of the pharynx and for the development of novel therapies to treat related upper airway disorders. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The Prevalence of Undiagnosed Age-Related Sight-Threatening Diseases in Self-Proclaimed Healthy Individuals

alwin shared this article with you from Inoreader The Prevalence of Undiagnosed Age-Related Sight-Threatening Diseases in Self-Proclaimed Healthy Individuals Via Hindawi Publishing Corporation Background. Age-related conditions such as glaucoma, age-related macular degeneration, diabetic retinopathy, and cataract have become the major cause of visual impairment and blindness in high-income countries. The aim of the current study is to investigate the prevalence of these eye diseases in a cohort of self-proclaimed healthy elderly and thus get a rough estimation of the prevalence of undiagnosed age-related eye conditions in the Belgian population. Methods. Individuals aged 55 and older without ophthalmological complaints were asked to fill in a general medical questionnaire and underwent an ophthalmological examination, which included a biomicroscopic examination, intraocular pressure measurement, axial length measurement, and acquisition of fundus pictures and optical coherence tomography scans. Information regarding follow-up was collected in those who received the advice of referral to an ophthalmologist or the advice to have more frequent follow-up visits, based on their study evaluation. Results. The cohort included 102 people and comprised 46% men (median age 70 years, range 57–85 years). Referral for additional examinations was made in 26 participants (25%). The advice to have more regular follow-up ophthalmologist visits was given to nine additional participants (9%). No significant correlations between baseline characteristics and the need for referral could be identified. Follow-up information was available for 25 out of 26 referred volunteers. Out of these, four underwent a therapeutic intervention based on study referral, up until 18 months after study participation. All four interventions took place in the age group 65–74 years. Conclusions. This study shows that, even in an elderly population with self-proclaimed healthy eyes and good general health, a sign ificant proportion of subjects showed ocular findings that need regular follow-up and/or intervention. The frequency of prior ophthalmological examinations does not seem to be relevant to this proportion, meaning that everyone above 55 years old needs a routine ophthalmological evaluation. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The Contributive Role of IGFBP-3 and Mitochondria in Synoviocyte-Induced Osteoarthritis through Hypoxia/Reoxygenation Injury: A Pathogenesis-Focused Literature Review

alwin shared this article with you from Inoreader The Contributive Role of IGFBP-3 and Mitochondria in Synoviocyte-Induced Osteoarthritis through Hypoxia/Reoxygenation Injury: A Pathogenesis-Focused Literature Review Via Hindawi Publishing Corporation Osteoarthritis (OA), one of the most common joint disorders, is characterized by chronic progressive cartilage degradation, osteophyte formation, and synovial inflammation. OA lesions are not only located in articular cartilage but also in the entire synovial joint. Nevertheless, most of the early studies done mostly focused on the important role of chondrocyte apoptosis and cartilage degeneration in the pathogenesis and progress of OA. The increased expression of hypoxia-inducible factors (HIF-1α and HIF-2α) is known to be the cellular and biochemical signal that mediates the response of chondrocytes to hypoxia. The role of the synovium in OA pathogenesis had been poorly evaluated. Being sensitive to hypoxia/reoxygeneration (H/R) injury, fibroblast-like synoviocytes (FLS) play an essential role in carti lage degradation during the course of this pathology. Insulin-like growth factor binding protein 3 (IGFBP-3) acts as the main carrier of insulin-like growth factor I (IGF-I) in the circulation and remains the most abundant among the six IGFBPs. Synovial fluids of OA patients have markedly increased levels of IGFBP-3. We aim to discuss the interconnected behavior of IGFBP-3 and synoviocytes during the course of osteoarthritis pathogenesis, especially under the influence of hypoxia-inducible factors. In this review, we present information related to the essential role that is played by IGFBP-3 and mitochondria in synoviocyte-induced osteoarthritis through H/R injury. Little research has been done in this area. However, strong evidences show that the level of IGFBP-3 in synovial fluid significantly increased in OA, inhibiting the binding of IGF-1 to IGFR 1 (IGF receptor-1) and therefore the inhibition of cell proliferation. To the best of our knowledge, this is the first paper providin g a comprehensive explanatory contribution of IGFBP-3 and mitochondria in synovial cell-induced osteoarthritis through hypoxia/reoxygenation mechanism. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The Antitumor and Immunogenic Properties of Silver and Sodium Dichloroacetate Combination against Melanoma

alwin shared this article with you from Inoreader In Vivo Evaluation of the Antitumor and Immunogenic Properties of Silver and Sodium Dichloroacetate Combination against Melanoma Via Hindawi Publishing Corporation Our main focus was to evaluate the efficacy of silver and sodium dichloroacetate as dual-function agents to be used in melanoma treatment. This strategy is designed to increase the activity of these two compounds that affect DNA integrity and the mitochondria at different levels. Furthermore, we evaluated if the cell death mechanism induced by our treatments was immunogenic cell death. To evaluate antitumor efficacy, we assessed tumor volume and production of tumor necrosis factor-α, nuclear factor κ B (both by ELISA), and nitric oxide levels (Nitrate/Nitrite colorimetric assay kit); for immunogenic cell death, we evaluated the release of danger-associated molecular patterns using immunohistochemistry and flow cytometry, as well as an in vivo challenge. Our results showed that the combination of colloidal s ilver and sodium dichloroacetate is more effective than each treatment alone and that the antitumor mechanism is not through immunogenic cell death. Furthermore, this study can broadly contribute to the development of dichloroacetate-loaded silver nanoparticles and to the design targeted pharmacological formulations to fight melanoma as well as other types of cancer. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.