Inhibition of G protein-coupled receptor kinase 2 promotes unbiased downregulation of IGF-1 receptor and restrains malignant cell growth

alwin shared this article with you from Inoreader Inhibition of G protein-coupled receptor kinase 2 promotes unbiased downregulation of IGF-1 receptor and restrains malignant cell growth Via Cancer Research Online First Articles The ability of a receptor to preferentially activate only a subset of available downstream signal cascades is termed biased signaling. While comprehensively recognized for the G protein-coupled receptors (GPCR), this process is scarcely explored downstream of receptor tyrosine kinases (RTK), including the cancer-relevant insulin-like growth factor-1 receptor (IGF-1R). Successful IGF-1R targeting requires receptor downregulation, yet therapy-mediated removal from the cell surface activates cancer-protective β-arrestin-biased signaling (β-arr-BS). As these overlapping processes are initiated by the β-arr/IGF-1R interaction and controlled by GPCR-kinases (GRK), we explored GRKs as potential anti-cancer therapeutic targets to disconnect IGF-1R downregulation and β-arr-BS. Transgenic modulation demonstrated that GRK2-inhibition or GRK6-overexpression enhanced degradation of IGF-1R, but both scenarios sustained IGF-1-induced β-arr-BS. Pharmacological inhibition of GRK2 by the cl inically approved antidepressant, serotonin reuptake inhibitor paroxetine (PX), recapitulated the effects of GRK2-silencing with dose- and time-dependent IGF-1R downregulation without associated β-arr-BS. In vivo, PX-treatment caused substantial downregulation of IGF-1R, suppressing the growth of Ewing's sarcoma xenografts. Functional studies reveal that PX exploits the antagonism between β-arrestin isoforms: in low ligand conditions, PX favored β-arrestin1/Mdm2-mediated ubiquitination/degradation of IGF-1R, a scenario usually exclusive to ligand abundancy, making PX more effective than antibody-mediated IGF-1R downregulation. This study provides the rationale, molecular mechanism, and validation of a clinically feasible concept for 'system bias' targeting of the IGF-1R to uncouple downregulation from signaling. Demonstrating system bias as an effective anti-cancer approach, our study reveals a novel strategy for the rational design or repurposing of therapeutics to selectively c ross-target the IGF-1R or other RTK. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Loss of ARID1A promotes epithelial-mesenchymal transition and sensitizes pancreatic tumors to proteotoxic stress

alwin shared this article with you from Inoreader Loss of ARID1A promotes epithelial-mesenchymal transition and sensitizes pancreatic tumors to proteotoxic stress Via Cancer Research Online First Articles Cellular de-differentiation is a key mechanism driving cancer progression. Acquisition of mesenchymal features has been associated with drug resistance, poor prognosis, and disease relapse in many tumor types. Therefore, successful targeting of tumors harboring these characteristics is a priority in oncology practice. The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex has also emerged as a critical player in tumor progression, leading to the identification of several SWI/SNF complex genes as potential disease biomarkers and targets of anti-cancer therapies. AT-rich interaction domain-containing protein 1A (ARID1A) is a component of SWI/SNF, and mutations in ARID1A represent one of the most frequent molecular alterations in human cancers. ARID1A mutations occur in ~10% of pancreatic ductal adenocarcinomas (PDAC), but whether these mutations confer a therapeutic opportunity remains unclear. Here we demonstrate that loss of ARID1A promotes an epithelial-mese nchymal transition (EMT) phenotype and sensitizes PDAC cells to a clinical inhibitor of HSP90, NVP-AUY922, both in vitro and in vivo. While loss of ARID1A alone did not significantly affect proliferative potential or rate of apoptosis, ARID1A-deficient cells were sensitized to HSP90 inhibition, potentially by promoting the degradation of intermediate filaments driving EMT, resulting in cell death. Our results describe a mechanistic link between ARID1A defects and a quasi-mesenchymal phenotype, suggesting that deleterious mutations in ARID1A associated with protein loss exhibits potential as a biomarker for PDAC patients who may benefit by HSP90-targeting drugs treatment. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

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.