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Topic Review
Insulin-like Growth Factor 1 Signaling in Mammalian Hearing
Insulin-like growth factor 1 (IGF-1) is a peptide hormone belonging to the insulin family of proteins. Almost all of the biological effects of IGF-1 are mediated through binding to its high-affinity tyrosine kinase receptor (IGF1R), a transmembrane receptor belonging to the insulin receptor family. Factors, receptors and IGF-binding proteins form the IGF system, which has multiple roles in mammalian development, adult tissue homeostasis, and aging. Consequently, mutations in genes of the IGF system, including downstream intracellular targets, underlie multiple common pathologies and are associated with multiple rare human diseases. Here we review the contribution of the IGF system to our understanding of the molecular and genetic basis of human hearing loss by describing, (i) the expression patterns of the IGF system in the mammalian inner ear; (ii) downstream signaling of IGF-1 in the hearing organ; (iii) mouse mutations in the IGF system, including upstream regulators and downstream targets of IGF-1 that inform cochlear pathophysiology; and (iv) human mutations in these genes causing hearing loss.
  • 1.6K
  • 22 Oct 2021
Topic Review
GOLPH3, a PI(4)P Binding Protein
Golgi phosphoprotein 3 (GOLPH3), a Phosphatidylinositol 4-Phosphate [PI(4)P] effector at the Golgi, is required for several intracellular functions, including Golgi ribbon structure maintenance, Golgi glycosylation and vesicle trafficking. It is amplified in several solid tumor types and its overexpression correlates with poor prognosis. GOLPH3 influences tumorigenesis through (i) regulation of Golgi-to-plasma membrane trafficking; (ii) turnover and glycosylation of cancer-relevant glycoproteins; (iii) influence on DNA damage response and maintenance of genomic stability.
  • 1.6K
  • 27 Oct 2020
Topic Review
Immune Checkpoint Inhibitor-Related Myositis
Immune checkpoint inhibitor (ICI)-related inflammatory diseases, including polymyositis (PM) and dermatomyositis (DM), in patients suffering from neoplastic disorders represent a medical challenge. The treatment of these conditions has taken on new urgency due to the successful and broad development of cancer-directed immunological-based therapeutic strategies. While primary and secondary PM/DM phenotypes have been pathophysiologically characterized, a rational, stepwise approach to the treatment of patients with ICI-related disease is lacking. In the absence of high-quality evidence to guide clinical judgment, the available data must be critically assessed. In this literature review, we examine partially neglected immunological and clinical findings to obtain insights into the biological profiles of ICI-related PM/DM and potential treatment options. We show that differential diagnosis is essential to stratifying patients according to prognosis and therapeutic impact. Finally, we provide a comprehensive assessment of druggable targets and suggest a stepwise patient-oriented approach for the treatment of ICI-related PM/DM.
  • 1.6K
  • 28 Oct 2020
Topic Review
Hyperinsulinemia
For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality.
  • 1.6K
  • 02 Aug 2021
Topic Review
Adnexotropic Variants of Interface Dermatitides
Interface dermatitis is a pathological pattern characterized by the presence of basal cell vacuolization and apoptotic keratinocytes. A variety of dermatoses exhibit interface dermatitis on pathology including the lichenoid dermatoses, graft versus host disease, connective tissue diseases, and drug reactions, among others. Several entities of interface dermatitides are known to have distinct rare adnexotropic variants whereby the inflammation involves the adnexa of the skin such as the hair follicle or the sweat gland. In lichen planus for example, follicular and syringotropic variants have been classically described. Adnexal involvement can also at times be seen on histopathology of the interface dermatitides that do not have distinct adnexotropic variants. For example, adnexal inflammation can be seen in lichen striatus or in pityriasis lichenoides.
  • 1.6K
  • 22 Sep 2021
Topic Review
Cardiac Involvement in Hereditary Hemochromatosis
Hereditary hemochromatosis (HH) is a genetic disease leading to excessive iron absorption, its accumulation, and oxidative stress induction causing different organ damage, including the heart. The process of cardiac involvement is slow and lasts for years. Cardiac pathology manifests as an impaired diastolic function and cardiac hypertrophy at first and as dilatative cardiomyopathy and heart failure with time. From the moment of heart failure appearance, the prognosis is poor. Therefore, it is crucial to prevent those lesions by upfront therapy at the preclinical phase of the disease. The most useful diagnostic tool for detecting cardiac involvement is echocardiography. However, during an early phase of the disease, when patients do not present severe abnormalities in serum iron parameters and severe symptoms of other organ involvement, heart damage may be overlooked due to the lack of evident signs of cardiac dysfunction. Considerable advancement in echocardiography, with particular attention to speckle tracking echocardiography, allows detecting discrete myocardial abnormalities and planning strategy for further clinical management before the occurrence of substantial heart damage. 
  • 1.6K
  • 19 Aug 2021
Topic Review
Bacteriophages in Cancer
Bacteriophages are a class of prokaryotic viruses with different sizes and shapes (icosahedral, such as T4, T7, or λ; filamentous, such as M13), which infect the host bacterial cell initiating either a lytic or a lysogenic cycle.
  • 1.6K
  • 03 Jun 2021
Topic Review
Esophageal and Gastric Tumors
Gastric and esophageal tumors are diverse neoplasms that involve mucosal and submucosal tissue layers and include squamous cell carcinomas, adenocarcinomas, spindle cell neoplasms, neuroendocrine tumors, marginal B cell lymphomas, along with less common tumors. The worldwide burden of esophageal and gastric malignancies is significant, with esophageal and gastric cancer representing the ninth and fifth most common cancers, respectively. The approach to diagnosis and staging of these lesions is multimodal and includes a combination of gastrointestinal endoscopy, endoscopic ultrasound, and cross-sectional imaging. Likewise, therapy is multidisciplinary and combines therapeutic endoscopy, surgery, radiotherapy, and systemic chemotherapeutic tools. Future directions for diagnosis of esophageal and gastric malignancies are evolving rapidly and will involve advances in endoscopic and endosonographic techniques including tethered capsules, optical coherence tomography, along with targeted cytologic and serological analyses. 
  • 1.6K
  • 23 Feb 2021
Topic Review
Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements
Inherited retinal dystrophies and optic neuropathies cause chronic disabling loss of visual function. The development of recombinant adeno-associated viral vectors (rAAV) gene therapies in all disease fields have been promising, but the translation to the clinic has been slow. The safety and efficacy profiles of rAAV are linked to the dose of applied vectors. DNA changes in the rAAV gene cassette affect potency, the expression pattern (cell-specificity), and the production yield. Here, we present a library of rAAV vectors and elements that provide a workflow to design novel vectors. We first performed a meta-analysis on recombinant rAAV elements in clinical trials (2007-2020) for ocular gene therapies. We analyzed 33 unique rAAV gene cassettes used in 57 ocular clinical trials. The rAAV gene therapy vectors used six unique capsid variants, 16 different promoters, and six unique polyadenylation sequences. Further, we compiled a list of promoters, enhancers, and other sequences used in current rAAV gene cassettes in preclinical studies. Then, we give an update on pro-viral plasmid backbones used to produce the gene therapy vectors, inverted terminal repeats, production yield, and rAAV safety considerations. Finally, we assess rAAV transgene and bioactivity assays applied to cells or organoids in vitro, explants ex vivo, and clinical studies.
  • 1.6K
  • 22 Jun 2020
Topic Review
Total Knee Arthroplasty
Total knee arthroplasty (TKA) is a highly effective procedure for advanced osteoarthritis of the knee. Thirty-day hospital readmission is an adverse outcome related to complications, which can be mitigated by identifying associated risk factors. 
  • 1.6K
  • 21 Jan 2021
Topic Review
Human Gut Mycobiome in IBD
The human microbiota is a diverse microbial ecosystem associated with many beneficial physiological functions, as well as numerous disease etiologies. Dominated by bacteria, the microbiota also includes commensal populations of fungi, viruses, archaea, and protists. Unlike bacterial microbiota, which was extensively studied in the past two decades, these non-bacterial microorganisms, their functional roles, and their interaction with one another or with host immune system have not been as widely explored. This review covers the recent findings on the fungal communities of the human gastrointestinal microbiota, termed the “mycobiome”, and their involvement in health and disease, with particular focus on the pathophysiology of inflammatory bowel disease.
  • 1.6K
  • 25 Apr 2020
Topic Review
Pharmacological Chaperones
Pharmacological chaperones are small molecular weight drugs that are used when the primary cause of a disease is the instability of a particular protein. The hallmark of pharmacological chaperones is their ability to bind and stabilize their targets specifically. Pharmacological chaperones offer a hope to cure some genetic diseases with small drugs that can be administered orally and reach the central nervous system. This will not be possible for all the genotypes associated to a given diseases but requires a personalized approach.
  • 1.6K
  • 30 Oct 2020
Topic Review
HSP in Diabetes and Alzheimer
Type 2 diabetes (T2D) and Alzheimer’s disease (AD) are growing in prevalence worldwide. The development of T2D increases the risk of AD disease, while AD patients can show glucose imbalance due to an increased insulin resistance. T2D and AD share similar pathological features and underlying mechanisms, including the deposition of amyloidogenic peptides in pancreatic islets (i.e., islet amyloid polypeptide; IAPP) and brain (β-Amyloid; Aβ). Both IAPP and Aβ can undergo misfolding and aggregation and accumulate in the extracellular space of their respective tissues of origin. As a main response to protein misfolding, there is evidence of the role of heat shock proteins (HSPs) in moderating T2D and AD. HSPs play a pivotal role in cell homeostasis by providing cytoprotection during acute and chronic metabolic stresses. In T2D and AD, intracellular HSP (iHSP) levels are reduced, potentially due to the ability of the cell to export HSPs to the extracellular space (eHSP). The increase in eHSPs can contribute to oxidative damage and is associated with various pro-inflammatory pathways in T2D and AD.
  • 1.6K
  • 27 Jan 2021
Topic Review
Hearing Loss in Mucopolysaccharidoses
Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by a deficiency of one of the enzymes involved in the degradation of glycosaminoglycans. Hearing loss is a common clinical presentation in MPS. MPS VI presents primarily with conductive hearing loss, while the other subtypes (MPS I, MPS II, MPS III, MPS IVA, and MPS VII) can present with any type of hearing loss (conductive, sensorineural, or mixed hearing loss). However, hearing loss is absent in MPS IVB and MPS IX. The sensorineural component develops as the disease progresses, but there is no consensus on the etiology of the sensorineural component. Enzyme replacement therapy (ERT) is the most common therapy utilized for MPS, but the effects of ERT on hearing function have been inconclusive. This review highlights a need for more comprehensive and multidisciplinary research on hearing function that includes behavioral testing, objective testing, and temporal bone imaging. This information would allow for better understanding of the progression and etiology of hearing loss. Owing to the prevalence of hearing loss in MPS, early diagnosis of hearing loss and annual comprehensive audiological evaluations are recommended.
  • 1.6K
  • 14 Aug 2020
Topic Review
Microglia
Microglia, the innate immune cells of the brain, are commonly perceived as resident macrophages of the central nervous system (CNS). This definition, however, requires further specification, as under healthy homeostatic conditions, neither morphological nor functional properties of microglia mirror those of classical macrophages.
  • 1.6K
  • 04 Feb 2021
Topic Review
Diabetic Cardiac Fibroblast Phenotype
Diabetic cardiomyopathy involves remodeling of the heart in response to diabetes that includes microvascular damage, cardiomyocyte hypertrophy, and cardiac fibrosis. Cardiac fibrosis is a major contributor to diastolic dysfunction that can ultimately result in heart failure with preserved ejection fraction. Under high glucose conditions cardiac fibroblasts, the final effector cell in the process of cardiac fibrosis, respond by making increased amounts of extracellular matrix. This process involves multiple molecular pathways.
  • 1.6K
  • 27 Oct 2020
Topic Review
Oxidative Stress in Human Pathology
Accumulating evidence shows that oxidative stress plays an essential role in the pathogenesis and progression of many diseases. The imbalance between the production of reactive oxygen species (ROS) and the antioxidant systems has been extensively studied in pulmonary, neurodegenerative and cardiovascular disorders; however, its contribution is still debated in gastrointestinal disorders. Evidence suggests that oxidative stress affects gastrointestinal motility in obesity, and post-infectious disorders by favoring the smooth muscle phenotypic switch toward a synthetic phenotype. Here is to gain insight into the role played by oxidative stress in gas-trointestinal pathologies (GIT), and the involvement of ROS in the signaling underlying the mus-cular alterations of the gastrointestinal tract (GIT).
  • 1.5K
  • 12 Oct 2021
Topic Review
Human Permanent Denervated Muscles Recovery
We demonstrated the long-term clinical value of co-activating thigh muscles through hbFES strategy using high currents and large surface electrodes. This Vienna Strategy is able to reverse, at clinically relevant levels, the adverse effects of Spinal Cord Injury (SCI), even in the worst-case scenario of complete lesion of lower motor neurons, as it may occur in complete conus and cauda equina syndrome. Continued regularly, hbFES for denervated, degenerating muscles helps to maintain healthier leg muscles and skin, reducing the risks of life-threatening SCI complications. By products of these studies are new approaches for counteracting aging muscle atrophy, new color clinical imaging of muscle tissue and Machine Learning Predictive Systems for skeletal muscle diagnostics and managements.
  • 1.5K
  • 01 Mar 2021
Topic Review
Scleroderma
Vitamin D status has been linked to immune system and autoimmune disorders; in fact, low levels of vitamin D are common in many autoimmune disorders. The aims of our study were to assess the prevalence of vitamin D insufficiency and the possible correlation with clinical parameters in systemic sclerosis (SSc). We recruited 40 patients (38 female and two male) with scleroderma and 40 healthy controls matched for age and gender. Demographic and clinical parameters were recorded and the 25-hydroxivitamin D3 serum levels were measured. Serum 25-hydroxivitamin D3 levels were significantly lower in patients with systemic sclerosis than in the control group. The prevalence of 25-hydroxivitamin D3 insufficiency was 50% in the patients and 22.5% in the control group. A statistically significant association was observed between the insufficiency of 25-hydroxivitamin D3 and skin involvement (p = 0.02) and echocardiography systolic pulmonary artery pressure >35 mmHg (p = 0.02). Our data show that the systemic sclerosis group has significantly lower serum 25-hydroxivitamin D3 concentrations compared to the control group; skin involvement and pulmonary hypertension are associated with vitamin D3 insufficiency.
  • 1.5K
  • 01 Nov 2020
Topic Review
Diabetic Foot Ulcers
The main factors contributing to the development of diabetic foot ulcers are peripheral neuropathy (sensory, motor and autonomic) and peripheral arterial disease. Both complications predispose to the development of lesions and the destruction or infection of tissue, which are the precursors to amputations in most cases. Currently, we have a great deal of information on preventive and therapeutic interventions aimed at reducing the sequence of events (foot at risk, injury and subsequent amputation); but other aspects, such as patient mortality and how certain clinical factors, blood glucose control, ulcer evolution and severity influence patient survival, are less well known. 
  • 1.5K
  • 05 Nov 2020
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