Skeletal Muscle Microvascular Dysfunction in Obesity-Related Insulin Resistance: Pathophysiological Mechanisms and Therapeutic Perspectives

Obesity is a worrisomely escalating public health problem globally and one of the leading causes of morbidity and mortality from noncommunicable disease. The epidemiological link between obesity and a broad spectrum of cardiometabolic disorders has been well documented; however, the underlying pathophysiological mechanisms are only partially understood, and effective treatment options remain scarce. Given its critical role in glucose metabolism, skeletal muscle has increasingly become a focus of attention in understanding the mechanisms of impaired insulin function in obesity and the associated metabolic sequelae. We examined the current evidence on the relationship between microvascular dysfunction and insulin resistance in obesity. A growing body of evidence suggest an intimate and reciprocal relationship between skeletal muscle microvascular and glucometabolic physiology. The obesity phenotype is characterized by structural and functional changes in the skeletal muscle microcirculation which contribute to insulin dysfunction and disturbed glucose homeostasis. Several interconnected etiologic molecular mechanisms have been suggested, including endothelial dysfunction by several factors, extracellular matrix remodelling, and induction of oxidative stress and the immunoinflammatory phenotype. We further correlated currently available pharmacological agents that have deductive therapeutic relevance to the explored pathophysiological mechanisms, highlighting a potential clinical perspective in obesity treatment.     

Immunotherapy for Biliary Tract Cancer in the Era of Precision Medicine: Current Knowledge and Future Perspectives

Biliary tract cancers (BTC) represent a heterogeneous and aggressive group of tumors with dismal prognosis. For a long time, BTC has been considered an orphan disease with very limited therapeutic options. In recent years a better understanding of the complex molecular landscape of biology is rapidly changing the therapeutic armamentarium. However, while 40–50% of patients there are molecular drivers susceptible to target therapy, for the remaining population new therapeutic options represent an unsatisfied clinical need. The role of immunotherapy in the continuum of treatment of patients with BTC is still debated. Despite initial signs of antitumor-activity, single-agent immune checkpoint inhibitors (ICIs) demonstrated limited efficacy in an unselected population. Therefore, identifying the best partner to combine ICIs and predictive biomarkers represents a key challenge to optimize the efficacy of immunotherapy. This review provides a critical analysis of completed trials, with an eye on future perspectives and possible biomarkers of response.     

Novel Therapeutic Opportunities in Neoadjuvant Setting in Urothelial Cancers: A New Horizon Opened by Molecular Classification and Immune Checkpoint Inhibitors

Muscle invasive bladder cancer (MIBC) is a widespread malignancy with a worse prognosis often related to a late diagnosis. For early-stage MIBC pts, a multidisciplinary approach is mandatory to evaluate the timing of neoadjuvant chemotherapy (NAC) and surgery. The current standard therapy is platinum-based NAC (MVAC-methotrexate, vinblastine, doxorubicin, and cisplatin or Platinum–Gemcitabine regimens) followed by radical cystectomy (RC) with lymphadenectomy. However, preliminary data from Vesper trial highlighted that dose-dense NAC MVAC is endowed with a good pathological response but shows low tolerability. In the last few years, translational-based research approaches have identified several candidate biomarkers of NAC esponsiveness, such as ERCC2, ERBB2, or DNA damage response (DDR) gene alterations. Moreover, the recent consensus MIBC molecular classification identified six molecular subtypes, characterized by different sensitivity to chemo- or targeted or immunotherapy, that could open a novel procedure for patient selection and also for neoadjuvant therapies. The Italian PURE-01 phase II Trial extended data on efficacy and resistance to Immune Checkpoint Inhibitors (ICIs) in this setting. In this review, we summarize the most relevant literature data supporting NAC use in MIBC, focusing on novel therapeutic strategies such as immunotherapy, considering the better patient stratification and selection emerging from novel molecular classification.     

A PSS‐Free PEDOT Conductive Film Supported by a Hierarchical Nanoporous Layer Glass

The importance of transparent conductive film is increasing due to its use in applications such as touch‐panel devices. Although indium tin oxide is widely used because of its high conductivity and transparency, conductive polymers are being studied as alternative materials that avoid the use of rare metals and the brittleness associated with existing systems. Polyethylene dioxythiophene (PEDOT)/polyethylene sulfonic acid (PSS) is drawing a lot of attention due to its well‐balanced conductivity, transparency, film formability, and chemical stability. The nonconductive PSS reportedly covers the conductive PEDOT. The PSS shell provides carrier and film‐formability to PEDOT but is also a barrier that hinders electrical conductivity. Therefore, the PEDOT film formability is explored supported by a substrate without the addition of PSS. The “hierarchical nanoporous layer glass” holds the PSS‐free PEDOT with its nanopores to form a homogeneous, transparent film. The PSS‐free PEDOT film thus achieves transparency of over 85% and resistivity of below 500 Ω sq^?1.     

Grid current regulation of a three-phase voltage source inverter with an LCL input filter

Many grid connected power electronic systems, such as STATCOMs, UPFCs, and distributed generation system interfaces, use a voltage source inverter (VSI) connected to the supply network through a filter. This filter, typically a series inductance, acts to reduce the switching harmonics entering the distribution network. An alternative filter is a LCL network, which can achieve reduced levels of harmonic distortion at lower switching frequencies and with less inductance, and therefore has potential benefits for higher power applications. However, systems incorporating LCL filters require more complex control strategies and are not commonly presented in literature. This paper proposes a robust strategy for regulating the grid current entering a distribution network from a three-phase VSI system connected via a LCL filter. The strategy integrates an outer loop grid current regulator with inner capacitor current regulation to stabilize the system. A synchronous frame PI current regulation strategy is used for the outer grid current control loop. Linear analysis, simulation, and experimental results are used to verify the stability of the control algorithm across a range of operating conditions. Finally, expressions for ""harmonic impedance" of the system are derived to study the effects of supply voltage distortion on the harmonic performance of the system.     

New Standards Release Sets Stage for 5G Future

Over the past year or so,wireless companies have begun to roll out fifth-generation (5G),the latest generation wireless network[1].For today's consumers,moving ...