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Kirsten rat sarcoma viral oncogene homolog (KRAS) somatic mutations occur in 30% to 40% of patients with colorectal cancer (CRC). These were thought to equally affect prognosis and resistance to anti–epidermal growth factor receptor agents; however, recent data show the activity of KRAS-G12C and pan-RAS inhibitors. The effects of uncommon KRAS(uKRAS) variants are largely unexplored. The distribution and pathogenicity of uKRASmutations and their relationship with patients’ clinicopathologic features were assessed. A total of 2427 CRCs were profiled for KRASusing next-generation sequencing (NGS). The study and control groups included patients with uKRAS(<1% frequency in CRC data sets on cBioPortal) and canonical KRASmutations, respectively. In silicoprotein structure modifications and prediction analyses were performed by using PyMOL, trRosetta, and PolyPhen-2. uKRASmutations affected 35 cases (1.5%), with G13C (28.6%), G12R (20%), and V14I (8.6%) being most common. Missense mutations (D33E, G12W, G12F, Q22H, Q61L, and L19F) occurred in nine cases (25.7%). Duplications (G10dup and L52_G60dup) affected two cases. Pathogenicity analyses showed that G12W, Q22R, L56V, and A130I mutations are probably damaging, with scores between 0.928 and 1.000. No differences were seen in clinicopathologic features. uKRASmutants had lower event-free survival but no difference in overall survival compared with controls. Although these data are hypothesis generating and need further confirmation, they highlight the importance of NGS-based profiling to identify CRC patients with uKRASmutations as candidates for personalized therapy.

Aim:This work aimed to test peptides against the planktonic and biofilm form of Cryptococcusspp. and in vitrotoxicity using three-dimensional (3D) cells characterized and evaluate in vivotoxicity in Galleria mellonella.Materials & methods:Susceptibility tests were conducted on the planktonic form and biofilm formation. The toxicity of the peptides was evaluated in lung and brain cells in monolayer (2D) and 3D mono- and co-culture, in addition to in vivoanalysis with G. mellonella.Results:Susceptibility values ranged from 31.25 to over 250 µg/ml with a fungicidal profile. Regarding toxicity, the PepM2 peptide was not toxic in 3D culture (500 µg/ml). G. mellonella, showed a survival rate of more than 85% In assays with brain and lung cell lines, concentrations ranged from 4 × 104to 4 × 103cells/well for brain cells and 1 × 103cells/well for lung cells. Cocultures used 1 × 105brain and 1 × 103lung cells.Conclusion:This study shows that the peptides have great potential against cryptococcosis, and all spheroids were characterized as having a spheroidal and compact structure.

Study design: Experimental Animal Study. Objective: To continue validating an antibody which targets an epitope of neurofilament light chain (NF-L) only available during neurodegeneration and to utilize the antibody to describe the pattern of axonal degeneration 10 days post-unilateral C4 contusion in the rat. Setting: University of Florida laboratory in Gainesville, USA. Methods: Sprague Dawley rats received either a unilateral 150kdyne C4 contusion (n = 4 females, n = 5 males) or a laminectomy control surgery (n = 2 females, n = 3 males). Ten days following SCI or laminectomy, spinal cords and brainstems were processed for immunohistochemistry. Serial spinal cord and brainstem cross-sections were stained with the degeneration-specific NF-L antibody (MCA-6H63) and dual labeled with either an antibody against the C-terminus portion of NF-L (NF-L-Ct), to label healthy axons, or an antibody against amyloid precursor protein (APP), considered the current “gold standard” for identifying axonal injury. The pattern of ongoing axonal degeneration was assessed. Results: Spinal cord and brainstem cross-sections from injured rats had punctate MCA-6H63 positive fibers with a pathological appearance, loss of anti-NF-L-Ct colabeling, and frequent colocalization with APP. Immunopositive fibers were abundant rostral and caudal to the lesion in white matter tracts that would be disrupted by the unilateral C4 contusion. This pattern of staining was not observed in control tissue. Conclusions: The MCA-6H63 antibody labels degenerating axons following SCI and offers a tool to quantify axonal degeneration.

ABSTRACTIntroductionThe E3 ubiquitin ligase Cbl-b is a novel target in immune-oncology, with critical roles in regulating T-cell activation and signaling pathways. By facilitating the ubiquitination and degradation of key signaling proteins, Cbl-b modulates immune responses, maintaining immune homeostasis and preventing unwarranted T-cell proliferation. The therapeutic potential of Cbl-b as a cancer immunotherapy target is underscored by its contribution to an immunosuppressive tumor microenvironment, with efforts currently underway to develop small-molecule inhibitors.Areas coveredWe reviewed the small molecules, and antibody-drug conjugates targeting Cbl-b from 2018 to 2024. The patents were gathered through publicly available databases and analyzed with in-house developed cheminformatic workflow, described within the manuscript.Expert opinionTargeting Cbl-b presents a promising approach in immuno-oncology, offering a novel pathway to potentiate the immune system’s ability to combat cancer beyond PDL1/PD1 inhibition. The development and clinical advancement of Cbl-b inhibitors, as evidenced by the ongoing trials, mark a significant step toward harnessing this target for therapeutic benefits. Overall, the strategic inhibition of Cbl-b holds substantial promise for improving cancer immunotherapy outcomes, heralding a new era in the fight against cancer.

Nanomaterials with electroactive properties have taken a big leap for tissue repair and regeneration due to their unique physiochemical properties and biocompatibility. MXenes, an emerging class of electroactive materials have generated considerable interest for their biomedical applications from bench to bedside. Recently, the application of these two-dimensional wonder materials have been extensively investigated in the areas of biosensors, bioimaging and repair of electroactive organs, owing to their outstanding electromechanical properties, photothermal capabilities, hydrophilicity, and flexibility. The currently available data reports that there is significant potential to employ MXene nanomaterials for repair, regeneration and functioning of electroactive tissues and organs such as brain, spinal cord, heart, bone, skeletal muscle and skin. The current review is the first report that compiles the most recent advances in the application of MXenes in bioelectronics and the development of biomimetic scaffolds for repair, regeneration and functioning of electroactive tissues and organs including heart, nervous system, skin, bone and skeletal muscle. The content in this article focuses on unique features of MXenes, synthesis process, with emphasis on MXene-based electroactive tissue engineering constructs, biosensors and wearable biointerfaces. Additionally, a section on the future of MXenes is presented with a focus on the clinical applications of MXenes.

In biomedical image processing, Deep Learning (DL) is increasingly exploited in various forms and for diverse purposes. Despite unprecedented results, the huge number of parameters to learn, which necessitates a substantial number of annotated samples, remains a significant challenge. In medical domains, obtaining high-quality labelled datasets is still a challenging task. In recent years, several works have leveraged data augmentation to face this issue, mostly thanks to the introduction of generative models able to produce artificial samples having the same characteristics as the acquired ones. However, we claim that biological principles must be considered in this process, as all medical imaging techniques exploit one or more physical laws or properties directly associated with the physiological characteristics of the tissues under analysis. A notable example is the Dynamic Contrast Enhanced-Magnetic Resonance Imaging (DCE-MRI), in which the kinetic of the contrast agent (CA) highlights both morphological and physiological aspects. In this paper, we introduce a novel generative approach explicitly relying on Physiologically Based Pharmacokinetic (PBPK) modelling and on an Intrinsic Deforming Autoencoder (DAE) to implement a physiologically-aware data augmentation strategy. As a case of study, we consider breast DCE-MRI. In particular, we tested our proposal on two private and one public datasets with different acquisition protocols, demonstrating that the proposed method significantly improves the performance of several DL-based lesion classifiers.

In this study, we introduce a novel antenna design method for superdirective antennas that combines low complexity with high radiation efficiency, while being impedance-matched to $50~\Omega $ . We applied this approach to design, fabricate, and measure a superdirective antenna array (SDA) with a high realized antenna gain (i.e., 6.3 dBi) and radiation efficiency (i.e., 99.3%), consisting of two strip dipole elements operating at a frequency of 3.5 GHz. The fabricated antenna has an electrical size of 1.55, underscoring its compactness in addition to its high gain. Our approach is distinguished by its ability to achieve high directivity and radiation efficiency, along with impedance-matching to $50~\Omega $ , through meticulous adjustments of the strip dimensions (i.e., length and width) and the phase difference between elements. This method eliminates the need for external impedance-matching networks, amplifiers, attenuators, parasitic elements, or loads, marking a significant advancement in the development of practical superdirective antenna designs.

In industrial sectors such as automotive, aeronautics or medical, among others, anticorrosive, antibacterial, self-cleaning, and anti-sticking surfaces are demanded. Thus, the production of these surfaces by scalable processes is currently a subject of intense research but the processes are often complex, slow and use expensive and harmful chemical reagents. In this work, the micro-milling technique with ball nose tools has been proposed as a scalable and environmentally friendly way to improve water repellency on surfaces processed in a 5000 series aluminium and then treated with a hydrophobic coating. Thus, a novel arch-pyramidal protrusion-based surface texture generated by milling has been optimized by means of an experimental set up according to Taguchi's method, evaluating the influence of the process variables on surface hysteresis and hydrophobic capacity of the processed surfaces by means of static, sliding, advancement and receding angle measurements. Classical wettability models have made it possible to define hydrophobic specimens and the appropriate relationships between the water droplet size (d) and the radial milling step (p) have been identified to obtain the better hydrophobic behaviour. So, textures with lower values of crest height (h) and lower roughness factor (r) have shown better hydrophobicity for bigger water droplets of 50–100 μl and when the ratio d/p is higher. After undergoing over 60 cycles of a peel wear test standardized according to ASTM D 3359-09, the micromilled hydrophobic surfaces exhibit sustained hydrophobic properties, with sliding angles slightly increasing but stabilizing around 11°, indicative of preserved hydrophobicity.

Approximately 740 million symptomatic patients are affected by otitis media every year. Being an inflammatory disease affecting the middle ear, it is one of the primary causes of tympanic membrane (TM) perforations, often resulting in impaired hearing abilities. Antibiotic therapy using broad-spectrum fluoroquinolones, such as ciprofloxacin (CIP), is frequently employed and considered the optimal route to treat otitis media. However, patients often get exposed to high dosages to compensate for the low drug concentration reaching the affected site. Therefore, this study aims to integrate tissue engineering with drug delivery strategies to create biomimetic scaffolds promoting TM regeneration while facilitating a localized release of CIP. Distinct electrospinning (ES) modalities were designed in this regard either by blending CIP into the polymer ES solution or by incorporating nanoparticles-based co-ES/electrospraying. The combination of these modalities was investigated as well. A broad range of release kinetic profiles was achieved from the fabricated scaffolds, thereby offering a wide spectrum of antibiotic concentrations that could serve patients with diverse therapeutic needs. Furthermore, the incorporation of CIP into the TM patches demonstrated a favorable influence on their resultant mechanical properties. Biological studies performed with human mesenchymal stromal cells confirmed the absence of any cytotoxic or anti-proliferative effects from the released antibiotic. Finally, antibacterial assays validated the efficacy of CIP-loaded scaffolds in suppressing bacterial infections, highlighting their promising relevance for TM applications.

Thyroid hormones (THs) are critical regulators of muscle metabolism in both healthy and unhealthy conditions. Acting concurrently as powerful anabolic and catabolic factors, THs are endowed with a vital role in muscle mass maintenance. As a result, thyroid dysfunctions are the leading cause of a wide range of muscle pathologies, globally identified as myopathies. Whether muscle wasting is a common feature in patients with hyperthyroidism and is mainly caused by THs-dependent stimulation of muscle proteolysis, also muscle growth is often associated with hyperthyroid conditions, linked to THs-dependent stimulation of muscle protein synthesis. Noteworthy, also hypothyroid status negatively impacts on muscle physiology, causing muscle weakness and fatigue. Most of these symptoms are due to altered balance between muscle protein synthesis and breakdown. Thus, a comprehensive understanding of THs-dependent skeletal muscle protein turnover might facilitate the management of physical discomfort or weakness in conditions of thyroid disease.

ABSTRACTIntroductionInfluenza affects individuals of all ages and poses a significant threat during pandemics, epidemics, and sporadic outbreaks. Neuraminidase inhibitors (NAIs) are currently the first choice in the treatment and prevention of influenza, but their use can be hindered by viral resistance.Areas coveredThis review summarizes current NAIs pharmacological profiles, their current place in therapy, and the mechanisms of viral resistance and outlines possible new indications, ways of administration, and novel candidate NAIs compounds.Expert opinionNAIs represent a versatile group of compounds with diverse administration methods and pharmacokinetics. While the prevalence of influenza virus resistance to NAIs remains low, there is heightened vigilance due to the pandemic potential of influenza. Several novel NAIs and derivatives are currently under assessment at various stages of development for the treatment and prevention of influenza.

The gut microbiome is acknowledged as a key determinant of human health, and technological progress in the past two decades has enabled the deciphering of its composition and functions and its role in human disorders. Therefore, manipulation of the gut microbiome has emerged as a promising therapeutic option for communicable and non-communicable disorders. Full exploitation of current therapeutic microbiome modulators (including probiotics, prebiotics, and faecal microbiota transplantation) is hindered by several factors, including poor precision, regulatory and safety issues, and the impossibility of providing reproducible and targeted treatments. Artificial microbiota therapeutics (which include a wide range of products, such as microbiota consortia, bacteriophages, bacterial metabolites, and engineered probiotics) have appeared as an evolution of current microbiota modulators, as they promise safe and reproducible effects, with variable levels of precision via different pathways. We describe the landscape of artificial microbiome therapeutics, from those already on the market to those still in the pipeline, and outline the major challenges for positioning these therapeutics in clinical practice.

The aberrant aggregation of α-synuclein (αS) into amyloid fibrils is associated with a range of highly debilitating neurodegenerative conditions, including Parkinson’s disease. Although the structural properties of mature amyloids of αS are currently understood, the nature of transient protofilaments and fibrils that appear during αS aggregation remains elusive. Using solid-state nuclear magnetic resonance (ssNMR), cryogenic electron microscopy (cryo-EM), and biophysical methods, we here characterized intermediate amyloid fibrils of αS forming during the aggregation from liquid-like spherical condensates to mature amyloids adopting the structure of pathologically observed aggregates. These transient amyloid intermediates, which induce significant levels of cytotoxicity when incubated with neuronal cells, were found to be stabilized by a small core in an antiparallel β-sheet conformation, with a disordered N-terminal region of the protein remaining available to mediate membrane binding. In contrast, mature amyloids that subsequently appear during the aggregation showed different structural and biological properties, including low levels of cytotoxicity, a rearranged structured core embedding also the N-terminal region, and a reduced propensity to interact with the membrane. The characterization of these two fibrillar forms of αS, and the use of antibodies and designed mutants, enabled us to clarify the role of critical structural elements endowing intermediate amyloid species with the ability to interact with membranes and induce cytotoxicity.

The issue of suboptimal drug regimen adherence in secondary cardiovascular prevention presents a significant barrier to improving patient outcomes. To address this, the utilization of drug combinations, specifically single pill combinations (SPCs) and polypills, was proposed as a strategy to simplify treatment regimens. This approach aims to enhance treatment accessibility, affordability, and adherence, thereby reducing healthcare costs and improving patient health. The document is an Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) scientific statement on simplifying drug regimens for secondary cardiovascular prevention. It discusses the underuse of treatments despite available, effective, and accessible options, highlighting a significant gap in secondary prevention across different socio-economic statuses and countries. The statement explores barriers to implementing evidence-based treatments, including patient, healthcare provider, and system-related challenges. The paper also reviews international guidelines, the role of SPCs and polypills in clinical practice, and their economic impact, advocating for their use in secondary prevention to improve patient outcomes and adherence.

Cardio-oncology rehabilitation (CORE) is not only an essential component of cancer rehabilitation but also a pillar of preventive cardio-oncology. Cardio-oncology rehabilitation is a comprehensive model based on a multitargeted approach and its efficacy has been widely documented; when compared with an ‘exercise only’ programme, comprehensive CORE demonstrates a better outcome. It involves nutritional counselling, psychological support, and cardiovascular (CV) risk assessment, and it is directed to a very demanding population with a heavy burden of CV diseases driven by physical inactivity, cancer therapy-induced metabolic derangements, and cancer therapy-related CV toxicities. Despite its usefulness, CORE is still underused in cancer patients and we are still at the dawning of remote models of rehabilitation (tele-rehabilitation). Not all CORE is created equally: a careful screening procedure to identify patients who will benefit the most from CORE and a multidisciplinary customized approach are mandatory to achieve a better outcome for cancer survivors throughout their cancer journey. The aim of this paper is to provide an updated review of CORE not only for cardiologists dealing with this peculiar population of patients but also for oncologists, primary care providers, patients, and caregivers. This multidisciplinary team should help cancer patients to maintain a healthy and active life before, during, and after cancer treatment, in order to improve quality of life and to fight health inequities.

It has been well assessed that women have been widely under-represented in cardiovascular clinical trials. Moreover, a significant discrepancy in pharmacological and interventional strategies has been reported. Therefore, poor outcomes and more significant mortality have been shown in many diseases. Pharmacokinetic and pharmacodynamic differences in drug metabolism have also been described so that effectiveness could be different according to sex. However, awareness about the gender gap remains too scarce. Consequently, gender-specific guidelines are lacking, and the need for a sex-specific approach has become more evident in the last few years. This paper aims to evaluate different therapeutic approaches to managing the most common women’s diseases.

Obesity is a chronic and relapsing disease characterized by the interaction between individual predispositions and an obesogenic environment. Recent advances in understanding the mechanisms of energetic homoeostasis paved the way to more effective therapeutic approaches compared with traditional treatments. Since obesity is a complex disease, it necessitates a multi-disciplinary approach whose implementation remains challenging. Nonetheless, emerging pharmacological interventions appear promising. Currently, therapeutic success is discreet in the short term but often fails to maintain long-term weight loss due to a high likelihood of weight regain. Cardiologists play a key role in managing patients with obesity, yet often lack familiarity with its comprehensive management. The aim of this document is to summarize knowledge to consolidate essential knowledge for clinicians to effectively treat patients living with obesity. The paper emphasizes the pivotal role of a strong patient–clinician relationship in navigating successful treatment. We analyse the criteria commonly used to diagnose obesity and point out the strengths and limitations of different criteria. Furthermore, we discuss the role of obesiologists and the contributions of cardiologists. In addition, we detail key components of effective therapeutic strategies, including educational aspects and pharmacological options.

Introduction: The first complete long-acting antiretroviral therapy (ART) regimen, cabotegravir + rilpivirine long-acting (CAB + RPV LA) injectable, was approved in the US for HIV-1 treatment in individuals on a stable antiretroviral regimen with a viral load &lt; 50 copies/mL, no treatment failure history, and no resistance to either cabotegravir or rilpivirine. We describe injection schedule adherence and virologic effectiveness of CAB + RPV LA in routine clinical care in the US. Methods: From the OPERA®cohort, all adults with HIV who received their first CAB + RPV LA injection and ≥ 1 continuation injections between 21 January 2021 and 15 March 2022 were included. The injection target date was updated monthly and set to the same date of the month as the previous injection. Continuation injections administered within 7 days before or after the target date were considered on time, as per the label. Virologic undetectability (viral load &lt; 50 copies/mL), suppression (viral load &lt; 200 copies/mL), and confirmed virologic failure (2 consecutive viral loads ≥ 200 copies/mL or 1 viral load ≥ 200 copies/mL followed by discontinuation) were described among individuals with a viral load &lt; 50 copies/mL at initiation and ≥ 1 follow-up viral load. Results: Among 321 individuals on CAB + RPV LA, 90% of the continuation injections were administered on time (within ± 7 days of the target date). Of the 237 individuals with a viral load &lt; 50 copies/mL at initiation and ≥ 1 follow-up viral load, nearly all were undetectable (95%) or suppressed (99%) at their last viral load measurement, 96% maintained virologic suppression with all measured viral loads &lt; 200 copies/mL, and four confirmed virologic failures were observed. Injection delays were infrequent, and did not affect virologic outcomes over the short term. Conclusion: In this large US cohort, most monthly CAB + RPV LA injections were administered on time and high levels of virologic control were achieved. These results suggest that CAB + RPB LA injectable can be administered effectively during routine clinical care.