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PURPOSE:To evaluate the efficacy and safety of topical cenegermin (recombinant human nerve growth factor) in patients with neurotrophic keratopathy. DESIGN:Multicenter, randomized, double-masked, vehicle-controlled trial. PARTICIPANTS:Patients with neurotrophic persistent epithelial defect with or without stromal thinning. METHODS:The NGF0214 trial, conducted among 11 sites in the United States, randomized 48 patients 1:1 to cenegermin 20 μg/ml or vehicle eye drops, 6 drops daily for 8 weeks of masked treatment. Follow-up was 24 weeks. Safety was assessed in all patients who received study drug. Efficacy was assessed by intention to treat. MAIN OUTCOME MEASURES:The primary end point was healing of the neurotrophic lesion (persistent epithelial defect or corneal ulcer) after 8 weeks of masked treatment. Masked central readers measured neurotrophic lesions in randomized clinical pictures, then assessed healing status conventionally (

Background: Cancer-related fatigue (CRF) occurs in nearly all patients with metastatic breast cancer (MBC). Objectives: This real-world analysis aimed to describe the prevalence and importance of fatigue in patients with MBC within 3 months of treatment with single-agent taxane-based chemotherapy during the timeframe of 2020–2022 in the United States and Europe. It was also conducted to assess whether there was a difference in relapsed patients compared to patients diagnosed de novo. Design: Electronic health records were analyzed from approximately 150 million patients to identify patients with MBC who underwent taxane treatment. Results: In 2021, 50,490 patients had MBC, of whom 16,170 were diagnosed de novo and 34,330 experienced relapse. The proportion of patients undergoing taxane-based chemotherapy was 7.5% (n = 1220) and 13.4% (n = 4590), respectively, and the prevalence of any fatigue and CRF was similar between the groups (24.6% versus 25.7% and 6.6% versus 5.4%, respectively). Conclusion: At least one in four patients with MBC undergoing taxane-based treatment will experience fatigue. This highlights the importance of validating screening tools to identify CRF, which is necessary to advance clinical trials aimed at investigating treatment strategies to improve patient-centered outcomes for fatigue. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a severe form of acute respiratory failure characterised by extensive inflammatory injury to the alveolocapillary barrier leading to alveolar oedema, impaired gas exchange and, ultimately, hypoxaemia necessitating the use of supplemental oxygen combined with some degree of positive airway pressure. Although much heterogeneity exists regarding the aetiology, localisation and endotypic characterisation of ARDS, what remains largely undisputed is the role of the innate immune system, and in particular of neutrophils, in precipitating and propagating lung injury. Activated neutrophils, recruited to the lung through chemokine gradients, promote injury by releasing oxidants, proteases and neutrophil extracellular traps, which ultimately cause platelet aggregation, microvascular thrombosis and cellular death. Among various neutrophilic chemoattractants, interleukin-8/ C-X-C motif ligand 8 and related chemokines, collectively called ELR+ chemokines, acting on neutrophils through the G protein-coupled receptors CXCR1 and CXCR2, are pivotal in orchestrating the neutrophil activation status and chemotaxis in the inflamed lung. This allows efficient elimination of infectious agents while at the same time minimising collateral damage to host tissue. Therefore, understanding how CXCR1 and CXCR2 receptors are regulated is important if we hope to effectively target them for therapeutic use in ARDS. In the following narrative review, we provide an overview of the role of ELR+ chemokines in acute lung injury (ALI) and ARDS, we summarise the relevant regulatory pathways of their cognisant receptors CXCR1/2 and highlight current preclinical and clinical evidence on the therapeutic role of CXCR1 and CXCR2 inhibition in animal models of ALI, as well as in ARDS patients. [ABSTRACT FROM AUTHOR]

Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions and plays immunopathological roles in inflammatory diseases, we investigated whether the C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill patients with COVID-19 compared with patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular traps-dependent (NETs-dependent) immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonists of C5aR1 could be useful for COVID-19 treatment., Introduction COVID-19 is the major acute global public health issue in this century. Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS), which may progress to organ dysfunction and [...]

Introduction: During aging, sarcopenia and decline in physiological processes lead to partial loss of muscle strength, atrophy, and increased fatigability. Muscle changes may be related to a reduced intake of essential amino acids playing a role in proteostasis. We have recently shown that branched-chain amino acid (BCAA) supplements improve atrophy and weakness in models of muscle disuse and aging. Considering the key roles that the alteration of Ca2+-related homeostasis and store-operated calcium entry (SOCE) play in several muscle dysfunctions, this study has been aimed at gaining insight into the potential ability of BCAAbased dietary formulations in aged mice on various players of Ca2+ dyshomeostasis. Methods: Seventeen-month-old male C57BL/6J mice received a 12-week supplementation with BCAAs alone or boosted with two equivalents of L-alanine (2-Ala) or with dipeptide L-alanyl-L-alanine (Di-Ala) in drinking water. Outcomes were evaluated on ex vivo skeletal muscles indices vs. adult 3-month-old male C57BL/6J mice. Results: Ca2+ imaging confirmed a decrease in SOCE and an increase of resting Ca2+ concentration in aged vs. adult mice without alteration in the canonical components of SOCE. Aged muscles vs. adult muscles were characterized by a decrease in the expression of ryanodine receptor 1 (RyR1), the SarcoEndoplasmic Reticulum Calcium ATPase (SERCA) pump, and sarcalumenin together with an alteration of the expression of mitsugumin 29 and mitsugumin 53, two recently recognized players in the SOCE mechanism. BCAAs, particularly the formulation BCAAs+2-Ala, were able to ameliorate all these alterations. Discussion: These results provide evidence that Ca2+ homeostasis dysfunction plays a role in the functional deficit observed in aged muscle and supports the interest of dietary BCAA supplementation in counteracting sarcopenia-related SOCE dysregulation. [ABSTRACT FROM AUTHOR]

Nerve growth factor (NGF), the first neurotrophin to be discovered, has a long and eventful research journey with a series of turning points, setbacks, and achievements. Since the groundbreaking investigations led by Nobel Prize winner Rita Levi-Montalcini, advancements in the comprehension of NGF's functions have revolutionized the field of neuroscience, offering new insights and opportunities for therapeutic innovation. However, the clinical application of NGF has historically been hindered by challenges in determining appropriate dosing, administration strategies, and complications related to the production process. Recent advances in the production and scientific knowledge of recombinant NGF have enabled its clinical development, and in 2018, the United States Food and Drug Administration approved cenegermin-bkbj, a recombinant human NGF, for the treatment of all stages of neurotrophic keratitis. This review traces the evolutionary path that transformed NGF from a biological molecule into a novel therapy with potential research applications beyond the eye. Special emphasis is put on the studies that advanced NGF from discovery to the first medicinal product approved to treat a human disease. [ABSTRACT FROM AUTHOR]

Chronic neuropathic pain (NP) is an increasingly prevalent disease and leading cause of disability which is challenging to treat. Several distinct classes of drugs are currently used for the treatment of chronic NP, but each drug targets only narrow components of the underlying pathophysiological mechanisms, bears limited efficacy, and comes with dose-limiting side effects. Multimodal therapies have been increasingly proposed as potential therapeutic approaches to target the multiple mechanisms underlying nociceptive transmission and modulation. However, while preclinical studies with combination therapies showed promise to improve efficacy over monotherapy, clinical trial data on their efficacy in specific populations are lacking and increased risk for adverse effects should be carefully considered. Drug-drug co-crystallization has emerged as an innovative pharmacological approach which can combine two or more different active pharmaceutical ingredients in a single crystal, optimizing pharmacokinetic and physicochemical characteristics of the native molecules, thus potentially capitalizing on the synergistic efficacy between classes of drugs while simplifying adherence and minimizing the risk of side effects by reducing the doses. In this work, we review the current pharmacological options for the treatment of chronic NP, focusing on combination therapies and their ongoing developing programs and highlighting the potential of co-crystals as novel approaches to chronic NP management. [ABSTRACT FROM AUTHOR]