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Abstract Platinum (PT)-resistant Epithelial Ovarian Cancer (EOC) grows as a metastatic disease, disseminating in the abdomen and pelvis. Very few options are available for PT-resistant EOC patients, and little is known about how the acquisition of PT-resistance mediates the increased spreading capabilities of EOC. Here, using isogenic PT-resistant cells, genetic and pharmacological approaches, and patient-derived models, we report that Integrin α6 (ITGA6) is overexpressed by PT-resistant cells and is necessary to sustain EOC metastatic ability and adhesion-dependent PT-resistance. Using in vitro approaches, we showed that PT induces a positive loop that, by stimulating ITGA6 transcription and secretion, contributes to the formation of a pre-metastatic niche enabling EOC cells to disseminate. At molecular level, ITGA6 engagement regulates the production and availability of insulin-like growth factors (IGFs), over-stimulating the IGF1R pathway and upregulating Snail expression. In vitro data were recapitulated using in vivo models in which the targeting of ITGA6 prevents PT-resistant EOC dissemination and improves PT-activity, supporting ITGA6 as a promising druggable target for EOC patients.

Introduction: The production of ultrasonic energy during phacoemulsification is associated with heat generation that could damage ocular tissues, particularly at the corneoscleral wound site. Case Presentation: This study presents an 89-year-old patient with senile hypermature cataract and Fuchs endothelial dystrophy developing severe thermal corneoscleral injury during phacoemulsification. At presentation, visual acuity was finger count at 40 cm and there was a 1 × 2-mm area of corneal melting at the corneal tunnel with diffuse corneal oedema. After 1 month, a temporal circular corneal patch graft was applied to the corneal burn. A penetrating keratoplasty was performed 16 months after the first surgery. Conclusion: Corneal surgery, including lamellar patch grafts and full-thickness penetrating grafts, could be used, when necessary, to restore the cornea’s integrity. These procedures could eliminate corneal scarring, decrease astigmatism, and improve vision in patients with phacoemulsification burns.

Background The optimal treatment for acute minor ischemic stroke is still undefined. and options include dual antiplatelet treatment (DAPT), intravenous thrombolysis (IVT), or their combination. We aimed to investigate benefits and risks of combining IVT and DAPT versus DAPT alone in patients with MIS. Methods and Results This is a prespecified propensity score‐matched analysis from a prospective multicentric real‐world study (READAPT [Real‐Life Study on Short‐Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or Transient Ischemic Attack]). We included patients with MIS (National Institutes of Health Stroke Scale score at admission ≤5), without prestroke disability (modified Rankin scale [mRS] score ≤2). The primary outcomes were 90‐day mRS score of 0 to 2 and ordinal mRS distribution. The secondary outcomes included 90‐day risk of stroke and other vascular events and 24‐hour early neurological improvement or deterioration (≥2‐point National Institutes of Health Stroke Scale score decrease or increase from the baseline, respectively). From 1373 patients with MIS, 240 patients treated with IVT plus DAPT were matched with 427 patients treated with DAPT alone. At 90 days, IVT plus DAPT versus DAPT alone showed similar frequency of mRS 0 to 2 (risk difference, 2.3% [95% CI −2.0% to 6.7%]; P=0.295; risk ratio, 1.03 [95% CI 0.98–1.08]; P=0.312) but more favorable ordinal mRS scores distribution (odds ratio, 0.57 [95% CI 0.41–0.79]; P

Sex differences are consistently identified in determining the prevalence, manifestation, and response to therapies in several systemic disorders, including those affecting the cardiovascular (CV), skeletal muscle, and nervous system. Interestingly, such differences are often more noticeable as we age. For example, premenopausal women experience a lower risk of CV disease than men of the same age. While at an advanced age, with menopause, the risk of cardiovascular diseases and adverse outcomes increases exponentially in women, exceeding that of men. However, this effect appears to be reversed in diseases such as pulmonary hypertension, where women are up to seven times more likely than men to develop an idiopathic form of the disease with symptoms developing ten years earlier than their male counterparts. Explaining this is a complex question. However, several factors and mechanisms have been identified in recent decades, including a role for sex hormones, particularly estrogens and their related receptors. Furthermore, an emerging role in these sex differences has also been suggested for β-adrenergic receptors (βARs), which are essential regulators of mammalian physiology. It has in fact been shown that βARs interact with estrogen receptors (ER), providing further demonstration of their involvement in determining sexual differences.Based on these premises, this review article focused on the β3AR subtype, which shows important activities in adipose tissue but with new and interesting roles in regulating the function of cardiomyocytes and vascular cells. In detail, we examined how β3AR and ER signaling are intertwined and whether there would be sex- and age-dependent specific effects of these receptor systems.

Enzyme nanogels (ENGs) offer a convenient method to protect therapeutic proteins from in vivo stressors. Current methodologies to prepare ENGs rely on either covalent modification of surface residues or the noncovalent assembly of monomers at the protein surface. In this study, we report a new method for the preparation of noncovalent ENGs that utilizes a heterobifunctional, photocleavable monomer as a hybrid approach. Initial covalent modification with this monomer established a polymerizable handle at the protein surface, followed by radical polymerization with poly(ethylene glycol) methacrylate monomer and ethylene glycol dimethacrylate crosslinker in solution. Final photoirradiation cleaved the linkage between the polymer and protein to afford the noncovalent ENGs. The enzyme phenylalanine ammonia lyase (PAL) was utilized as a model protein yielding well-defined nanogels 80 nm in size by dynamic light scattering (DLS) and 76 nm by atomic force microscopy. The stability of PAL after exposure to trypsin or low pH was assessed and was found to be more stable in the noncovalent nanogel compared to PAL alone. This approach may be useful for the stabilization of active enzymes.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient supplies. PDAC aggressiveness largely relies on its extraordinary capability to thrive and progress in a challenging tumor microenvironment. Dysregulation of the onco-suppressor miR-15a has been extensively documented in PDAC. Here, we identified the transcription factor Fos-related antigen-2 (Fra-2) as a miR-15a target mediating the adaptive mechanism of PDAC to nutrient deprivation. We report that the IGF1 signaling pathway was enhanced in nutrient deprived PDAC cells and that Fra-2 and IGF1R were significantly overexpressed in miR-15a downmodulated PDAC patients. Mechanistically, we discovered that miR-15a repressed IGF1R expression via Fra-2 targeting. In miR-15a-low context, IGF1R hyperactivated mTOR, modulated the autophagic flux and sustained PDAC growth in nutrient deprivation. In a genetic mouse model, Mir15aKO PDAC showed Fra-2 and Igf1r upregulation and mTOR activation in response to diet restriction. Consistently, nutrient restriction improved the efficacy of IGF1R inhibition in a Fra-2 dependent manner. Overall, our results point to a crucial role of Fra-2 in the cellular stress response due to nutrient restriction typical of pancreatic cancer and support IGF1R as a promising and vulnerable target in miR-15a downmodulated PDAC.

Abstract The extracellular matrix (ECM) is an important component of the tumor microenvironment and undergoes extensive remodeling during both initiation and progression of breast cancer (BC). EMILIN1 is an ECM glycoprotein, whose function has been linked to cancer and metastasis. However, EMILIN1 role during mammary gland and BC development has never been investigated. In silico and molecular analyses of human samples from normal mammary gland and BC showed that EMILIN1 expression was lower in tumors than in healthy mammary tissue and it predicted poor prognosis, particularly in HER2-positive BC. HER2+ BC accounts for 15-20% of all invasive BC and is characterized by high aggressiveness and poor prognosis. The Δ16HER2 isoform, a splice variant with very high oncogenic potential, is frequently expressed in HER2+ BC and correlates with metastatic disease. To elucidate the role of EMILIN1 in BC, we analyzed the phenotype of MMTV-Δ16HER2 transgenic mice, developing spontaneous multifocal mammary adenocarcinomas, crossed with EMILIN1 knock-out (KO) animals. We observed that Δ16HER2/EMILIN1 KO female mice exhibited an accelerated normal mammary gland development and a significantly anticipated appearance of palpable tumors (13.32 vs 15.28 weeks). This accelerated tumor initiation was corroborated by an increased number of tumor foci observed in mammary glands from Δ16HER2/EMILIN1 KO mice compared to the wild-type counterpart. Altogether our results underscore the centrality of ECM in the process of BC initiation and point to a role for EMILIN1 during normal mammary gland development and in protecting from HER2-driven breast tumorigenesis.

Gastroesophageal reflux disease (GERD) is a digestive disorder that can lead to chronic mucosal damage, causing esophagitis, Barrett’s esophagus and esophageal cancer. GERD currently affects about 13% of the world’s population and represent a major public health concern due to the increasing prevalence and incidence. The aim of this study was to explore complementary strategies for GERD management based the natural compound palmitoylethanolamide (PEA), alone or associated with plant extracts with demonstrated anti-GERD activity (Zingiber officinale, Musa × paradisiaca, Opuntia ficus-indica and Olea europaea). For this purpose, two in vitro models based on the esophageal mucosa CP-B cell line were chosen. The first one was based on the exposure of esophageal cells to HCl, while the second one was based on lipopolysaccharide (LPS) treatment to cause a strong inflammatory cell response. Inflammation induced was assessed using a Luminex® assay, measuring the secretion of IL-1β, IL-6, IL-10, IL-8 and TNF-α. Results obtained demonstrate that PEA strongly decreased the inflammatory response elicited by HCl exposure. Moreover, the effect of PEA was enhanced by the presence of natural extracts of Zingiber officinale, Musa × paradisiaca, Opuntia ficus-indica and Olea europaea. PEA should be considered as an anti-GERD natural compound of interest.

Background: This study aimed to investigate the characteristics and outcomes of patients diagnosed with Brugada syndrome (BrS) who underwent implantable loop recorder (ILR) insertion during routine clinical activity. Methods: We conducted a comprehensive screening of all consecutive patients diagnosed with BrS at our institution. We analyzed baseline clinical characteristics, arrhythmic findings, and outcomes. Results: Out of 147 BrS patients, 42 (29 %) received an ILR, 13 (9 %) underwent implantable cardioverter-defibrillator (ICD) placement, and 92 patients (63 %) continued regular cardiological follow-up. Patients who received an ILR had a higher prevalence of suspected arrhythmic syncope (43 % vs. 22 %, p = 0.012) and tended to be younger (median age 38 years, interquartile range 30–52, vs. 43 years, 35–55, p = 0.044) with a higher presence of SCN5A gene mutations (17 % vs. 6 %, p = 0.066) compared to those who continued regular follow-up. Additionally, compared to patients with an ICD, those with an ILR had a significantly lower frequency of positive programmed ventricular stimulation (0 % vs. 91 %, p

MicroRNA (miRNA), by post-transcriptionally regulating the expression of genes involved in stroke response, represents important effectors in stroke pathophysiology. Recently, the 103/107 miRNA family emerged as a possible therapeutic target in stroke, as it controls the expression of sodium calcium exchanger 1, a plasma membrane transporter that plays a fundamental role in stroke pathophysiology. Although the neuroprotective properties of this and other miRNAs are promising, several pharmacokinetic drawbacks remain to be faced for the development of a translatable therapy based on small RNAs in CNS diseases. In the present study, to overcome these limitations, the anti-miRNA103/107 was encapsulated in specific preparations of lipid nanoparticles (LNPs), and their effectiveness was evaluated both in an in vitro model of hypoxia represented by primary neuronal cortical cultures exposed to oxygen and glucose deprivation followed by reoxygenation, and in an in vivo model of stroke obtained in rats exposed to transient occlusion of the middle cerebral artery. The results of the present study demonstrated that the encapsulation of anti-miRNA103/107 in transferrin-conjugated PEG-stabilized LNPs allowed the blood-brain barrier crossing and significantly reduced brain ischemic damage. The present achievements pave the way for the exploitation of a systemic intravenous miRNA delivery strategy in stroke therapy.

Abstract Obesity has a major socio-economic health impact. There are profound sex differences in adipose tissue deposition and obesity-related conditions. The underlying mechanisms driving sexual dimorphism in obesity and its associated metabolic disorders remain unclear. Histone variant macroH2A1.1 is a candidate epigenetic mechanism linking environmental and dietary factors to obesity. Here, we used a mouse model genetically depleted of macroH2A1.1 to investigate its potential epigenetic role in sex dimorphic obesity, metabolic disturbances and gut dysbiosis. Whole body macroH2A1 knockout (KO) mice, generated with the Cre/loxP technology, and their control littermates were fed a high fat diet containing 60% of energy derived from fat. The diet was administered for three months starting from 10 to 12 weeks of age. We evaluated the progression in body weight, the food intake, and the tolerance to glucose by means of a glucose tolerance test. Gut microbiota composition, visceral adipose and liver tissue morphology were assessed. In addition, adipogenic gene expression patterns were evaluated in the visceral adipose tissue. Female KO mice for macroH2A1.1 had a more pronounced weight gain induced by high fat diet compared to their littermates, while the increase in body weight in male mice was similar in the two genotypes. Food intake was generally increased upon KO and decreased by high fat diet in both sexes, with the exception of KO females fed a high fat diet that displayed the same food intake of their littermates. In glucose tolerance tests, glucose levels were significantly elevated upon high fat diet in female KO compared to a standard diet, while this effect was absent in male KO. There were no differences in hepatic histology. Upon a high fat diet, in female adipocyte cross-sectional area was larger in KO compared to littermates: activation of proadipogenic genes (ACACB, AGT, ANGPT2, FASN, RETN, SLC2A4) and downregulation of antiadipogenic genes (AXIN1, E2F1, EGR2, JUN, SIRT1, SIRT2, UCP1, CCND1, CDKN1A, CDKN1B, EGR2) was detected. Gut microbiota profiling showed increase in Firmicutes and a decrease in Bacteroidetes in females, but not males, macroH2A1.1 KO mice. MacroH2A1.1 KO mice display sexual dimorphism in high fat diet-induced obesity and in gut dysbiosis, and may represent a useful model to investigate epigenetic and metabolic differences associated to the development of obesity-associated pathological conditions in males and females.

Abstract Background Insulin resistance (IR) is a major metabolic disorder observed in heart failure (HF) and is tightly associated with patients’ poor prognosis. The triglyceride-glucose index (TyG) has been proposed as a surrogate marker of IR in HF. Yet, whether TyG is a reliable clinical marker is still under debate. Hence, we aimed to respond to this relevant question via a systematic review and meta-analysis of existing studies. Methods A systematic search was conducted in PubMed, Embase, Scopus, and Web of Science to find studies investigating the TyG index in patients with HF or its association with the incidence of HF. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were pooled through random-effect meta-analysis. HRs were calculated using TyG as a continuous variable (1 unit increase) and by comparing the group with the highest TyG to the lowest TyG group. Results Thirty studies, involving 772,809 participants, were included in this systematic review. Meta-analysis of seven studies comparing the highest-TyG to the lowest-TyG group showed a significantly increased risk of HF in the former group (HR 1.21, 95% CI 1.14 to 1.29, P