Female blind baseball players against gender discrimination: the "red diamonds" experience.

Background: Sport has the well-known power of improving body awareness, self-esteem, and social interaction, thus promoting quality of life and psychophysical wellbeing. Specifically referring to adapted disciplines, habitual practice often becomes an effective integration and self-efficacy booster. Among disabilities, visual impairment deeply alters body image perception, autonomy, and environmental/social interaction heavily reducing sport or leisure involvement opportunities. In particular, visually impaired women represent one of the most vulnerable categories to gender and disability discrimination. Moreover, even when congenitally sightless, they perceive social pressure of mainstream beauty ideals, mostly spread by media, comparable to their sighted peers. On these premises and the previously demonstrated psychophysical benefits of Italian blind baseball practice on this target population, the present study aimed to deepen the social and educative potentialities of such adapted sport applying a more sociological research approach. Methods: The "red diamonds" event, namely, the first ever female blind baseball match, was the setting for the administration of our structured online survey. In detail, our survey comprised different evaluation tools such as the 18-item Psychological Well-Being Scale, the 12-item Short Form questionnaire, the Dresden Body Image questionnaire, the Rosenberg Self-Esteem Scale, and sociological model designed questions. Quality of life, psychological wellbeing, self-esteem, body image, and perceived female sport psychological violence were investigated in the whole women sample (n = 33) voluntarily adhering to the game. Results: Survey results revealed no statistically significant differences between visually impaired players (n = 13; mean age: 32.84 ± 12.05 years) and sighted on-field subjects (i.e., coaches, assistants, and referees; n = 20; mean age: 47.15 ± 12.31 years) in almost all the inquired variables, thus remarking the social and functional benefits of adapted sport through the "dual embodiment" and empowerment phenomenon. Conclusions: Given that the event was inspired by and performed on the World Day against women violence, our study deepened not only the topic of disability discrimination but also the currently alarming gender-related one. In such a context, the present research might provide interesting cues for further investigations on disability and gender disparities in sports, hence spreading interest in this under-investigated field. In perspective, the "red diamonds" experience could also contribute to inspiring and progressively developing educative tools against any kind of discrimination by promoting integration and social growth through regular sports practice.

Sialylation status and its relationship with morphofunctional changes in human adult testis during sexually mature life and aging: A narrative review.

Sialic acids (Sias) are a family of electronegatively charged nine-carbon monosaccharides containing a carboxylic acid, mostly found as terminal residues in glycans of glycoproteins and glycolipids. They are bound to galactose or N-acetylgalactosamine via α2,3 or α2,6 linkage, or to other Sias especially via α2,8 linkage, which results in monomeric, oligomeric, and polymeric forms. Sias play determinant roles in a multitude of biological processes in human tissues from development to adult life until aging. In this review, we summarized the current knowledge on the sialylation status in the human testis with a main focus on sexually mature life and aging, when this organ shows significant morphofunctional changes resulting into variations of hormonal levels, as well as changes in molecules involved in mitochondrial function, receptors, and signaling proteins. Evidence suggests that Sias may have crucial morphofunctional roles in the different testicular components during the sexually mature age. With advancing age, significant loss of Sias and/or changes in sialylation status occur in all the testicular components, which seems to contribute to morphofunctional changes characteristic of the aging testis. Based on the current knowledge, further in-depth investigations will be necessary to better understand the mechanistic role of Sias in the biological processes of human testicular tissue and the significance of their changes during the aging process. Future investigations might also contribute to the development of novel prophylactic and/or therapeutic approaches that, by maintaining/restoring the correct sialylation status, could help in slowing down the testis aging process, thus preserving the testicular structure and functionality and preventing age-related pathologies.

Pharmacological Stimulation of Soluble Guanylate Cyclase Counteracts the Profibrotic Activation of Human Conjunctival Fibroblasts.

Conjunctival fibrosis is a serious clinical concern implicated in a wide spectrum of eye diseases, including outcomes of surgery for pterygium and glaucoma. It is mainly driven by chronic inflammation that stimulates conjunctival fibroblasts to differentiate into myofibroblasts over time, leading to abnormal wound healing and scar formation. Soluble guanylate cyclase (sGC) stimulation was found to suppress transforming growth factor ß (TGFß)-induced myofibroblastic differentiation in various stromal cells such as skin and pulmonary fibroblasts, as well as corneal keratocytes. Here, we evaluated the in vitro effects of stimulation of the sGC enzyme with the cell-permeable pyrazolopyridinylpyrimidine compound BAY 41-2272 in modulating the TGFß1-mediated profibrotic activation of human conjunctival fibroblasts. Cells were pretreated with the sGC stimulator before challenging with recombinant human TGFß1, and subsequently assayed for viability, proliferation, migration, invasiveness, myofibroblast marker expression, and contractile properties. Stimulation of sGC significantly counteracted TGFß1-induced cell proliferation, migration, invasiveness, and acquisition of a myofibroblast-like phenotype, as shown by a significant downregulation of FAP, ACTA2, COL1A1, COL1A2, FN1, MMP2, TIMP1, and TIMP2 mRNA levels, as well as by a significant reduction in α-smooth muscle actin, N-cadherin, COL1A1, and FN-EDA protein expression. In addition, pretreatment with the sGC stimulator was capable of significantly dampening TGFß1-induced acquisition of a contractile phenotype by conjunctival fibroblasts, as well as phosphorylation of Smad3 and release of the proinflammatory cytokines IL-1ß and IL-6. Taken together, our findings are the first to demonstrate the effectiveness of pharmacological sGC stimulation in counteracting conjunctival fibroblast-to-myofibroblast transition, thus providing a promising scientific background to further explore the feasibility of sGC stimulators as potential new adjuvant therapeutic compounds to treat conjunctival fibrotic conditions.

Sex Bias in Diagnostic Delay: Are Axial Spondyloarthritis and Ankylosing Spondylitis Still Phantom Diseases in Women? A Systematic Review and Meta-Analysis.

Diagnostic delay (DD) is associated with poor radiological and quality of life outcomes in axial spondyloarthritis (ax-SpA) and ankylosing spondylitis (AS). The female (F) population is often misdiagnosed, as classification criteria were previously studied mostly in males (M). We conducted a systematic review to investigate (i) the difference in DD between the sexes, the impact of HLA*B27 and clinical and social factors (work and education) on this gap, and (ii) the possible influence of the year of publication (before and after the 2009 ASAS classification criteria), geographical region (Europe and Israel vs. extra-European countries), sample sources (mono-center vs. multi-center studies), and world bank (WB) economic class on DD in both sexes. We searched, in PubMed and Embase, studies that reported the mean or median DD or the statistical difference in DD between sexes, adding a manual search. Starting from 399 publications, we selected 26 studies (17 from PubMed and Embase, 9 from manual search) that were successively evaluated with the modified Newcastle-Ottawa Scale (m-NOS). The mean DD of 16 high-quality (m-NOS > 4/8) studies, pooled with random-effects meta-analysis, produces results higher in F (1.48, 95% CI 0.83-2.14, p < 0.0001) but with significant results at the second analysis only in articles published before the 2009 ASAS classification criteria (0.95, 95% CI 0.05-1.85, p < 0.0001) and in extra-European countries (3.16, 95% CI 2.11-4.22, p < 0.05). With limited evidence, some studies suggest that DD in F might be positively influenced by HLA*B27 positivity, peripheral involvement, and social factors.

The differential crosstalk of the skin-gut microbiome axis as a new emerging actor in systemic sclerosis.

OBJECTIVES: We characterized the microbiota in SSc, focusing on the skin-oral-gut axis and the serum and faecal free fatty acid (FFA) profile. METHODS: Twenty-five SSc patients with ACA or anti-Scl70 autoantibodies were enrolled. The microbiota of faecal, saliva and superficial epidermal samples was assessed through next-generation sequencing analysis. GC-MS was used to quantify faecal and serum FFAs. Gastrointestinal symptoms were investigated with the University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument (UCLA GIT-2.0) questionnaire. RESULTS: The ACA+ and anti-Scl70+ groups displayed different cutaneous and faecal microbiota profiles. The classes of cutaneous Sphingobacteriia and Alphaproteobacteria, the faecal phylum Lentisphaerae, the levels of the classes Lentisphaeria and Opitutae, and the genus NA-Acidaminococcaceae were significantly higher in faecal samples from the ACA+ patients than in samples from the anti-Scl70+ patients. The cutaneous Sphingobacteria and the faecal Lentisphaerae were significantly correlated (rho = 0.42; P = 0.03). A significant increase in faecal propionic acid was observed in ACA+ patients. Moreover, all levels of faecal medium-chain FFAs and hexanoic acids were significantly higher in the ACA+ group than in the anti-Scl70+ group (P < 0.05 and P < 0.001, respectively). In the ACA+ group, the analysis of the serum FFA levels showed an increasing trend in valeric acid. CONCLUSION: Different microbiota signatures and FFA profiles were found for the two groups of patients. Despite being in different body districts, the cutaneous Sphingobacteria and faecal Lentisphaerae appear interdependent.

The contribution of endothelial cells to tissue fibrosis.

PURPOSE OF REVIEW: Tissue fibrosis is an increasingly prevalent condition associated with various diseases and heavily impacting on global morbidity and mortality rates. Growing evidence indicates that common cellular and molecular mechanisms may drive fibrosis of diverse cause and affecting different organs. The scope of this review is to highlight recent findings in support for an important role of vascular endothelial cells in the pathogenesis of fibrosis, with a special focus on systemic sclerosis as a prototypic multisystem fibrotic disorder. RECENT FINDINGS: Although transition of fibroblasts to chronically activated myofibroblasts is widely considered the central profibrotic switch, the endothelial cell involvement in development and progression of fibrosis has been increasingly recognized over the last few years. Endothelial cells can contribute to the fibrotic process either directly by acting as source of myofibroblasts through endothelial-to-myofibroblast transition (EndMT) and concomitant microvascular rarefaction, or indirectly by becoming senescent and/or secreting a variety of profibrotic and proinflammatory mediators with consequent fibroblast activation and recruitment of inflammatory/immune cells that further promote fibrosis. SUMMARY: An in-depth understanding of the mechanisms underlying EndMT or the acquisition of a profibrotic secretory phenotype by endothelial cells will provide the rationale for novel endothelial cell reprogramming-based therapeutic approaches to prevent and/or treat fibrosis.

Physical activity and sport practice to improve balance control of visually impaired individuals: a narrative review with future perspectives.

Visual disability negatively impacts balance, everyday self-efficacy, and mobility and often leads affected subjects to perceive physical exercise as a burdensome challenge thus discouraging them from practicing. Despite the well-proven benefits of regular physical activity in visually impaired people, especially addressing postural control, there are no specific guidelines and most of the available literature seems to be flawed by critical issues. Given the wide heterogeneity and the multidimensional needs of this population, a more realistic and target-specific perspective is needed in order to properly investigate and promote exercise practice and adherence for balance improvement. On this basis, through a critical overview of the recent literature, the present article aimed to enrich the current knowledge about this topic by providing innovative suggestions, both practical and methodological, and specifically deepening the disability-related deficits and peculiarities of different age ranges. Moreover, since a multidisciplinary approach is advisable when designing and leading exercise protocols tailored to visually impaired individuals, such innovative hints also highlighted the central role of the adapted physical activity specialist, hence contributing to foster its official professional recognition and involvement in this field.

Immunohistochemical and ultrastructural identification of telocytes in the lamina propria of human vaginal mucosa.

Since their relatively recent discovery, telocytes (TCs) have been described as peculiar cells strategically positioned in the stromal tissue component of multiple organ systems of the mammalian body including female reproductive organs (i.e., ovary, uterine tube, and uterus). Nevertheless, current knowledge of TCs in the vagina is very limited. The present study was therefore undertaken to investigate the existence and characteristics of TCs in the stromal tissue of human vaginal mucosa by means of immunohistochemistry, immunofluorescence confocal microscopy, and transmission electron microscopy. In the vaginal lamina propria, TCs were first identified by CD34 immunohistochemistry that revealed the presence of CD34+ stromal cells arranged in networks, especially around blood vessels. Double immunofluorescence confocal microscopy allowed to precisely distinguish the perivascular networks of CD34+ stromal cells lacking CD31 immunoreactivity from adjacent CD31+ microvessels. All the perivascular networks of TCs/CD34+ stromal cells situated in the vaginal lamina propria coexpressed platelet-derived growth factor receptor α, which strengthened their identification as TCs. Instead, vaginal mucosal TCs were immunophenotypically negative for c-kit/CD117. The ultrastructural examination confirmed the presence of TCs, namely stromal cells with characteristic cytoplasmic processes (i.e., telopodes) forming labyrinthine networks around blood vessels and releasing extracellular vesicles. Together, our morphological findings provide the first comprehensive demonstration that TCs reside in the human vaginal lamina propria, thus paving the way for further investigation of their putative functions in vaginal mucosal homeostasis and pathophysiology.

Lymphatic Endothelial-to-Myofibroblast Transition: A Potential New Mechanism Underlying Skin Fibrosis in Systemic Sclerosis.

At present, only a few reports have addressed the possible contribution of the lymphatic vascular system to the pathogenesis of systemic sclerosis (SSc). Based on the evidence that blood vascular endothelial cells can undertake the endothelial-to-myofibroblast transition (EndMT) contributing to SSc-related skin fibrosis, we herein investigated whether the lymphatic endothelium might represent an additional source of profibrotic myofibroblasts through a lymphatic EndMT (Ly-EndMT) process. Skin sections from patients with SSc and healthy donors were immunostained for the lymphatic endothelial cell-specific marker lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) in combination with α-smooth muscle actin (α-SMA) as the main marker of myofibroblasts. Commercial human adult dermal lymphatic microvascular endothelial cells (HdLy-MVECs) were challenged with recombinant human transforming growth factor-ß1 (TGFß1) or serum from SSc patients and healthy donors. The expression of lymphatic endothelial cell/myofibroblast markers was measured by quantitative real-time PCR, Western blotting and immunofluorescence. Collagen gel contraction assay was performed to assess myofibroblast-like cell contractile ability. Lymphatic endothelial cells in intermediate stages of the Ly-EndMT process (i.e., coexpressing LYVE-1 and α-SMA) were found exclusively in the fibrotic skin of SSc patients. The culturing of HdLy-MVECs with SSc serum or profibrotic TGFß1 led to the acquisition of a myofibroblast-like morphofunctional phenotype, as well as the downregulation of lymphatic endothelial cell-specific markers and the parallel upregulation of myofibroblast markers. In SSc, the Ly-EndMT might represent a previously overlooked pathogenetic process bridging peripheral microlymphatic dysfunction and skin fibrosis development.

Reactive Agility and Pitching Performance Improvement in Visually Impaired Competitive Italian Baseball Players: An Innovative Training and Evaluation Proposal.

Visual input significantly affects kinesthesis skills and, hence, visually impaired individuals show less developed sensorimotor control, especially in an unfamiliar outdoor environment. Regular blind baseball practice can counteract such a deficit but, given the complex kinetic chain model required, a targeted workout proposal is needed to improve the main athletic gesture performance. On these premises, we investigated, for the first time, the running and pitching performance of a competitive Italian blind baseball team through quantitative tools and parameters such as Libra Easytech sensorized proprioceptive board, goniometric active range of motion, chronometric speed, and pitching linear length. Moreover, the perceived physical exertion was assessed by the Borg CR10 scale. Consequently, an adapted athletic training protocol was designed and tested on the field during the competitive season, with the aim to strengthen sport specific-gesture coordination and efficacy as well as to prevent injuries. Quantitative assessments showed an improvement in ankle stability index, bilateral upper limb and hip mobility, reactive agility, running braking phase control during second base approaching, and auditory target-related pitching accuracy along with a decrease in perceived physical exertion. This protocol might therefore represent an effective and easily reproducible training and evaluation approach to tailor management of visually impaired baseball players, and safely improve their athletic performance under the supervision of an adapted exercise specialist.

Sialylation status in placentas from pregnancies with SARS-CoV-2 infection.

INTRODUCTION: Recent investigations suggest the potential negative impact of SARS-CoV-2 infection on pregnant women and pregnancy outcome. In addition, some studies have described pathological changes in the placental tissue of SARS-CoV-2-positive mothers, which are related or not to the infection severity and/or infection trimester. Among the various molecules involved in the normal structure and functionality of the placenta, sialic acids (Sias) seem to play an important role. Hence, we aimed to investigate possible changes in the distribution and content of Sias with different glycosidic linkages, namely α2,3 and α2,6 Galactose- or N-acetyl-Galactosamine-linked Sias and polymeric Sia (PolySia), in placentas from pregnant women infected by SARS-CoV-2 during the three different pregnancy trimesters. METHODS: α2,3 and α2,6 Galactose-linked Sias were evaluated by lectin histochemistry (Maackia amurensis agglutinin (MAA) and Sambucus nigra agglutinin (SNA), respectively), while immunohistochemistry was used for PolySia detection. RESULTS: Data showed lower levels of α2,3 Galactose-linked Sias in the trophoblast and underlying basement membrane/basal plasma membrane in placentas from women infected during the second and third infection trimester compared with uninfected cases and those infected during first trimester. On the other hand, higher levels of PolySia were detected in the trophoblast during the second and third infection trimester. CONCLUSIONS: Our findings suggest that changes in the sialylation status of trophoblast and its basement membrane/basal plasma membrane, together with other concomitant factors, could be at the basis of the most common placental histopathological alterations and gestational complications found especially in pregnancies with SARS-CoV-2 infection during the second and third trimester.

Extracellular Lactic Acidosis of the Tumor Microenvironment Drives Adipocyte-to-Myofibroblast Transition Fueling the Generation of Cancer-Associated Fibroblasts.

Lactic acidosis characterizes the tumor microenvironment (TME) and is involved in the mechanisms leading to cancer progression and dissemination through the reprogramming of tumor and local host cells (e.g., endothelial cells, fibroblasts, and immune cells). Adipose tissue also represents a crucial component of the TME which is receiving increasing attention due to its pro-tumoral activity, however, to date, it is not known whether it could be affected by the acidic TME. Now, emerging evidence from chronic inflammatory and fibrotic diseases underlines that adipocytes may give rise to pathogenic myofibroblast-like cells through the adipocyte-to-myofibroblast transition (AMT). Thus, our study aimed to investigate whether extracellular acidosis could affect the AMT process, sustaining the acquisition by adipocytes of a cancer-associated fibroblast (CAF)-like phenotype with a pro-tumoral activity. To this purpose, human subcutaneous adipose-derived stem cells committed to adipocytes (acADSCs) were cultured under basal (pH 7.4) or lactic acidic (pH 6.7, 10 mM lactate) conditions, and AMT was evaluated with quantitative PCR, immunoblotting, and immunofluorescence analyses. We observed that lactic acidosis significantly impaired the expression of adipocytic markers while inducing myofibroblastic, pro-fibrotic, and pro-inflammatory phenotypes in acADSCs, which are characteristic of AMT reprogramming. Interestingly, the conditioned medium of lactic acidosis-exposed acADSC cultures was able to induce myofibroblastic activation in normal fibroblasts and sustain the proliferation, migration, invasion, and therapy resistance of breast cancer cells in vitro. This study reveals a previously unrecognized relationship between lactic acidosis and the generation of a new CAF-like cell subpopulation from adipocytic precursor cells sustaining tumor malignancy.

Advances in Systemic Sclerosis: From Pathogenetic Pathways toward Novel Therapeutic Targets.

Systemic sclerosis (SSc, or scleroderma) is a multifaceted rare connective tissue disease [...].

Current Trends in Vascular Biomarkers for Systemic Sclerosis: A Narrative Review.

Systemic sclerosis (SSc, scleroderma) is a multifaceted rare connective tissue disease whose pathogenesis is dominated by immune dysregulation, small vessel vasculopathy, impaired angiogenesis, and both cutaneous and visceral fibrosis. Microvascular impairment represents the initial event of the disease, preceding fibrosis by months or years and accounting for the main disabling and/or life-threatening clinical manifestations, including telangiectasias, pitting scars, periungual microvascular abnormalities (e.g., giant capillaries, hemorrhages, avascular areas, ramified/bushy capillaries) clinically detectable by nailfold videocapillaroscopy, ischemic digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. Despite a variety of available treatment options, treatment of SSc-related vascular disease remains problematic, even considering SSc etherogenity and the quite narrow therapeutic window. In this context, plenty of studies have highlighted the great usefulness in clinical practice of vascular biomarkers allowing clinicians to assess the evolution of the pathological process affecting the vessels, as well as to predict the prognosis and the response to therapy. The current narrative review provides an up-to-date overview of the main candidate vascular biomarkers that have been proposed for SSc, focusing on their main reported associations with characteristic clinical vascular features of the disease.

Soluble guanylate cyclase stimulation fosters angiogenesis and blunts myofibroblast-like features of systemic sclerosis endothelial cells.

OBJECTIVES: In SSc, angiogenesis impairment advances in parallel with the development of fibrosis orchestrated by myofibroblasts originating from different sources, including endothelial-to-mesenchymal transition (EndoMT). Soluble guanylate cyclase (sGC) stimulation has shown antifibrotic effects in SSc skin fibroblasts and mouse models. Here, we investigated the effects of pharmacological sGC stimulation on impaired angiogenesis and myofibroblast-like features of SSc dermal microvascular endothelial cells (SSc-MVECs). METHODS: To determine whether sGC stimulation affected cell viability/proliferation, SSc-MVECs and healthy dermal MVECs (H-MVECs) were challenged with the sGC stimulator (sGCS) MK-2947 and assayed by annexin V/propidium iodide flow cytometry and the water-soluble tetrazolium salt (WST-1) assay. To study angiogenesis and EndoMT, MK-2947-treated SSc-MVECs were subjected to wound healing and capillary morphogenesis assays and analysed for the expression of endothelial/myofibroblast markers and contractile ability. RESULTS: MK-2947 treatment did not affect H-MVEC viability/proliferation, while it significantly increased SSc-MVEC proliferation, wound healing capability and angiogenic performance. After MK-2947 treatment, SSc-MVECs exhibited significantly increased proangiogenic MMP9 and decreased antiangiogenic MMP12 and PTX3 gene expression. A significant increase in the expression of CD31 and vascular endothelial cadherin paralleled by a decrease in α-smooth muscle actin, S100A4, type I collagen and Snail1 mesenchymal markers was also found in MK-2947-treated SSc-MVECs. Furthermore, stimulation of sGC with MK-2947 significantly counteracted the intrinsic ability of SSc-MVECs to contract collagen gels and reduced phosphorylated-extracellular signal-regulated kinases 1 and 2 protein levels. CONCLUSION: These findings demonstrate for the first time that pharmacological sGC stimulation effectively ameliorates the angiogenic performance and blunts the myofibroblast-like profibrotic phenotype of SSc-MVECs, thus providing new evidence for repurposing sGCSs for SSc.

The Soluble Guanylate Cyclase Stimulator BAY 41-2272 Attenuates Transforming Growth Factor ß1-Induced Myofibroblast Differentiation of Human Corneal Keratocytes.

Corneal transparency, necessary for vision and depending on the high organization of stromal extracellular matrix, is maintained by keratocytes. Severe or continuous corneal injuries determine exaggerated healing responses resulting in the formation of irreversible fibrotic scars and vision impairment. Soluble guanylate cyclase (sGC) stimulation demonstrated antifibrotic effects in both experimental fibrosis and human lung and skin fibroblasts. Here, we assessed whether sGC stimulation with BAY 41-2272 could attenuate transforming growth factor ß1 (TGFß1)-induced myofibroblast differentiation of human corneal keratocytes. Cells were challenged with TGFß1, with/without BAY 41-2272 preincubation, and subsequently assessed for viability, proliferation, migration, chemoinvasion, as well for the expression of myofibroblast/fibroblast activation markers and contractile abilities. Treatment with BAY 41-2272 did not affect keratocyte viability, while preincubation of cells with the sGC stimulator was able to inhibit TGFß1-induced proliferation, wound healing capacity, and invasiveness. BAY 41-2272 was also able to attenuate TGFß1-induced myofibroblast-like profibrotic phenotype of keratocytes, as demonstrated by the significant decrease in ACTA2, COL1A1, COL1A2, FN1 and PDPN gene expression, as well as in α-smooth muscle actin, α-1 chain of type I collagen, podoplanin, vimentin and N-cadherin protein expression. Finally, BAY 41-2272 significantly counteracted the TGFß1-induced myofibroblast-like ability of keratocytes to contract collagen gels, reduced phosphorylated Smad3 protein levels, and attenuated gene expression of proinflammatory cytokines. Collectively, our data show for the first time that BAY 41-2272 is effective in counteracting keratocyte-to-myofibroblast transition, thus providing the rationale for the development of sGC stimulators as novel promising modulators of corneal scarring and fibrosis.

Increased Circulating Soluble Junctional Adhesion Molecules in Systemic Sclerosis: Association with Peripheral Microvascular Impairment.

Systemic sclerosis (SSc, scleroderma) is a severe disease characterized by peripheral microcirculation abnormalities manifesting with Raynaud's phenomenon, nailfold videocapillaroscopic (NVC) changes, and even ischemic digital ulcers (DUs) that are often refractory to treatments. In the wake of previously described associations between the circulating levels of soluble junctional adhesion molecules (sJAMs) and SSc clinical features, here, we measured sJAM-A and sJAM-C levels by enzyme-linked immunosorbent assay in serum samples from a large case series of 110 SSc patients and 85 healthy controls, focusing on their possible association with peripheral vascular clinical features and their potential as biomarkers that are either diagnostic or mirror SSc-related microvasculopathy severity. Our data demonstrated that serum sJAM-A and sJAM-C are significantly increased in patients with SSc vs. healthy controls, especially in those featuring early/active NVC patterns and the presence of ischemic DUs. Moreover, circulating sJAM-C levels showed good diagnostic accuracy in discriminating between patients and controls, as assessed by receiver operator characteristics curve analysis. Finally, logistic regression revealed that, when comparing sJAM-A to sJAM-C, the latter might be better suited as a biomarker for SSc-related DUs. Our promising findings provide the necessary groundwork for longitudinal follow-up analyses of SSc patients aiming to assess whether circulating sJAM-C levels might be predictive for the development of new DUs, as well as DU recurrence and/or refractoriness to targeted therapies.

Adapted Physical Activity Protocol for Lower Limb Functional and Strength Recovery in a Young Athlete with Cutaneous Melanoma: Feasibility and Efficacy during COVID-19 Pandemic.

Adapted physical activity (APA) can improve psychophysical wellbeing and quality of life (QoL) in cancer survivors, a vulnerable population requiring a global management, especially during the recent pandemic. On this basis, we investigated for the first time the impact of a tailored APA intervention on a melanoma-affected 18-year-old female athlete to counteract treatment sequelae and promote lower limb functional and strength recovery. Patient was evaluated at baseline and post-protocol by a test battery focusing on mobility, muscle strength measured by dynamometry, and lower limb girths assessed at specific anatomical points. Moreover, health-related QoL, depression/anxiety, psychological distress and pain intensity were evaluated by Functional Assessment of Cancer Therapy-Melanoma (FACT-M), Hospital Anxiety and Depression Scale (HADS), distress thermometer, and numerical rating scale (NRS) questionnaires, respectively. An almost doubled up increase in lower limb strength, along with hip mobility improvement, and post-surgical edema and pain reduction were observed following the protocol. Concerning the QoL assessment, a moderate post-intervention improvement in physical and emotional wellbeing was detected, while depression state worsened though remaining within the normality range. Our findings show that a specialist-supervised structured APA protocol based on a patient-centered multidisciplinary approach may represent an effective strategy to recover functional and psychophysical efficiency, thus promoting a quick return to daily life activities and offering a concrete chance of resuming competitive sport practice.

Circulating Neurovascular Guidance Molecules and Their Relationship with Peripheral Microvascular Impairment in Systemic Sclerosis.

Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease whose earliest clinical manifestations are microvascular tone dysregulation and peripheral microcirculatory abnormalities. Following previous evidence of an association between circulating neurovascular guidance molecules and SSc disturbed angiogenesis, here, we measured the levels of soluble neuropilin 1 (sNRP1), semaphorin 3E (Sema3E), and Slit2 by enzyme-linked immunosorbent assay in serum samples from a large case series of 166 SSc patients vs. 110 healthy controls. We focused on their possible correlation with vascular disease clinical features and applied logistic regression analysis to determine which of them could better reflect disease activity and severity. Our results demonstrate that, in SSc: (i) sNRP1 is significantly decreased, with lower sNRP1 serum levels correlating with the severity of nailfold videocapillaroscopy (NVC) abnormalities and the presence of ischemic digital ulcers (DUs); (ii) both Sema3E and Slit2 are increased, with Sema3E better reflecting early NVC abnormalities; and (iii) higher Sema3E correlates with the absence of DUs, while augmented Slit2 associates with the presence of DUs. Receiver operator characteristics curve analysis revealed that both circulating sNRP1 and Sema3E show a moderate diagnostic accuracy. Moreover, logistic regression analysis allowed to identify sNRP1 and Sema3E as more suitable independent biomarkers reflecting the activity and severity of SSc-related peripheral microvasculopathy.