A metabolic dependency of EBV can be targeted to hinder B cell transformation.

Following infection of B cells, Epstein Barr virus (EBV) engages host pathways that mediate cell proliferation and transformation, contributing to the propensity of the virus to drive immune dysregulation and lymphomagenesis. We found that the EBV protein EBNA2 initiates NAD de novo biosynthesis by driving expression of the metabolic enzyme IDO1 in infected B cells. Virus-enforced NAD production sustained mitochondrial complex I activity, to match ATP-production with bioenergetic requirements of proliferation and transformation. In transplant patients, IDO1 expression in EBV-infected B cells, and a serum signature of increased IDO1 activity, preceded development of lymphoma. In humanized mice infected with EBV, IDO1 inhibition reduced both viremia and lymphomagenesis. Virus-orchestrated NAD biosynthesis is, thus, a druggable metabolic vulnerability of EBV-driven B cell transformation-opening therapeutic possibilities for EBV-related diseases.

Drug-Induced Liver Injury in Pregnancy: The U.S. Drug-Induced Liver Injury Network Experience.

There are limited data on the causative agents and characteristics of drug-induced liver injury in pregnant individuals. Data from patients with drug-induced liver injury enrolled in the ongoing multicenter Drug-Induced Liver Injury Network between 2004 and 2022 and occurring during pregnancy or 6 months postpartum were reviewed and compared with cases of drug-induced liver injury in nonpregnant women of childbearing age. Among 325 individuals of childbearing age in the Drug-Induced Liver Injury Network, 16 cases of drug-induced liver injury (5%) occurred during pregnancy or postpartum. Compared with drug-induced liver injury in nonpregnant women, pregnancy-related drug-induced liver injury was more severe ( P <.05). One elective termination and three miscarriages were documented; there were no maternal deaths. We recommend that isoniazid for latent tuberculosis be deferred to the postpartum period whenever feasible and that ß-blockers or calcium channel blockers rather than methyldopa be used for hypertension management during pregnancy.

Neuroprotective effects of niclosamide on disease progression via inflammatory pathways modulation in SOD1-G93A and FUS-associated amyotrophic lateral sclerosis models.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease influenced by genetic, epigenetic, and environmental factors, resulting in dysfunction in cellular and molecular pathways. The limited efficacy of current treatments highlights the need for combination therapies targeting multiple aspects of the disease. Niclosamide, an anthelminthic drug listed as an essential medicine, has been repurposed in clinical trials for different diseases due to its anti-inflammatory and anti-fibrotic properties. Niclosamide can inhibit various molecular pathways (e.g., STAT3, mTOR) that are dysregulated in ALS, suggesting its potential to disrupt these altered mechanisms associated with the pathology. We administered niclosamide intraperitoneally to two transgenic murine models, SOD1-G93A and FUS mice, mimicking key pathological processes of ALS. The treatment was initiated at the onset of symptoms, and we assessed disease progression by neurological scores, rotarod and wire tests, and monitored survival. Furthermore, we investigated cellular and molecular mechanisms affected by niclosamide in the spinal cord and muscle of ALS mice. In both models, the administration of niclosamide resulted in a slowdown of disease progression, an increase in survival rates, and an improvement in tissue pathology. This was characterised by reduced gliosis, motor neuron loss, muscle atrophy, and inflammatory pathways. Based on these results, our findings demonstrate that niclosamide can impact multiple pathways involved in ALS. This multi-targeted approach leads to a slowdown in the progression of the disease, positioning niclosamide as a promising candidate for repurposing in the treatment of ALS.

Classification of preeclampsia according to molecular clusters with the goal of achieving personalized prevention.

The prevention of pre-eclampsia is difficult due to the syndromic nature and multiple underlying mechanisms of this severe complication of pregnancy. The current clinical distinction between early- and late-onset disease, although clinically useful, does not reflect the true nature and complexity of the pathologic processes leading to pre-eclampsia. The current gaps in knowledge on the heterogeneous molecular pathways of this syndrome and the lack of adequate, specific diagnostic methods are major obstacles to early screening and tailored preventive strategies. The development of novel diagnostic tools for detecting the activation of the identified disease pathways would enable early, accurate screening and personalized preventive therapies. We implemented a holistic approach that includes the utilization of different proteomic profiling methods of maternal plasma samples collected from various ethnic populations and the application of systems biology analysis to plasma proteomic, maternal demographic, clinical characteristic, and placental histopathologic data. This approach enabled the identification of four molecular subclasses of pre-eclampsia in which distinct and shared disease mechanisms are activated. The current review summarizes the results and conclusions from these studies and the research and clinical implications of our findings.

Surgical site infections after kidney transplantation are independently associated with graft loss.

Surgical site infections (SSIs) are common health care-associated infections. SSIs after kidney transplantation (K-Tx) can endanger patient and allograft survival. Multicenter studies on this early posttransplant complication are scarce. We analyzed consecutive adult K-Tx recipients enrolled in the Swiss Transplant Cohort Study who received a K-Tx between May 2008 and September 2020. All data were prospectively collected with the exception of the categorization of SSI which was performed retrospectively according to the Centers for Disease Control and Prevention criteria. A total of 58 out of 3059 (1.9%) K-Tx recipients were affected by SSIs. Deep incisional (15, 25.9%) and organ/space infections (34, 58.6%) predominated. In the majority of SSIs (52, 89.6%), bacteria were detected, most frequently Escherichia coli (15, 28.9%), Enterococcus spp. (14, 26.9%), and coagulase-negative staphylococci (13, 25.0%). A BMI ≥25 kg/m2 (multivariable OR 2.16, 95% CI 1.07-4.34, P = .023) and delayed graft function (multivariable OR 2.88, 95% CI 1.56-5.34, P = .001) were independent risk factors for SSI. In Cox proportional hazard models, SSI was independently associated with graft loss (multivariable HR 3.75, 95% CI 1.35-10.38, P = .011). In conclusion, SSI was a rare complication after K-Tx. BMI ≥25 kg/m2 and delayed graft function were independent risk factors. SSIs were independently associated with graft loss.

C9orf72 Toxic Species Affect ArfGAP-1 Function.

Compelling evidence indicates that defects in nucleocytoplasmic transport contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). In particular, hexanucleotide (G4C2) repeat expansions in C9orf72, the most common cause of genetic ALS, have a widespread impact on the transport machinery that regulates the nucleocytoplasmic distribution of proteins and RNAs. We previously reported that the expression of G4C2 hexanucleotide repeats in cultured human and mouse cells caused a marked accumulation of poly(A) mRNAs in the cell nuclei. To further characterize the process, we set out to systematically identify the specific mRNAs that are altered in their nucleocytoplasmic distribution in the presence of C9orf72-ALS RNA repeats. Interestingly, pathway analysis showed that the mRNAs involved in membrane trafficking are particularly enriched among the identified mRNAs. Most importantly, functional studies in cultured cells and Drosophila indicated that C9orf72 toxic species affect the membrane trafficking route regulated by ADP-Ribosylation Factor 1 GTPase Activating Protein (ArfGAP-1), which exerts its GTPase-activating function on the small GTPase ADP-ribosylation factor 1 to dissociate coat proteins from Golgi-derived vesicles. We demonstrate that the function of ArfGAP-1 is specifically affected by expanded C9orf72 RNA repeats, as well as by C9orf72-related dipeptide repeat proteins (C9-DPRs), indicating the retrograde Golgi-to-ER vesicle-mediated transport as a target of C9orf72 toxicity.

Molecular subclasses of preeclampsia characterized by a longitudinal maternal proteomics study: distinct biomarkers, disease pathways and options for prevention.

OBJECTIVES: The heterogeneous nature of preeclampsia is a major obstacle to early screening and prevention, and a molecular taxonomy of disease is needed. We have previously identified four subclasses of preeclampsia based on first-trimester plasma proteomic profiles. Herein, we expanded this approach by using a more comprehensive panel of proteins profiled in longitudinal samples. METHODS: Proteomic data collected longitudinally from plasma samples of women who developed preeclampsia (n=109) and of controls (n=90) were available from our previous report on 1,125 proteins. Consensus clustering was performed to identify subgroups of patients with preeclampsia based on data from five gestational-age intervals by using select interval-specific features. Demographic, clinical, and proteomic differences among clusters were determined. Differentially abundant proteins were used to identify cluster-specific perturbed KEGG pathways. RESULTS: Four molecular clusters with different clinical phenotypes were discovered by longitudinal proteomic profiling. Cluster 1 involves metabolic and prothrombotic changes with high rates of early-onset preeclampsia and small-for-gestational-age neonates; Cluster 2 includes maternal anti-fetal rejection mechanisms and recurrent preeclampsia cases; Cluster 3 is associated with extracellular matrix regulation and comprises cases of mostly mild, late-onset preeclampsia; and Cluster 4 is characterized by angiogenic imbalance and a high prevalence of early-onset disease. CONCLUSIONS: This study is an independent validation and further refining of molecular subclasses of preeclampsia identified by a different proteomic platform and study population. The results lay the groundwork for novel diagnostic and personalized tools of prevention.

Reimagining urban destinations: Adaptive and transformative city brand attributes and values in the pandemic crisis.

This paper contributes to the post-Covid urban tourism debate. It focuses on how cities respond to the pandemic asking how and to what extent urban destination brands are leverged by city marketers for coping with the Covid-19 crisis. It explores city brand values and attributes change as a component of the urban approach to facing the current crisis. Content analysis is carried out on pre- and post-pandemic brand communication of four Italian iconic cultural destinations (Rome, Florence, Venice and Milan) on Instagram. Findings suggest adaptive and transformative brand responses to the pandemic crisis, projecting the cities into future development scenarios. This research contributes to the recovery versus reform debate on post-Covid urban contexts and opens research on the pandemic effects on values, images and tourism stakeholders' mindsets and brand experimentation on social media platforms.

Follow Up Imaging in Hepatocellular Cancer Ultrasound Screening Exams With Poor Visualization Scores.

OBJECTIVES: The Ultrasound Liver Imaging Reporting and Data Systems (LI-RADS) provides standardized terminology and reporting for ultrasound (US) examinations performed for hepatocellular cancer (HCC) screening. However, there are no recommendations regarding follow up imaging for visualization scores with suboptimal visualization. Therefore, the aim of this study is to examine follow up imaging practices in the setting of US studies scored as B (moderate limitations) and C (severe limitations). METHODS: A single center retrospective analysis of studies from 2017 to 2021 with HCC US screening visualization scores of B and C was performed. Follow up imaging with US, CT, or MRI within 6 months with visualization score B or C on initial US were included. RESULTS: Five hundred and sixty HCC US studies with suboptimal imaging were reviewed. Of those with follow up imaging, patients with a visualization score of B underwent US in more than half (58%) of the cases while those with visualization score of C underwent more CT/MRI studies (62.5%, P = .12) Patients with visualization score of B had more MRI exams performed (55%) while patients with a visualization score of C underwent more CT exams (70%, P = .16). CONCLUSIONS: Currently, there are no guidelines instructing follow up imaging on HCC screening ultrasounds with poor visualization, and the data suggests that providers have taken a heterogeneous approach. This suggests a need for society recommendations on how to approach HCC screening ultrasounds in patients with suboptimal studies.

Collaborative Challenges of Multi-Cohort Projects in Pharmacogenetics-Why Time Is Essential for Meaningful Collaborations.

Multi-cohort projects in medicine provide an opportunity to investigate scientific questions beyond the boundaries of a single institution and endeavor to increase the sample size for obtaining more reliable results. However, the complications of these kinds of collaborations arise during management, with many administrative hurdles. Hands-on approaches and lessons learned from previous collaborations provide solutions for optimized collaboration models. Here, we use our experience in running PGX-link, a Swiss multi-cohort project, to show the strategy we used to tackle different challenges from project setup to obtaining the relevant permits, including ethics approval. We set PGX-link in an international context because our struggles were similar to those encountered during the SYNCHROS (SYNergies for Cohorts in Health: integrating the ROle of all Stakeholders) project. We provide ad hoc solutions for cohorts, general project management strategies, and suggestions for unified protocols between cohorts that would ease current management hurdles. Project managers are not necessarily familiar with medical projects, and even if they are, they are not aware of the intricacies behind decision-making and consequently, of the time needed to set up multi-cohort collaborations. This paper is meant to be a brief overview of what we experienced with our multi-cohort project and provides the necessary practices for future managers.

Central nervous system infections in solid organ transplant recipients: Results from the Swiss Transplant Cohort Study.

OBJECTIVES: To describe the epidemiology and clinical presentation of central nervous system (CNS) infections in solid organ transplant (SOT) recipients in the current era of transplantation. METHODS: Patients from the Swiss Transplant Cohort Study (STCS) transplanted between 2008 and 2018 were included with a median follow-up of 3.8 years. Epidemiological, microbiological, and clinical data were extracted from the STCS database and patients' medical records. We calculated incidence rates and 90-day survival of transplant recipients with CNS infection. RESULTS: Among 4762 patients, 42 episodes of CNS infection in 41 (0.8%) SOT recipients were identified, with an overall incidence rate of 2.06 per 1000 patient-years. Incidence of CNS infections was similar across all types of transplantations. Time to CNS infection onset ranged from 0.6 to 97 months after transplant. There were 22/42 (52.4%) cases of viral infections, 11/42 (26.2%) of fungal infections, 5/42 (11.9%) of bacterial infections and 4/42 (9.5%) of probable viral/bacterial etiology. Clinical presentation was meningitis/encephalitis in 25 cases (59.5%) and brain-space occupying lesions in 17 cases (40.5%). Twenty-three cases (60.5%) were considered opportunistic infections. Diagnosis were achieved mainly by brain biopsy/necropsy (15/42, 36%) or by cerebrospinal fluid analysis (20/42, 48%). Up to 40% of cases (17/42) had concurrent extra-neurological disease localizations. Overall, 90-day mortality rate was 29.0% (73.0% for fungal, 14.0% for viral and 11.0% for bacterial and probable infections, p<0.0001). CONCLUSIONS: CNS infections were rare in the STCS, with viral meningoencephalitis being the most common disease. Fungal infections were associated with a high mortality.

Early pathways, biomarkers, and four distinct molecular subclasses of preeclampsia: The intersection of clinical, pathological, and high-dimensional biology studies.

Preeclampsia is a syndromic disease of the mother, fetus, and placenta. The main limitation in early and accurate diagnosis of preeclampsia is rooted in the heterogeneity of this syndrome as reflected by diverse molecular pathways, symptoms, and clinical outcomes. Gaps in our knowledge preclude successful early diagnosis, personalized treatment, and prevention. The advent of "omics" technologies and systems biology approaches addresses this problem by identifying the molecular pathways associated with the underlying mechanisms and clinical phenotypes of preeclampsia. Here, we provide a brief overview on how the field has progressed, focusing on studies utilizing state-of-the-art transcriptomics and proteomics methods. Moreover, we summarize our systems biology studies involving maternal blood proteomics and placental transcriptomics, which identified early maternal and placental disease pathways and showed that their interaction influences the clinical presentation of preeclampsia. We also present an analysis of maternal blood proteomics data which revealed distinct molecular subclasses of preeclampsia and their molecular mechanisms. Maternal and placental disease pathways behind these subclasses are similar to those recently reported in studies on the placental transcriptome. These findings may promote the development of novel diagnostic tools for the distinct subtypes of preeclampsia syndrome, enabling early detection and personalized follow-up and tailored care of patients.

The MELD upgrade exception: a successful strategy to optimize access to liver transplantation for patients with high waiting list mortality.

BACKGROUND: MELD exceptions are designed to equipoise liver transplant waiting list survival. We aimed to analyze the impact of the MELD Upgrade rule and all other MELD exceptions on the liver transplant waiting list outcomes during 2012-2017 in Switzerland. METHODS: We conducted a nationwide cohort study including all adult patients registered on the Swiss liver transplant waiting list between 2012 and 2017. Waiting list mortality and access to transplantation were analyzed, considering MELD exceptions as time-dependent covariates. RESULTS: 730 patients were included. Patients with MELD Upgrade exceptions had a higher risk of dying while on the waiting list (OR 2.13; CI 95% 1.30-3.47) and also an increased likelihood of receiving a liver transplantation, when compared to patients without MELD exceptions. Patients with any type of MELD exceptions were more likely to be transplanted when compared to patients without MELD exceptions. The proportion of patients with MELD exceptions increased from 2012 to 2017 (44% vs 88%). Allocation MELD at the time of transplantation showed an annual increase (23 ± 8 points vs 32 ± 5 points, p < 0.001). CONCLUSION: Only patients with MELD Upgrade exceptions had the expected combination of higher waiting list mortality and quicker access to liver transplantation.

Value of liver biopsy in the diagnosis of drug-induced liver injury.

BACKGROUND & AIMS: The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. The aim of this study was to determine whether liver histology impacted causality assessment in suspected DILI using a novel simulation model. METHODS: Fifty patients enrolled in the DILI Network (DILIN) who had liver biopsies performed within 60 days of DILI onset were randomly selected. All had standard DILIN consensus causality scoring using a 5-point scale (1=definite, 2=highly likely, 3=probable, 4=possible, 5=unlikely) based on 6-month post-injury data. Three experienced hepatologists independently performed a causality assessment using redacted case records, with the biopsy and selected post-biopsy laboratory data removed. The 3 hepatologists also reviewed the liver histology with a hepatopathologist and then repeated causality assessment for each case. RESULTS: Of the 50 cases, there were 42 high causality DILI cases (1, 2 or 3) and 8 low causality cases (4 and 5). The hepatologists judged that liver biopsy was indicated in 62% of patients; after histology review, biopsy was judged to have been helpful in 70% of patients. Histology review changed the causality score in 68% of patients, with an increase in DILI likelihood in 48% and a decrease in 20%. Biopsy results changed diagnostic certainty from less certain (3 or 4) to highly certain (1, 2 or 5) in 38% of patients. CONCLUSIONS: Liver histologic findings may help clarify the diagnosis of DILI. Histology appears to be particularly helpful in cholestatic or equivocal cases of DILI (possible or probable), shifting assessment toward a greater or lower certainty of a DILI diagnosis. LAY SUMMARY: The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. Herein, we show that, in patients with suspected DILI, a liver biopsy can help physicians diagnose DILI or other causes of liver injury with more certainty.

Proof-of-concept study to evaluate the safety and efficacy of saroglitazar in patients with primary biliary cholangitis.

BACKGROUND & AIM: Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual agonistic properties (α/γ). Due to a strong mechanistic rationale, we aimed to test the safety and efficacy of saroglitazar in patients with primary biliary cholangitis (PBC) who were either ursodeoxycholic acid (UDCA) resistant or intolerant. METHODS: In this double-blind, phase II proof-of-concept trial, 37 patients with PBC were randomized to saroglitazar 4 mg (n = 13), saroglitazar 2 mg (n = 14), or placebo (n = 10) daily for 16 weeks. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at Week 16. RESULTS: A significant reduction of mean ALP levels was observed at Week 16 relative to baseline in both the saroglitazar 4 mg (least-squares [LS] mean =-163.3 U/L, SE = 25.1, p <0.001) and 2 mg (LS mean =-155.8 U/L, SE = 24.4, p <0.001) groups, compared with placebo (LS mean =-21.1 U/L, SE = 28.9). Treatment with saroglitazar resulted in a rapid reduction of ALP concentration at Week 4 that was sustained through the study duration. At least 1 treatment-emergent adverse event occurred in 11 (84.6%) patients in the saroglitazar 4 mg group, in 12 (85.7%) patients in the 2 mg group and in 8 (80%) patients in the placebo group. Study drug was discontinued in 4 patients (3 patients in the 4 mg group and 1 patient in the 2 mg group) due to aminotransferase increases that promptly returned to baseline values after drug discontinuation. CONCLUSIONS: Saroglitazar at 2 mg and 4 mg daily was tolerated and resulted in rapid and sustained improvements in ALP. Further studies are underway at a daily dose of 2 mg and 1 mg due to the higher incidence of elevated liver enzymes observed with the 4 mg dose. CLINICALTRIALS. GOV IDENTIFIER: NCT03112681 LAY SUMMARY: Saroglitazar resulted in a rapid and sustained improvement in alkaline phosphatase levels in patients with primary biliary cholangitis. The mean percentage reductions in alkaline phosphatase levels were 49% and 51% in the saroglitazar 4 mg and 2 mg groups compared to 3% in the placebo group.

Placental galectins regulate innate and adaptive immune responses in pregnancy.

Introduction: Galectins are master regulators of maternal immune responses and placentation in pregnancy. Galectin-13 (gal-13) and galectin-14 (gal-14) are expressed solely by the placenta and contribute to maternal-fetal immune tolerance by inducing the apoptosis of activated T lymphocytes and the polarization of neutrophils toward an immune-regulatory phenotype.Furthermore, their decreased placental expression is associated with pregnancy complications, such as preeclampsia and miscarriage. Yet, our knowledge of the immunoregulatory role of placental galectins is incomplete. Methods: This study aimed to investigate the effects of recombinant gal-13 and gal-14 on cell viability, apoptosis, and cytokine production of peripheral blood mononuclear cells (PBMCs) and the signaling pathways involved. Results: Herein, we show that gal-13 and gal-14 bind to the surface of non-activated PBMCs (monocytes, natural killer cells, B cells, and T cells) and increase their viability while decreasing the rate of their apoptosis without promoting cell proliferation. We also demonstrate that gal-13 and gal-14 induce the production of interleukin (IL)-8, IL-10, and interferon-gamma cytokines in a concentration-dependent manner in PBMCs. The parallel activation of Erk1/2, p38, and NF-ĸB signaling evidenced by kinase phosphorylation in PBMCs suggests the involvement of these pathways in the regulation of the galectin-affected immune cell functions. Discussion: These findings provide further evidence on how placenta-specific galectins assist in the establishment and maintenance of a proper immune environment during a healthy pregnancy.

Dysfunction of RNA/RNA-Binding Proteins in ALS Astrocytes and Microglia.

Amyotrophic Lateral Sclerosis is a neurological disease that primarily affects motor neurons in the cortex, brainstem, and spinal cord. The process that leads to motor neuron degeneration is strongly influenced by non-motor neuronal events that occur in a variety of cell types. Among these, neuroinflammatory processes mediated by activated astrocytes and microglia play a relevant role. In recent years, it has become clear that dysregulation of essential steps of RNA metabolism, as a consequence of alterations in RNA-binding proteins (RBPs), is a central event in the degeneration of motor neurons. Yet, a causal link between dysfunctional RNA metabolism and the neuroinflammatory processes mediated by astrocytes and microglia in ALS has been poorly defined. In this review, we will discuss the available evidence showing that RBPs and associated RNA processing are affected in ALS astrocytes and microglia, and the possible mechanisms involved in these events.

Natriuretic peptides are neuroprotective on in vitro models of PD and promote dopaminergic differentiation of hiPSCs-derived neurons via the Wnt/ß-catenin signaling.

Over the last 20 years, the efforts to develop new therapies for Parkinson's disease (PD) have focused not only on the improvement of symptomatic therapy for motor and non-motor symptoms but also on the discovering of the potential causes of PD, in order to develop disease-modifying treatments. The emerging role of dysregulation of the Wnt/ß-catenin signaling in the onset and progression of PD, as well as of other neurodegenerative diseases (NDs), renders the targeting of this signaling an attractive therapeutic opportunity for curing this brain disorder. The natriuretic peptides (NPs) atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), are cardiac and vascular-derived hormones also widely expressed in mammalian CNS, where they seem to participate in numerous brain functions including neural development/differentiation and neuroprotection. We recently demonstrated that ANP affects the Wnt/ß-catenin pathway possibly through a Frizzled receptor-mediated mechanism and that it acts as a neuroprotective agent in in vitro models of PD by upregulating this signaling. Here we provide further evidence supporting the therapeutic potential of this class of natriuretic hormones. Specifically, we demonstrate that all the three natriuretic peptides are neuroprotective for SHSY5Y cells and primary cultures of DA neurons from mouse brain, subjected to neurotoxin insult with 6-hydroxydopamine (6-OHDA) for mimicking the neurodegeneration of PD, and these effects are associated with the activation of the Wnt/ß-catenin pathway. Moreover, ANP, BNP, CNP are able to improve and accelerate the dopaminergic differentiation and maturation of hiPSCs-derived neural population obtained from two differed healthy donors, concomitantly affecting the canonical Wnt signaling. Our results support the relevance of exogenous ANP, BNP, and CNP as attractive molecules for both neuroprotection and neurorepair in PD, and more in general, in NDs for which aberrant Wnt signaling seems to be the leading pathogenetic mechanism.

Pro-coagulant imbalance in patients with community acquired pneumonia assessed on admission and one month after hospital discharge.

OBJECTIVES: Patients hospitalized because of community-acquired-pneumonia (CAP) are at risk of cardiovascular diseases. Although plasma procoagulant imbalance play a role, mechanisms are not completely understood. We aimed to investigate whether there is a measurable state of procoagulant imbalance following inflammation determined by CAP. METHODS: We analyzed blood from 51 CAP patients at admission and 51 healthy subjects (HS) for (i) pro and anticoagulants, (ii) thrombin generation (TG) with or without thrombomodulin (TM), which is the physiologic activator of the protein C anticoagulant pathway and(iii) by assessing the ratio between von Willebrand-factor (VWF) and its protease ADAMTS13. Thirty patients were re-analyzed one month after discharge when CAP was resolved. RESULTS: Median levels of TG parameters, including the endogenous thrombin potential (ETP), the ETP-TM-ratio (with/without TM), peak-thrombin and velocity index were higher in patients at baseline than HS. In particular, the median (IQR) ETP-TM-ratio in patients vs. HS was 0.88 (0.83-0.91) vs. 0.63 (0.48-0.71), p<0.001. Factor (F)VIII, a potent procoagulant involved in TG was higher in patients at baseline than HS [195 U/dL (100-388) vs. 127(108-145)], p<0.001]. The ratio of VWF/ADAMTS13 was higher at baseline than HS. Cumulatively, the findings indicate a state of pro-coagulant imbalance, which (although reduced), remained high [i.e., ETP-TM-ratio, 0.80 (0.74-0.84); FVIII, 152 U/dL (122-190)] one month after discharge when the infection was resolved. CONCLUSIONS: Patients with CAP possess a state of pro-coagulant imbalance, which remains substantially high, even when the infection is resolved. The findings suggest CAP patients as candidates for antithrombotic prophylaxis even after the resolution of infection. Clinical trials are warranted to assess the benefit/risk ratio of prophylaxis extension.

Targeting S100A4 with niclosamide attenuates inflammatory and profibrotic pathways in models of amyotrophic lateral sclerosis.

BACKGROUND: An increasing number of studies evidences that amyotrophic lateral sclerosis (ALS) is characterized by extensive alterations in different cell types and in different regions besides the CNS. We previously reported the upregulation in ALS models of a gene called fibroblast-specific protein-1 or S100A4, recognized as a pro-inflammatory and profibrotic factor. Since inflammation and fibrosis are often mutual-sustaining events that contribute to establish a hostile environment for organ functions, the comprehension of the elements responsible for these interconnected pathways is crucial to disclose novel aspects involved in ALS pathology. METHODS: Here, we employed fibroblasts derived from ALS patients harboring the C9orf72 hexanucleotide repeat expansion and ALS patients with no mutations in known ALS-associated genes and we downregulated S100A4 using siRNA or the S100A4 transcriptional inhibitor niclosamide. Mice overexpressing human FUS were adopted to assess the effects of niclosamide in vivo on ALS pathology. RESULTS: We demonstrated that S100A4 underlies impaired autophagy and a profibrotic phenotype, which characterize ALS fibroblasts. Indeed, its inhibition reduces inflammatory, autophagic, and profibrotic pathways in ALS fibroblasts, and interferes with different markers known as pathogenic in the disease, such as mTOR, SQSTM1/p62, STAT3, α-SMA, and NF-κB. Importantly, niclosamide in vivo treatment of ALS-FUS mice reduces the expression of S100A4, α-SMA, and PDGFRß in the spinal cord, as well as gliosis in central and peripheral nervous tissues, together with axonal impairment and displays beneficial effects on muscle atrophy, by promoting muscle regeneration and reducing fibrosis. CONCLUSION: Our findings show that S100A4 has a role in ALS-related mechanisms, and that drugs such as niclosamide which are able to target inflammatory and fibrotic pathways could represent promising pharmacological tools for ALS.