The positive side of the Alzheimer's disease amyloid cross-interactions: The case of the Aβ 1-42 peptide with tau, TTR, CysC, and ApoA1

Alzheimer's disease (AD) represents a progressive amyloidogenic disorder whose advancement is widely recognized to be connected to amyloid-β peptides and Tau aggregation. However, several other processes likely contribute to the development of AD and some of them might be related to protein-protein interactions. Amyloid aggregates usually contain not only single type of amyloid protein, but also other type of proteins and this phenomenon can be rationally explained by the process of protein cross-seeding and co-assembly. Amyloid cross-interaction is ubiquitous in amyloid fibril formation and so a better knowledge of the amyloid interactome could help to further understand the mechanisms of amyloid related diseases. In this review, we discuss about the cross-interactions of amyloid-β peptides, and in particular Aβ1-42, with other amyloids, which have been presented either as integrated part of Aβ neurotoxicity process (such as Tau) or conversely with a preventive role in AD pathogenesis by directly binding to Aβ (such as transthyretin, cystatin C and apolipoprotein A1). Particularly, we will focus on all the possible therapeutic strategies aiming to rescue the Aβ toxicity by taking inspiration from these protein-protein interactions

The cross-talk between thrombosis and inflammatory storm in acute and long-covid-19: Therapeutic targets and clinical cases

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) commonly complicates with coagulopathy. A syndrome called Long-COVID-19 is emerging recently in COVID-19 survivors, characterized, in addition to the persistence of symptoms typical of the acute phase, by alterations in inflammatory and coagulation parameters due to endothelial damage. The related disseminated intravascular coagulation (DIC) can be associated with high death rates in COVID-19 patients. It is possible to find a prothrombotic state also in Long-COVID-19. Early administration of anticoagulants in COVID-19 was suggested in order to improve patient outcomes, although exact criteria for their application were not well-established. Low-molecular-weight heparin (LMWH) was commonly adopted for counteracting DIC and venous thromboembolism (VTE), due to its pharmacodynamics and anti-inflammatory properties. However, the efficacy of anticoagulant therapy for COVID-19-associated DIC is still a matter of debate. Thrombin and Factor Xa (FXa) are well-known components of the coagulation cascade. The FXa is known to strongly promote inflammation as the consequence of increased cytokine expression. Endothelial cells and mononuclear leucocytes release cytokines, growth factors, and adhesion molecules due to thrombin activation. On the other hand, cytokines can activate coagulation. The cross-talk between coagulation and inflammation is mediated via protease-activated receptors (PARs). These receptors might become potential targets to be considered for counteracting the clinical expressions of COVID-19. SARS-CoV-2 is effectively able to activate local and circulating coagulation factors, thus inducing the generation of disseminated coagula. LMWH may be considered as the new frontier in the treatment of COVID-19 and Long-COVID-19. Indeed, direct oral anticoagulants (DOACs) may be an alternative option for both early and later treatment of COVID-19 patients due to their ability to inhibit PARs. The aim of this report was to evaluate the role of anticoagulants—and DOACs in particular in COVID-19 and Long-COVID-19 patients. We report the case of a COVID-19 patient who, after administration of enoxaparin developed DIC secondary to virosis and positivity for platelet factor 4 (PF4) and a case of Long-COVID with high residual cardiovascular risk and persistence of blood chemistry of inflammation and procoagulative state

Activation of carbonic anhydrases from human brain by amino alcohol oxime ethers: towards human carbonic anhydrase VII selective activators

The synthesis and carbonic anhydrase (CA; EC 4.2.1.1) activating effects of a series of oxime ether-based amino alcohols towards four human (h) CA isoforms expressed in human brain, hCA I, II, IV and VII, are described. Most investigated amino alcohol derivatives induced a consistent activation of the tested CAs, with KAs spanning from a low micromolar to a medium nanomolar range. Specifically, hCA II and VII, putative main CA targets when central nervous system (CNS) diseases are concerned, were most efficiently activated by these oxime ether derivatives. Furthermore, a multitude of selective hCA VII activators were identified. As hCA VII is one of the key isoforms involved in brain metabolism and other brain functions, the identified potent and selective hCA VII activators may be considered of interest for investigations of various therapeutic applications or as lead compounds in search of even more potent and selective CA activators

Renal venous pattern: A new parameter for predicting prognosis in heart failure outpatients

Aim of the study: In chronic heart failure (CHF) patients, renal congestion plays a key role in determining the progression of renal dysfunction and a worse prognosis. The aim of this study was to define the role of Doppler venous patterns reflecting renal congestion that predict heart failure progression. Methods: We enrolled outpatients affected by CHF, in stable clinical conditions and in conventional therapy. All patients underwent a clinical evaluation, routine chemistry, an echocardiogram and a renal echo-Doppler. Pulsed Doppler flow recording was performed at the level of interlobular renal right veins in the tele-expiratory phase. The venous flow patterns were divided into five groups according to the fluctuations of the flow. Type A and B were characterized by a continuous flow, whereas type C was characterized by a short interruption or reversal flow during the end-diastolic or protosystolic phase. Type D and E were characterized by a wide interruption and/or reversal flow. The occurrence of death and/or of heart transplantation and/or of hospitalization due to heart failure worsening was considered an event during follow-up. Results: During a median follow-up of 38 months, 126 patients experienced the considered end-point. Venous pattern C (HR 4.04; 95% CI: 2.14-7.65; p < 0.001), pattern D (HR 7.16; 95% CI: 3.69-13.9; p < 0.001) and pattern E (HR 8.94; 95% CI: 4.65-17.2; p < 0.001) were all associated with events using an univariate Cox regression analysis. Moreover, both the presence of pattern C (HR: 1.79; 95% CI: 1.09-2.97; p: 0) and of pattern D or E (HR: 1.90; 95% CI: 1.16-3.12; p: 0.011) remained significantly associated to events using a multivariate Cox regression analysis after correction for a reference model with an improvement of the overall net reclassification index (0.46; 95% CI 0.24-0.68; p < 0.001). Conclusions: Our findings demonstrate the independent and incremental role of Doppler venous patterns reflecting renal congestion in predicting HF progression among CHF patients, thus suggesting its possible utility in daily clinical practice to better characterize patients with cardio-renal syndrome

A Systematic Review of the Efficacy and Safety of Direct Oral Anticoagulants in Atrial Fibrillation Patients with Diabetes Using a Risk Index

Diabetes mellitus (DM) represents an independent risk factor for chronic AF and is associated with unfavorable outcomes. We aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF), with and without diabetes mellitus (DM), using a new risk index (RI) defined as: RI = Rate of Events/Rate of Patients at Risk. In particular, an RI lower than 1 suggests a favorable treatment effect. We searched MEDLINE, MEDLINE In-Process, EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials. The risk index (RI) was calculated in terms of efficacy (rate of stroke/systemic embolism (stroke SEE)/rate of patients with and without DM; rate of cardiovascular death/rate of patients with and without DM) and safety (rate of major bleeding/rate of patients with and without DM) outcomes. AF patients with DM (n = 22,057) and 49,596 without DM were considered from pivotal trials. DM doubles the risk index for stroke/SEE, major bleeding (MB), and cardiovascular (CV) death. The RI for stroke/SEE, MB, and CV death was comparable in patients treated with warfarin or DOACs. The lowest RI was in DM patients treated with Rivaroxaban (stroke/SEE, RI = 0.08; CV death, RI = 0.13). The RIs for bleeding were higher in DM patients treated with Dabigatran (RI110 = 0.32; RI150 = 0.40). Our study is the first to use RI to homogenize the efficacy and safety data reported in the DOACs pivotal studies against warfarin in patients with and without DM. Anticoagulation therapy is effective and safe in DM patients. DOACs appear to have a better efficacy and safety profile than warfarin. The use of DOACs is a reasonable alternative to vitamin-K antagonists in AF patients with DM. The RI can be a reasonable tool to help clinicians choose between DOACs or warfarin in the peculiar set of AF patients with DM

IFI16 reduced expression is correlated with unfavorable outcome in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Its clinical course is typically indolent; however, based on a series of pathobiological, clinical, genetic, and phenotypic parameters, patient survival varies from less than 5 to more than 20 years. In this paper, we show for the first time that the expression of the interferon-inducible DNA sensor IFI16, a member of the PYHIN protein family involved in proliferation inhibition and apoptosis regulation, is associated with the clinical outcome in CLL. We studied 99 CLLs cases by immunohistochemistry and 10 CLLs cases by gene expression profiling. We found quite variable degrees of IFI16 expression among CLLs cases. Noteworthy, we observed that a reduced IFI16 expression was associated with a very poor survival, but only in cases with ZAP70/CD38 expression. Furthermore, we found that IFI16 expression was associated with a specific gene expression signature. As IFI16 can be easily detected by immunohistochemistry or flow cytometry, it may become a part of phenotypic screening in CLL patients if its prognostic role is confirmed in independent series

Statistical analysis plan for the stepped wedge clinical trial Healing Right Way—enhancing rehabilitation services for Aboriginal Australians after brain injury

Background Aboriginal Australians are known to suffer high levels of acquired brain injury (stroke and traumatic brain injury) yet experience significant barriers in accessing rehabilitation services. The aim of the Healing Right Way trial is to evaluate a culturally secure intervention for Aboriginal people with newly acquired brain injury to improve their rehabilitation experience and quality of life. Following publication of the trial protocol, this paper outlines the statistical analysis plan prior to locking the database. Methods The trial involves a stepped wedge design with four steps over 3 years. Participants were 108 adult Aboriginal Australians admitted to one of eight hospitals (four rural, four urban) in Western Australia within 6 weeks of onset of a new stroke or traumatic brain injury who consented to follow-up for 26 weeks. All hospital sites started in a control phase, with the intervention assigned to pairs of sites (one metropolitan, one rural) every 26 weeks until all sites received the intervention. The two-component intervention involves training in culturally safe care for hospital sites and enhanced support provided to participants by Aboriginal Brain Injury Coordinators during their hospital stay and after discharge. The primary outcome is quality of life as measured by the Euro QOL–5D-3L VAS. A mixed effects linear regression model will be used to assess the between-group difference at 26 weeks post-injury. The model will control for injury type and severity, age at recruitment and time since commencement of the trial, as fixed effects. Recruitment site and participant will be included as random effects. Secondary outcomes include measurements of function, independence, anxiety and depression, carer strain, allied health occasions of service received and hospital compliance with minimum processes of care based on clinical guidelines and best practice models of care. Discussion The trial will provide the first data surrounding the effectiveness of an intervention package for Aboriginal people with brain injury and inform future planning of rehabilitation services for this population. The statistical analysis plan outlines the analyses to be undertaken. Trial registration Australia New Zealand Clinical Trials Registry ACTRN12618000139279. Registered 30 January, 2018

Similar levels of efficacy of two different maintenance doses of adalimumab on clinical severity and quality of life of patients with hidradenitis suppurativa

Adalimumab is the only biologic agent approved for the treatment of moderate-to-severe hidradenitis suppurativa (HS) patients (i.e., with Hurley II or III), which is recommended in two different maintenance doses (i.e., 40 mg weekly or 80 mg every two weeks). We conducted a prospective multicentric study to measure outcomes related to the severity of disease and quality of life (QoL) of patients affected by moderate-to-severe HS, treated with adalimumab at a maintenance dosing of 40 mg or 80 mg. Assessments were performed at baseline (T0) and after 32 weeks of treatment (T32). We enrolled 85 moderate-to-severe HS Italian patients, 43 men (50.6%) and 42 women, aged between 16 and 62 years (median 31 years, interquartile range 24.4-43.8). Statistically significant improvements were observed for clinical status (with a mean reduction of 7.1 points for the International Hidradenitis Suppurativa Severity Score System (IHS4)), pain levels (3.1 mean decrease in VAS), and QoL (3.4 mean improvement in DLQI score). Patients with no comorbidities, and those with higher levels of perceived pain showed significantly greater improvement in QoL than their counterpart from T0 to T32. As for the proportion of patients who at follow-up reached the minimal clinical important difference (MCID) in QoL, significantly higher proportions of success were observed for age (patients in the 29-39 category), pain (patients with higher reported pain), and Hurley stage III. While both treatment regimen groups (i.e., 40 vs. 80 mg) improved significantly, no statistical differences were observed when comparing the two treatment dosages

Identification of a Novel p53 Modulator Endowed with Antitumoural and Antibacterial Activity through a Scaffold Repurposing Approach

Intracellular pathogens, such as Chlamydia trachomatis, have been recently shown to induce degradation of p53 during infection, thus impairing the protective response of the host cells. Therefore, p53 reactivation by disruption of the p53-MDM2 complex could reduce infection and restore pro-apoptotic effect of p53. Here, we report the identification of a novel MDM2 inhibitor with potential antitumoural and antibacterial activity able to reactivate p53. A virtual screening was performed on an in-house chemical library, previously synthesised for other targets, and led to the identification of a hit compound with a benzo[a]dihydrocarbazole structure, RM37. This compound induced p53 up-regulation in U343MG glioblastoma cells by blocking MDM2-p53 interaction and reduced tumour cell growth. NMR studies confirmed its ability to dissociate the MDM2-p53 complex. Notably, RM37 reduced Chlamydia infection in HeLa cells in a concentration-dependent manner and ameliorated the inflammatory status associated with infection