Publications by authors named "Daniela Rossi"

170 Publications

An agent-to-agent real life comparison study of tocilizumab versus abatacept in giant cell arteritis.

Clin Exp Rheumatol 2021 Feb 23. Epub 2021 Feb 23.

CMID-Nephrology and Dialysis Unit (ERK-net Member) Center of Research of Nephrology, Rheumatology, and Rare Diseases, Interregional Coordinating Centre of the Network of Rare Diseases, G. Bosco Hospital and University of Turin, Italy.

Objectives: The present study aimed at evaluating the efficacy of abatacept (ABA) compared to tocilizumab (TCZ), assumed as a gold standard biologic treatment in the management of patients with giant cell arteritis (GCA).

Methods: Thirty-three biospy-proven GCA consecutive patients were prospectively collected. Odd patients (from 1 to 33) were assigned to TCZ, given either intravenously (IV 8 mg/kg/month), #8 cases, or subcutaneously (SC 162 mg/week) #9, based on patient's preference. ABA was administered subcutaneously at the dose of 125 mg/week in 16 even patients (from 2 to 32). Biological therapies were prescribed in addition to oral prednisone.

Results: A single biologic agent was administered in 28 patients out of 33 (85%) (8 TCZ IV, 9 TCZ SC and 16 ABA). Five patients (15%) needed a therapeutic switch (one patient from TCZ to ABA, and 4 patients from ABA to TCZ). Among the TCZ IV group, all patients experienced a response (57% complete response and 43% partial response). Among the TCZ SC group, 7 experienced a clinical response (complete in 67% and partial in 16%). Among the ABA group, 10 patients (62%) achieved either complete (5 patients) or partial (5) response, respectively. After 12 months of therapy, 100% of patients in TCZ groups, both IV and SC, and 7 (43%) of ABA group were receiving doses of oral prednisone not exceeding 7.5 mg/day as maintenance.

Conclusions: Both TCZ and ABA can be proposed as an effective therapeutic option in GCA with relevant inflammatory symptoms. ABA can be considered in the patient with absolute or relative or contraindications to TCZ.
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February 2021

Incidence of a First Thrombo-Embolic Event in Patients With Systemic Lupus Erythematosus and Anti-phosphatidylserine/prothrombin Antibodies: A Prospective Study.

Front Med (Lausanne) 2021 1;8:621590. Epub 2021 Feb 1.

Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases - Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, Division of Nephrology and Dialysis, S. Giovanni Bosco Hospital, Turin, Italy.

This study aimed to prospectively investigate the incidence of first thromboembolic events (TEs) in a cohort of systemic lupus erythematosus (SLE) patients. The patients were positive for anti-phosphatidylserine/prothrombin (aPS/PT) antibodies and tested negative for anticardiolipin (aCL) and anti-β2-glycoprotein I (aβ2GPI) antibodies [regardless of their Lupus Anticoagulant (LA) status]. Inclusion criteria included: (a) SLE with no previous TEs; (b) no concomitant anti-thrombotic therapy; (c) isolated confirmed positive test for aPS/PT. From the total of 52 SLE patients (42, 80.8% women), 18 patients (34.6%) were found to be positive for aPS/PT (IgG/IgM). During a mean follow-up (3.9 ± 1.1 years), 3 TEs occurred (1.3%/year). The overall cumulative incidence of TEs was 5.8% after 2 years, and up to 16.7% when focusing on aPS/PT positive patients. All the TEs events (two cerebrovascular events and one thrombotic kidney microangiopathy) occurred in the aPS/PT positive group. When focusing on IgG aPS/PT, we found that patients who tested positive were at a significantly higher risk for TEs (crude HR 19.6, 95%; CI 1.1 to 357.6; < 0.05) compared to patients with negative aPS/PT. This study observed a rate of TEs of 1.3%/year, in aPS/PT positive only patients. Our prospective data suggest that aPS/PT might confer an increased risk for the development of TEs in SLE patients.
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http://dx.doi.org/10.3389/fmed.2021.621590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882486PMC
February 2021

Microwave-Assisted Extraction and HPLC-UV-CD Determination of (S)-usnic Acid in .

Molecules 2021 Jan 16;26(2). Epub 2021 Jan 16.

Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy.

During the years, many usnic acid (UA) conjugates have been synthesized to obtain potent endowed with biological properties. Since ()-UA is less abundant in nature than ()-enantiomer, it is difficult to source, thus precluding a deeper investigation. Among the lichens producing UA, is a valuable (S)-UA source. In the present work, we report on a rapid HPLC-UV/PAD-CD protocol suitable for the analysis and the identification of the main secondary metabolites present in extract. Best results were achieved using XBridge Phenyl column and acetonitrile and water, which were both added with formic acid as mobile phase in gradient elution. By combining analytical, spectroscopical, and chiroptical analysis, the most abundant analyte was unambiguously identified as ()-UA. Accordingly, a versatile microwave-assisted extractive (MAE) protocol, assisted by a design of experiment (DoE), to quantitatively recover ()-UA was set up. The best result in terms of UA extraction yield was obtained using ethanol and heating at 80 °C under microwave irradiation for 5 min. Starting from 100 g of dried , 420 mg of ()-UA were achieved. Thus, our extraction method resulted in a suitable protocol to produce ()-UA from for biological and pharmaceutical investigation or commercial purposes.
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http://dx.doi.org/10.3390/molecules26020455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830470PMC
January 2021

A 3-Year Observational Study of Patients with Progressive Systemic Sclerosis Treated with an Intensified B Lymphocyte Depletion Protocol: Clinical and Immunological Response.

J Clin Med 2021 Jan 14;10(2). Epub 2021 Jan 14.

Center of Research of Rheumatology, Nephrology and Rare Diseases, Coordinating Center of the Interregional Network of Rare Diseases of Piedmont and Aosta Valley, SCDU CMID-Nephrology and Dialysis G. Bosco Hospital and University of Turin, 10154 Turin, Italy.

Background: B-cells have been suggested to play a role in the pathogenesis of systemic sclerosis (SSc), representing, therefore, a potential therapeutic target.

Objectives: We aimed at investigating the 36-month outcomes of 20 SSc patients who underwent an intensified B-depletion therapy (IBCDT) scheme, including both Rituximab (RTX) and cyclophosphamide (CYC).

Methods: Data from 20 severe patients (18 females and 2 males, mean age 66.7 ± 11.0 years) with diffuse SSc (anti-topoisomerase I antibody in 95%) patients with multiorgan involvement including interstitial lung disease (ILD) treated with an IBCDT were prospectively collected. IBCDT comprehended: RTX 375 mg/m administered for four weekly doses (on days 1, 8, 15, and 22), followed by two additional doses after 30 and 60 days, in addition to two administrations of 10 mg/kg of intravenous CYC plus three methylprednisolone pulses (15 mg/kg) and subsequently followed by oral prednisone rapidly tapered to low minimum dosage of 5 mg daily. In addition, 10 patients with more severe functional respiratory impairment at baseline were also treated with RTX 500 mg every 4 months during the first year and two times a year during the second and the third year.

Results: After 36 months of follow-up, we recorded significant amelioration in N-terminal-pro-brain natriuretic peptide (NT-proBNP) levels (mean 385.4 ± 517 pg/mL at baseline to 279 ± 543 after 36 months). In addition, a significant radiological improvement of ILD in 20% of patients (4/20) and a radiological stabilization with no sign of progression of interstitial involvement in 13/20 (65%) were documented. A total of 3 out of 20 (15%) patients experienced a worsening of the ILD. No patient showed further decrease in functional respiratory parameters, including forced vital capacity, forced expiratory volume in one second, and mean values of diffusing capacity for carbon monoxide Moreover, no patient showed any change in the ejection fraction and pulmonary artery pressure when comparing values at baseline and after 24 and 36 months of observation. No severe infection, renal flare, RTX-related side effects were observed. No patient died.

Conclusions: Our findings support that the IBCDT was well tolerated and might be a promising therapeutic option for the management of SSc, especially in those subjects with multiorgan involvement that includes ILD.
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http://dx.doi.org/10.3390/jcm10020292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830314PMC
January 2021

Enantiomeric Resolution and Absolute Configuration of a Chiral δ-Lactam, Useful Intermediate for the Synthesis of Bioactive Compounds.

Molecules 2020 Dec 19;25(24). Epub 2020 Dec 19.

Department of Drug Sciences, University of Pavia, via Taramelli 12, 27100 Pavia, Italy.

During the past several years, the frequency of discovery of new molecular entities based on γ- or δ-lactam scaffolds has increased continuously. Most of them are characterized by the presence of at least one chiral center. Herein, we present the preparation, isolation and the absolute configuration assignment of enantiomeric 2-(4-bromophenyl)-1-isobutyl-6-oxopiperidin-3-carboxylic acid (-). For the preparation of racemic -, the Castagnoli-Cushman reaction was employed. (Semi)-preparative enantioselective HPLC allowed to obtain enantiomerically pure - whose absolute configuration was assigned by X-ray diffractometry. Compound (+)-()- represents a reference compound for the configurational study of structurally related lactams.
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http://dx.doi.org/10.3390/molecules25246023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766352PMC
December 2020

Hypoxia Shapes Autophagy in LPS-Activated Dendritic Cells.

Front Immunol 2020 30;11:573646. Epub 2020 Nov 30.

Cellular and Molecular Physiology Unit, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.

During their lifespan, dendritic cells (DCs) are exposed to different pO levels that affect their differentiation and functions. Autophagy is one of the adaptive responses to hypoxia with important implications for cell survival. While the autophagic machinery in DCs was shown to impact signaling of TLRs, its regulation by the MD-2/TLR4 ligand LPS is still unclear. The aim of this study was to evaluate whether LPS can induce autophagy in DCs exposed to either aerobic or hypoxic conditions. Using human monocyte-derived DCs and the combination of immunofluorescence confocal analysis, measure of mitochondrial membrane potential, Western blotting, and RT-qPCR, we showed that the ability of LPS to modulate autophagy was strictly dependent upon pO levels. Indeed, LPS inhibited autophagy in aerobic conditions whereas the autophagic process was induced in a hypoxic environment. Under hypoxia, LPS treatment caused a significant increase of functional lysosomes, LC3B and Atg protein upregulation, and reduction of SQSTM1/p62 protein levels. This selective regulation was accompanied by activation of signalling pathways and expression of cytokines typically associated with DC survival. Bafilomycin A1 and chloroquine, which are recognized as autophagic inhibitors, confirmed the induction of autophagy by LPS under hypoxia and its impact on DC survival. In conclusion, our results show that autophagy represents one of the mechanisms by which the activation of the MD-2/TLR4 ligand LPS promotes DC survival under hypoxic conditions.
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http://dx.doi.org/10.3389/fimmu.2020.573646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734254PMC
November 2020

Pan-Sigma Receptor Modulator RC-106 Induces Terminal Unfolded Protein Response In Pancreatic Cancer Model.

Int J Mol Sci 2020 Nov 27;21(23). Epub 2020 Nov 27.

Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.

Pancreatic cancer (PC) remains one of the most lethal cancers worldwide. Sigma receptors (SRs) have been proposed as cancer therapeutic targets. Their main localization suggests they play a potential role in ER stress and in the triggering of the unfolded protein response (UPR). Here, we investigated the mechanisms of action of , a novel pan-SR modulator, to characterize therapeutically exploitable role of SRs in tumors. Two PC cell lines were used in all the experiments. Terminal UPR activation was evaluated by quantifying BiP, ATF4 and CHOP by Real-Time qRT-PCR, Western Blot, immunofluorescence and confocal microscopy. Cell death was studied by flow cytometry. Post-transcriptional gene silencing was performed to study the interactions between SRs and UPR key proteins. activated ER stress sensors in a dose- and time-dependent manner. It also induced ROS production accordingly with ATF4 upregulation at the same time reducing cell viability of both cell lines tested. Moreover, exerted its effect through the induction of the terminal UPR, as shown by the activation of some of the main transducers of this pathway. Post-transcriptional silencing studies confirmed the connection between SRs and these key proteins. Overall, our data highlighted a key role of SRs in the activation of the terminal UPR pathway, thus indicating pan-SR ligands as candidates for targeting the UPR in pancreatic cancer.
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http://dx.doi.org/10.3390/ijms21239012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734580PMC
November 2020

Cryoglobulinemic glomerulonephritis: clinical presentation and histological features, diagnostic pitfalls, and controversies in the management. State of the art and the experience on a large monocentric cohort treated with B cell depletion therapy.

Minerva Med 2020 Nov 16. Epub 2020 Nov 16.

Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy -

Cryoglobulinemia is defined by the presence of immunoglobulins having the following characteristics: forming a gel when temperature is < 37°C, precipitate in a reversible manner in the serum, and re-dissolve after re-warming. The presence of either of polyclonal IgG and monoclonal IgM (type II), or of polyclonal IgG and polyclonal IgM (type Ill) indentifies the mixed cryoglobulinemia (MC). The identification of the HCV infection in most of the cases previously defined as "essential" represented a cornerstone in the understanding the pathogenesis of this condition. The picture of MC comprehends heterogeneous clinical presentations: from arthralgias, mild palpable purpura, fatigue to severe vasculitis features with skin necrotic pattern, peripheral neuropathy and, less commonly, lungs, central nervous system, gastrointestinal tract, and heart involvement. Nevertheless, the kidney represents the most common organ presentation and the presence of glomerulonephritis is a key element when considering prognosis. In this review, we discuss the clinical presentation and histological features, diagnostic pitfalls, and controversies in the management of patients with cryoglobulinemic glomerulonephritis, with a special focus on reporting our experience in treating patients with B cell depletion therapy.
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http://dx.doi.org/10.23736/S0026-4806.20.07076-7DOI Listing
November 2020

Tackling Antimicrobial Resistance with Small Molecules Targeting LsrK: Challenges and Opportunities.

J Med Chem 2020 12 5;63(24):15243-15257. Epub 2020 Nov 5.

Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.

Antimicrobial resistance (AMR) is a growing threat with severe health and economic consequences. The available antibiotics are losing efficacy, and the hunt for alternative strategies is a priority. Quorum sensing (QS) controls biofilm and virulence factors production. Thus, the quenching of QS to prevent pathogenicity and to increase bacterial susceptibility to antibiotics is an appealing therapeutic strategy. The phosphorylation of autoinducer-2 (a mediator in QS) by LsrK is a crucial step in triggering the QS cascade. Thus, LsrK represents a valuable target in fighting AMR. Few LsrK inhibitors have been reported so far, allowing ample room for further exploration. This perspective aims to provide a comprehensive analysis of the current knowledge about the structural and biological properties of LsrK and the state-of-the-art technology for LsrK inhibitor design. We elaborate on the challenges in developing novel LsrK inhibitors and point out promising avenues for further research.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01282DOI Listing
December 2020

Setup and Validation of a Reliable Docking Protocol for the Development of Neuroprotective Agents by Targeting the Sigma-1 Receptor (S1R).

Int J Mol Sci 2020 Oct 18;21(20). Epub 2020 Oct 18.

Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, V.le Taramelli 12, 27100 Pavia, Italy.

Sigma-1 receptor (S1R) is a promising molecular target for the development of novel effective therapies against neurodegenerative diseases. To speed up the discovery of new S1R modulators, herein we report the development of a reliable in silico protocol suitable to predict the affinity of small molecules against S1R. The docking method was validated by comparing the computational calculated values of a test set of new aryl-aminoalkyl-ketone with experimental determined binding affinity. The druggability profile of the new compounds, with particular reference to the ability to cross the blood-brain barrier (BBB) was further predicted in silico. Moreover, the selectivity over Sigma-2 receptor (S2R) and N-methyl-D-aspartate (NMDA) receptor, another protein involved in neurodegeneration, was evaluated. 1-([1,1'-biphenyl]-4-yl)-4-(piperidin-1-yl)butan-1-one () performed as the best compound and was further investigated for acetylcholinesterase (AchE) inhibitor activity and determination of antioxidant activity mediated by aquaporins (AQPs). With a good affinity against both S1R and NMDA receptor, good selectivity over S2R and favorable BBB penetration potential together with its AChE inhibitory activity and its ability to exert antioxidant effects through modulation of AQPs, represents a viable candidate for further development as a neuroprotective agent.
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http://dx.doi.org/10.3390/ijms21207708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589021PMC
October 2020

Sorcin is an early marker of neurodegeneration, Ca dysregulation and endoplasmic reticulum stress associated to neurodegenerative diseases.

Cell Death Dis 2020 10 15;11(10):861. Epub 2020 Oct 15.

Institute of Molecular Biology and Pathology, Italian National Research Council, IBPM-CNR, Rome, Italy.

Dysregulation of calcium signaling is emerging as a key feature in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), and targeting this process may be therapeutically beneficial. Under this perspective, it is important to study proteins that regulate calcium homeostasis in the cell. Sorcin is one of the most expressed calcium-binding proteins in the human brain; its overexpression increases endoplasmic reticulum (ER) calcium concentration and decreases ER stress in the heart and in other cellular types. Sorcin has been hypothesized to be involved in neurodegenerative diseases, since it may counteract the increased cytosolic calcium levels associated with neurodegeneration. In the present work, we show that Sorcin expression levels are strongly increased in cellular, animal, and human models of AD, PD, and HD, vs. normal cells. Sorcin partially colocalizes with RyRs in neurons and microglia cells; functional experiments with microsomes containing high amounts of RyR2 and RyR3, respectively, show that Sorcin is able to regulate these ER calcium channels. The molecular basis of the interaction of Sorcin with RyR2 and RyR3 is demonstrated by SPR. Sorcin also interacts with other ER proteins as SERCA2 and Sigma-1 receptor in a calcium-dependent fashion. We also show that Sorcin regulates ER calcium transients: Sorcin increases the velocity of ER calcium uptake (increasing SERCA activity). The data presented here demonstrate that Sorcin may represent both a novel early marker of neurodegenerative diseases and a response to cellular stress dependent on neurodegeneration.
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http://dx.doi.org/10.1038/s41419-020-03063-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566454PMC
October 2020

Daratumumab Monotherapy in Severe Patients with AL Amyloidosis and Biopsy-Proven Renal Involvement: A Real Life Experience.

J Clin Med 2020 Oct 9;9(10). Epub 2020 Oct 9.

CMID-Nephrology and Dialysis Unit (ERK-net Member)-Center of Research of Nephrology, Rheumatology, and Rare Diseases, Interregional Coordinating Center of the Network of Rare Diseases, G. Bosco Hospital and University of Turin, 10152 Turin, Italy.

Objectives: This paper aims to describe the clinical experience with Daratumumab (DARA), a first-in-class anti-CD38 human monoclonal IgG1κ antibody monotherapy, in severe patients with AL and biopsy-proven renal involvement. Immunoglobulin light chain (AL) amyloidosis with multi-organ involvement is characterized by short survival. Novel powerful drugs are expanding the therapeutic options. Current treatment of AL amyloidosis, which has been adopted from multiple myeloma (MM), is based on chemotherapy targeting the underlying plasma cell clone. DARA is effective in treating MM. The clinical activity and toxicity profile of DARA as a single agent in the treatment of AL amyloidosis is currently under evaluation.

Patients And Methods: DARA was administered in a series of patients with severe AL amyloidosis and biopsy-proven renal involvement. Five patients(mean age 64.2 years) were treated. One patient was refractory and one intolerant to conventional bortezomib-based therapy, two were treated with DARA for relapsing disease, and one was treated front-line.

Results: Data showed that DARA monotherapy resulted in good clinical results, with the disappearance of M-proteins in four out of five patients and with serum free light chains (sFLC) ratio normalization in three out of four and a remarkable amelioration in the remaining patient. The four patients with still preserved renal function at baseline also showed serum creatinine stabilization or improvement and a decrease in proteinuria. These data were paralleled by the reduction of the N-terminal prohormone of brain natriuretic peptide (NT pro-BNP)values.

Conclusions: Our data show that monotherapy with DARA had significant clinical efficacy in pretreated/naïve patients with severe AL amyloidosis and biopsy-proven renal involvement.
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http://dx.doi.org/10.3390/jcm9103232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600836PMC
October 2020

Remote Monitoring Empowerment of Patients with IBDs during the SARS-CoV-2 Pandemic.

Healthcare (Basel) 2020 Oct 1;8(4). Epub 2020 Oct 1.

National Institute of Gastroenterology, "Saverio de Bellis" Research Hospital, 70013 Castellana Grotte, Italy.

Once the WHO declared the Sars-CoV-2 pandemic, the world had to reprogram numerous clinical activities, particularly those related to highly disabling diseases such as inflammatory bowel diseases (IBDs). In this study, 1083 IBD patients were assessed, affected by Crohn's Disease (CD) and Ulcerative Colitis (UC), and subdivided into two groups. The first group included patients who needed treatment in person at the outpatients clinic, while the second group could be tele-monitored because they were able to self-administer therapy. The tele-monitoring was based on telecommunication applications via smartphone, driven by a dedicated clinical control room in the IBD Clinic. The aim of this study was to assess the quality of life (using IBDQ32) of UC patients and tele-monitored CD patients (tele-monitoring group) as compared to those patients who underwent assessment in person in the outpatients clinic (control group). Despite observing a lower number of relapses in the control group than the tele-monitoring group, there were no statistically significant differences between the groups in terms of the IBD32Q scores. Tele-monitoring of patients who are able to self-administer the IBD therapy can be an effective vicarious system as compared to the clinical evaluation in person, that could lead to important changes to avoid the overcrowding of the IBD outpatients clinic, especially during public health crises like the present pandemic.
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http://dx.doi.org/10.3390/healthcare8040377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711761PMC
October 2020

Exploring the RC-106 Chemical Space: Design and Synthesis of Novel ()-1-(3-Arylbut-2-en-1-yl)-4-(Substituted) Piperazine Derivatives as Potential Anticancer Agents.

Front Chem 2020 30;8:495. Epub 2020 Jun 30.

Medicinal Chemistry and Pharmaceutical Technology Section, Department of Drug Sciences, University of Pavia, Pavia, Italy.

Despite the fact that significant advances in treatment of common cancers have been achieved over the years, orphan tumors still represent an important unmet medical need. Due to their complex multifactorial origin and limited number of cases, such pathologies often have very limited treatment options and poor prognosis. In the search for new anticancer agents, our group recently identified , a Sigma receptor modulator endowed with proteasome inhibition activity. This compound showed antiproliferative activity toward different cancer cell lines, among them glioblastoma (GB) and multiple myeloma (MM), two currently unmet medical conditions. In this work, we directed our efforts toward the exploration of chemical space around to identify new active compounds potentially useful in cancer treatment. Thanks to a combinatorial approach, we prepared 41 derivatives of the compound and evaluated their cytotoxic potential against MM and GB. Three novel potential anticancer agents have been identified.
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http://dx.doi.org/10.3389/fchem.2020.00495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338850PMC
June 2020

Towards a novel target therapy for renal diseases related to plasma cell dyscrasias: The example of AL amyloidosis.

Autoimmun Rev 2020 Sep 12;19(9):102622. Epub 2020 Jul 12.

Nephrology and Dialysis Unit-CMID, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital of Turin, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.

Immunoglobulin light chain amyloidosis is a rare systemic disease caused by monoclonal light chains (LCs) depositing in tissue as insoluble fibrils resulting in irreversible damage of vital organs. The mechanisms involved in aggregation and deposition of LCs are not fully understood, but CD138/38 plasma cells are undoubtedly involved in monoclonal LC production. We are reporting favorable effects on AL amyloidosis patients with renal involvement using the anti-CD38 monoclonal antibody Daratumumab. We speculate that research for the near future should be devoted to design similar therapeutic approaches for other diseases attributable to a plasma cell dyscrasia.
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http://dx.doi.org/10.1016/j.autrev.2020.102622DOI Listing
September 2020

Sigma-1 receptor antagonists: promising players in fighting neuropathic pain.

Pharm Pat Anal 2020 May 16;9(3):77-85. Epub 2020 Jun 16.

Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100, Pavia, Italy.

Sigma-1 receptors (S1Rs) are strongly correlated to neuropathic pain (NP), since their inactivation may decrease allodynia or dysesthesia, promoting analgesic effects. In the recent patent landscape, S1R antagonists endowed with nanomolar S1Rs affinity emerged as potent antinociceptive agents. So far, three patented compounds have been proposed for counteracting NP. Particularly and , disclosed by the University of Pavia (Italy) and Anavex, respectively, showed good analgesic activity in preclinical studies. Moreover, developed by Esteve (Spain) has been proved to be effective, both in preclinical and Phase II clinical trials, against several symptoms of NP. These patents ascertain S1R antagonists as potential drugs, alone or in combination with other analgesic drugs, for managing NP in humans.
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http://dx.doi.org/10.4155/ppa-2020-0007DOI Listing
May 2020

CD38 and Anti-CD38 Monoclonal Antibodies in AL Amyloidosis: Targeting Plasma Cells and beyond.

Int J Mol Sci 2020 Jun 10;21(11). Epub 2020 Jun 10.

Nephrology and Dialysis Unit & CMID (Center of Research of Immunopathology and Rare Diseases), Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hub Hospital of Turin, and Department of Clinical and Biological Sciences, University of Turin, 10154 Turin, Italy.

Immunoglobulin light chain amyloidosis (AL amyloidosis) is a rare systemic disease characterized by monoclonal light chains (LCs) depositing in tissue as insoluble fibrils, causing irreversible tissue damage. The mechanisms involved in aggregation and deposition of LCs are not fully understood, but CD138/38 plasma cells (PCs) are undoubtedly involved in monoclonal LC production.CD38 is a pleiotropic molecule detectable on the surface of PCs and maintained during the neoplastic transformation in multiple myeloma (MM). CD38 is expressed on T, B and NK cell populations as well, though at a lower cell surface density. CD38 is an ideal target in the management of PC dyscrasia, including AL amyloidosis, and indeed anti-CD38 monoclonal antibodies (MoAbs) have promising therapeutic potential. Anti-CD38 MoAbs act both as PC-depleting agents and as modulators of the balance of the immune cells. These aspects, together with their interaction with Fc receptors (FcRs) and neonatal FcRs, are specifically addressed in this paper. Moreover, the initiallyavailable experiences with the anti-CD38 MoAb DARA in AL amyloidosis are reviewed.
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http://dx.doi.org/10.3390/ijms21114129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312896PMC
June 2020

Calsequestrin, a key protein in striated muscle health and disease.

J Muscle Res Cell Motil 2020 Jun 2. Epub 2020 Jun 2.

Molecular Medicine Section, Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro, 2, 53100, Siena, Italy.

Calsequestrin (CASQ) is the most abundant Ca binding protein localized in the sarcoplasmic reticulum (SR) of skeletal and cardiac muscle. The genome of vertebrates contains two genes, CASQ1 and CASQ2. CASQ1 and CASQ2 have a high level of homology, but show specific patterns of expression. Fast-twitch skeletal muscle fibers express only CASQ1, both CASQ1 and CASQ2 are present in slow-twitch skeletal muscle fibers, while CASQ2 is the only protein present in cardiomyocytes. Depending on the intraluminal SR Ca levels, CASQ monomers assemble to form large polymers, which increase their Ca binding ability. CASQ interacts with triadin and junctin, two additional SR proteins which contribute to localize CASQ to the junctional region of the SR (j-SR) and also modulate CASQ ability to polymerize into large macromolecular complexes. In addition to its ability to bind Ca in the SR, CASQ appears also to be able to contribute to regulation of Ca homeostasis in muscle cells. Both CASQ1 and CASQ2 are able to either activate and inhibit the ryanodine receptors (RyRs) calcium release channels, likely through their interactions with junctin and triadin. Additional evidence indicates that CASQ1 contributes to regulate the mechanism of store operated calcium entry in skeletal muscle via a direct interaction with the Stromal Interaction Molecule 1 (STIM1). Mutations in CASQ2 and CASQ1 have been identified, respectively, in patients with catecholamine-induced polymorphic ventricular tachycardia and in patients with some forms of myopathy. This review will highlight recent developments in understanding CASQ1 and CASQ2 in health and diseases.
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http://dx.doi.org/10.1007/s10974-020-09583-6DOI Listing
June 2020

Outcome of patients with severe AL amyloidosis and biopsy-proven renal involvement ineligible for bone marrow transplantation.

J Nephrol 2021 02 29;34(1):231-240. Epub 2020 May 29.

Nephrology and Dialysis Unit and CMID, University of Turin and San Giovanni Hospital, Piazza del Donatore di Sangue 3, 10054, Turin, Italy.

Introduction: AL amyloidosis is caused by a clone of plasma cell. Due to the impact of the disease on patient survival, careful evaluation of organ involvement is essential and treatment should be tailored to single patient's risk.

Aim: We analyzed the clinical, laboratory and histological characteristics of 21 elderly patients (pts) (mean age 74.7 ± 7.97 years, range 55-81) with AL amyloidosis, including 17 patients (81%) with biopsy-proven renal involvement, who were ineligible for bone marrow transplantation, and evaluated the impact of renal impairment on survival.

Results: Cardiac and renal involvement was found in 14 (67%) cases. Among the 17 patients with renal involvement, 12 had renal failure with proteinuria, and one showed isolated renal failure and vascular amyloid deposition. Hematological response occurred in 57.1% after first line therapy (75% after three cycles). In six of the patients with renal involvement, proteinuria decreased from 4.2 to 1.1 g/24 h (range 0.2-3 g/24 h), serum Creatinina (sCr) levels declined or stabilized. Severe renal failure at diagnosis was found to directly influence patient survival, while the Staging System for Renal Outcome in AL Amyloidosis did not associate with outcomes.

Conclusions: To the best of our knowledge this is the first case series in which the whole cohort of patients with urinary or functional abnormalities underwent a histological evaluation. None of the patients were eligible for bone marrow transplantation. Hematologic response was 57.1%, while renal response was much lower (35%). Of note, the Staging System did not completely apply to this peculiar setting of patients in whom renal involvement was not presumptive but biopsy-proven. More aggressive approaches may be needed in these patients to avoid the inexorable progression of the disease.
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http://dx.doi.org/10.1007/s40620-020-00748-7DOI Listing
February 2021

BOPC1 Enantiomers Preparation and HuR Interaction Study. From Molecular Modeling to a Curious DEEP-STD NMR Application.

ACS Med Chem Lett 2020 May 28;11(5):883-888. Epub 2020 Jan 28.

Department of Drug Sciences, Medicinal Chemistry and Technology Section, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy.

The Hu family of RNA-binding proteins plays a crucial role in post-transcriptional processes; indeed, Hu-RNA complexes are involved in various dysfunctions (i.e., inflammation, neurodegeneration, and cancer) and have been recently proposed as promising therapeutic targets. Intrigued by this concept, our research efforts aim at identifying small molecules able to modulate HuR-RNA interactions, with a focus on subtype HuR, upregulated and dysregulated in several cancers. By applying structure-based design, we had already identified racemic - as promising HuR binder. In this Letter, we accomplished the enantio-resolution, the assignment of the absolute configuration, and the recognition study with HuR of enantiomerically pure -. For the first time, we apply DEEP (differential epitope mapping)-STD NMR to study the interaction of with HuR and compare its enantiomers, gaining information on ligand orientation and amino acids involved in the interaction, and thus increasing focus on the binding site model.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236254PMC
May 2020

Tailoring Tofacitinib Oral Therapy in Rheumatoid Arthritis: The TuTORApp-A Usability Study.

Int J Environ Res Public Health 2020 05 15;17(10). Epub 2020 May 15.

Center of Research of Immunopathology and Rare Diseases-Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, and SCDU Nephrology and Dialysis-ERKnet Member, S. Giovanni Bosco Hospital, Department of Clinical and Biological Sciences, 10154 Turin, Italy.

Objective: To create a mobile application able to help patients follow medical treatments properly.

Methods: We designed and developed a custom Android/iOS App to remind patients of the pharmaceutical drugs to be taken, of the visits and exams to attend, and to detect their compliance with their personal therapeutic plan. In this paper we describe the App development, UX/UI design, Gamification. TuTOR is an Android and iOS application designed to remind patients of the drugs to be taken, giving them all the information related to their therapeutic plans in a simple and non-invasive way. Thanks to a dedicated back-office, specially designed to meet specific medical information needs, the App can also help physicians detect their patients' compliance with their treatments and modify prescriptions in real time. The App also ensures a state-of-the-art approach to data security and privacy protection. The main feature of TuTOR is the smart therapy assistant, which features dedicated alarms to remind users of taking their prescription drugs. Thanks to the automatic synchronization with a local database, the alert system works even without connection to the Internet. Particular attention was paid during the App's design process: we looked to create an intuitive interface to ensure absolute ease of use, with state-of-the-art visual design aimed at maximizing user experience. Other relevant features include the App's ability to givevisual evidence of the most important drugs to be taken and its note-taking feature, which gives patients the possibility to note down indications on why a specific drug was skipped. The App also keeps track of upcoming medical exams, laboratory tests, and visits on a devoted calendar. It also helps patients by listing therapy contacts, such as physicians' phone numbers, and indicates all medical references by showing, for example, locations of relevant clinics and pharmacies on a map. Thanks to specific visual progress indicators and an innovative gamification approach, the App encourages users to faithfully follow therapy guidelines. With TuTOR, assessing the therapy's state of completion is quick and easy.Thanksto the privacy-by-design approach used, all data managed by the system is compliant with the European Privacy Regulation and it is not available to third parties.

Expected Results: A mobile App for medication adherence might increase objectively and subjectively measured adherence.
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http://dx.doi.org/10.3390/ijerph17103469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277549PMC
May 2020

Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19.

Clin Exp Rheumatol 2020 May-Jun;38(3):529-532. Epub 2020 May 1.

CMID, Centre of Research of Immunopathology and Rare Diseases, Coordinating Centre of the Network for Rare Diseases of Piemonte and Valle d'Aosta, ASL Città di Torino, Department of Clinical and Biological Sciences, University of Torino, and ASL Città di Torino, Italy.

Objectives: No agent has yet been proven to be effective for the treatment of patients with severe COVID-19.

Methods: We conducted a pilot prospective open, single-arm multicentre study on off-label use of tocilizumab (TCZ) involving 63 hospitalised adult patients (56 males, age 62.6±12.5) with severe COVID-19. Clinical and laboratory parameters were prospectively collected at baseline, day 1, 2, 7 and 14. No moderate-to-severe adverse events attributable to TCZ were recorded.

Results: We observed a significant improvement in the levels of ferritin, C-reactive protein, D-dimer. The ratio of the partial pressure of oxygen (Pa02) to the fraction of inspired oxygen (Fi02) improved (mean±SD Pa02/Fi02 at admission: 152±53; at day 7: 283.73±115.9, at day 14: 302.2±126, p<0.05). The overall mortality was 11%; D-dimer level at baseline, but not IL-6 levels were predictors of mortality. TCZ administration within 6 days from admission in the hospital was associated with an increased likelihood of survival (HR 2.2 95%CI 1.3-6.7, p<0.05).

Conclusions: In hospitalised adult patients with severe COVID-19, TCZ could be a safe option. An improvement in respiratory and laboratory parameters was observed. Future controlled trials in patients with severe illness are urgently needed to confirm the definite benefit with IL-6 target therapy.
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May 2020

Exploring Novel Molecular Targets for the Treatment of High-Grade Astrocytomas Using Peptide Therapeutics: An Overview.

Cells 2020 02 20;9(2). Epub 2020 Feb 20.

Istituti Clinici Scientifici Maugeri IRCCS, Laboratory for Research on Neurodegenerative Disorders, 27100 Pavia, Italy.

Diffuse astrocytomas are the most aggressive and lethal glial tumors of the central nervous system (CNS). Their high cellular heterogeneity and the presence of specific barriers, i.e., blood-brain barrier (BBB) and tumor barrier, make these cancers poorly responsive to all kinds of currently available therapies. Standard therapeutic approaches developed to prevent astrocytoma progression, such as chemotherapy and radiotherapy, do not improve the average survival of patients. However, the recent identification of key genetic alterations and molecular signatures specific for astrocytomas has allowed the advent of novel targeted therapies, potentially more efficient and characterized by fewer side effects. Among others, peptides have emerged as promising therapeutic agents, due to their numerous advantages when compared to standard chemotherapeutics. They can be employed as (i) pharmacologically active agents, which promote the reduction of tumor growth; or (ii) carriers, either to facilitate the translocation of drugs through brain, tumor, and cellular barriers, or to target tumor-specific receptors. Since several pathways are normally altered in malignant gliomas, better outcomes may result from combining multi-target strategies rather than targeting a single effector. In the last years, several preclinical studies with different types of peptides moved in this direction, providing promising results in murine models of disease and opening new perspectives for peptide applications in the treatment of high-grade brain tumors.
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http://dx.doi.org/10.3390/cells9020490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072800PMC
February 2020

Insight into GEBR-32a: Chiral Resolution, Absolute Configuration and Enantiopreference in PDE4D Inhibition.

Molecules 2020 Feb 19;25(4). Epub 2020 Feb 19.

Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy.

Alzheimer's disease is the most common type of dementia, affecting millions of people worldwide. One of its main consequences is memory loss, which is related to downstream effectors of cyclic adenosine monophosphate (cAMP). A well-established strategy to avoid cAMP degradation is the inhibition of phosphodiesterase (PDE). In recent years, GEBR-32a has been shown to possess selective inhibitory properties against PDE type 4 family members, resulting in an improvement in spatial memory processes without the typical side effects that are usually correlated with this mechanism of action. In this work, we performed the HPLC chiral resolution and absolute configuration assignment of GEBR-32a. We developed an efficient analytical and semipreparative chromatographic method exploiting an amylose-based stationary phase, we studied the chiroptical properties of both enantiomers and we assigned their absolute configuration by H-NMR (nuclear magnetic resonance). Lastly, we measured the IC values of both enantiomers against both the PDE4D catalytic domain and the long PDE4D3 isoform. Results strongly support the notion that GEBR-32a inhibits the PDE4D enzyme by interacting with both the catalytic pocket and the regulatory domains.
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http://dx.doi.org/10.3390/molecules25040935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070305PMC
February 2020

Anti-beta-2-glycoprotein I domain 1 identifies antiphospholipid antibodies-related injuries in patients with concomitant lupus nephritis.

J Nephrol 2020 Aug 23;33(4):757-762. Epub 2020 Jan 23.

Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, SCDU Nephrology and Dialysis, S. Giovanni Bosco Hospital, Piazza del Donatore di Sangue 3, 10154, Turin, Italy.

Background: In this study we aimed to evaluate the usefulness of domain profiling of Beta-2-glycoprotein I(β2GPI)-Domain-1 (D1) antibodies in relation to antiphospholipid antibodies (aPL)-related nephropathy (aPL-N) in patients with biopsy-proven lupus nephritis (LN).

Methods: Of 124 consecutive patients (96 women, mean age 45.5 ± 12.3 years, mean disease duration 14.7 ± 9.6 years) fulfilling the 1982 criteria for systemic lupus erythematosus (SLE), we identified 39 patients (mean age 39.84 ± 8.6 years, mean disease duration 11.3 ± 7.7 years) with the following characteristics: (a) biopsy-proven LN; (b) no previous diagnosis of antiphospholipid syndrome (APS) according to the current classification criteria.

Results: Patients with both LN and aPL-N had higher median aβ2GPI-D1 antibody titres (220.1 CU, 25-75th IQ 29.1-334.2) as compared those with LN alone (46.5 CU, 25-75th IQ 12.5-75.1) (p = 0.0087). Median aβ2GPI-D1 antibody titres were higher in patients with acute thrombotic microangiopathy (aTMA) (N = 7) (250.1 CU, 25-75th IQ 61.2-334.2) vs. with LN alone (46.5 CU, 25-75th IQ 12.5-75.1 CU) (p = 0.0009). Having a Global Antiphospholipid Syndrome Score > 10 confers an increased probability of having acute features of aTMA (OR 6.25, 95%CI 1.2-31.8). As compared to other aPL, aβ2GPI-D1 antibodies have the best diagnostic accuracy for aTMA as evaluated by performances in Area Under the Curves in a ROC analysis.

Conclusions: aβ2GPI-D1 antibodies detection might provide a second-line assay to be performed in aβ2GPI positive patients with LN, allowing more accurate stratification of the renal vascular involvement risk, thus potentially leading to a more tailored management.
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http://dx.doi.org/10.1007/s40620-019-00698-9DOI Listing
August 2020

Reelin reverts biochemical, physiological and cognitive alterations in mouse models of Tauopathy.

Prog Neurobiol 2020 03 20;186:101743. Epub 2019 Dec 20.

Vall d'Hebron Institut de Recerca, 08035, Barcelona, Spain; Department of Cell Biology, Physiology and Immunology, and Institute of Neurosciences, University of Barcelona, 08028, Barcelona, Spain; Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031, Madrid, Spain; ICREA Academia, 08010, Barcelona, Spain. Electronic address:

Reelin is an extracellular protein crucial for adult brain plasticity. Moreover, Reelin is protective against amyloid-β (Aβ) pathology in Alzheimer's Disease (AD), reducing plaque deposition, synaptic loss and cognitive decline. Given that Tau protein plays a key role in AD pathogenesis, and that the Reelin pathway modulates Tau phosphorylation, here we explored the involvement of Reelin in AD-related Tau pathology. We found that Reelin overexpression modulates the levels of Tau phosphorylation in AD-related epitopes in VLW mice expressing human mutant Tau. in vitro, Reelin reduced the Aβ-induced missorting of axonal Tau and neurofilament proteins to dendrites. Reelin also reverted in vivo the toxic somatodendritic localization of phosphorylated Tau. Finally, overexpression of Reelin in VLW mice improved long-term potentiation and long-term memory cognitive performance thus masking the cognitive and physiological deficits in VLW mice. These data suggest that the Reelin pathway, which is also protective against Aβ pathology, modulates fundamental traits of Tau pathology, strengthening the potential of Reelin as a therapeutic target in AD.
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http://dx.doi.org/10.1016/j.pneurobio.2019.101743DOI Listing
March 2020

Identifying phenotypes of patients with antiphospholipid antibodies: results from a cluster analysis in a large cohort of patients.

Rheumatology (Oxford) 2019 Dec 16. Epub 2019 Dec 16.

Center of Research of Immunopathology and Rare Diseases/Nephrology and Dialysis Unit, Department of Clinical and Biological Sciences, S. Giovanni Bosco Hospital, Turin, Italy.

Objectives: To identify the aggregation of patients with aPL into different subgroups sharing common features in terms of clinical and laboratory phenotypes.

Methods: We applied a hierarchical cluster analysis from the multiple correspondence analysis to determine subgroups of patients according to clinical and laboratory characteristics in a cohort of subjects with confirmed aPL positivity who presented to our outpatient clinics from 2006 to 2018.

Results: A total of 486 patients [403 women; age 41.7 years (26)] were included, resulting in five clusters. Cluster 1 (n= 150) presented with thrombotic events (65.3% with venous thrombosis), with triple aPL positivity found in 34.7% of them (the highest rate among the different clusters). All the patients from cluster 2 (n = 91) had a confirmed diagnosis of SLE and the highest rate of anti-dsDNA positivity (91.7%). Cluster 3 included 79 women with pregnancy morbidity. Triple positivity was present in 3.8%, significantly lower when compared with Cluster 1 (34.7% versus 3.8%, P <0.01). Cluster 4 included 67 patients, 28 (41.8%) of whom with APS. Thrombotic events were observed in 23.9% patients. Cluster 4 had the highest rate of cytopenia, with thrombocytopenia as high 41.8% with no anti-dsDNA antibodies. Cluster 5 included 94 asymptomatic aPL carriers.

Conclusion: While clusters 1, 2, 3 and 5 corresponded to well-known entities, cluster 4 might represent a bridging condition between pure primary APS and defined SLE, with lower thrombotic risk when compared with primary APS but higher general features such as ANA and cytopenia (mainly thrombocytopenia).
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http://dx.doi.org/10.1093/rheumatology/kez596DOI Listing
December 2019

Thermography in systemic sclerosis patients and other rheumatic diseases: Diagnosis, disease activity assessment, and therapeutic monitoring.

Autoimmun Rev 2020 Feb 12;19(2):102449. Epub 2019 Dec 12.

Center of Research of Immunopathology and Rare Diseases, Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, SCDU Nephrology and Dialysis, S. Giovanni Bosco Hospital, Turin, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.autrev.2019.102449DOI Listing
February 2020

New Insights into the Opening of the Occluded Ligand-Binding Pocket of Sigma1 Receptor: Binding of a Novel Bivalent RC-33 Derivative.

J Chem Inf Model 2020 02 20;60(2):756-765. Epub 2019 Dec 20.

Center for Bioinformatics and Molecular Simulation , Universidad de Talca , 1 Poniente , 1141 Talca , Chile.

Significant progresses have been made to understand the molecular basis of the Sigma1 receptor (S1R) operating in normal and pathological conditions. S1R is a transmembrane protein that participates in a wide variety of processes at the central nervous system; hence, its function has been associated with mental and neurological disorders. Several ligands have been proposed to regulate the function of S1R revealing a high plasticity of the ligand-binding pocket. Previous drug-design studies have been mainly based on pharmacophore models; however, the recently revealed crystal structure of S1R provides an excellent opportunity for verifying previous predictions and for evaluating the binding of novel compounds. Interestingly, the crystal structure shows that the binding pocket of S1R is highly occluded from solvent; therefore, it is not clear how ligands access this site. In the present work, we applied steered molecular dynamics (SMD) simulations to open the occluded ligand-binding pocket in the S1R crystal structure and to determine the preferred ligand pathway to enter and exit the binding site. The intracellular surface of the β-barrel ligand-binding region was found the most favorable route to accommodate ligands. This route supports the binding of RC-33 (our in-house-developed S1R modulator) and a new bivalent derivative that constitutes the first divalent structure shown to interact with S1R. Free energy calculations of these compounds associated with S1R agree with experimental values and provide molecular insights of the binding mode of modulators that could access the S1R ligand-binding pocket through the cytoplasmic region.
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http://dx.doi.org/10.1021/acs.jcim.9b00649DOI Listing
February 2020

ALS-Associated SOD1(G93A) Decreases SERCA Pump Levels and Increases Store-Operated Ca Entry in Primary Spinal Cord Astrocytes from a Transgenic Mouse Model.

Int J Mol Sci 2019 Oct 17;20(20). Epub 2019 Oct 17.

Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons (MNs), probably by a combination of cell- and non-cell-autonomous processes. The past decades have brought many important insights into the role of astrocytes in nervous system function and disease, including the implication in ALS pathogenesis possibly through the impairment of Ca-dependent astrocyte-MN cross-talk. In this respect, it has been recently proposed that altered astrocytic store-operated Ca entry (SOCE) may underlie aberrant gliotransmitter release and astrocyte-mediated neurotoxicity in ALS. These observations prompted us to a thorough investigation of SOCE in primary astrocytes from the spinal cord of the SOD1(G93A) ALS mouse model in comparison with the SOD1(WT)-expressing controls. To this purpose, we employed, for the first time in the field, genetically-encoded Ca indicators, allowing the direct assessment of Ca fluctuations in different cell domains. We found increased SOCE, associated with decreased expression of the sarco-endoplasmic reticulum Ca-ATPase and lower ER resting Ca concentration in SOD1(G93A) astrocytes compared to control cells. Such findings add novel insights into the involvement of astrocytes in ALS MN damage.
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http://dx.doi.org/10.3390/ijms20205151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829245PMC
October 2019