Equated hospitalization rate of patients with inflammatory rheumatic diseases as compared to normal population in 2°wave SARSCoV2 infection.

OBJECTIVE: To investigate the clinical manifestations and outcome of COVID-19 in patients with inflammatory rheumatic and musculoskeletal disease (iRMD) as compared with the general population. METHODS: This is a case-control study of patients selected from the South-Tyrol public health service-Italy with and without iRMD affected by COVID-19. We included patients ≥18 years and with a positive SARS-CoV-2 PCR test between 1.10.2020 and 01.03.2021. Cases were identified by linking the diagnosis of a rheumatic disease with PCR test positivity; these were matched in a 1:1.8 (planned 1:2) ratio for age, sex, and date of COVID-19 diagnosis with people from the general population. The outcomes of primary interest were hospitalization and severe course (intensive care unit, mechanical ventilation/extracorporeal membrane oxygenation, death). RESULTS: The study population consisted of 561 COVID-19 patients, of which 201 (mean age 60.4 years; 65.2% female) were patients with iRMD and 360 were controls from the general population (59.8 years; 64.7% female). The majority of iRMD patients (88.6%) received an immunosuppressive drug at time of COVID-19 diagnosis, 36.3% were under glucocorticoids. COVID-19 related hospitalization (12.4% vs 10.6%, p= 0.49), severe course (5.0% vs 5.3%, p= 1.00), and mortality (3.5% vs 4.4%, p= 0.66) were similar between groups. Among hospitalized patients, mechanic ventilation was more common in iRMD patients than in controls [n = 5 (20.0%) vs n = 1 (2.6%), p= 0.035]. CONCLUSIONS: Our study indicates similar rates for admission, severe course and mortality between patients with iRMD and controls affected by COVID-19. Among hospitalized patients, mechanical ventilation was more frequently required in the iRMD group.

Bacaryolanes A-C, Rare Bacterial Caryolanes from a Mangrove Endophyte.

Caryolanes are known as typical plant-derived sesquiterpenes. Here we describe the isolation and full structure elucidation of three caryolanes, bacaryolane A-C (1-3), that are produced by a bacterial endophyte (Streptomyces sp. JMRC:ST027706) of the mangrove plant Bruguiera gymnorrhiza. By 2D NMR, analysis of the first X-ray crystallographic data of a caryolane (bacaryolane C), CD spectroscopy, and comparison with data for plant-derived caryolanes, we rigorously established the absolute configuration of the bacaryolanes and related compounds from bacteria. Bacterial caryolanes appear as the mirror images of typical plant caryolanes. Apparently plant and bacteria harbor stereodivergent biosynthetic pathways, which may be used as metabolic signatures. The discovery of plant-like volatile terpenes in endophytes not only is an important addition to the bacterial terpenome but may also point to complex molecular interactions in the plant-microbe association.

Synthesis and antiproliferative activity of 2,5-bis(3'-indolyl)pyrroles, analogues of the marine alkaloid nortopsentin.

2,5-bis(3'-Indolyl)pyrroles, analogues of the marine alkaloid nortopsentin, were conveniently prepared through a three step procedure in good overall yields. Derivatives 1a and 1b exhibited concentration-dependent antitumor activity towards a panel of 42 human tumor cell lines with mean IC50 values of 1.54 µM and 0.67 µM, respectively. Investigating human tumor xenografts in an ex-vivo clonogenic assay revealed selective antitumor activity, whereas sensitive tumor models were scattered among various tumor histotypes.

Pachydictyols B and C: new diterpenes from Dictyota dichotoma Hudson.

Two new diterpenoids, pachydictyol B (1a/1b) and C (2), were isolated from the dichloromethane extract of the marine brown alga, Dictyota dichotoma, collected from the Red Sea coast of Egypt, along with the known metabolites, pachydictyol A (3a), dictyol E (4), cis-africanan-1α-ol (5a), fucosterol (6), tetrahydrothiophen-1,1-dioxide and poly-ß-hydroxybutyric acid. GC-MS analysis of the nonpolar fractions also indicated the presence of ß-bourbonene and nonanal, along with three hydrocarbons and five fatty acids or their simple derivatives, respectively. GC-MS analysis of the unsaponifiable algal petroleum ether extract revealed the presence of a further eight compounds, among them 2,2,6,7-tetramethyl-10-oxatricyclo[4.3.0.1(1,7)]decan-5-one (7), N-(4-bromo-n-butyl)-pipe ridin-2-one (8) and tert-hexadecanethiol. Structures 1-6 were assigned by 1D and 2D NMR, mass spectra (EI, CI, HREI and HRESI) and by comparison with data from related structures. The crude algal extract was potently active against the breast carcinoma tumor cell line, MCF7 (IC50 = 0.6 µg mL⁻¹); pachydictyol B (1a) and dictyol E (4) showed weak antimicrobial properties, and the other compounds were inactive. Pachydictyols B (1a) and C (2) demonstrated a weak and unselective cytotoxicity against twelve human tumor cell lines with a mean IC50 of >30.0 µM.

A patient-driven registry on Behçet's disease: the AIDA for patients pilot project.

Introduction: This paper describes the creation and preliminary results of a patient-driven registry for the collection of patient-reported outcomes (PROs) and patient-reported experiences (PREs) in Behçet's disease (BD). Methods: The project was coordinated by the University of Siena and the Italian patient advocacy organization SIMBA (Associazione Italiana Sindrome e Malattia di Behçet), in the context of the AIDA (AutoInflammatory Diseases Alliance) Network programme. Quality of life, fatigue, socioeconomic impact of the disease and therapeutic adherence were selected as core domains to include in the registry. Results: Respondents were reached via SIMBA communication channels in 167 cases (83.5%) and the AIDA Network affiliated clinical centers in 33 cases (16.5%). The median value of the Behçet's Disease Quality of Life (BDQoL) score was 14 (IQR 11, range 0-30), indicating a medium quality of life, and the median Global Fatigue Index (GFI) was 38.7 (IQR 10.9, range 1-50), expressing a significant level of fatigue. The mean Beliefs about Medicines Questionnaire (BMQ) necessity-concern differential was 0.9 ± 1.1 (range - 1.8-4), showing that the registry participants prioritized necessity belief over concerns to a limited extent. As for the socioeconomic impact of BD, in 104 out of 187 cases (55.6%), patients had to pay from their own pocket for medical exams required to reach the diagnosis. The low family socioeconomic status (p < 0.001), the presence of any major organ involvement (p < 0.031), the presence of gastro-intestinal (p < 0.001), neurological (p = 0.012) and musculoskeletal (p = 0.022) symptoms, recurrent fever (p = 0.002), and headache (p < 0.001) were associated to a higher number of accesses to the healthcare system. Multiple linear regression showed that the BDQoL score could significantly predict the global socioeconomic impact of BD (F = 14.519, OR 1.162 [CI 0.557-1.766], p < 0.001). Discussion: Preliminary results from the AIDA for Patients BD registry were consistent with data available in the literature, confirming that PROs and PREs could be easily provided by the patient remotely to integrate physician-driven registries with complementary and reliable information.

In vivo topoisomerase I inhibition attenuates the expression of hypoxia-inducible factor 1α target genes and decreases tumor angiogenesis.

Topoisomerase I is a privileged target for widely used anticancer agents such as irinotecan. Although these drugs are classically considered to be DNA-damaging agents, increasing evidence suggests that they might also influence the tumor environment. This study evaluates in vivo cellular and molecular modifications induced by irinotecan, a topoisomerase I-directed agent, in patient-derived colon tumors subcutaneously implanted in athymic nude mice. Irinotecan was given intraperitoneally at 40 mg/kg five times every 5 d, and expression profiles were evaluated at d 25 in tumors from treated and untreated animals. Unexpectedly, the in vivo antitumor activity of irinotecan was closely linked to a downregulation of hypoxia-inducible factor-1α (HIF1A) target genes along with an inhibition of HIF1A protein accumulation. The consequence was a decrease in tumor angiogenesis leading to tumor size stabilization. These results highlight the molecular basis for the antitumor activity of a widely used anticancer agent, and the method used opens the way for mechanistic studies of the in vivo activity of other anticancer therapies.

Kandenols A-E, eudesmenes from an endophytic Streptomyces sp. of the mangrove tree Kandelia candel.

Five novel eudesmene-type sesquiterpenes, kandenols A-E (1-5), have been isolated from Streptomyces sp. HKI0595 derived from the mangrove plant Kandelia candel. Their structures were established through NMR and mass spectrometry, and absolute configurations were established by the Mosher method and comparison of CD spectra with α-rotunol and ß-rotunol. The kandenols are reminiscent of various plant-derived eudesmenes, yet kandenols B and C are unusual because of their hydroperoxide moieties. Kandenol E is the first bacterial agarofuran, which belongs to an important group of antibiotics. Whereas the kandenols display no cytotoxicity against 12 human cell lines, weak to moderate antimicrobial activities were detected against Bacillus subtilis ATCC 6633 and Mycobacterium vaccae IMET 10670.

Elaiomycins D-F, antimicrobial and cytotoxic azoxides from Streptomyces sp. strain HKI0708.

Five new congeners of elaiomycin featuring the rare azoxy function were isolated from Streptomyces sp. strain HKI0708. Individual elaiomycins exhibit specific antimycobacterial, anti-Aspergillus, and cytotoxic activities, providing provisional data on structure-activity relationships. The co-occurrence of the azoxide variants indicates a biogenetic relationship that illustrates new diversification steps in elaiomycin biosynthesis.

Development and Implementation of the AIDA International Registry for Patients With Still's Disease.

Objective: Aim of this paper is to present the design, construction, and modalities of dissemination of the AutoInflammatory Disease Alliance (AIDA) International Registry for patients with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD), which are the pediatric and adult forms of the same autoinflammatory disorder. Methods: This Registry is a clinical, physician-driven, population- and electronic-based instrument implemented for the retrospective and prospective collection of real-world data. The collection of data is based on the Research Electronic Data Capture (REDCap) tool and is intended to obtain evidence drawn from routine patients' management. The collection of standardized data is thought to bring knowledge about real-life clinical research and potentially communicate with other existing and future Registries dedicated to Still's disease. Moreover, it has been conceived to be flexible enough to easily change according to future scientific acquisitions. Results: Starting from June 30th to February 7th, 2022, 110 Centers from 23 Countries in 4 continents have been involved. Fifty-four of these have already obtained the approval from their local Ethics Committees. Currently, the platform counts 290 users (111 Principal Investigators, 175 Site Investigators, 2 Lead Investigators, and 2 data managers). The Registry collects baseline and follow-up data using 4449 fields organized into 14 instruments, including patient's demographics, history, clinical manifestations and symptoms, trigger/risk factors, therapies and healthcare access. Conclusions: This international Registry for patients with Still's disease will allow a robust clinical research through collection of standardized data, international consultation, dissemination of knowledge, and implementation of observational studies based on wide cohorts of patients followed-up for very long periods. Solid evidence drawn from "real-life" data represents the ultimate goal of this Registry, which has been implemented to significantly improve the overall management of patients with Still's disease. NCT05200715 available at https://clinicaltrials.gov/.

Development and Implementation of the AIDA International Registry for Patients With VEXAS Syndrome.

Objective: The aim of this paper is to present the AutoInflammatory Disease Alliance (AIDA) international Registry dedicated to Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome, describing its design, construction, and modalities of dissemination. Methods: This Registry is a clinical, physician-driven, population- and electronic-based instrument designed for the retrospective and prospective collection of real-life data. Data gathering is based on the Research Electronic Data Capture (REDCap) tool and is intended to obtain real-world evidence for daily patients' management. The Registry may potentially communicate with other on-line tools dedicated to VEXAS syndrome, thus enhancing international collaboration and data sharing for research purposes. The Registry is practical enough to be easily modified to meet future needs regarding VEXAS syndrome. Results: To date (April 22nd, 2022), 113 Centers from 23 Countries in 4 continents have been involved; 324 users (114 Principal Investigators, 205 Site Investigators, 2 Lead Investigators, and 3 data managers) are currently able to access the registry for data entry (or data sharing) and collection. The Registry includes 4,952 fields organized into 18 instruments designed to fully describe patient's details about demographics, clinical manifestations, symptoms, histologic details about skin and bone marrow biopsies and aspirate, laboratory features, complications, comorbidities, therapies, and healthcare access. Conclusion: This international Registry for patients with VEXAS syndrome will allow the achievement of a comprehensive knowledge about this new disease, with the final goal to obtain real-world evidence for daily clinical practice, especially in relation to the comprehension of this disease about the natural history and the possible therapeutic approaches. This Project can be found on https://clinicaltrials.gov NCT05200715.

Long-term Outcome of Children Born to Women with Autoimmune Rheumatic Diseases: A Multicentre, Nationwide Study on 299 Randomly Selected Individuals.

The concern about the offspring's health is one of the reasons for a reduced family size of women with rheumatic diseases (RD). Increased risk of autoimmune diseases (AD) and neurodevelopmental disorders (ND) has been reported in children born to patients with RD. Within a nationwide survey about reproductive issues of women with RD, we aimed at exploring the long-term outcome of their children. By surveying 398 patients who received their diagnosis of RD during childbearing age (before the age of 45), information about the offspring were obtained from 230 women who declared to have had children. A total of 148 (64.3%) patients were affected by connective tissue diseases (CTD) and 82 (35.7%) by chronic arthritis. Data on 299 children (156 males, 52.1%; mean age at the time of interview 17.1 ± 9.7 years) were collected. Twelve children (4.0%), who were born to patients with CTD in 75% of the cases, were affected by AD (8 cases of celiac disease). Eleven children had a certified diagnosis of ND (3.6%; 6 cases of learning disabilities); 9 of them were born to mothers with CTD (5 after maternal diagnosis). No association was found between ND and prenatal exposure to either maternal autoantibodies or anti-rheumatic drugs. Absolute numbers of offspring affected by AD and ND were low in a multicentre cohort of Italian women with RD. This information can be helpful for the counselling about reproductive issues, as the health outcomes of the offspring might not be an issue which discourage women with RD from having children.

Development and implementation of the AIDA International Registry for patients with Behçet's disease.

Purpose of the present paper is to point out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to pediatric and adult patients with Behçet's disease (BD). The Registry is a clinical physician-driven non-population- and electronic-based instrument implemented for the retrospective and prospective collection of real-life data about demographics, clinical, therapeutic, laboratory, instrumental and socioeconomic information from BD patients; the Registry is based on the Research Electronic Data Capture (REDCap) tool, which is thought to collect standardised information for clinical real-life research, and has been realised to change over time according to future scientific acquisitions and potentially communicate with other existing and future Registries dedicated to BD. Starting from January 31st, 2021, to February 7th, 2022, 110 centres from 23 countries in 4 continents have been involved. Fifty-four of these have already obtained the approval from their local Ethics Committees. Currently, the platform counts 290 users (111 Principal Investigators, 175 Site Investigators, 2 Lead Investigators, and 2 data managers). The Registry collects baseline and follow-up data using 5993 fields organised into 16 instruments, including patient's demographics, history, clinical manifestations and symptoms, trigger/risk factors, therapies and healthcare access. The development of the AIDA International Registry for BD patients will facilitate the collection of standardised data leading to real-world evidence, enabling international multicentre collaborative research through data sharing, international consultation, dissemination of knowledge, inclusion of patients and families, and ultimately optimisation of scientific efforts and implementation of standardised care.Trial registration NCT05200715 in 21/01/2022.

Efficacy and safety of tocilizumab in adult-onset Still's disease: Real-life experience from the international AIDA registry.

BACKGROUND/OBJECTIVES: Long-term efficacy and safety of tocilizumab (TCZ) in adult-onset Still's disease (AOSD) mostly derive from small case series. Herein we report a registry-based study investigating TCZ efficacy and safety in a cohort of patients with AOSD evaluated by clinical and serum inflammatory markers as well as drug retention rate analysis. METHODS: This is an international multicentre study analyzing data from patients with AOSD regularly enrolled in the AIDA registry. TCZ efficacy was evaluated between baseline and last follow-up assessment in terms of changes in the Pouchot score and laboratory findings. Drug-retention rate was estimated by the Kaplan-Meier method, while Cox-regression analysis was employed to detect potential predictive factors of treatment withdrawal. RESULTS: Data from 31 patients (15 men, 16 women) refractory to the conventional therapies and treated with TCZ were extracted from the AIDA registry. Mean ± SD time of treatment duration with TCZ was 24.32 ± 20.57 months. Median (IRQ) Pouchot score significantly decreased throughout the study period (p=0.001) with a significant difference between baseline [2.00 (4.00)] and 6 month-follow-up [0.00 (0.00)] (p=0.003) and between baseline and last follow-up assessment [0.00 (0.00)] (p=0.032), while no differences were observed between 6 month-evaluation and last follow-up assessment (p=0.823). Similarly, laboratory parameters significantly decreased from baseline to the last follow-up visit. With regard to drug survival, cumulative TCZ retention rate at 12-, 24-, and 36-month follow-up visit were 83.1%, 71.7% and 63.7%, respectively, without significant differences between biologic naïve patients and those previously treated with other biologics (p=0.329). Likewise, no significant differences were observed between chronic articular course of AOSD and other types of disease course (p=0.938) or between patients co-administered with conventional immunosuppressants and patients receiving TCZ as monotherapy (p=0.778). Cox-regression analysis identified no variable associated with a higher hazard of treatment withdrawal. Treatment was discontinued in 9 patients due to long-term remission (n=4), adverse events (n=2), loss of efficacy (n=1), non-medical reason (n=1) and unspecified cause (n=1). Mean glucocorticosteroids daily dose significantly decreased from baseline (18.36 ± 24.72 mg) to the last follow-up assessment (4.02 ± 4.99 mg, p=0.003). CONCLUSIONS: TCZ allows control of disease activity as well as normalization of serum inflammatory markers in both systemic and chronic articular form of AOSD. Additionally, TCZ displays an excellent drug retention rate while minimizing the risk of long-term exposure to corticosteroids.

Histone deacetylase inhibitor MGCD0103 synergizes with gemcitabine in human pancreatic cells.

Histone deacetylase inhibitors are a group of recently developed compounds that modulate cell growth and survival. We evaluated the effects of the histone deacetylase inhibitor MGCD0103 on growth of pancreatic carcinoma models following single agent treatment and in combination with gemcitabine. MGCD0103 inhibited tumor cell growth and acted synergistically with gemcitabine to enhance its cytotoxic effects. Gene expression analysis identified the cell cycle pathway as one of the most highly modulated gene groups. Our data suggest that MGCD0103 + gemcitabine might be an effective treatment for gemcitabine-refractory pancreatic cancer.

Molecular editing and assessment of the cytotoxic properties of iejimalide and progeny.

Systematic variation of all substructures embedded into the framework of iejimalide B (2) led to a panel of synthetic analogues of this polyunsaturated macrolide, featuring structural modifications that are not accessible by derivatization of the natural lead compound itself. The assessment of the cytotoxicity of these compounds with the aid of a monolayer proliferation assay (12 human tumor cell lines in vitro) as well as a colony formation assay (24 human tumor xenografts ex vivo) revealed the exceptional potency of 2 and several of its synthetic congeners, with IC(50) values in the picomolar range for the most sensitive cell lines. Whereas structural modifications of the macrocycle or of the side chain generally lead to a decrease in activity, changes of the peptidic terminus are not only well accommodated but engender increased tumor selectivity as well. 2 and two of the most promising analogues were selected for in vivo studies in mice, in which their activity against human tumor xenografts of breast cancer (MAXF 401) and prostate cancer (PRXF PC-3M) was tested. In contrast to a previous report in the literature however, which had claimed in vivo activity for the parent iejimalides, these tests did not show a significant therapeutic effect against the chosen solid tumors upon intraperitoneal administration.

Hydrazidomycins, cytotoxic alkylhydrazides from Streptomycesatratus.

Three unusual alkyhydrazide natural products, named hydrazidomycin A (1), B (2) and C (3), were isolated from the chloroform extract of a Streptomycesatratus culture, and their structures were elucidated by MS and NMR techniques. Hydrazidomycins A-C exhibited moderate to strong cytotoxic activities in a panel of 42 cell lines, with hydrazidomycin A being the most potent compound (mean IC(50)=0.37 µM).

A family of multicyclic indolosesquiterpenes from a bacterial endophyte.

Three novel indolosesquiterpenes, xiamycin B (1b), indosespene (2), and sespenine (3), along with the known xiamycin A (1a) were isolated from the culture broth of Streptomyces sp. HKI0595, a bacterial endophyte of the widespread mangrove tree Kandelia candel. Agar diffusion assays revealed moderate to strong antimicrobial activities against several bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis, while no cytotoxicity against human tumor cell lines was observed. Together with the previously reported oridamycin, the endophyte metabolites represent the first indolosesquiterpenes isolated from prokaryotes.

Xiamycin, a pentacyclic indolosesquiterpene with selective anti-HIV activity from a bacterial mangrove endophyte.

A novel pentacyclic indolosesquiterpene, named xiamycin (1), and its methyl ester (2) have been obtained from Streptomyces sp. GT2002/1503, an endophyte from the mangrove plant Bruguiera gymnorrhiza. The structures were established by 1D and 2D NMR, MS, and X-ray crystallography, and the absolute configuration of 1 was elucidated by the modified Mosher method. Compound 1 exhibits selective anti-HIV activity; it specifically blocks R5 but has no effects on X4 tropic HIV-1 infection. In a panel of cytotoxicity assays, compound 2 showed to be more potent (geometric mean IC(50)=10.13 µM) compared to compound 1 (geometric mean IC(50) >30 µM), with antitumor potency being generally less pronounced. Xiamycin represents one of the first examples of indolosesquiterpenes isolated from prokaryotes.

Mode of action of epoxyphomalins A and B and characterization of related metabolites from the marine-derived fungus Paraconiothyrium sp.

Epoxyphomalins A (1) and B (2) are highly potent cytotoxic fungal metabolites. During the course of purifying larger quantities of 1 and 2 from Paraconiothyrium sp. fermentation extracts, three new epoxyphomalins (3-5) were isolated and characterized, showing modifications to the oxidation pattern of the cyclohexene moiety or of C-9 of the decalin system. IC(50) values for cytotoxicity against a panel of 36 human tumor cell lines were determined for all new compounds. Compound 4 was found to be cytotoxic particularly toward prostate PC3M (IC(50) = 0.72 µM) and bladder BXF 1218 L (IC(50) = 1.43 µM) cancer cell lines. In addition, inhibition of chymotrypsin-, caspase-, and trypsin-like activity of purified 20S proteasomes was determined for epoxyphomalins A (1) and B (2). The results indicate that compounds 1 and 2 exert their cytotoxic effect through potent inhibition of the 20S proteasome.