19 research outputs found
The "Click-tail approach" for the design and synthesis of novel carbonic anhydrase inhibitors
The Carbonic Anhydrases (CAs) are a family of zinc enzymes deputed to the interconversion of carbonic dioxide to hydrogen carbonate. Herein, we report on a sustainable modular strategy, also called "clicktail approach", used to obtain two series of 4-(4-substituted-lH-l,2,3-triazol-lyl) benzenesulfonamides. Design and synthesis strategies, x-ray derived CA-ligand binding mode and enzyme-based inhibition results will be presented
Galectin-3: An early predictive biomarker of modulation of airway remodeling in patients with severe asthma treated with omalizumab for 36 months
Background: Bronchial asthma is a heterogeneous disease characterized by three cardinal features: chronic inflammation, variable airflow obstruction, and airway hyperresponsiveness. Asthma has traditionally been defined using nonspecific clinical and physiologic variables that encompass multiple phenotypes and are treated with nonspecific anti-inflammatory therapies. Based on the modulation of airway remodeling after 12 months of anti-immunoglobulin E (IgE) treatment, we identified two phenotypes (omalizumab responder, OR; and non-omalizumab responder, NOR) and performed morphometric analysis of bronchial biopsy specimens. We also found that these two phenotypes were correlated with the presence/absence of galectin-3 (Gal-3) at baseline (i.e., before treatment). The aims of the present study were to investigate the histological and molecular effects of long-term treatment (36 months) with anti-IgE and to analyze the behavior of OR and NOR patients. Methods: All patients were treated with the monoclonal antibody anti-IgE omalizumab for 36 months. The bronchial biopsy specimens were evaluated using morphometric, eosinophilic, and proteomic analysis (MudPIT). New data were compared with previous data, and unsupervised cluster analysis of protein profiles was performed. Results: After 36 months of treatment with omalizumab, reduction of reticular basement membrane (RBM) thickness was confirmed in OR patients (Gal-3-positive at baseline); similarly, the protein profiles (over 500 proteins identified) revealed that, in the OR group, levels of proteins specifically related to fibrosis and inflammation (e.g., smooth muscle and extracellular matrix proteins (including periostin), Gal-3, and keratins decreased by between 5- and 50-fold. Eosinophil levels were consistent with molecular data and decreased by about tenfold less in ORs and increased by twofold to tenfold more in NORs. This tendency was confirmed (p < 0.05) based on both fold change and DAVE algorithms, thus indicating a clear response to anti-IgE treatment in Gal-3-positive patients. Conclusions: Our results showed that omalizumab can be considered a disease-modifying treatment in OR. The proteomic signatures confirmed the presence of Gal-3 at baseline to be a biomarker of long-term reduction in bronchial RBM thickness, eosinophilic inflammation, and muscular and fibrotic components in omalizumab-treated patients with severe asthma. Our findings suggest a possible relationship between Gal-3 positivity and improved pulmonary function
Severe Asthma Standard-of-Care Background Medication Reduction With Benralizumab: ANDHI in Practice Substudy
Background: The phase IIIb, randomized, parallel-group, placebo-controlled ANDHI double-blind (DB) study extended understanding of the efficacy of benralizumab for patients with severe eosinophilic asthma. Patients from ANDHI DB could join the 56-week ANDHI in Practice (IP) single-arm, open-label extension substudy. Objective: Assess potential for standard-of-care background medication reductions while maintaining asthma control with benralizumab. Methods: Following ANDHI DB completion, eligible adults were enrolled in ANDHI IP. After an 8-week run-in with benralizumab, there were 5 visits to potentially reduce background asthma medications for patients achieving and maintaining protocol-defined asthma control with benralizumab. Main outcome measures for non-oral corticosteroid (OCS)-dependent patients were the proportions with at least 1 background medication reduction (ie, lower inhaled corticosteroid dose, background medication discontinuation) and the number of adapted Global Initiative for Asthma (GINA) step reductions at end of treatment (EOT). Main outcomes for OCS-dependent patients were reductions in daily OCS dosage and proportion achieving OCS dosage of 5 mg or lower at EOT. Results: For non-OCS-dependent patients, 53.3% (n = 208 of 390) achieved at least 1 background medication reduction, increasing to 72.6% (n = 130 of 179) for patients who maintained protocol-defined asthma control at EOT. A total of 41.9% (n = 163 of 389) achieved at least 1 adapted GINA step reduction, increasing to 61.8% (n = 110 of 178) for patients with protocol-defined EOT asthma control. At ANDHI IP baseline, OCS dosages were 5 mg or lower for 40.4% (n = 40 of 99) of OCS-dependent patients. Of OCS-dependent patients, 50.5% (n = 50 of 99) eliminated OCS and 74.7% (n = 74 of 99) achieved dosages of 5 mg or lower at EOT. Conclusions: These findings demonstrate benralizumab's ability to improve asthma control, thereby allowing background medication reduction
How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons
COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p < 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p < 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p < 0.0001) or urgent (20.4% vs. 38.5%; p < 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p < 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice
Omalizumab modulates bronchial reticular basement membrane thickness and eosinophil infiltration in severe persistent allergic asthma patients.
Anal mycobacterial infectionsâ€
Background: Mycobacterial infections are a serious public health problem worldwide. Involvement of the anal canal and perineum is very rare, but constitute an important differential diagnosis with other equally serious pathologies that may affect the region, such as malignant neoplasms and Crohn’s disease. Objectives: To conduct a literature review on mycobacterial infections of the perianal region considering the most recent information for diagnostic and therapeutic guidance of this disease. Methods: Research was performed on the PUBMED and LILACS databases with the expressions Mycobacterium, Anal, Infection and Tuberculosis. We reviewed articles referring to series of treated cases, clinical reports and literature review published since 2005. Results: Information was compiled on the epidemiology of mycobacterial infections; the clinical behavior of affected individuals; diagnostic options and their validity in clinical practice; and, finally, therapeutic options. Conclusions: Mycobacterial infections of the anus and perineum are rare. The most common clinical presentations are the presence of ulceration and fistulization. The diagnosis involves more than one procedure for identifying the bacilli and should consider the presence of manifestations in more than one organ. The treatment is based on pharmacological intervention. Surgery is recommended for acute complications or chronic sequelae of the disease. Resumo: Introdução: Infecções micobacterianas constituem um grave problema de saĂşde pĂşblica a nĂvel mundial. As manifestações anoperineais sĂŁo raras, mas constituem um importante diagnĂłstico diferencial com outras patologias igualmente graves que podem acometer a regiĂŁo, como as neoplasias malignas e a doença de Crohn. Objetivos: Realizar um levantamento da literatura sobre infecções micobacterianas da regiĂŁo anoperineal, considerando as informações mais atuais para orientação diagnĂłstica e terapĂŞutica dessa enfermidade. MĂ©todos: Foi realizada pesquisa nos bancos de dados PUBMED e LILACS com as expressões Mycobacterium, Anal, Infection e Tuberculosis. Foram revisados artigos referentes a sĂ©ries de casos tratados, relatos clĂnicos e revisĂŁo da literatura publicada a partir de 2005. Resultados: Foram compiladas informações sobre a epidemiologia das infecções micobacterianas; o comportamento clĂnico dos indivĂduos afetados; opções diagnĂłsticas e sua validade na prática clĂnica; e, por fim, opções terapĂŞuticas. Conclusões: Infecções micobacterianas da regiĂŁo anoperineal sĂŁo raras. As apresentações clĂnicas mais comuns sĂŁo a formação de ulceras e a fistulização. O diagnĂłstico envolve mais de um procedimento para identificação dos bacilos, e deve considerar a presença de manifestações em mais de um ĂłrgĂŁo. O tratamento Ă© principalmente medicamentoso, sendo a cirurgia recomendada nas complicações agudas ou sequelas crĂ´nicas da doença. Keywords: Mycobacterial infections, Tuberculosis, Anal canal, Fistula in ano, Palavras-chave: Infecções por micobactĂ©ria, Tuberculose, Canal anal, FĂstula ana
Carbonic Anhydrase Inhibition with Benzenesulfonamides and Tetrafluorobenzenesulfonamides Obtained via Click Chemistry
A series
of novel benzene- and 2,3,5,6-tetrafluorobenzenesulfonamide was synthesized
by using a click chemistry approach starting from azido-substituted
sulfonamides and alkynes, incorporating aryl, alkyl, cycloalkyl, and
amino-/hydroxy-/halogenoalkyl moieties. The new compounds were medium
potency inhibitors of the cytosolic carbonic anhydrase (CA, EC 4.2.1.1)
isoforms I and II and low nanomolar/subnanomolar inhibitors of the
tumor-associated hCA IX and XII isoforms. The X-ray crystal structure
of two such sulfonamides in adduct with hCA II allowed us to understand
the factors governing inhibitory power
Clinical and Functional Characteristics of COPD Patients Across GOLD Classifications: Results of a Multicenter Observational Study
Exacerbation Burden in COPD and Occurrence of Mortality in a Cohort of Italian Patients: Results of the Gulp Study
Objective: To describe the burden of moderate to severe exacerbations and all-cause mortality; the secondary objectives were to analyze treatment patterns and changes over follow-up.
Design: Observational, multicenter, retrospective, cohort study with a three year follow-up period.
Setting: Ten Italian academic secondary- and tertiary-care centers.
Participants: Patients with a confirmed diagnosis of COPD referring to the outpatient clinics of the participating centers were retrospectively recruited.
Primary and secondary outcome measures: Annualized frequency of moderate and severe exacerbations stratified by exacerbation history prior to study enrollment. Patients were classified according to airflow obstruction, GOLD risk categories, and divided in 4 groups: A = no exacerbations; B = 1 moderate exacerbation; C = 1 severe exacerbation; D = ≥2 moderate and/or severe exacerbations. Overall all-cause mortality stratified by age, COPD category, and COPD therapy. A logistic regression model assessed the association of clinical characteristics with mortality.
Results: 1111 patients were included (73% males), of which 41.5% had a history of exacerbations. As expected, the proportion of patients experiencing ≥1 exacerbation during follow-up increased according to pre-defined study risk categories (B: 79%, C: 84%, D: 97.4%). Overall, by the end of follow-up, 45.5% of patients without a history of exacerbation experienced an exacerbation (31% of which severe), and 13% died. Deceased patients were significantly older, more obstructed and hyperinflated, and more frequently active smokers compared with survivors. Severe exacerbations were more frequent in patients that died (23.5%, vs 10.2%; p-value: 0.002). Chronic heart failure and ischemic heart disease were the only comorbidities associated with a higher odds ratio (OR) for death (OR: 2.2, p-value: 0.001; and OR: 1.9, p-value: 0.007). Treatment patterns were similar in patients that died and survivors.
Conclusion: Patients with a low exacerbation risk are exposed to a significant future risk of moderate/severe exacerbations. Real life data confirm the strong association between mortality and cardiovascular comorbidities in COPD
MOESM5 of Galectin-3: an early predictive biomarker of modulation of airway remodeling in patients with severe asthma treated with omalizumab for 36Ă‚Â months
Additional file 5. Changes of abundance levels, expressed as natural logarithm of score fold change (ln[T36/T0]), for Gal-3 in OR and NOR patients at baseline (T0) and after 36 months (T36) of anti-IgE treatment. Negative value indicates decrease of Gal-3 at T36; on the contrary, positive value indicates increase of Gal-3 at T36 (see Additional file 1). OR and NOR classification is related to reduction (OR) or not (NOR) of RBM thickness after 12 months of anti-IgE treatment