5 results on '"Leandro L. Santos"'
Search Results
2. Modulation of Disease-Associated Pathways in Hidradenitis Suppurativa by the Janus Kinase 1 Inhibitor Povorcitinib: Transcriptomic and Proteomic Analyses of Two Phase 2 Studies
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Huiqing Liu, Leandro L. Santos, and Susan H. Smith
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Inorganic Chemistry ,hidradenitis suppurativa ,inflammatory skin diseases ,proteomics ,transcription ,INCB054707 ,JAK1 ,povorcitinib ,Organic Chemistry ,General Medicine ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Catalysis ,Computer Science Applications - Abstract
Janus kinase (JAK)/signal transducer and activator of transcription signaling (STAT) has been implicated in the pathophysiology of hidradenitis suppurativa (HS). This study evaluated treatment-related transcriptomic and proteomic changes in patients with moderate-to-severe HS treated with the investigational oral JAK1-selective inhibitor povorcitinib (INCB054707) in two phase 2 trials. Lesional skin punch biopsies (baseline and Week 8) were taken from active HS lesions of patients receiving povorcitinib (15 or 30 mg) once daily (QD) or a placebo. RNA-seq and gene set enrichment analyses were used to evaluate the effects of povorcitinib on differential gene expression among previously reported gene signatures from HS and wounded skin. The number of differentially expressed genes was the greatest in the 30 mg povorcitinib QD dose group, consistent with the published efficacy results. Notably, the genes impacted reflected JAK/STAT signaling transcripts downstream of TNF-α signaling, or those regulated by TGF-β. Proteomic analyses were conducted on blood samples obtained at baseline and Weeks 4 and 8 from patients receiving povorcitinib (15, 30, 60, or 90 mg) QD or placebo. Povorcitinib was associated with transcriptomic downregulation of multiple HS and inflammatory signaling markers as well as the reversal of gene expression previously associated with HS lesional and wounded skin. Povorcitinib also demonstrated dose-dependent modulation of several proteins implicated in HS pathophysiology, with changes observed by Week 4. The reversal of HS lesional gene signatures and rapid, dose-dependent protein regulation highlight the potential of JAK1 inhibition to modulate underlying disease pathology in HS. more...
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- 2023
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Catalog
3. Janus kinase 1 inhibitor INCB054707 for patients with moderate-to-severe hidradenitis suppurativa: results from two phase II studies
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Afsaneh Alavi, Iltefat Hamzavi, Kurt Brown, Leandro L. Santos, Zhaoyin Zhu, Huiqing Liu, Michael D. Howell, and Joslyn S. Kirby
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Adult ,Adolescent ,Dermatology ,Janus Kinase 1 ,Middle Aged ,Severity of Illness Index ,Hidradenitis Suppurativa ,Young Adult ,Clinical Trials, Phase II as Topic ,Treatment Outcome ,Double-Blind Method ,Humans ,Janus Kinase Inhibitors ,Multicenter Studies as Topic ,Aged ,Randomized Controlled Trials as Topic - Abstract
Janus kinase (JAK)-mediated cytokine signalling contributes to local and systemic inflammation in hidradenitis suppurativa (HS).To describe the safety and efficacy results from two multicentre phase II trials of the JAK1 inhibitor INCB054707 in patients with moderate-to-severe HS.Patients received open-label INCB054707 15 mg once daily (QD; Study 1) or were randomized to INCB054707 30, 60 or 90 mg QD or placebo (3 : 1 within each cohort; Study 2) for 8 weeks. Eligible patients were aged 18-75 years and had moderate-to-severe HS (Hurley stage II/III disease), lesions present in at least two anatomical locations, and a total abscess and inflammatory nodule count ≥ 3. The primary endpoint for both studies was safety and tolerability. Secondary endpoints included HS Clinical Response (HiSCR) and other efficacy measures.Ten patients were enrolled in Study 1 (15 mg INCB054707) and 35 in Study 2 (INCB054707: 30 mg, n = 9; 60 mg, n = 9; 90 mg, n = 8; placebo, n = 9). Overall, 70% of patients in Study 1 and 81% of patients receiving INCB054707 in Study 2 experienced at least one treatment-emergent adverse event; 30% and 42% of patients, respectively, had at least one treatment-related adverse event. Among the evaluable patients, three (43%) in Study 1 and 17 (65% overall: 30 mg, 56%; 60 mg, 56%; 90 mg, 88%) receiving INCB054707 vs. 4 patients (57%) receiving placebo in Study 2 achieved HiSCR at week 8.INCB054707 was well tolerated, with responses observed in patients with moderate-to-severe HS. The safety and efficacy findings from these studies demonstrate proof of concept for JAK1 inhibition in HS. The studies are registered on ClinicalTrials.gov (NCT03569371 and NCT03607487). more...
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- 2021
4. Expression of Endothelin-1, Endothelin Receptor-A, and Endothelin Receptor-B in facial melasma compared to adjacent skin.
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da Silva CN, Miot HA, Grassi TF, Dias-Melício LA, Santos L, and Espósito ACC
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Background/objectives: Although melasma is highly prevalent, its pathogenesis is not yet fully understood. In the skin, endothelin-1 (ET-1) is primarily produced by keratinocytes in response to UVB exposure, which is mediated by an increase in IL-1α or reactive oxygen species. ET-1 plays a role in melanogenesis by binding to specific receptor B (ERB) or receptor A (ERA). However, the expression of ET-1, ERA, and ERB in melasma has not been systematically investigated. The objective of this study was to evaluate the expression of ET-1, ERA, and ERB in facial melasma compared to the adjacent unaffected skin., Methods: Cross-sectional study, with 40 skin samples (20: facial melasma; 20: adjacent unaffected skin) from women with facial melasma without treatment for 30 days except for sunscreen. A triple staining immunofluorescence technique was performed for anti-vimentin, DAPI, plus one of the following antibodies: (a) anti-ET1, (b) anti-ERA; (c) anti-ERB. Interfollicular areas on the slides of each topography (melasma; unaffected skin) were photographed in triplicate under confocal laser microscopy. The mean staining intensities of the image histograms (0-255 pixels intensity) were estimated for different types of cells (suprabasal keratinocytes, basal layer, and upper dermis) and were blindly compared between topographies., Results: The mean (SD) age of the participants was 44.9 (9.2). The expression of ET-1 was increased in the whole epidermis with melasma when compared to the adjacent skin, being 32.8% (CI95% 14.7%-52.6%) higher in the spinous layer (p=0.013), 30.4% (CI95% 13.7%-47.9%) higher in the basal layer (p=0.014), and 29.7% (CI95% 11.4%-49.7%) higher in the melanocytes (p=0.006). There was no noticeable expression of ET-1 within the cells on the upper dermis. Neither ERA nor ERB resulted in differential epidermal expression between melasma and unaffected skin (p≥0.1)., Conclusion: ET-1 is expressed more intensely on the epidermis from the skin with facial melasma compared to the unaffected adjacent skin., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 da Silva et al.) more...
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- 2023
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5. Effect of resistance training on bioelectrical phase angle in older adults: a systematic review with Meta-analysis of randomized controlled trials.
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Campa F, Colognesi LA, Moro T, Paoli A, Casolo A, Santos L, Correia RR, Lemes ÍR, Milanez VF, Christofaro DD, Cyrino ES, and Gobbo LA
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- Humans, Aged, Electric Impedance, Randomized Controlled Trials as Topic, Aging, Body Composition, Resistance Training
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Resistance training has been proposed as a valid practice to counteract the aging effect on body mass and its components, which can be easily evaluated though the bioelectrical impedance analysis. This study aimed to achieve a systematic review with meta-analysis on the impact of resistance training on bioelectrical proprieties in older adults.A literature review was done in four electronic databases up to 1 January 2022. The inclusion criteria were: (i) participants aged ≥ 60 years; (ii) resistance training lasted ≥ 8 weeks; (iii) measurement of raw bioelectrical parameters in randomized controlled study designs.The outcomes of the trial had to be bioelectrical phase angle (PhA), resistance (R), and reactance (Xc). The methodological quality was assessed using the Rosendal scale.Overall, seven studies with a total of 344 participants were eligible for the analysis. The quality assessment yielded a score of 71.3%. Bioelectrical PhA (0.52 degree [95%CI 0.32, 0.71], p < 0.001) and Xc (3.58 ohms [95%CI 1.97, 5.19], p < 0.001) increased, whereas R decreased (-28.50 ohms [95%CI -41.39, -15.60], p < 0.001) after the resistance training programs.In this meta-analysis, resistance training promoted increases of PhA, which result from an increase in Xc concomitant with a reduction in R. According to the bioimpedance vector analysis, resistance-trained people experienced a beneficial leftward vector displacement, whilst inactivity induced a rightward vector displacement within the R-Xc graph. In future, more sophisticated and rigorous studies that address specific criteria, methods and targeted designs are required to identify which equipment and protocols allow for an optimization of the resistance training effects.Registration code in PROSPERO: CRD42020168057., (© 2022. The Author(s).) more...
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- 2023
- Full Text
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