The influence of climatic factors on landslides triggers and displacement rates is a crucial research topic, especially due to the growing need to understand the evolution of climate change in ...historical periods of intense precipitation and anomalous temperature increases. Italy, highly prone to hydrogeological instability, extremely its mountainous regions such as the Alps, stands as a pertinent subject area for instability scenarios. However, the interpretation of climate effects on landslides is still an open issue. This work proposed a simplified methodology for investigating the displacements of three slow-moving landslides located in the Western Alps of Piemonte region, in response to significant meteorological events evaluated from reference normal of precipitation and temperature trends over the reference period 1991–2020. Another purpose is to emphasize the advantages of using different monitoring techniques by comparing displacement time series measured with
in situ
and remote sensing instruments, to detect ground deformation processes of these gravitational phenomena. The existence of a robust monitoring network, coupled with InSAR dataset support, has allowed detecting climatic factors’ impact on displacement rates for the outlined case studies. The results have demonstrated the relationships between the identified climatic events and variations in displacement time series, as well as the potential of integrating field observations and InSAR techniques to improve the interpretation of landslide dynamics. Although this study has laid the basis for understanding the influence of climatic factors on landslide displacements, there is still much to investigate and refine. The proposed preliminary analysis will further improve the ability to predict, monitor and mitigate landslide risk under changing climate conditions.
There is a growing demand for the development of experimental strategies for efficient articular cartilage repair. Current tissue engineering-based regenerative strategies make use of human ...mesenchymal stromal cells (hMSCs). However, when implanted in a cartilage defect, control of hMSCs differentiation toward the chondrogenic lineage remains a significant challenge. We have recently demonstrated that silencing the antichondrogenic regulator microRNA-221 (miR-221) was highly effective in promoting in vitro chondrogenesis of monolayered hMSCs in the absence of the chondrogenic induction factor TGF-β. Here we investigated the feasibility of this approach first in conventional 3D pellet culture and then in an in vivo model. In pellet cultures, we observed that miR-221 silencing was sufficient to drive hMSCs toward chondrogenic differentiation in the absence of TGF-β. In vivo, the potential of miR-221 silenced hMSCs was investigated by first encapsulating the cells in alginate and then by filling a cartilage defect in an osteochondral biopsy. After implanting the biopsy subcutaneously in nude mice, we found that silencing of miR-221 strongly enhanced in vivo cartilage repair compared to the control conditions (untreated hMSCs or alginate-only). Notably, miR-221 silenced hMSCs generated in vivo a cartilaginous tissue with no sign of collagen type X deposition, a marker of undesired hypertrophic maturation. Altogether our data indicate that silencing miR-221 has a prochondrogenic role in vivo, opening new possibilities for the use of hMSCs in cartilage tissue engineering. Stem Cells 2016;34:1801-1811.
Biologic therapy for moderate-to-severe psoriasis with anti-IL-23 and anti-IL-17 does not reduce the humoral and T-cell-mediated immune responses after COVID infection or vaccination; on the ...contrary, anti-IL-23 treatment was associated with a higher level of specific IgG following vaccination. In contrast, conventional therapies and TNF-α blockade reduce the production of specific antibodies.
In this work we present and compare the results of extensive molecular dynamics simulations of model systems comprising an Aβ1–40 peptide in water in interaction with short peptides (β-sheet ...breakers) mimicking the 17–21 region of the Aβ1–40 sequence. Various systems differing in the customized β-sheet breaker structure have been studied. Specifically we have considered three kinds of β-sheet breakers, namely Ac-LPFFD-NH2 and two variants thereof, one obtained by substituting the acetyl group with the sulfonic amino acid taurine (Tau-LPFFD-NH2) and a second novel one in which the aspartic acid is substituted by an asparagine (Ac-LPFFN-NH2). Thioflavin T fluorescence, circular dichroism, and mass spectrometry experiments have been performed indicating that β-sheet breakers are able to inhibit in vitro fibril formation and prevent the β sheet folding of portions of the Aβ1–40 peptide. We show that molecular dynamics simulations and far UV circular dichroism provide consistent evidence that the new Ac-LPFFN-NH2 β-sheet breaker is more effective than the other two in stabilizing the native α-helix structure of Aβ1–40. In agreement with these results thioflavin T fluorescence experiments confirm the higher efficiency in inhibiting Aβ1–40 aggregation. Furthermore, mass spectrometry data and molecular dynamics simulations consistently identified the 17–21 Aβ1–40 portion as the location of the interaction region between peptide and the Ac-LPFFN-NH2 β-sheet breaker.
Background: β-Amyloid aggregates are at the basis of Alzheimer disease development. Short synthetic peptides are seen to inhibit polymerization.
Results: Various synthetic peptides have been studied by MD simulations and tested experimentally.
Conclusion: Combined results indicate Ac-LPFFN-NH2 as an effective lead compound able to slow down Aβ1–40 aggregation.
Significance: Designing potential Aβ aggregation inhibitors will help fight Alzheimer disease.
The autoantigens LL37 and ADAMTSL5 contribute to induce pathogenetic T-cells responses in a subset of psoriatic patients. Whether the presence of LL37-and/or ADAMTS5-reactive T-cells influences the ...clinical response to treatment is still unknown.
The aim of the study is to evaluate the clinical responses to the anti-IL-23 risankizumab in LL37 and/or ADAMTSL5-reactive patients in comparison with non-reactive ones and to assess whether genetics (HLA-Cw06.02) or BMI influences the response to treatment. Patients were screened at baseline for the presence of circulating LL37 or/and ADAMTSL5-reactive T-cells and were treated as per protocol with risankizumab. Effectiveness data (PASI scores) were collected at weeks 4, 16, 28, 40 and 52. Data were also analyzed based on HLA-Cw06.02 status and BMI.
The overall response to treatment of patients with autoreactivity to LL37 or ADAMTSL5 did not differ compared to the non-reactive cohort as measured as PASI75/90/100 at different time points; however, subjects that had autoreactive T-cells to both LL37 and ADAMTS5 demonstrated suboptimal response to treatment starting at week16. HLA-Cw06:02+ patients demonstrated faster response to risankizumab at week 4 compared to HLA-Cw06:02-. Additionally, the response to treatment was influenced by the BMI with slower responses seen in overweight and obese patients at week 4 and week16.
In conclusion, while the presence of either LL37-and ADAMTS5-reactive circulating T-cells do not influence the clinical response to risankizumab, the presence of the double reactivity to both LL37 and ADAMTS5 decreases the clinical responses. Moreover, we evidenced that HLA-Cw06+ respond faster to IL-23 inhibition and that BMI, associated to autoreactivity, can influence the speed in response.
•Single auto-reactivity to either LL37 or ADAMTSL5 does not influence the clinical response to risankizumab.•Double auto-reactivity to both LL37 and ADAMTSL5 is associated with a decrease in the clinical response to risankizumab.•HLA-Cw06+ patients demonstrated to respond faster.•Patients with higher BMI showed slower responses to IL-23 inhibition.
Summary
Background
Understanding genetic variations is important in predicting treatment response and forms the basis for identifying new pharmacogenetic and pharmacogenomic targets for psoriasis ...treatment. There are limited data on the efficacy of secukinumab in relation to genetic markers.
Objectives
To evaluate the efficacy and safety of secukinumab 300 mg in HLA‐Cw6‐positive (Cw6‐POS) and HLA‐Cw6‐negative (Cw6‐NEG) patients with moderate‐to‐severe chronic plaque‐type psoriasis.
Methods
SUPREME was a 24‐week, phase IIIb study with an extension period up to 72 weeks. Primary end point was Psoriasis Area Severity Index (PASI) 90 response rate after 16 weeks.
Results
In total, 434 patients were recruited: 185 (42·6%) were Cw6‐POS and 246 (56·7%) were Cw6‐NEG (three not assessed). Mean ± SD age was 45·2 ± 13·2 years (Cw6‐POS 42·7 ± 13·1; Cw6‐NEG 47·2 ± 12·9). The baseline PASI score was comparable between the cohorts Cw6‐POS 20·7 ± 8·99; Cw6‐NEG 21·5 ± 9·99 (P = 0·777). At week 16, PASI 90 was achieved in 80·4% of Cw6‐POS and 79·7% of Cw6‐NEG patients (difference 0·76; 95% confidence interval −7·04 to 8·23). No differences in absolute PASI at week 16 (Cw6‐POS 1·36 ± 3·58; Cw6‐NEG 1·18 ± 2·29) were observed. The overall safety profile of secukinumab was consistent with that previously reported. No statistically significant difference was detected in the rate of treatment‐emergent adverse events Cw6‐POS 42·7%; Cw6‐NEG 49·6% (P = 0·295). A high PASI 90 response was achieved with secukinumab with a fast reduction in absolute PASI.
Conclusions
Determination of HLA‐Cw6 status for secukinumab therapy is unnecessary, as it is highly effective regardless of HLA‐Cw6 status.
What's already known about this topic?
HLA‐Cw6 is associated with the phenotypic features of psoriasis and positive response to ustekinumab and is present in approximately 40–80% of cases.
Secukinumab is a fully human monoclonal antibody neutralizing interleukin‐17A and it has demonstrated a rapid onset of action and sustained responses with a favourable safety profile in moderate‐to‐severe psoriasis, psoriatic arthritis and ankylosing spondylitis.
What does this study add?
Although HLA‐Cw6‐positive and HLA‐Cw6‐negative patients have distinct clinical features, the present study showed that secukinumab achieved similar clinical responses in both cohorts after 24 weeks of treatment.
There was no difference in efficacy regarding HLA‐Cw6 status.
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The field of cartilage repair has exponentially been growing over the past decade. Here, we discuss the possibility to achieve satisfactory regeneration of articular cartilage by means of human ...mesenchymal stem cells (hMSCs) depleted of anti-chondrogenic factors and implanted in the site of injury. Different types of molecules including transcription factors, transcriptional co-regulators, secreted proteins, and microRNAs have recently been identified as negative modulators of chondroprogenitor differentiation and chondrocyte function. We review the current knowledge about these molecules as potential targets for gene knockdown strategies using RNA interference (RNAi) tools that allow the specific suppression of gene function. The critical issues regarding the optimization of the gene silencing approach as well as the delivery strategies are discussed. We anticipate that further development of these techniques will lead to the generation of implantable hMSCs with enhanced potential to regenerate articular cartilage damaged by injury, disease, or aging.
Aim: To establish the normal range of frontonasal angle (FNA) at 11+0 to 13+6 weeks of gestation and the feasibility of FNA measurement, evaluate the correlation of such a parameter with crown‐rump ...length (CRL) and nuchal translucency (NT) and assess the potential of FNA in improving the performance of first trimester sonographic and biochemical screening for trisomy 21.
Methods: We conducted a prospective study in 400 singleton uncomplicated pregnancies. FNA was obtained during maternal screening for trisomy 21. NT thickness and FNA were measured by 2D ultrasound in a midsagittal plane of the fetal profile. FNA was measured between the line along the upper surface of the frontal bone and the superior edge of the nasal profile until the echogenic tip. Determination of maternal serum free β‐human chorionic gonadotropin (β‐hCG) and pregnancy‐associated plasma protein‐A (PAPP‐A) was committed and concomitantly evaluated by blood sample. Patient‐specific risk was calculated using Fetal Medicine Foundation software (Astraia Software GMBH, Munich, Germany).
Results: Mean FNA increased with CRL from 119.80° at CRL 45 mm to 125.85° at CRL 84 mm. A significant association between the FNA and NT thickness was detected, while no significant association was found between FNA and serum PAPP‐A or β‐hCG.
Conclusion: At 11+0 to 13+6 weeks FNA increases with fetal CRL and NT thickness. Such an increase is not related to serum biochemistry.
Dataset related to article "The impact of biologic therapy for moderate-to-severe psoriasis on the immune responses to SARS-CoV-2 infection and vaccination"
In our study we explored the impact of ...biologics and conventional therapies on humoral and T-cellular responses to SARS-CoV-2 infection and vaccine, comparing the results with the healthy donors’ immune responses. The main findings of our study are that while biologic therapy for moderate-to-severe psoriasis with anti-IL23 and IL-17 has no significant effect on the humoral and T-cell mediated immune response; in contrast, conventional therapies and TNF-a blockade reduce the production of specific antibodies. Moreover, our results suggest that treatment with anti-IL-23 can enhance anti-covid responses induced by the vaccine since we found higher antibody levels in vaccinated patients treated with IL-23 inhibitors with an effect on follicular T helper cells.
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