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Abstract Introduction The introduction of biological therapies has revolutionized the treatment of moderate-to-severe plaque psoriasis. In particular, ixekizumab, an inhibitor of interleukin-17A, has shown great results in terms of efficacy and safety in both clinical trials and real-world experiences. However, there is a lack of long-term real-world data available for ixekizumab. Methods We conducted a multicenter real-life study to evaluate the effectiveness and safety of ixekizumab in patients with moderate-to-severe plaque psoriasis. Psoriasis Area and Severity Index score (PASI) was collected at baseline and after 1, 2, 3, 4, and 5 years. The occurrence of any adverse events was recorded at each time point. Results We enrolled 1096 patients treated with ixekizumab for at least 1 year. At week 52, the percentages of PASI 90 and PASI 100 were 85.04% and 69.07%, respectively. After 5 years of treatment with ixekizumab, out of 145 patients, a PASI 90 response was achieved by 86.90% of patients, while complete skin clearance was reached by 68.28% of patients. We did not observe any new significant safety findings throughout the study period. Conclusion This study supports the long-term effectiveness and safety of ixekizumab in a real-world setting.

Abstract Background The DNA-dependent protein kinase (DNA-PK) complex comprises a catalytic (PRKDC) and two requisite DNA-binding (Ku70/Ku80) subunits. The role of the complex in repairing double-stranded DNA breaks (DSBs) is established, but its role in inflammation, as a complex or individual subunits, remains elusive. While only ~ 1% of PRKDC is necessary for DNA repair, we reported that partial inhibition blocks asthma in mice without causing SCID. Methods We investigated the central role of PRKDC in inflammation and its potential association with DNA repair. We also elucidated the relationship between inflammatory cytokines (e.g., TNF-α) and PRKDC by analyzing its connections to inflammatory kinases. Human cell lines, primary human endothelial cells, and mouse fibroblasts were used to conduct the in vitro studies. For animal studies, LPS- and oxazolone-induced mouse models of acute lung injury (ALI) and delayed-type hypersensitivity (DHT) were used. Wild-type, PRKDC+/−, or Ku70+/− mice used in this study. Results A ~ 50% reduction in PRKDC markedly blocked TNF-α-induced expression of inflammatory factors (e.g., ICAM-1/VCAM-1). PRKDC regulates Th1-mediated inflammation, such as DHT and ALI, and its role is highly sensitive to inhibition achieved by gene heterozygosity or pharmacologically. In endothelial or epithelial cells, TNF-α promoted rapid PRKDC phosphorylation in a fashion resembling that induced by, but independent of, DSBs. Ku70 heterozygosity exerted little to no effect on ALI in mice, and whatever effect it had was associated with a specific increase in MCP-1 in the lungs and systemically. While Ku70 knockout blocked VP-16-induced PRKDC phosphorylation, it did not prevent TNF-α − induced phosphorylation of the kinase, suggesting Ku70 dispensability. Immunoprecipitation studies revealed that PRKDC transiently interacts with p38MAPK. Inhibition of p38MAPK blocked TNF-α-induced PRKDC phosphorylation. Direct phosphorylation of PRKDC by p38MAPK was demonstrated using a cell-free system. Conclusions This study presents compelling evidence that PRKDC functions independently of the DNA-PK complex, emphasizing its central role in Th1-mediated inflammation. The distinct functionality of PRKDC as an individual enzyme, its remarkable sensitivity to inhibition, and its phosphorylation by p38MAPK offer promising therapeutic opportunities to mitigate inflammation while sparing DNA repair processes. These findings expand our understanding of PRKDC biology and open new avenues for targeted anti-inflammatory interventions.

The alluvial aquifer of the transnational Roya River watershed is an important water resource for drinking water supply. Through successive European projects, a monitoring network has been implemented over the alluvial plain to improve the understanding of the functioning of this aquifer. For instance, studies highlighted the predominant role of surface water in the recharge of the aquifer. Following the storm Alex and the resulting exceptional flood event in the Roya valley in October 2020, a general decrease of the piezometric levels was observed in the alluvial aquifer. Changes in the river morphology and in the granulometry of the hyporheic zone have impacted surface water – groundwater exchanges and reduced the aquifer recharge.

BackgroundMalnutrition, defined as weight loss and unsatisfactory nutrient intake, is very common in patients with head and neck squamous cell carcinoma (HNSCC) in either the early or palliative setting. Despite increased awareness, nutritional programs are not yet adequately implemented in these patients. There are several reasons for this delay: differences in composition, the expertise of the multidisciplinary teams involved in HNSCC patients’ treatment, and economic and network resources conditioning faster or slower nutritional supply delivery. This situation affects the outcomes and the quality of life of HNSCC patients.Materials and methodsWe investigated available literature about nutritional support in HNSCC patients and its impact on outcomes, prognosis, and quality of life, and we focused on the role of the multidisciplinary team. We considered 8,491 articles, and after excluding duplicates and manuscripts not written in English, 1,055 were analyzed and 73 were deemed eligible for the present work.ResultsAfter the literature review, we can state that malnutrition, sarcopenia, and cachexia are associated with systemic inflammation and closely correlated with poor outcomes. An evaluation of the nutritional status of the multidisciplinary team before, during, and after therapy could improve patient outcomes, as the goal of the therapeutic approach is widely designed.ConclusionsWe suggest that the treatment workflow definition is fundamental and propose a tailored nutritional approach that could benefit HNSCC patients’ outcomes and quality of life. These results could be achieved by a multidisciplinary team.

Abstract Introduction Several systemic therapies have been approved for the treatment of severe AD. In particular, Janus kinase inhibitors (JAKi), including abrocitinib, baricitinib, and upadacitinib, recently received approval for the treatment of patients with severe AD after being evaluated in several clinical trials. However, a few concerns have been raised regarding their long-term safety and the management of these drugs in real-world clinical practice. In this article we described the results of a Delphi consensus aimed at describing the knowledge on JAKi and focusing, in particular, on providing clinical recommendations for dermatologists in daily practice regarding the use of these drugs. Methods Twelve Italian dermatologists reviewed the most recent literature regarding the efficacy and safety profiles of JAKi and proposed 24 statements. Results Agreement was reached for statements focusing on three main topics: (1) place in therapy of JAKi in patients with moderate-to-severe AD; (2) effectiveness and safety of JAK inhibitors in different phenotypes; (3) different approaches to the management of patients treated with JAKi in clinical practice. The panel proposed several recommendations regarding all the statements. Conclusion Given the wide use of JAKi in clinical practice, it is crucial to establish a specific follow-up for each patient’s phenotype in order to achieve the best possible clinical outcome and minimize potential adverse events.

Luciano Ibba,1,2 Luigi Gargiulo,1,2 Carlo Alberto Vignoli,1,2 Giovanni Fiorillo,1,2 Mario Valenti,1,2 Antonio Costanzo,1,2 Alessandra Narcisi1 1Dermatology Unit, IRCCS Humanitas Research Hospital, Milan, Italy; 2Department of Biomedical Sciences, Humanitas University, Milan, ItalyCorrespondence: Luciano Ibba, Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, 20089, Italy, Email luciano.ibba@humanitas.itAbstract: Upadacitinib is a selective Janus kinase inhibitor approved for the treatment of severe atopic dermatitis (AD). This systematic review aims to summarize the most recent data in terms of effectiveness and safety of upadacitinib in the treatment of severe AD in a real-world setting. The review included a comprehensive search of databases, including PubMed, Google Scholar and Web of Science, according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The literature search initially identified 242 studies. Of these, 214 were excluded after reviewing their titles and abstracts. We then conducted a full-text review of 25 studies, of which 17 met our inclusion criteria and were therefore included in our systematic review. The analysis of real-world studies showed high effectiveness of upadacitinib, in terms of both clinical signs and subjective symptoms, in different patient populations, including those resistant to other treatments. No new significant safety concerns have emerged as compared to randomized clinical trials.Keywords: JAKi, real-life, upadacitinib, atopic dermatitis, systematic review

AbstractPurpose Tildrakizumab is a selective inhibitor of IL-23 approved for the treatment of moderate-to-severe plaque psoriasis in two dosages. We conducted a 16-week multicenter retrospective study to compare the effectiveness and safety of tildrakizumab 200 mg versus tildrakizumab 100 mg in patients with a high disease burden or high body weight.Materials and methods Our retrospective study included 134 patients treated with tildrakizumab 200 mg and 364 patients treated with tildrakizumab 100 mg from 28 Italian Dermatology Units affected by moderate-to-severe plaque psoriasis. The patients had a body weight above 90 kg or a high disease burden (Psoriasis Area and Severity Index [PASI] ≥ 16 or the involvement of difficult-to-treat areas). We evaluated the effectiveness of tildrakizumab at the week-16 visit in terms of PASI90, PASI100 and absolute PASI ≤ 2.Results After 16 weeks of treatment with tildrakizumab 200 mg, PASI90 was reached by 57.5% of patients and PASI100 by 39.6% of patients. At the same time point, 34.3% and 24.2% of patients treated with tildrakizumab 100 mg achieved PASI90 and PASI100, respectively.Conclusions Our data suggest that tildrakizumab 200 mg has better effectiveness than tildrakizumab 100 mg in patients with a body weight ≥ 90 kg and a high disease burden.

Mild cognitive impairment (MCI) is a heterogeneous condition definable as the intermediate clinical state between normal aging and dementia. As a pre-dementia condition, there is a recent growing interest in the identification of non-invasive markers able to predict the progression from MCI to a more advanced stage of the disease. Previous evidence showed the close link between gut microbiota and neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's disease (PD). Conversely, the actual relationship between gut microbiota and MCI is yet to be clarified. In this work, we provide an overview about the current knowledge regarding the role of gut microbiota in the context of MCI, also assessing the potential for microbiota-targeted therapies. Through the review of the most recent studies focusing on this topic, we found evidence of an increase of Bacteroidetes at phylum level and Bacteroides at genus level in MCI subjects with respect to healthy controls and patients with AD. Despite such initial evidence, the definitive identification of a typical microbiota profile associated with MCI is still far from being achieved. These preliminary results, however, are growingly encouraging research on the role of gut microbiota modulation in improving the cognitive status of pre-dementia subjects. To date, few studies evaluated the role of probiotics in MCI subjects, and they showed favorable results, although still biased by small sample size, heterogeneity of study design and short follow-up.

Introduction: Genital involvement is observed in approximately 60% of patients with psoriasis, presenting clinicians with formidable challenges in treatment. While new biologic drugs have emerged as safe and effective options for managing psoriasis, their efficacy in challenging-to-treat areas remains inadequately explored. Intriguingly, studies have shown that interleukin (IL)-17 inhibitors exhibit effectiveness in addressing genital psoriasis. Objectives: We aimed to determine the effectiveness profile of bimekizumab in patients affected by moderate-to-severe plaque psoriasis with involvement of genitalia. Methods: Bimekizumab, a dual inhibitor of both IL-17A and IL-17F, was the focus of our 16-week study, demonstrating highly favorable outcomes for patients with genital psoriasis. The effectiveness of bimekizumab was evaluated in terms of improvement in Static Physician's Global Assessment of Genitalia (sPGA-G) and Psoriasis Area and Severity Index. Results: Sixty-five adult patients were enrolled. Remarkably, 98.4% of our participants achieved a clear sPGA-G score (s-PGA-g=0) within 16 weeks. Moreover, consistent improvements were observed in PASI scores, accompanied by a significant reduction in the mean Dermatology Life Quality Index (DLQI), signifying enhanced quality of life. Notably, none of the patients reported a severe impairment in their quality of life after 16 weeks of treatment. In our cohort of 65 patients, subgroup analyses unveiled that the effectiveness of bimekizumab remained unaffected by prior exposure to other biologics or by obesity. Conclusions: Our initial findings suggest that bimekizumab may serve as a valuable treatment option for genital psoriasis. Nevertheless, further research with larger sample sizes and longer-term follow-up is imperative to conclusively validate these results.

Bacterial antibiotic persistence is a phenomenon where bacteria are exposed to an antibiotic and the majority of the population dies while a small subset enters a low metabolic, persistent, state and are able to survive. Once the antibiotic is removed the persistent population can resuscitate and continue growing. Several different molecular mechanisms and pathways have been implicated in this phenomenon. A common mechanism that may underly bacterial antibiotic persistence is perturbations in protein synthesis. To investigate this mechanism, we characterized four distinct metG mutants for their ability to increase antibiotic persistence. Two metG mutants encode changes near the catalytic site of MetRS and the other two mutants changes near the anticodon binding domain. Mutations in metG are of particular interest because MetRS is responsible for aminoacylation both initiator tRNAMet and elongator tRNAMet indicating that these mutants could impact translation initiation and/or translation elongation. We observed that all the metG mutants increased the level of antibiotic persistence as did reduced transcription levels of wild type metG. Although, the MetRS variants did not have an impact on MetRS activity itself, they did reduce translation rates. It was also observed that the MetRS variants affected the proofreading mechanism for homocysteine and that these mutants’ growth is hypersensitive to homocysteine. Taken together with previous findings, our data indicate that both reductions in cellular Met-tRNAMet synthetic capacity and reduced proofreading of homocysteine by MetRS variants are positive determinants for bacterial antibiotic persistence.

The use of plant growth-promoting bacteria as bioinoculants is a powerful tool to increase crop yield and quality and to improve nitrogen use efficiency (NUE) from fertilizers in plants. This study aimed to bioprospecting a native bacterial consortium (Bacillus cabrialesii subsp. cabrialesii TE3T, Priestia megaterium TRQ8, and Bacillus paralicheniformis TRQ65), through bioinformatic analysis, and to quantify the impact of its inoculation on NUE (measured through 15N-isotopic techniques), grain yield, and grain quality of durum wheat variety CIRNO C2008 grown under three doses of urea (0, 120, and 240 kg N ha−1) during two consecutive agricultural cycles in the Yaqui Valley, Mexico. The inoculation of the bacterial consortium (BC) to the wheat crop, at a total N concentration of 123–225 kg N ha−1 increased crop productivity and maintained grain quality, resulting in a yield increase of 1.1 ton ha−1 (6.0 vs. 7.1 ton ha−1, 0 kg N ha−1 added, 123 kg N ha−1 in the soil) and of 2.0 ton ha−1 (5.9 vs. 7.9 ton ha−1, 120 kg N ha−1 added, 104 kg N ha−1 in the soil) compared to the uninoculated controls at the same doses of N. The genomic bioinformatic analysis of the studied strains showed a great number of biofertilization-related genes regarding N and Fe acquisition, P assimilation, CO2 fixation, Fe, P, and K solubilization, with important roles in agroecosystems, as well as genes related to the production of siderophores and stress response. A positive effect of the BC on NUE at the studied initial N content (123 and 104 kg N ha−1) was not observed. Nevertheless, increases of 14 % and 12.5 % on NUE (whole plant) were observed when 120 kg N ha−1 was applied compared to when wheat was fully fertilized (240 kg N ha−1). This work represents a link between bioinformatic approaches of a native bacterial inoculant and the quantification of its impact on durum wheat.

IntroductionThe development of several effective biological drugs for moderate-to-severe plaque psoriasis has dramatically changed the lives of patients. Despite the wide use of interleukin (IL) inhibitors, limited data are available to date regarding long-term treatment persistence.MethodThis multicenter retrospective real-world study evaluated 5932 treatment courses across 5300 patients, all treated with interleukin inhibitors. Drug survival was expressed by using the Kaplan-Meier estimator for each biological drug at 6, 12, 24, 36 and 48 months. We also stratified by discontinuation associated with primary or secondary ineffectiveness.ResultsIn our study, the most prescribed drugs were secukinumab (1412), ixekizumab (1183), and risankizumab (977). After four years of follow-up, risankizumab emerged as the treatment with the highest drug survival overall, as 91.6% of patients were still on treatment. The overall probability of drug survival at four years was comparable for tildrakizumab (83.5%), ixekizumab (82.6%), guselkumab (82.4%) and brodalumab (81.8%). When evaluating only patients who discontinued the treatment because of ineffectiveness, once again risankizumab was the molecule with the highest drug survival at 4 years (93.4%), this time followed by ixekizumab (87%). Our study, in which all IL inhibitors were adequately represented, confirmed a slightly better treatment persistence for IL-23 inhibitors, consistent with other real-world studies.ConclusionOur experience showed that IL-23 inhibitors, and risankizumab in particular, had a higher probability of drug survival overall during a 4-year follow-up. Risankizumab and ixekizumab were less likely to be discontinued because of ineffectiveness after four years.

Central to the diversity of wheat products was the origin of hexaploid bread wheat, which added the D-genome of Aegilops tauschii to tetraploid wheat giving rise to superior dough properties in leavened breads. The polyploidization, however, imposed a genetic bottleneck, with only limited diversity introduced in the wheat D-subgenome. To understand genetic variants for quality, we sequenced 273 accessions spanning the known diversity of Ae. tauschii. We discovered 45 haplotypes in Glu-D1, a major determinant of quality, relative to the two predominant haplotypes in wheat. The wheat allele 2 + 12 was found in Ae. tauschii Lineage 2, the donor of the wheat D-subgenome. Conversely, the superior quality wheat allele 5 + 10 allele originated in Lineage 3, a recently characterized lineage of Ae. tauschii, showing a unique origin of this important allele. These two wheat alleles were also quite similar relative to the total observed molecular diversity in Ae. tauschii at Glu-D1. Ae. tauschii is thus a reservoir for unique Glu-D1 alleles and provides the genomic resource to begin utilizing new alleles for end-use quality improvement in wheat breeding programs.

The nutritional status in inflammatory bowel disease (IBD) is often impaired, and adherence to the Mediterranean diet (MedDiet) remains under-investigated. The aim of this study was to assess diet quality (DQ) and adherence to MedDiet in a cohort of Sardinian IBD patients. We conducted a case-control study in which 50 Crohn’s disease (CD) and 50 ulcerative colitis (UC) patients were matched with 100 healthy controls each. The Diet Quality Index (DQI-I) and Medi-Lite were used to assess DQ and adherence to MedDiet, respectively. Subgroup analysis by disease characteristics and use of advanced therapies were also carried out. DQI-I scored significantly lower in IBD, independently of disease localization and behavior (CD) and disease extent (UC): [DQI-I: CD 34.5 (IQR 33–37) vs. CTRL 40 (IQR 38.5–43) p < 0.0001; UC 34.5 (IQR 33–37) vs. CTRL 42 (IQR 40–44) p < 0.0001]. Medi-Lite scores were significantly lower in stricturing and ileo-colonic CD and in extensive UC: [Medi-Lite CD 7.5 (IQR 7–9)] vs. CTRL 9 (IQR 7–10) p = 0.0379]; [UC 8 (IQR7–10) vs. CTRL 9 (IQR 8–10.5) p = 0.0046]. IBD patients had a low DQ independently of disease type and phenotype. Patients with ileo-colonic stenosing CD or extensive UC had lower MedDiet adherence, suggesting that its benefits may be mitigated by low acceptance in specific subgroups.

Implementing genomic-based prediction models in genomic selection requires an understanding of the measures for evaluating prediction accuracy from different models and methods using multi-trait data. In this study, we compared prediction accuracy using six large multi-trait wheat data sets (quality and grain yield). The data were used to predict 1 year (testing) from the previous year (training) to assess prediction accuracy using four different prediction models. The results indicated that the conventional Pearson's correlation between observed and predicted values underestimated the true correlation value, whereas the corrected Pearson's correlation calculated by fitting a bivariate model was higher than the division of the Pearson's correlation by the squared root of the heritability across traits, by 2.53-11.46%. Across the datasets, the corrected Pearson's correlation was higher than the uncorrected by 5.80-14.01%. Overall, we found that for grain yield the prediction performance was highest using a multi-trait compared to a single-trait model. The higher the absolute genetic correlation between traits the greater the benefits of multi-trait models for increasing the genomic-enabled prediction accuracy of traits.

The identification of new effective therapeutic options for non-small-cell lung cancer (NSCLC) represents a crucial challenge in oncology. Recent studies indicate that cancer-associated fibroblasts (CAFs) participate in tumor progression by establishing a favorable microenvironment that promotes cancer progression. Therefore, the development of strategies inhibiting the interplay between CAFs and cancer cells is considered a winning approach for the development of effective anti-cancer drugs. Among other factors, the signal transducer and activator of transcription-3 (STAT3) has been reported as a key mediator of CAF oncogenic actions, representing a promising therapeutic target. Here, we applied an aptamer-based conjugate (named Gint4.T-STAT3), containing a STAT3 siRNA linked to an aptamer binding and inhibiting the platelet-derived growth factor receptor (PDGFR)β, to obtain STAT3-specific silencing and interfere with CAF pro-tumorigenic functions. We demonstrated that this molecule effectively delivers the STAT3 siRNA in NSCLC cells, and blocks CAF-induced cancer cell growth and migration and reduced spheroid dimension. In addition, we found that Gint4.T-STAT3 alters CAF phenotype, thus functioning as a double-acting molecule able to inhibit the entire tumor bulk. Our data provide a proof of principle for the targeting of CAF pro-tumor functions through an aptamer-based drug, and can open innovative horizons in NSCLC therapy.