Sonia Facchin - Academia.edu (original) (raw)

Papers by Sonia Facchin

Biochemical Journal, Jun 1, 2002

The Saccharomyces cere isiae YGR262c\BUD32 gene, whose disruption causes a severe pleiotropic phe... more The Saccharomyces cere isiae YGR262c\BUD32 gene, whose disruption causes a severe pleiotropic phenotype, encodes a 261residue putative protein kinase, piD261, whose structural homologues have been identified in a variety of organisms, including humans, and whose function is unknown. We have demonstrated previously that piD261, expressed in Escherichia coli as a recombinant protein, is a Ser\Thr kinase, as judged by its ability to autophosphorylate and to phosphorylate casein. Here we describe a mutational analysis showing that, despite low sequence similarity, the invariant residues representing the signature of protein kinases are conserved in piD261 and in its structural homologues, but are embedded in an altered context, suggestive of unique mechanistic properties. Especially noteworthy are : (i) three unique inserts of unknown function within the N-terminal lobe, (ii) the lack of a lysyl residue which in all other Ser\Thr

Digestive and Liver Disease, Oct 1, 2022

BACKGROUND Oncostatin M was recently highlighted as a promising biomarker for therapeutic effecti... more BACKGROUND Oncostatin M was recently highlighted as a promising biomarker for therapeutic effectiveness in inflammatory bowel diseases (IBD), with particular regard for infliximab. The primary aim was to evaluate the ability of serum oncostatin M to predict endoscopic response to different drugs in IBD. METHODS We selected two different cohorts of patients with IBD, treated with anti-TNF (infliximab and adalimumab) or with vedolizumab. Therapeutic response was evaluated at week 54 in terms of mucosal healing. Serum oncostatin M and C-reactive protein were measured at baseline; fecal calprotectin was measured at baseline and after 14 weeks of treatment. We evaluated the association of these biomarkers with mucosal healing at week 54. RESULTS Among 66 patients treated with anti-TNFs and 68 treated with vedolizumab, 35 and 31 attained mucosal healing, respectively. Mucosal healing at 54 weeks was significantly associated with low oncostatin M levels at baseline in the anti-TNF cohort; the diagnostic accuracy of oncostatin M at baseline in predicting mucosal healing was 0.91 (95% CI 0.84 to 0.99) in the anti-TNF cohort and 0.56 (95% CI 0.43 to 0.70, P < 0.001) in the vedolizumab cohort. Mucosal healing was also associated with low fecal calprotectin levels at week 14 in both cohorts. CONCLUSION Our study suggests that serum oncostatin M is a drug-specific biomarker, since it could be used to predict therapeutic effectiveness to anti-TNFs but not to vedolizumab. Moreover, these results emphasize the utility of serum oncostatin M measurement in patients treated with anti-TNF.

Journal of Crohn's and Colitis, May 1, 2021

Primary and secondary outcome measures included safety and PK. Exploratory endpoints included cha... more Primary and secondary outcome measures included safety and PK. Exploratory endpoints included changes in fecal calprotectin, histology, and stool microbiome. Results: AMT-101 was safe and well tolerated; all AEs were mild to moderate and self limiting. No systemic toxicities associated with prior administration of IL-10 (e.g.anemia or thrombocytopenia) were observed. Systemic levels of AMT-101 were below limit of quantitation, given the GI restricted design. 1 mg and 3 mg AMT-101 led to placebo-adjusted mean reductions of FCP of 44% and 27%, respectively, in patients with baseline FCP>150 μg/g. Paired biopsy samples were centrally read in a blinded manner using the Geboes scoring system. Improvements were observed in 60% (6/10) of patients on AMT-101, compared with 0% (0/2) patients treated with placebo. Microbiome analyses revealed changes in phyla abundance in the 1mg and 3mg treatment cohorts (Bacteroidetes: 28.3% ± 31.4 to 51.3% ± 21.6; Firmicutes: 21.8% ± 12.7 to 30% ± 7.3), including Roseburia hominis and Faecalibacterium prausnitzii species. Conclusion: The results of this Phase 1b study confirm that once daily, oral AMT-101 was safe and well tolerated without SAEs previously observed with systemic IL-10 and without systemic exposure, by design. Doses at 10 mg or less suggest potential clinical efficacy paired with an enhancement of favorable enteric commensal bacteria after only 14 days of treatment. These findings support AMT-101 as actively exerting an immunomodulatory effect in the intestinal lamina propria and support ongoing Ph2 trials of AMT-101.

Journal of Digestive Diseases, Jan 22, 2020

Objective: Analyze disability determinants in a cohort of Argentine patients with rheumatoid arth... more Objective: Analyze disability determinants in a cohort of Argentine patients with rheumatoid arthritis (RA). Material and Methods: Consecutive patients with RA, according to ACR'87 criteria, were recruited from 6 rheumatology centers. Demographic and socioeconomic data, family history, comorbid diseases, extra-articular manifestations and information about received treatments were provided. Disease activity was assessed using Disease Activity Score 28 (DAS 28) and the Health Assessment Questionnaire (HAQ)-A was used for the functional capacity. Hand and feet radiographs were assessed using Sharp-van der Heijde score. Results: A total of 640 patients with RA were included, of which 85.2% were females. Mean age was 53 years (interquartile range ͓IQR͔, 44-62) and mean disease duration was 8 years (IQR, 4-14). DAS 28 mean was 2.72 (IQR, 1.7-3.7) and HAQ-A mean was 0.62 (IQR, 0.13-1.25). Multiple linear regression showed that the main variables associated with disability were DAS 28, radiologic damage and age. Main predictors of functional disability in the multiple logistic regression using severe HAQ (Ͼ2) as dependent variable were DAS 28 (OR, 2; P Ͻ 0.0001); age (OR, 1; P ϭ 0.008); and structural damage (OR, 1; P ϭ 0.001). Conclusions: In this population, the disease activity was the variable that showed the highest impact on the physical function. Radiologic damage affected HAQ as the disease progressed.

Journal of Crohn's and Colitis, Jan 16, 2018

Background: At present, drug response to infliximab is monitored by through levels (TL) and anti-... more Background: At present, drug response to infliximab is monitored by through levels (TL) and anti-drug antibody levels (ATI). Recently, another pathway of drug degradation has been hypothesised since MMP3 and MMP9 were found to be able to cleave IgG, like infliximab, in both animal and human experimental studies. Methods: We collected serum samples in 102 patients (27 Crohn's disease and 75 ulcerative colitis) treated with stable doses of infliximab for at least 6 months (t0) and 6 months thereafter (t1). In each patient TL, ATI values and MMP3 levels were assessed at t0 and t1 by ELISA. In addition, MMP3 levels were also determined in 28 healthy subjects as controls. Clinical (HBI or Mayo score) and biochemical (CRP, fecal calprotectin)markers were assessed to define disease remission/activity. TL were considered therapeutic if > 3.8 μg/ml, ATI were considered positive if >10 μg/ml. Data are presented as mean ± SEM. Comparison among groups was performed by non-parametric tests. Results: MMP3 levels were similar at t0 and t1 in patients which maintained therapeutic TL (14.5 ± 1.7 pg/ml and 15.0 ± 1.6 pg/ ml, respectively) and in healthy controls (13.1 ± 0.8 pg/ml). Patients with low TL but ATI negative had significantly higher MMP3 levels compared with the group with low TL and ATI positive (33.2 ± 3.0 and 20.0 ± 2.7, respectively, p = 0.0003), showing another pathway of drug degradation. 21 patients lost response between t0 and t1: 15 out of 21 patients demonstrated high levels of MMP3 (22.0 ± 2.1 pg/ ml) already at t0; in addition, 17 of these 21 patients were in clinical remission at t0, while at t1 all patients had disease activity. Conclusions: Serum MMP3 levels are useful in predicting loss of response to anti TNFα in patients with low TL but without ATI. High MMP3 levels predict with 90.5% accuracy loss of response over the next 6 months.

FEBS Journal, Oct 30, 2008

The Saccharomyces cerevisiae atypical protein kinase Bud32p is a member of the nuclear endopeptid... more The Saccharomyces cerevisiae atypical protein kinase Bud32p is a member of the nuclear endopeptidase-like, kinase, chromatin-associated/kinase, endopeptidase-like and other protein of small size (EKC/KEOPS) complex, known to be involved in the control of transcription and telomere homeostasis. Complex subunits (Pcc1p, Pcc2p, Cgi121p, Kae1p) represent, however, a small subset of the proteins able to interact with Bud32p, suggesting that this protein may be endowed with additional roles unrelated to its participation in the EKC/KEOPS complex. In this context, we investigated the relationships between Bud32p and the nuclear glutaredoxin Grx4p, showing that it is actually a physiological substrate of the kinase and that Bud32p contributes to the full functionality of Grx4p in vivo. We also show that this regulatory system is influenced by the phosphorylation of Bud32p at Ser258, which is specifically mediated by the Sch9p kinase [yeast homolog of mammalian protein kinase B (Akt/PKB)]. Notably, Ser258 phosphorylation of Bud32p does not alter the catalytic activity of the protein kinase per se, but positively regulates its ability to interact with Grx4p and thus to phosphorylate it. Interestingly, this novel signaling pathway represents a function of Bud32p that is independent from its role in the EKC/KEOPS complex, as the known functions of the complex in the regulation of transcription and telomere homeostasis are unaffected when the cascade is impaired. A similar relationship has already been observed in humans between Akt/PKB and p53-related protein kinase (Bud32p homolog), and could indicate that this pathway is conserved throughout evolution.

Digestive and Liver Disease, Mar 1, 2019

Digestive and Liver Disease, Mar 1, 2018

Cell and Tissue Research, Nov 7, 2020

The expression of leptin and leptin receptor (Ob-R) has been partially elucidated in colon of pat... more The expression of leptin and leptin receptor (Ob-R) has been partially elucidated in colon of patients with inflammatory bowel diseases (IBDs), even though leptin is involved in angiogenesis and inflammation. We previously reported overexpression of GLUT5 fructose transporter, in aberrant clusters of lymphatic vessels in lamina propria of IBD and controls. Here, we examine leptin and Ob-R expression in the same biopsies. Specimens were obtained from patients with ulcerative colitis (UC), Crohn's disease (CD) and controls who underwent screening for colorectal cancer, follow-up after polypectomy or with a history of lower gastrointestinal symptoms. Immunohistochemistry revealed leptin in apical and basolateral membranes of short epithelial portions, Ob-R on the apical pole of epithelial cells. Leptin and Ob-R were also identified in structures and cells scattered in the lamina propria. In UC, a significant correlation between leptin and Ob-R in the lamina propria was found in all inflamed samples, beyond non-inflamed samples of the proximal tract, while in CD, it was found in inflamed distal samples. Most of the leptin and Ob-R positive areas in the lamina propria were also GLUT5 immunoreactive in inflamed and non-inflamed mucosa. A significant correlation of leptin or Ob-R expression with GLUT5 was observed in the inflamed distal samples from UC. Our findings suggest that there are different sites of leptin and Ob-R expression in large intestine and those in lamina propria do not reflect the status of mucosal inflammation. The co-localization of leptin and/or Ob-R with GLUT5 may indicate concomitance effects in colorectal lamina propria areas.

Therapeutic Advances in Gastroenterology, 2021

Background: Current literature still lacks studies evaluating the effectiveness and safety of swi... more Background: Current literature still lacks studies evaluating the effectiveness and safety of switching from Infliximab originator to SB2 biosimilar in Inflammatory Bowel Diseases (IBDs). We aimed to verify the ability of SB2 to maintain the clinical and biochemical response induced by originator after switching. As secondary outcome, we aimed to verify safety, tolerability and immunogenicity of SB2 biosimilar compared with its IFX originator. Methods: We prospectively enrolled all patients who switched from originator to SB2 at three Italian IBD Units from August 2018 to April 2020. We collected clinical and biochemical data at the time of switch (T0), and at the first (T1) and the second (T2) visits after switching (mean time from switching: 135 and 329 days, respectively). In addition, data regarding therapeutic drug monitoring at T0 and T1 were recorded. Results: Eighty-five IBD patients (28 with Ulcerative Colitis and 57 with Crohn’s Disease) were included in the study. At T1, we observed statistically significant modifications in clinical activity of disease (70 patients were in clinical remission at baseline and 60 at T1 p = 0.02), but not at T2 (p = 0.3). Fecal calprotectin values were not different both at T1 and T2 (both p = 0.9) as well as the rate of concomitant treatment with steroids (p = 0.2 and p = 0.1) or immunosuppressants (p = 0.1 and p = 1.0). Moreover, the need for therapeutic optimization from T0 to T1 and from T1 to T2 was found significant (both p = 0.01). No anti-drug antibodies were identified at T1, and no serious adverse events were recorded. Conclusions: Overall, our data show that most of the patients switching from Infliximab originator to SB2 maintain the clinical and biochemical remission for at least 1 year. Further data are necessary to understand the clinical implications of these findings in the long term.

Digestive and Liver Disease, Sep 1, 2021

Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on ... more Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Alimentary Pharmacology & Therapeutics, Dec 11, 2017

the European society of gastrointestinal endoscopy (ESGE), European helicobacter study group (EHS... more the European society of gastrointestinal endoscopy (ESGE), European helicobacter study group (EHSG), European society of pathology (ESP), and the Socieda de portuguesa de endoscopia digestiva (SPED).

Alimentary Pharmacology & Therapeutics, Jun 17, 2022

SummaryBackgroundData on the role of the microbiome in adult patients with eosinophilic oesophagi... more SummaryBackgroundData on the role of the microbiome in adult patients with eosinophilic oesophagitis (EoE) are limited.AimsTo prospectively collect and characterise the salivary, oesophageal and gastric microbiome in patients with EoE, further correlating the findings with disease activity.MethodsAdult patients with symptoms of oesophageal dysfunction undergoing upper endoscopy were consecutively enrolled. Patients were classified as EoE patients, in case of more than 15 eosinophils per high‐power field, or non‐EoE controls, in case of lack of eosinophilic infiltration. Before and during endoscopy, saliva, oesophageal and gastric fundus biopsies were collected. Microbiota assessment was performed by 16 s rRNA analysis. A Sparse Partial Least Squares Discriminant Analysis (sPLS‐DA) was implemented to identify biomarkers.ResultsSaliva samples were collected from 29 EoE patients and 20 non‐EoE controls;, biopsies from 25 EoE and 5 non‐EoE controls. In saliva samples, 23 Amplicon Sequence Variants (ASVs) were positively associated with EoE and 27 ASVs with controls, making it possible to discriminate between EoE and non‐EoE patients with a classification error (CE) of 24%. In a validation cohort, the accuracy, sensitivity, specificity, positive predictive value and negative predictive value of this model were 78.6%, 80%, 75%, 80% and 60%, respectively. Moreover, the analysis of oesophageal microbiota samples observed a clear microbial pattern able to discriminate between active and inactive EoE (CE = 8%).ConclusionOur preliminary data suggest that salivary metabarcoding analysis in combination with machine learning approaches could become a valid, cheap, non‐invasive test to segregate between EoE and non‐EoE patients.

Journal of Crohn's and Colitis, May 1, 2021

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</j... more <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Adalimumab (ADL) is a therapeutic monoclonal antibody that targets the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) and has been shown to effectively induce and maintain disease remission in patients with Inflammatory Bowel Disease (IBD). However, some patients fail to respond to this treatment, experiencing primary failure (no response to induction therapy), while others initially respond but lose efficacy over time (secondary failure). Therapeutic Drug Monitoring (TDM), in clinical practice, may lead to maintain therapeutic drug concentration thereby optimizing individual dosage regimen and improving treatment response. Recently, a point of care testing (POCT) has been developed to rapidly measure trough levels in patients taking ADL. Comparative data with current gold standard are lacking.</jats:p> </jats:sec> <jats:sec> <jats:title>Aim</jats:title> <jats:p>To determine the degree of analytical correlation between a recently developed POCT (ProciseDx) ADL assay which analyze capillary whole blood and the comparative enzyme linked immunosorbent assays (ELISA) from serum samples.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>From December 2020 to February 2021, consecutive patients (aged ≥ 18 years) taking ADA (Humira, Amgevita, Imraldi) were recruited at Gastroenterology Unit, Padua University Hospital, during outpatient visits. In each patient, ADL levels from capillary whole blood collected by finger stick were performed using the ProciseDx ADL assay with reportable range between 1.3 µg/mL - 51.5 µg/mL; at the same time, a serum sample from venous blood was collected to carry out Grifols' Promonitor ELISA test (range ≤ 0.024 – 12 µg/mL). A Deming regression test was used to identify the correlation between the two methods.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Sixty patients were enrolled (67% males with mean age of 3±14), with 80% of them having CD, 17% UC and 3% an undetermined-Inflammatory Bowel Disease (IBD-U). The assessment with ProciseDx POCT was feasible and required a turnaround time of 3±0.2 minutes while serum ELISA analysis required the collection of at least 40 samples (around three weeks at our centre) and 3 hours to be performed. Thirty patients (63% males with mean age of 41±14) had therapeutic levels as assessed by ProciseDx ADL assay lower than 1.3 or greater than 12 µg/mL, in accordance with ELISA assessment. Among the remaining 30 patients (70% males with mean age of 43±15), the correlation between the two tests was high (r of 0.858 (95% CI 0.720 – 0.930)).</jats:p> <jats:p /> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>The ProciseDx POCT has similar accuracy but was more rapid and easy to be performed in providing the results of TDM in outpatients taking ADL. This could lead to a more rapid and effective optimization of the biological drug, thus avoiding treatment failure.</jats:p> </jats:sec>

Alimentary Pharmacology & Therapeutics, Jul 25, 2022

Journal of Crohn's and Colitis, 2019

Background: Inflammatory bowel disease (IBD) is characterised by severe inflammation of the small... more Background: Inflammatory bowel disease (IBD) is characterised by severe inflammation of the small bowel and/or the colon leading to recurrent diarrhoea and abdominal pain. Butyrate represents one of the final product of saccharolytic fermentation of complex and non-digestible polysaccharides by anaerobic bacteria and has shown anti-inflammatory and regenerative properties, providing symptomatic relief when orally supplemented in patients suffering from a various range of colonic diseases. 1 We investigate the effect of a microencapsulated form of sodium Butyrate (MSB, ButyroseR, SILA, Noale, Italy) on the faecal microbiota of patients with IBD Methods: In this prospective-randomised-placebo-controlled study, 49 IBD patients, 19 CD and 30 UC with mild-to-moderate clinical activity were enrolled (Figure 1)

Journal of Crohn's and Colitis, 2019

in the study. IFX-induced skin lesions were identified in 40 patients (23.4%): among them eczema ... more in the study. IFX-induced skin lesions were identified in 40 patients (23.4%): among them eczema (45%), psoriasis (20%), xerosis (10%) and others (25%). Twenty-one patients (52.2%) had skin lesions for more than half a year. Skin lesions did not have an important impact on any of the studied domains (Figure 1). Infliximab-induced skin lesions and their impact on QoL Conclusions: In our study, we confirmed the high incidence of infliximab-induced skin lesions. However, the new finding is that the impact of these lesions on quality of life is not great.

Journal of Crohn's and Colitis, Jan 25, 2019

Demographics and clinical characteristics at baseline for the 955 IBD patients treated with anti-... more Demographics and clinical characteristics at baseline for the 955 IBD patients treated with anti-TNF. Figure 1. (A) Cumulative probability of remaining on the first anti-TNF treatment (Crohn's disease). (B) Cumulative probability of remaining on the second anti-TNF treatment (Crohn's disease). Reason for discontinuation was lack/loss of response. Conclusions: Drug survival duration was longer for adalimumab compared with infliximab both when used as first anti-TNF agent and when used as second-line treatment. The consistent pattern indicates that these differences are not only explained by channelling bias (differential prescribing behaviour).

Journal of Crohn's and Colitis, Jan 25, 2019

Background: Anti-TNF treatment reduces requirement for surgical resection in CD; but whether biol... more Background: Anti-TNF treatment reduces requirement for surgical resection in CD; but whether biologic agents reduce colectomy rates in UC is not clear. Between February 2015 and June 2015, NICE and the Scottish Medicines Consortium approved the use of infliximab, adalimumab, golimumab and vedolizumab for medically refractory UC. Prior to this date biologic use in UC across Scotland was restricted to infliximab rescue therapy. We therefore aimed to describe UC colectomy rates before and after the advent of biologic use for moderately to severely active UC. Methods: We performed a retrospective analysis of UC colectomy rates in a single Scottish health board (NHS Lothian) from January 2009 to December 2017. Surgical resections for UC were identified from the Lothian Pathology database and/ or theatre record. Electronic medical records were screened to describe UC phenotype and operation details. Colectomies were termed 'elective' if operative decision was made prior to admission, 'emergency' if colectomy occurred during admission and 'fulminant' if within 3 months of diagnosis. Biologic prescriptions details for all UC patients from January 2009 to June 2017 were retrieved from the Edinburgh Biologics Registry. Extent and severity of disease were defined using the Montreal classification at colectomy or at initiation of biologic for those who did not undergo colectomy. Linear regression was used to assess change in rates of colectomy and biologic use over the study period. Results: There was a reduction in annual colectomy rate during the overall study period (p = 0.028) (Figure 1), with 39 (30-44) median (IQR) colectomies between 2009 and 14 and 25 (23-26) between 2014 and 17. This was driven by a reduction in non-fulminant colectomy rate (p = 0.028); there was no change in the rate of fulminant colectomies. Over the same time, in keeping with national guidelines in Feb 2015, there was a significant increase in biologic prescribing (p < 0.001). In total, 296 patients underwent colectomy consisting of 193 (65%) emergency and 97 (33%) elective operations (Table 1). The first age pouch operation has seen a significant decline over the study period.

Biochemical Journal, Jun 1, 2002

The Saccharomyces cere isiae YGR262c\BUD32 gene, whose disruption causes a severe pleiotropic phe... more The Saccharomyces cere isiae YGR262c\BUD32 gene, whose disruption causes a severe pleiotropic phenotype, encodes a 261residue putative protein kinase, piD261, whose structural homologues have been identified in a variety of organisms, including humans, and whose function is unknown. We have demonstrated previously that piD261, expressed in Escherichia coli as a recombinant protein, is a Ser\Thr kinase, as judged by its ability to autophosphorylate and to phosphorylate casein. Here we describe a mutational analysis showing that, despite low sequence similarity, the invariant residues representing the signature of protein kinases are conserved in piD261 and in its structural homologues, but are embedded in an altered context, suggestive of unique mechanistic properties. Especially noteworthy are : (i) three unique inserts of unknown function within the N-terminal lobe, (ii) the lack of a lysyl residue which in all other Ser\Thr

Digestive and Liver Disease, Oct 1, 2022

BACKGROUND Oncostatin M was recently highlighted as a promising biomarker for therapeutic effecti... more BACKGROUND Oncostatin M was recently highlighted as a promising biomarker for therapeutic effectiveness in inflammatory bowel diseases (IBD), with particular regard for infliximab. The primary aim was to evaluate the ability of serum oncostatin M to predict endoscopic response to different drugs in IBD. METHODS We selected two different cohorts of patients with IBD, treated with anti-TNF (infliximab and adalimumab) or with vedolizumab. Therapeutic response was evaluated at week 54 in terms of mucosal healing. Serum oncostatin M and C-reactive protein were measured at baseline; fecal calprotectin was measured at baseline and after 14 weeks of treatment. We evaluated the association of these biomarkers with mucosal healing at week 54. RESULTS Among 66 patients treated with anti-TNFs and 68 treated with vedolizumab, 35 and 31 attained mucosal healing, respectively. Mucosal healing at 54 weeks was significantly associated with low oncostatin M levels at baseline in the anti-TNF cohort; the diagnostic accuracy of oncostatin M at baseline in predicting mucosal healing was 0.91 (95% CI 0.84 to 0.99) in the anti-TNF cohort and 0.56 (95% CI 0.43 to 0.70, P < 0.001) in the vedolizumab cohort. Mucosal healing was also associated with low fecal calprotectin levels at week 14 in both cohorts. CONCLUSION Our study suggests that serum oncostatin M is a drug-specific biomarker, since it could be used to predict therapeutic effectiveness to anti-TNFs but not to vedolizumab. Moreover, these results emphasize the utility of serum oncostatin M measurement in patients treated with anti-TNF.

Journal of Crohn's and Colitis, May 1, 2021

Primary and secondary outcome measures included safety and PK. Exploratory endpoints included cha... more Primary and secondary outcome measures included safety and PK. Exploratory endpoints included changes in fecal calprotectin, histology, and stool microbiome. Results: AMT-101 was safe and well tolerated; all AEs were mild to moderate and self limiting. No systemic toxicities associated with prior administration of IL-10 (e.g.anemia or thrombocytopenia) were observed. Systemic levels of AMT-101 were below limit of quantitation, given the GI restricted design. 1 mg and 3 mg AMT-101 led to placebo-adjusted mean reductions of FCP of 44% and 27%, respectively, in patients with baseline FCP>150 μg/g. Paired biopsy samples were centrally read in a blinded manner using the Geboes scoring system. Improvements were observed in 60% (6/10) of patients on AMT-101, compared with 0% (0/2) patients treated with placebo. Microbiome analyses revealed changes in phyla abundance in the 1mg and 3mg treatment cohorts (Bacteroidetes: 28.3% ± 31.4 to 51.3% ± 21.6; Firmicutes: 21.8% ± 12.7 to 30% ± 7.3), including Roseburia hominis and Faecalibacterium prausnitzii species. Conclusion: The results of this Phase 1b study confirm that once daily, oral AMT-101 was safe and well tolerated without SAEs previously observed with systemic IL-10 and without systemic exposure, by design. Doses at 10 mg or less suggest potential clinical efficacy paired with an enhancement of favorable enteric commensal bacteria after only 14 days of treatment. These findings support AMT-101 as actively exerting an immunomodulatory effect in the intestinal lamina propria and support ongoing Ph2 trials of AMT-101.

Journal of Digestive Diseases, Jan 22, 2020

Objective: Analyze disability determinants in a cohort of Argentine patients with rheumatoid arth... more Objective: Analyze disability determinants in a cohort of Argentine patients with rheumatoid arthritis (RA). Material and Methods: Consecutive patients with RA, according to ACR'87 criteria, were recruited from 6 rheumatology centers. Demographic and socioeconomic data, family history, comorbid diseases, extra-articular manifestations and information about received treatments were provided. Disease activity was assessed using Disease Activity Score 28 (DAS 28) and the Health Assessment Questionnaire (HAQ)-A was used for the functional capacity. Hand and feet radiographs were assessed using Sharp-van der Heijde score. Results: A total of 640 patients with RA were included, of which 85.2% were females. Mean age was 53 years (interquartile range ͓IQR͔, 44-62) and mean disease duration was 8 years (IQR, 4-14). DAS 28 mean was 2.72 (IQR, 1.7-3.7) and HAQ-A mean was 0.62 (IQR, 0.13-1.25). Multiple linear regression showed that the main variables associated with disability were DAS 28, radiologic damage and age. Main predictors of functional disability in the multiple logistic regression using severe HAQ (Ͼ2) as dependent variable were DAS 28 (OR, 2; P Ͻ 0.0001); age (OR, 1; P ϭ 0.008); and structural damage (OR, 1; P ϭ 0.001). Conclusions: In this population, the disease activity was the variable that showed the highest impact on the physical function. Radiologic damage affected HAQ as the disease progressed.

Journal of Crohn's and Colitis, Jan 16, 2018

Background: At present, drug response to infliximab is monitored by through levels (TL) and anti-... more Background: At present, drug response to infliximab is monitored by through levels (TL) and anti-drug antibody levels (ATI). Recently, another pathway of drug degradation has been hypothesised since MMP3 and MMP9 were found to be able to cleave IgG, like infliximab, in both animal and human experimental studies. Methods: We collected serum samples in 102 patients (27 Crohn's disease and 75 ulcerative colitis) treated with stable doses of infliximab for at least 6 months (t0) and 6 months thereafter (t1). In each patient TL, ATI values and MMP3 levels were assessed at t0 and t1 by ELISA. In addition, MMP3 levels were also determined in 28 healthy subjects as controls. Clinical (HBI or Mayo score) and biochemical (CRP, fecal calprotectin)markers were assessed to define disease remission/activity. TL were considered therapeutic if > 3.8 μg/ml, ATI were considered positive if >10 μg/ml. Data are presented as mean ± SEM. Comparison among groups was performed by non-parametric tests. Results: MMP3 levels were similar at t0 and t1 in patients which maintained therapeutic TL (14.5 ± 1.7 pg/ml and 15.0 ± 1.6 pg/ ml, respectively) and in healthy controls (13.1 ± 0.8 pg/ml). Patients with low TL but ATI negative had significantly higher MMP3 levels compared with the group with low TL and ATI positive (33.2 ± 3.0 and 20.0 ± 2.7, respectively, p = 0.0003), showing another pathway of drug degradation. 21 patients lost response between t0 and t1: 15 out of 21 patients demonstrated high levels of MMP3 (22.0 ± 2.1 pg/ ml) already at t0; in addition, 17 of these 21 patients were in clinical remission at t0, while at t1 all patients had disease activity. Conclusions: Serum MMP3 levels are useful in predicting loss of response to anti TNFα in patients with low TL but without ATI. High MMP3 levels predict with 90.5% accuracy loss of response over the next 6 months.

FEBS Journal, Oct 30, 2008

The Saccharomyces cerevisiae atypical protein kinase Bud32p is a member of the nuclear endopeptid... more The Saccharomyces cerevisiae atypical protein kinase Bud32p is a member of the nuclear endopeptidase-like, kinase, chromatin-associated/kinase, endopeptidase-like and other protein of small size (EKC/KEOPS) complex, known to be involved in the control of transcription and telomere homeostasis. Complex subunits (Pcc1p, Pcc2p, Cgi121p, Kae1p) represent, however, a small subset of the proteins able to interact with Bud32p, suggesting that this protein may be endowed with additional roles unrelated to its participation in the EKC/KEOPS complex. In this context, we investigated the relationships between Bud32p and the nuclear glutaredoxin Grx4p, showing that it is actually a physiological substrate of the kinase and that Bud32p contributes to the full functionality of Grx4p in vivo. We also show that this regulatory system is influenced by the phosphorylation of Bud32p at Ser258, which is specifically mediated by the Sch9p kinase [yeast homolog of mammalian protein kinase B (Akt/PKB)]. Notably, Ser258 phosphorylation of Bud32p does not alter the catalytic activity of the protein kinase per se, but positively regulates its ability to interact with Grx4p and thus to phosphorylate it. Interestingly, this novel signaling pathway represents a function of Bud32p that is independent from its role in the EKC/KEOPS complex, as the known functions of the complex in the regulation of transcription and telomere homeostasis are unaffected when the cascade is impaired. A similar relationship has already been observed in humans between Akt/PKB and p53-related protein kinase (Bud32p homolog), and could indicate that this pathway is conserved throughout evolution.

Digestive and Liver Disease, Mar 1, 2019

Digestive and Liver Disease, Mar 1, 2018

Cell and Tissue Research, Nov 7, 2020

The expression of leptin and leptin receptor (Ob-R) has been partially elucidated in colon of pat... more The expression of leptin and leptin receptor (Ob-R) has been partially elucidated in colon of patients with inflammatory bowel diseases (IBDs), even though leptin is involved in angiogenesis and inflammation. We previously reported overexpression of GLUT5 fructose transporter, in aberrant clusters of lymphatic vessels in lamina propria of IBD and controls. Here, we examine leptin and Ob-R expression in the same biopsies. Specimens were obtained from patients with ulcerative colitis (UC), Crohn's disease (CD) and controls who underwent screening for colorectal cancer, follow-up after polypectomy or with a history of lower gastrointestinal symptoms. Immunohistochemistry revealed leptin in apical and basolateral membranes of short epithelial portions, Ob-R on the apical pole of epithelial cells. Leptin and Ob-R were also identified in structures and cells scattered in the lamina propria. In UC, a significant correlation between leptin and Ob-R in the lamina propria was found in all inflamed samples, beyond non-inflamed samples of the proximal tract, while in CD, it was found in inflamed distal samples. Most of the leptin and Ob-R positive areas in the lamina propria were also GLUT5 immunoreactive in inflamed and non-inflamed mucosa. A significant correlation of leptin or Ob-R expression with GLUT5 was observed in the inflamed distal samples from UC. Our findings suggest that there are different sites of leptin and Ob-R expression in large intestine and those in lamina propria do not reflect the status of mucosal inflammation. The co-localization of leptin and/or Ob-R with GLUT5 may indicate concomitance effects in colorectal lamina propria areas.

Therapeutic Advances in Gastroenterology, 2021

Background: Current literature still lacks studies evaluating the effectiveness and safety of swi... more Background: Current literature still lacks studies evaluating the effectiveness and safety of switching from Infliximab originator to SB2 biosimilar in Inflammatory Bowel Diseases (IBDs). We aimed to verify the ability of SB2 to maintain the clinical and biochemical response induced by originator after switching. As secondary outcome, we aimed to verify safety, tolerability and immunogenicity of SB2 biosimilar compared with its IFX originator. Methods: We prospectively enrolled all patients who switched from originator to SB2 at three Italian IBD Units from August 2018 to April 2020. We collected clinical and biochemical data at the time of switch (T0), and at the first (T1) and the second (T2) visits after switching (mean time from switching: 135 and 329 days, respectively). In addition, data regarding therapeutic drug monitoring at T0 and T1 were recorded. Results: Eighty-five IBD patients (28 with Ulcerative Colitis and 57 with Crohn’s Disease) were included in the study. At T1, we observed statistically significant modifications in clinical activity of disease (70 patients were in clinical remission at baseline and 60 at T1 p = 0.02), but not at T2 (p = 0.3). Fecal calprotectin values were not different both at T1 and T2 (both p = 0.9) as well as the rate of concomitant treatment with steroids (p = 0.2 and p = 0.1) or immunosuppressants (p = 0.1 and p = 1.0). Moreover, the need for therapeutic optimization from T0 to T1 and from T1 to T2 was found significant (both p = 0.01). No anti-drug antibodies were identified at T1, and no serious adverse events were recorded. Conclusions: Overall, our data show that most of the patients switching from Infliximab originator to SB2 maintain the clinical and biochemical remission for at least 1 year. Further data are necessary to understand the clinical implications of these findings in the long term.

Digestive and Liver Disease, Sep 1, 2021

Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on ... more Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Alimentary Pharmacology & Therapeutics, Dec 11, 2017

the European society of gastrointestinal endoscopy (ESGE), European helicobacter study group (EHS... more the European society of gastrointestinal endoscopy (ESGE), European helicobacter study group (EHSG), European society of pathology (ESP), and the Socieda de portuguesa de endoscopia digestiva (SPED).

Alimentary Pharmacology & Therapeutics, Jun 17, 2022

SummaryBackgroundData on the role of the microbiome in adult patients with eosinophilic oesophagi... more SummaryBackgroundData on the role of the microbiome in adult patients with eosinophilic oesophagitis (EoE) are limited.AimsTo prospectively collect and characterise the salivary, oesophageal and gastric microbiome in patients with EoE, further correlating the findings with disease activity.MethodsAdult patients with symptoms of oesophageal dysfunction undergoing upper endoscopy were consecutively enrolled. Patients were classified as EoE patients, in case of more than 15 eosinophils per high‐power field, or non‐EoE controls, in case of lack of eosinophilic infiltration. Before and during endoscopy, saliva, oesophageal and gastric fundus biopsies were collected. Microbiota assessment was performed by 16 s rRNA analysis. A Sparse Partial Least Squares Discriminant Analysis (sPLS‐DA) was implemented to identify biomarkers.ResultsSaliva samples were collected from 29 EoE patients and 20 non‐EoE controls;, biopsies from 25 EoE and 5 non‐EoE controls. In saliva samples, 23 Amplicon Sequence Variants (ASVs) were positively associated with EoE and 27 ASVs with controls, making it possible to discriminate between EoE and non‐EoE patients with a classification error (CE) of 24%. In a validation cohort, the accuracy, sensitivity, specificity, positive predictive value and negative predictive value of this model were 78.6%, 80%, 75%, 80% and 60%, respectively. Moreover, the analysis of oesophageal microbiota samples observed a clear microbial pattern able to discriminate between active and inactive EoE (CE = 8%).ConclusionOur preliminary data suggest that salivary metabarcoding analysis in combination with machine learning approaches could become a valid, cheap, non‐invasive test to segregate between EoE and non‐EoE patients.

Journal of Crohn's and Colitis, May 1, 2021

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</j... more <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Adalimumab (ADL) is a therapeutic monoclonal antibody that targets the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) and has been shown to effectively induce and maintain disease remission in patients with Inflammatory Bowel Disease (IBD). However, some patients fail to respond to this treatment, experiencing primary failure (no response to induction therapy), while others initially respond but lose efficacy over time (secondary failure). Therapeutic Drug Monitoring (TDM), in clinical practice, may lead to maintain therapeutic drug concentration thereby optimizing individual dosage regimen and improving treatment response. Recently, a point of care testing (POCT) has been developed to rapidly measure trough levels in patients taking ADL. Comparative data with current gold standard are lacking.</jats:p> </jats:sec> <jats:sec> <jats:title>Aim</jats:title> <jats:p>To determine the degree of analytical correlation between a recently developed POCT (ProciseDx) ADL assay which analyze capillary whole blood and the comparative enzyme linked immunosorbent assays (ELISA) from serum samples.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>From December 2020 to February 2021, consecutive patients (aged ≥ 18 years) taking ADA (Humira, Amgevita, Imraldi) were recruited at Gastroenterology Unit, Padua University Hospital, during outpatient visits. In each patient, ADL levels from capillary whole blood collected by finger stick were performed using the ProciseDx ADL assay with reportable range between 1.3 µg/mL - 51.5 µg/mL; at the same time, a serum sample from venous blood was collected to carry out Grifols' Promonitor ELISA test (range ≤ 0.024 – 12 µg/mL). A Deming regression test was used to identify the correlation between the two methods.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Sixty patients were enrolled (67% males with mean age of 3±14), with 80% of them having CD, 17% UC and 3% an undetermined-Inflammatory Bowel Disease (IBD-U). The assessment with ProciseDx POCT was feasible and required a turnaround time of 3±0.2 minutes while serum ELISA analysis required the collection of at least 40 samples (around three weeks at our centre) and 3 hours to be performed. Thirty patients (63% males with mean age of 41±14) had therapeutic levels as assessed by ProciseDx ADL assay lower than 1.3 or greater than 12 µg/mL, in accordance with ELISA assessment. Among the remaining 30 patients (70% males with mean age of 43±15), the correlation between the two tests was high (r of 0.858 (95% CI 0.720 – 0.930)).</jats:p> <jats:p /> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>The ProciseDx POCT has similar accuracy but was more rapid and easy to be performed in providing the results of TDM in outpatients taking ADL. This could lead to a more rapid and effective optimization of the biological drug, thus avoiding treatment failure.</jats:p> </jats:sec>

Alimentary Pharmacology & Therapeutics, Jul 25, 2022

Journal of Crohn's and Colitis, 2019

Background: Inflammatory bowel disease (IBD) is characterised by severe inflammation of the small... more Background: Inflammatory bowel disease (IBD) is characterised by severe inflammation of the small bowel and/or the colon leading to recurrent diarrhoea and abdominal pain. Butyrate represents one of the final product of saccharolytic fermentation of complex and non-digestible polysaccharides by anaerobic bacteria and has shown anti-inflammatory and regenerative properties, providing symptomatic relief when orally supplemented in patients suffering from a various range of colonic diseases. 1 We investigate the effect of a microencapsulated form of sodium Butyrate (MSB, ButyroseR, SILA, Noale, Italy) on the faecal microbiota of patients with IBD Methods: In this prospective-randomised-placebo-controlled study, 49 IBD patients, 19 CD and 30 UC with mild-to-moderate clinical activity were enrolled (Figure 1)

Journal of Crohn's and Colitis, 2019

in the study. IFX-induced skin lesions were identified in 40 patients (23.4%): among them eczema ... more in the study. IFX-induced skin lesions were identified in 40 patients (23.4%): among them eczema (45%), psoriasis (20%), xerosis (10%) and others (25%). Twenty-one patients (52.2%) had skin lesions for more than half a year. Skin lesions did not have an important impact on any of the studied domains (Figure 1). Infliximab-induced skin lesions and their impact on QoL Conclusions: In our study, we confirmed the high incidence of infliximab-induced skin lesions. However, the new finding is that the impact of these lesions on quality of life is not great.

Journal of Crohn's and Colitis, Jan 25, 2019

Demographics and clinical characteristics at baseline for the 955 IBD patients treated with anti-... more Demographics and clinical characteristics at baseline for the 955 IBD patients treated with anti-TNF. Figure 1. (A) Cumulative probability of remaining on the first anti-TNF treatment (Crohn's disease). (B) Cumulative probability of remaining on the second anti-TNF treatment (Crohn's disease). Reason for discontinuation was lack/loss of response. Conclusions: Drug survival duration was longer for adalimumab compared with infliximab both when used as first anti-TNF agent and when used as second-line treatment. The consistent pattern indicates that these differences are not only explained by channelling bias (differential prescribing behaviour).

Journal of Crohn's and Colitis, Jan 25, 2019

Background: Anti-TNF treatment reduces requirement for surgical resection in CD; but whether biol... more Background: Anti-TNF treatment reduces requirement for surgical resection in CD; but whether biologic agents reduce colectomy rates in UC is not clear. Between February 2015 and June 2015, NICE and the Scottish Medicines Consortium approved the use of infliximab, adalimumab, golimumab and vedolizumab for medically refractory UC. Prior to this date biologic use in UC across Scotland was restricted to infliximab rescue therapy. We therefore aimed to describe UC colectomy rates before and after the advent of biologic use for moderately to severely active UC. Methods: We performed a retrospective analysis of UC colectomy rates in a single Scottish health board (NHS Lothian) from January 2009 to December 2017. Surgical resections for UC were identified from the Lothian Pathology database and/ or theatre record. Electronic medical records were screened to describe UC phenotype and operation details. Colectomies were termed 'elective' if operative decision was made prior to admission, 'emergency' if colectomy occurred during admission and 'fulminant' if within 3 months of diagnosis. Biologic prescriptions details for all UC patients from January 2009 to June 2017 were retrieved from the Edinburgh Biologics Registry. Extent and severity of disease were defined using the Montreal classification at colectomy or at initiation of biologic for those who did not undergo colectomy. Linear regression was used to assess change in rates of colectomy and biologic use over the study period. Results: There was a reduction in annual colectomy rate during the overall study period (p = 0.028) (Figure 1), with 39 (30-44) median (IQR) colectomies between 2009 and 14 and 25 (23-26) between 2014 and 17. This was driven by a reduction in non-fulminant colectomy rate (p = 0.028); there was no change in the rate of fulminant colectomies. Over the same time, in keeping with national guidelines in Feb 2015, there was a significant increase in biologic prescribing (p < 0.001). In total, 296 patients underwent colectomy consisting of 193 (65%) emergency and 97 (33%) elective operations (Table 1). The first age pouch operation has seen a significant decline over the study period.