Search

Ulcerative colitis (UC)-related mucosal inflammation is characterized by the production of various autoantibodies with limited clinical relevance. Recent studies have shown that circulating levels of IgG against integrin αvβ6 are increased in UC patients as compared to Crohn's disease (CD) patients and healthy controls (HC). The present study assessed the diagnostic value of circulating IgG anti-αvβ6 in UC. Sera were prospectively collected from 108 outpatients with UC, 103 patients with CD, and 62 HC, and the levels of IgG anti-αvβ6 were measured using a commercially available ELISA kit. The cut-off for positive results was defined as the 95th percentile of the values of the autoantibodies in HC serum samples. Levels of IgG anti-αvβ6 were significantly higher in UC than in CD patients, including those with colonic localization, and HC. Fifty-six of the 108 (51.8%) UC patients had a positive test whereas only 17/103 (16.5%) patients with CD, and among these, 4/16 (25%) patients with colonic CD, were positive. In UC, there was no statistical difference between patients with IgG anti-αvβ6 positivity and those negative in terms of clinical disease activity, fecal calprotectin values, and disease extent. The sensitivity, specificity, predictive positive value, and predictive negative value of the test to differentiate between UC and CD were 51.9% (C.I.42.4-61.3), 83.5% (C.I. 76.3-90.7), 76.7% (C.I. 67.0-86.4), and 62.3% (C.I. 54.2-70.4) respectively. Our study confirms that anti-αvβ6 antibodies are demonstrable in the serum of the majority of UC patients and suggests the necessity of further research to understand if the anti-αvβ6 antibody determination could have a place in the clinical decision-making of IBD., Competing Interests: Conflict of interest IM served as a speaker for Janssen, GM served as a consultant for First Wave BioPharma, as a speaker for Takeda and filed a patent related to the treatment of inflammatory bowel diseases with Smad7 antisense oligonucleotides. The remaining authors have no conflict of interest to disclose., (Copyright © 2023. Published by Elsevier Ltd.)

The term "immune-mediated inflammatory diseases (IMIDs)" refers to several inflammatory pathologies of multifactorial etiology and involving either simultaneously or sequentially more organs. IMIDs share some common pathogenic mechanisms, which account for some similarities in the clinical course and the impact that these diseases may have on other organs and systems of the body. However, there are some differences in the IMID-associated pathological process, including the synthesis and function of multiple inflammatory cytokines, which are supposed to perpetuate the tissue-damaging inflammation. This justifies the different indications and responsiveness to corticosteroids, immunosuppressors, small molecules, and biologics. Many individuals with IMIDs are, however, intolerant, or unresponsive to the current drugs, thus suggesting the necessity of novel therapeutic approaches, such as the combination of compounds that either inhibit more immuno-inflammatory networks selectively or simultaneously suppress inflammatory signals and activate counter-regulatory pathways. In this article, we highlight the most relevant features of IMIDs and discuss how clinicians can combat the detrimental immune response in such disorders., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Giovanni Monteleone reports a relationship with First Wave BioPharma that includes: consulting or advisory. Giovanni Monteleone reports a relationship with Takeda that includes: speaking and lecture fees. Giovanni Monteleone reports a relationship with Abbvie that includes: speaking and lecture fees. Giovanni Monteleone reports a relationship with Galapagos that includes: speaking and lecture fees. Giovanni Monteleone reports a relationship with Pfizer that includes: speaking and lecture fees. Irene Marafini reports a relationship with Janssen that includes: speaking and lecture fees. Irene Marafini reports a relationship with Galapagos that includes: speaking and lecture fees. Giovanni Monteleone has patent licensed to Licensee., (Copyright © 2023. Published by Elsevier B.V.)

Background: Association between Hidradenitis Suppurativa (HS) and Inflammatory Bowel Disease (IBD) has been suggested., Aims: To assess characteristics of HS and IBD in patients with or without concomitant IBD., Methods: In a prospective, nested case-control study, each IBD patient with concomitant HS (Case) was retrospectively matched with 4 patients with HS and no IBD (Controls) for gender and age (±5 years).HS was classified according to the Hurley score and the International Hidradenitis Suppurativa Severity Score System (IHS4). Data were expressed as mean (Standard Deviation). Statistical analysis included Student-t Test or Mann-Whitney Test, χ2 test, univariate and multivariate logistic regression., Results: The study population included 125 patients with HS: 25 with IBD, 100 matched Controls with no IBD. IBD group included 19 (76%) Crohn's disease and 6 (24%) Ulcerative Colitis patients. Obesity, familial HS and perianal HS were less frequent in Cases than in Controls (1[4%] vs 25(25%];p = 0.02; 1[4%] vs 21(21%];p = 0.04; 1[4%] vs 31(31%];p = 0.005, respectively).HS was less severe in Cases when assessed by the IHS4 (5.9 ± 4 vs 9 ± 6.7;p = 0.04).Complete drug-induced response for HS was more frequent in IBD (13[53%] vs28 (28%]; p = 0.04)., Conclusion: Clinical characteristics of HS and of patients differed between Cases and Controls. Present findings suggest the need to appropriately search and assess skin lesions compatible with HS in IBD., Competing Interests: Conflict of interest All authors declare no disclosures specifically related to the study. Biancone L: speaker fee from Takeda, Janssen, ViforPharma, Celltrion; Monteleone G: consultant for First Wave BioPharma and filed a patent related to the treatment of inflammatory bowel diseases with Smad7 antisense oligonucleotides; Calabrese E: speaker fee from Takeda, Janssen, MSD; Bianchi L: speaker or board member for Abbvie, Amgen, Novartis, Almirall, Sunpharma, Sanofi Genzyme, Biogen, Eli Lilly, Janssen, Leo Pharma; Campione E: advisory boards, lectures lee and research grants from Amgen, Almirall, Leo Pharma, UCB., (Copyright © 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Introduction: Metastasis to intraocular structures is a serious problem in lung cancer. Due to its rarity, however, limited information is available regarding the outcomes of treatment and prognosis. Literature often suggests a poor prognosis. We review current literature on the outcomes of systemic therapy and prognostic factors., Methods: We conducted a systematic review of English literature published during 2009 to 2022 identified via Medline and Google Scholar search. Publications reporting on tumor response in the eyes or overall survival of patients with intraocular metastasis due to lung cancer were included. Pooled analysis of patients receiving systemic therapy was performed, utilizing individual-level patient data., Results: A total of 79 publications contributed 92 patients into the analysis. Choroid was the most affected intraocular structure, in 82% of patients. Histology was small cell in 13% and non-small cell in 87%. Targeted therapy was utilized in 45% of patients. A pooled analysis demonstrated that the median overall survival was 27 months (95% CI: 21.8-32.2). Visual response among those with reported assessment showed that 92% of them had stable or improved vision while 8% experienced worsening of vision. Several factors including the year of treatment, age, targeted therapy, and radiation showed a significant association with survival. The strongest predictor of improved survival was the receipt of targeted therapy, with a hazard ratio of 0.31 (95% CI: 0.14-0.71), P = .005., Conclusions: For lung cancer patients with intraocular metastasis, systemic therapy can produce a favorable outcome. Particularly when a targeted therapy is feasible, long-term survival can be achieved., (Copyright © 2022. Published by Elsevier Inc.)

In the last decades, the better understanding of inflammatory bowel diseases (IBD) pathogenesis has contributed to the identification of new therapeutic targets that can be modulated to induce and maintain disease remission. Monoclonal antibodies against tumor necrosis factor, interleukin (IL)-12/IL-23p40, and the integrin α4β7 and inhibitors of Janus kinase molecules are valid compounds to limit the function of molecules implicated in the control of IBD-related inflammation. However, not all patients respond to treatment with such drugs, some of them lose response over time and others develop serious side effects, such as infections or malignancies, which lead to the discontinuation of the therapy. Thus, an intensive research is ongoing with the goal to identify new targets and develop novel therapeutic options. In this context, restoration of TGF-β activity and inhibition of phosphodiesterase 4 (PD4) represent two relevant strategies. TGF-β is an immunesuppressive cytokine, whose activity is severely impaired in IBD due to the abundance of the intracellular inhibitor Smad7. Knockdown of Smad7 with a specific antisense oligonucleotide restores TGF-β signalling and dampens effector immune responses in pre-clinical studies and initial clinical trials in Crohn's disease patients, even though a recent phase 3 trial was discontinued due to an apparent inefficacy. PD4 inhibition determines the increase of intracellular levels of cyclic adenosine monophosphate, a mechanism that decreases pro-inflammatory cytokine production. A recent phase 2 study has shown that oral administration of PD4 associates with clinical benefit in patients with ulcerative colitis. In this article, we review the rationale and the available data relative to the use of these two agents in IBD., Competing Interests: Declaration of Competing Interest Giovanni Monteleone has filed a patent related to the treatment of inflammatory bowel diseases with Smad7 antisense oligonucleotides and has served as an advisory board member for ABBVIE. The remaining authors have no conflict of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: We sought to define the variables associated with hospital outcome in preterm infants with patent ductus arteriosus (PDA) and identify the optimal timing for PDA closure to improve hospital outcome., Methods: Included were 201 premature babies (< or = 32 weeks gestational age), from January 2001 to June 2007, with PDA who received primary medical treatment with ibuprofen. Number of ibuprofen cycles, gestational age, body weight, and presence of symptomatic hypotension requiring vasoactive/inotropic drugs were related to hospital outcome, including hospital mortality, presence of necrotizing enterocolitis, acute renal failure, intraventricular hemorrhage, retinopathy and bronchopulmonary dysplasia at week 36. Data were analyzed with a logistic regression model., Results: Medical treatment was effective in 149 patients (75%), but 52 (25%) required surgical ligation after medical treatment failed. They had younger gestational age (25 weeks [IQR, 24 to 27 weeks] vs 27 weeks [IQR, 25 to 28 weeks], p < 0.0001), lower body weight at birth (730 g [IQR, 595 to 915 g] vs 840 g [IQR, 670 to 1016], p = 0.05), and a higher incidence of symptomatic hypotension (38 of 52 [73%] vs 56 of 149 [38%], p < 0.0001) than patients who responded to ibuprofen. More than two cycles of ibuprofen was significantly associated with an increased risk for bronchopulmonary dysplasia (odds ratio [OR], 2.81; p = 0.03) and acute renal failure (OR, 3.81; p = 0.09)., Conclusions: The prolonged patency of the ductus arteriosus in preterm infants is related to an increased morbidity. Surgical ligation of PDA is a safe and effective treatment and should be done soon after two complete cycles of ibuprofen, especially in selected patients, to improve clinical outcome.

Background: Upper and lower airways allergic disease is currently considered unitarily. Allergic inflammation in one site can extend to other sites of the respiratory tract., Objective: To evaluate bronchial inflammation before and after allergen-specific nasal challenge (ASNC) in rhinitic and asthmatic children, considering the different levels of allergen exposure, i.e. summer (low) and winter (high)., Methods: Fourteen children with rhinitis and 15 with rhinitis and asthma, all monosensitized to mites and 10 healthy controls were studied. Nasal IgE were measured before ASNC in summer and in winter season. Nasal clinical score, eosinophil cationic protein (ECP), nasal tryptase, bronchial clinical score, FEV(1), PEF, sputum ECP, sputum tryptase and exhaled nitric oxide (eNO) were evaluated before and after ASNC in summer and winter season., Results: Nasal scores significantly increased after ASNC in rhinitic and asthmatic children in both seasons. Nasal IgE were significantly higher in summer compared to winter. Bronchial symptoms, FEV(1) and PEF showed no mean differences in rhinitic and asthmatic children after ASNC, with an increase of bronchial symptoms and a decrease of FEV(1) and PEF occurring in 3/15 asthmatic children. In both groups nasal tryptase and ECP after ASNC significantly increased in summer and winter, while sputum tryptase was undetectable before or after ASNC in both groups. Sputum ECP and eNO at baseline were significantly higher in patients than in controls (summer P=0.002, winter P=0.001). Sputum ECP significantly increased after ASNC in 3/15 asthmatics in summer and in 11/15 in winter, as well as in 3/14 rhinitics in summer and in 4/14 in winter. eNO significantly increased after ASNC in 3/15 asthmatics in summer and in 10/15 in winter, and in 1/14 rhinitics in summer and in 4/14 in winter. A significant median increase of sputum ECP (P=0.0007) and eNO (P=0.0012) after ASNC in asthmatic and of eNO (P=0.013) in rhinitic children was also found in winter., Conclusions: Basal sputum ECP and eNO values, significantly higher before ASNC in rhinitic patients compared to control subjects, confirm the inflammatory link of upper and lower airways. The more frequent detection of inflammatory changes induced by ASNC in winter suggests that allergen exposure favours the transfer of nasal inflammation to lower airways.

We have raised a polyclonal antibody against a synthetic peptide chosen within the deduced sequence of the myotonic dystrophy gene product. This antibody binds to a protein whose molecular weight is in the range of 50-54 kDa in Western blotting of rat, rabbit and human muscles. Biochemical studies seem to indicate that this protein is a peripheral component of sarcoplasmic reticulum as well as of plasma membrane.

Calsequestrin from different muscle tissues and species has been phosphorylated by casein kinase-1 and casein kinase-2, in the conditions previously reported by Cala and Jones (J. Biol. Chem. 266, 391-398, 1991). Results indicates that rabbit cardiac and skeletal calsequestrin and frog skeletal calsequestrin are phosphorylated by both casein kinase-1 and casein kinase-2, at variance with chicken skeletal calsequestrin which is a poor substrate for both enzymes. We also observed that chicken calsequestrin is able to inhibit phosphorylation of cardiac calsequestrin, as well as other specific substrates, when added together to the assay medium.

Membrane fractions enriched in transverse tubules, either predominantly free or junctional, sarcoplasmic reticulum subfractions and purified sarcolemmal preparations have been isolated from rabbit skeletal muscle and examined for their contents of protein kinase C. Using activity measurements and immunoblotting methods, we have been able to detect substantial amounts of endogenous protein kinase C in T-tubules membranes and to a lesser extent, in muscle sarcolemma. Protein kinase C was found to be highest in junctional T-tubules and to be virtually absent from sarcoplasmic reticulum-derived membrane fractions. Immunofluorescence staining of muscle fibers is consistent with a T-tubule localization of the kinase. The T-tubule-associated protein kinase C enzyme phosphorylates several potentially important membrane proteins.

We have previously reported the amino terminal sequence of adult chicken calsequestrin, an intraluminal Ca2(+)-binding protein isolated from fast-twitch skeletal muscle. The partial sequence showed homology with mammalian calsequestrins contained in the PIR data bank and complete identity with the amino terminus of a putative laminin-binding protein of the extracellular matrix, aspartactin. Based on these data, oligonucleotide primers were synthesized for PCR amplification and direct DNA sequencing. We report herein the primary sequence of chicken calsequestrin, deduced from cDNA. The sequence has been verified by amino acid sequencing of internal tryptic peptides. Importantly, the data show the primary structure of calsequestrin to be identical to the amino acid sequence reported for aspartactin, with the exception of a single amino acid difference (ileu vs. val) which may be animal strain-related. Based on these data, calsequestrin and aspartactin are the same protein.

Calsequestrin was isolated from chicken fast-twitch skeletal muscle, and partial amino terminal sequence was determined. The sequence (NH2) EEGLNFPTYDGKDRVIDLNE shows high identity with known mammalian calsequestrins contained in the Protein Identification Resource data bank (1). Most importantly, this 20 amino acid sequence shares complete identity with the amino terminus of aspartactin, a putative laminin-binding protein of the extracellular matrix (2, 3). The possible relationship of aspartactin to calsequestrin is discussed.

It had been previously demonstrated that endoplasmic reticulum membranes from rat hepatocytes contain a major calsequestrin-like protein, on account of electrophoretic and Stains All-staining properties (Damiani et al., J. Biol. Chem. 263, 340-343). Here we show that a Ca2+-binding protein sharing characteristics in size and biochemical properties with this protein is likewise present in the isolated endoplasmic reticulum from human liver. Human calsequestrin-like protein was characterized as 62 kDa, highly acidic protein (pl 4.5), using an extraction procedure from whole tissue, followed by DEAE-Cellulose chromatography, that was originally developed for purification of skeletal muscle and cardiac calsequestrin. Liver calsequestrin-like protein bound Ca2+ at low affinity (Kd = 4 mM) and in high amounts (Bmax = 1600 nmol Ca2+/mg of protein), as determined by equilibrium dialysis, but differed strikingly from skeletal muscle calsequestrin for the lack of binding to phenyl-Sepharose resin in the absence of Ca2+, and of changes in intrinsic fluorescence upon binding of Ca2+. Thus, these results suggest that liver 62 kDa protein, in spite of its calsequestrin-like Ca2+-binding properties, does not contain a Ca2+-regulated hydrophobic site, which is a specific structural feature of the calsequestrin-class of Ca2+-binding proteins.