ImportanceOlamkicept, a soluble gp130-Fc-fusion-protein, selectively inhibits interleukin 6 (IL-6) trans-signaling by binding the soluble IL-6 receptor/IL-6 complex. It has anti-inflammatory activities in inflammatory murine models without immune suppression.ObjectiveTo assess the effect of olamkicept as induction therapy in patients with active ulcerative colitis.Design, Setting, and ParticipantsRandomized, double-blind, placebo-controlled phase 2 trial of olamkicept in 91 adults with active ulcerative colitis (full Mayo score ≥5, rectal bleeding score ≥1, endoscopy score ≥2) and an inadequate response to conventional therapy. The study was conducted at 22 clinical study sites in East Asia. Patients were recruited beginning in February 2018. Final follow-up occurred in December 2020.InterventionsEligible patients were randomized 1:1:1 to receive a biweekly intravenous infusion of olamkicept 600 mg (n = 30) or 300 mg (n = 31) or placebo (n = 30) for 12 weeks.Main Outcomes and MeasuresThe primary end point was clinical response at week 12 (defined as ≥3 and ≥30% decrease from baseline total Mayo score; range, 0-12 [worst] with ≥1 decrease and ≤1 in rectal bleeding [range, 0-3 {worst}]). There were 25 secondary efficacy outcomes, including clinical remission and mucosal healing at week 12.ResultsNinety-one patients (mean age, 41 years; 25 women [27.5%]) were randomized; 79 (86.8%) completed the trial. At week 12, more patients receiving olamkicept 600 mg (17/29 [58.6%]) or 300 mg (13/30 [43.3%]) achieved clinical response than placebo (10/29 [34.5%]), with adjusted difference vs placebo of 26.6% (90% CI, 6.2% to 47.1%; P = .03) for 600 mg and 8.3% (90% CI, −12.6% to 29.1%; P = .52) for 300 mg. Among patients randomized to receive 600 mg olamkicept, 16 of 25 secondary outcomes were statistically significant compared with placebo. Among patients randomized to receive 300 mg, 6 of 25 secondary outcomes were statistically significant compared with placebo. Treatment-related adverse events occurred in 53.3% (16/30) of patients receiving 600 mg olamkicept, 58.1% (18/31) receiving 300 mg olamkicept, and 50% (15/30) receiving placebo. The most common drug-related adverse events were bilirubin presence in the urine, hyperuricemia, and increased aspartate aminotransferase levels, and all were more common in the olamkicept groups compared with placebo.Conclusions and RelevanceAmong patients with active ulcerative colitis, biweekly infusion of olamkicept 600 mg, but not 300 mg, resulted in a greater likelihood of clinical response at 12 weeks compared with placebo. Further research is needed for replication and to assess longer-term efficacy and safety.Trial RegistrationClinicalTrials.gov Identifier: NCT03235752
Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1) is believed to function as a tumor suppressor, while Phosphoinositide-3-Kinase Regulatory Subunit 2 (PIK3R2) as a tumor driver. However, there is no systematic pan-cancer analysis of them. The pan-cancer study comprehensively investigated the gene expression, genetic alteration, DNA methylation, and prognostic significance of PIK3R1 and PIK3R2 in 33 different tumors based on the TIMER, GEPIA, UALCAN, HPA, cBioPortal, and Kaplan–Meier Plotter database. The results indicated that PIK3R1 is lowly expressed in most tumors while PIK3R2 is highly expressed in most tumors, and abnormal gene expression may be related to promoter methylation. Moreover, not only mutations, downregulation of PIK3R1 and upregulation of PIK3R2 were found to be detrimental to the survival of most cancer patients as well. Furthermore, the expression of both PIK3R1 and PIK3R2 was associated with the level of immune infiltration in multiple tumors, such as breast invasive carcinoma. Our study conducted a comparatively comprehensive analysis of the role of PIK3R1 and PIK3R2 in a variety of cancers, contributing to further study of their potential mechanisms in cancer occurrence and progression. Our findings suggested that PIK3R1 and PIK3R2 could serve as prognostic markers for several cancers.
Systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease (EBV+ T-LPD) is extremely rare. Primary acute or chronic active Epstein-Barr virus infection triggers EBV+ T-LPD's onset and the disease involves clonal proliferation of infected T-cells with activated cytotoxic phenotype. The adult-onset EBV+ T-LPD (ASEBV+ T-LPD) is even rarer and needs to be extensively studied. Further, according to literature review, it is a challenge to find patients who are immunocompetent and diagnosed with ASEBV+ T-LPD involving gastrointestinal tract. This case report discusses a previously healthy middle aged woman who presented with unique symptoms mimicking inflammatory bowel disease, and required a total colectomy and terminal ileum rectomy, as reveled by endoscopic examinations, due to severe gastrointestinal bleeding. Post-surgery histopathological findings were confirmatory for the diagnosis of ASEBV+ T-LPD (II: Borderline). This patient died 7 months after the diagnosis.
There have been growing reports regarding the presence of Epstein–Barr virus (EBV) in the intestine portions of patients suffering from ulcerative colitis and Crohn’s disease, collectively termed as inflammatory bowel disease (IBD). Indeed, the prevalence of EBV infection increases in IBD patients due to prolonged employment of immunosuppressive drugs including azathioprine and infliximab. In turn, coinfection with EBV increases the propensity of development of lymphoproliferative disorders in the gastrointestinal tract including Hodgkin lymphoma, non-Hodgkin lymphomas, and lymphoepithelioma-like cholangiocarcinoma. Therefore, it is recommended that IBD patients on prolonged immunomodulator therapy should be monitored for the presence of primary intestinal lymphoproliferative diseases. Moreover, coinfection of EBV complicates the clinical course of IBD by increasing the severity, chronicity, inducing refractoriness and increasing relapse incidences. Therefore, it is recommended that antiviral drugs should be added in the conventional IBD therapy in the suspected cases of EBV infection. Research has also revealed that EBV-induced colitis is very similar to IBD and there are chances of misdiagnosis of IBD in the presence of EBV colitis. The proper diagnosis of EBV infection along with its timely treatment is necessary to avoid the severe complications in patients of IBD. The present review discusses the role of EBV coinfection in increasing the clinical complications of IBD patients.
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