Multi-national observational study to assess quality of life and treatment preferences in patients with Crohn’s perianal fistulas

BACKGROUND Patients with Crohn’s disease(CD)are at risk of developing complications such as perianal fistulas.Patients with Crohn’s perianal fistulas(CPF)are affected by fecal incontinence(FI),bleeding,pain,swelling,and purulent perianal discharge,and METHODS This cross-sectional observational study was conducted in patients with CD aged 21-90 years via a web-enabled questionnaire in seven countries(April-August 2021).Patients were recruited into three cohorts:Cohort 1 included patients without perianal fistulas;cohort 2 included patients with perianal fistulas without fistula-related surgery;and cohort 3 included patients with perianal fistulas and fistula-related surgery.Validated patient-reported outcome measures were used to assess quality of life.Drivers of treatment preferences were measured using a discrete choice experiment(DCE).RESULTS In total,929 patients were recruited(cohort 1,n=620;cohort 2,n=174;cohort 3,n=135).Short Inflammatory Bowel Disease Questionnaire scores were worse for patients with CPF(cohorts 2 and 3)than for those with CD without CPF(cohort 1):Mean score 3.8 and 3.7 vs 4.1,respectively,(P<0.001).Similarly,mean Revised FI and FI Quality of Life scores were worse for patients with CPF than for those with CD without CPF.Quality of Life with Anal Fistula scores were similar in patients with CPF with or without CPF-related surgery(cohorts 2 and 3):Mean score 41 and 42,respectively.In the DCE,postoperative discomfort and fistula healing rate were the most important treatment attributes influencing treatment choice:Mean relative importance 35.7 and 24.7,respectively.CONCLUSION The burden of illness in CD is significantly higher for patients with CPF and patients rate lower postoperative discomfort and higher healing rates as the most desirable treatment attributes.

Maintenance for healed erosive esophagitis:PhaseⅢcomparison of vonoprazan with lansoprazole

AIM To compare vonoprazan 10 and 20 mg vs lansoprazole 15 mg as maintenance therapy in healed erosive esophagitis(EE).METHODS A total of 607 patients aged ≥ 20 years, with endoscopically-confirmed healed EE following 8 wk of treatment with vonoprazan 20 mg once daily, were randomized 1:1:1 to receive lansoprazole 15 mg(n = 201), vonoprazan 10 mg(n = 202), or vonoprazan 20 mg(n = 204), once daily. The primary endpoint of the study was the rate of endoscopically-confirmed EE recurrence during a 24-wk maintenance period. The secondary endpoint was the EE recurrence rate at Week 12 during maintenance treatment. Additional efficacy endpoints included the incidence of heartburn and acid reflux, and the EE healing rate 4 wk after the initiation of maintenance treatment. Safety endpoints comprised adverse events(AEs), vital signs, electrocardiogram findings, clinical laboratory results, serum gastrin and pepsinogen Ⅰ/Ⅱ levels, and gastric mucosa histopathology results.RESULTS Rates of EE recurrence during the 24-wk maintenance period were 16.8%, 5.1%, and 2.0% with lansoprazole 15 mg, vonoprazan 10 mg, and vonoprazan 20 mg, respectively. Vonoprazan was shown to be non-inferior to lansoprazole 15 mg(P < 0.0001 for both doses). In a post-hoc analysis, EE recurrence at Week 24 was significantly reduced with vonoprazan at both the 10 mg and the 20 mg dose vs lansoprazole 15 mg(5.1% vs 16.8%, P = 0.0002, and 2.0% vs 16.8%, P < 0.0001, respectively); by contrast, the EE recurrence rate did not differ significantly between the two doses of vonoprazan(P = 0.1090). The safety profiles of vonoprazan 10 and 20 mg were similar to that of lansoprazole 15 mg in patients with healed EE. Treatment-related AEs were reported in 11.4%, 10.4%, and 10.3% of patients in the lansoprazole 15 mg, vonoprazan 10 mg, and vonoprazan 20 mg arms, respectively.CONCLUSION Our findings confirm the non-inferiority of vonoprazan 10 and 20 mg to lansoprazole 15 mg as maintenance therapy for patients with healed EE.

Activities of nicotinic acetylcholine receptors modulate neurotransmission and synaptic architecture

The cholinergic system is involved in a broad spectrum of brain function, and its failure has been implicated in Alzheimer＇s disease. Acetylcholine transduces signals through muscarinic and nicotinic acetylcholine receptors, both of which influence synaptic plasticity and cognition. However, the mechanisms that relate the rapid gating of nicotinic acetylcholine receptors to persistent changes in brain function have remained elusive. Recent evidence indicates that nicotinic acetylcholine receptors activities affect synaptic morphology and density, which result in persistent rearrangements of neural connectivity. Further investigations of the relationships between nicotinic acetylcholine receptors and rearrangements of neural circuitry in the central nervous system may help understand the pathogenesis of Alzheimer＇s disease.

Vonoprazan 10 mg or 20 mg vs.lansoprazole 15 mg as maintenance therapy in Asian patients with healed erosive esophagitis:A randomized controlled trial

Background:Erosive esophagitis(EE)is a gastroesophageal reflux disease characterized by mucosal breaks in the esophagus.Proton pump inhibitors are widely used as maintenance therapy for EE,but many patients still relapse.In this trial,we evaluated the noninferiority of vonoprazan vs.lansoprazole as maintenance therapy in patients with healed EE.Methods:We performed a double-blind,double-dummy,multicenter,phase 3 clinical trial among non-Japanese Asian adults with endoscopically confirmed healed EE from April 2015 to February 2019.Patients from China,South Korea,and Malaysia were randomized to vonoprazan 10 mg or 20 mg once daily or lansoprazole 15 mg once daily for 24 weeks.The primary endpoint was endoscopically confirmed EE recurrence rate over 24 weeks with a noninferiority margin of 10%using a two-sided 95%confidence interval(CI).Treatment-emergent adverse events(TEAEs)were recorded.Results:Among 703 patients,EE recurrence was observed in 24/181(13.3%)and 21/171(12.3%)patients receiving vonoprazan 10 mg or 20 mg,respectively,and 47/184(25.5%)patients receiving lansoprazole(differences:-12.3%[95%CI,-20.3%to-4.3%]and-13.3%[95%CI,-21.3%to-5.3%],respectively),meeting the primary endpoint of noninferiority to lansoprazole in preventing EE recurrence at 24 weeks.Evidence of superiority(upper bound of 95%CI<0%)was also observed.At 12 weeks,endoscopically confirmed EE recurrence was observed in 5/18,2/20,and 7/20 of patients receiving vonoprazan 10 mg,vonoprazan 20 mg,and lansoprazole,respectively.TEAEs were experienced by 66.8%(157/235),69.0%(156/226),and 65.3%(158/242)of patients receiving vonoprazan 10 mg,vonoprazan 20 mg,and lansoprazole,respectively.The most common TEAE was upper respiratory tract infection in 12.8%(30/235)and 12.8%(29/226)patients in vonoprazan 10 mg and 20 mg groups,respectively and 8.7%(21/242)patients in lansoprazole group.Conclusion:Vonoprazan maintenance therapy was well-tolerated and noninferior to lansoprazole for preventing EE recurrence in Asian patients with healed EE.Trial Registration:https://clinicaltrials.gov;NCT02388737.

Cell:研究揭示SIRT3在调节线粒体健康中的关键作用

就蛋白而言，去乙酰化酶（sirtuin）是令人喜欢的，而且因它们与衰老和年龄相关疾病相关联而受到人们的广泛关注。作为去乙酰化酶的来源，线粒体，也因在健康和疾病中的作用而闻名于世。来自美国哈佛医学院的Marcia Haigis和她的团队从事基础研究。提出了一个较为深刻的问题：在细胞中。哪些蛋白与去乙酰化酶进行交谈？

Synthetic biology approaches for improving the specificity and efficacy of cancer immunotherapy

Immunotherapy has shown robust efficacy in treating a broad spectrum of hematological and solid cancers.Despite the transformative impact of immunotherapy on cancer treatment,several outstanding challenges remain.These challenges include on-target off-tumor toxicity,systemic toxicity,and the complexity of achieving potent and sustainable therapeutic efficacy.Synthetic biology has emerged as a promising approach to overcome these obstacles,offering innovative tools for engineering living cells with customized functions.This review provides an overview of the current landscape and future prospects of cancer immunotherapy,particularly emphasizing the role of synthetic biology in augmenting its specificity,controllability,and efficacy.We delineate and discuss two principal synthetic biology strategies:those targeting tumor surface antigens with engineered immune cells and those detecting intratumoral disease signatures with engineered gene circuits.This review concludes with a forwardlooking perspective on the enduring challenges in cancer immunotherapy and the potential breakthroughs that synthetic biology may contribute to the field.