默克制药公司

Human norovirus is a leading cause of acute gastroenteritis worldwide across all age groups, yet no licensed vaccine is available. The major capsid protein, VP1, self-assembles into highly immunogenic virus-like particles (VLPs) that have shown promise in clinical studies. Recently, mRNA has emerged as a compelling platform for norovirus vaccination. However, whether VP1-encoding mRNA can drive authentic VLP formation in human cells relevant to the vaccination environment has remained unknown. In this study, we used multiple human cell lines, including THP-1-derived macrophage-like cells, to model the post-vaccination environment. Transfection with norovirus GII.4 VP1 mRNA or lipid nanoparticle-formulated VP1 mRNA induced both intracellular and extracellular VP1 expression. Sucrose gradient purification and electron microscopy confirmed VLP assembly. These particles retained key antigenic and functional properties, including recognition by norovirus-specific antibodies in human serum and binding to histo-blood group antigens. Collectively, our findings provide direct evidence that VP1-encoding mRNA can generate structurally and functionally relevant norovirus VLPs in physiologically relevant human cell systems. These results strengthen the mechanistic rationale for mRNA-based norovirus vaccines and support their continued development.

Chronic obstructive pulmonary disease (COPD) is a lung disease that makes it hard to breathe and gets worse over time. People with COPD have damaged airways with swelling and increased mucus production. Ensifentrine is a novel agent that inhibits phosphodiesterase (PDE) 3 and PDE4, two enzymes that affect airway muscles, inflammation, and mucus removal from the lungs. This summary of research provides an overview of a previously published article on the results from the phase 3 ENHANCE trials, which studied the effect of ensifentrine in people with moderate to severe COPD who may have already been taking standard maintenance medications. Ensifentrine improved breathing, symptoms, and quality of life. It also reduced the rate and risk of flare-ups (called exacerbations) and was well tolerated. These results support the use of ensifentrine as an effective and well-tolerated treatment for people with COPD.

This is version 2.0.09 of the macromolecular CIF dictionary (mmCIF). The history and philosophy of this dictionary are described in Chapter 1.1 and a commentary on its use may be found in Chapter 3.6. The data names defined here include a modified representation of those in the core CIF dictionary (Chapter 4.1).

Standard of care (SoC) for resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is surgery with adjuvant radiotherapy (RT) or chemoradiotherapy (for tumors at high risk of recurrence). As long-term prognosis is suboptimal with SoC, this study aimed to summarize findings from recent studies comparing alternative treatments to SoC. A broad systematic literature review (search date: December 1, 2025) searched Embase, MEDLINE, and CENTRAL to identify randomized controlled trials evaluating surgery with RT and/or systemic treatments in the neoadjuvant and/or adjuvant setting in LA-HNSCC. Trials published since 2004 were included in this report if they compared interventions to SoC in terms of event-free survival (EFS) and overall survival (OS) or reported pathological response following neoadjuvant therapy. Fifty-six trials were included in the broader review, of which 25 were included in this report. Trials reporting EFS counted at least recurrence/progression and death as events, except one that did not provide a definition. Improvement in EFS (regardless of definition) was reported with the addition of perioperative pembrolizumab or addition of perioperative camrelizumab with neoadjuvant nab-paclitaxel + carboplatin to surgery + RT ± cisplatin, addition of adjuvant cetuximab or adjuvant cisplatin to surgery + RT, and addition of adjuvant nivolumab to surgery + RT + cisplatin. EFS with other interventions was comparable to SoC. OS was generally comparable between interventions and SoC. Across treatment arms with at least one neoadjuvant chemotherapy agent, pathological complete response rates ranged from 10.5

The tumor microenvironment is characterized by conditions that frequently lead to immunosuppression, allowing tumors to escape immune surveillance and potentially contributing to resistance to immuno-oncology therapeutics. A potential strategy for combination therapy with checkpoint inhibitors is to target the A(2A) and A(2B) receptors with a dual antagonist that could rescue T cells from adenosine-mediated suppression. Herein, we describe efforts toward highly potent and selective A(2A)/A(2B) dual receptor antagonists with improved pharmacokinetic and solubility profiles compared to initial lead compounds. We discovered that a 1,3-cyclobutane linker between our triazoloquinazoline core and a pendant aryl substituent decorated with a tertiary carbinamine provided a desirable balance of potency and physicochemical properties. Our lead molecule 34 demonstrated an exceptional effective half-life across multiple species. Chemistry advances guided by high-throughput experimentation (HTE) facilitated efficient, late-stage access to complex derivatives in this series.