The Makorin ring finger protein 1 (MKRN1) gene, also called RNF61, is located on the long arm of chromosome 7 and is a member of the RING finger protein family. The E3 ubiquitin ligase MKRN1 is closely linked to tumour development, but the exact mechanism needs to be elucidated. In this study, we aimed to investigate the specific mechanism and role of MKRN1 in colorectal cancer (CRC) development. MKRN1 expression in CRC was analysed using the Cancer Cell Line Encyclopaedia and the Cancer Genome Atlas (TCGA) databases. Rectal tumour tissues were frozen to explore the MKRN1 expression in CRC and its clinical significance. The impact of MKRN1 on CRC cell proliferation and migration was observed using CCK8, colony formation, wound healing, and transwell assays. A combination of MKRN1 quantitative proteomics, ubiquitination modification omics analysis, and a string of in vitro and in vivo experiments revealed the potential mechanisms by which MKRN1 regulates CRC metastasis. MKRN1 expression was significantly elevated in CRC tissues compared to paracancerous tissues and was positively linked with prognosis (P < 0.01). MKRN1 downregulation inhibits CRC cell proliferation, migration, and invasion. Conversely, MKRN1 overexpression promotes the proliferation, migration, and invasion of CRC cells. Mechanistically, MKRN1 induces epithelial-mesenchymal transition (EMT) in CRC cells via ubiquitination and degradation of Smad nuclear-interacting protein 1 (SNIP1). Furthermore, SNIP1 inhibits transforming growth factor-β (TGF-β) signalling, and MKRN1 promotes TGF-β signalling by degrading SNIP1 to induce EMT in CRC cells. Finally, using conditional knockout mice, intestinal lesions and metastatic liver microlesions were greatly reduced in the intestinal knockout MKRN1 group compared to that in the control group. High MKRN1 levels promote TGF-β signalling through ubiquitination and degradation of SNIP1, thereby facilitating CRC metastasis, and supporting MKRN1 as a CRC pro-cancer factor. The MKRN1/SNIP1/TGF-β axis may be a potential therapeutic target in CRC.

IntroductionMonoclonal antibodies (mAbs) against cytokines and chemokines or their receptors promise to be a potential therapeutic option to address chronic obstructive pulmonary disease (COPD). We aim to provide a comprehensive literature review of the improvement in FEV1 and safety when comparing mAbs with conventional dichotomous agents.MethodsWe systematically searched 3 electronic databases (PubMed, EMBASE, and CENTRAL) up to August 1, 2023 to collect eligible randomized controlled trials (RCTs). A frequentist network meta-analysis using a random-effects model was deployed to calculate mean differences (MD) for FEV1, relative risk (RR) of treatment-emergent adverse events (TEAEs), and estimate the surface under cumulative rankings (SUCRA). A higher SUCRA indicates a better outcome.ResultsThis study included 23 RCTs involving a total of 20,853 patients. Overall, except for Dupilumab, mAbs did not significantly improve FEV1 compared to traditional conventional dichotomous agents. Among all the interventions included, Aclidinium bromide/Formoterol (AB/FF) (SUCRA 97.7%) ranked highest, followed by Umeclidinium/vilanterol (UMEC/VI) (SUCRA 93.5%), and Glycopyrrolate Formoterol Fumarate (GFF) (SUCRA 84.7%). Dupilumab (SUCRA 66.9%) ranked the fourth among all interventions but ranked the first among all the mAbs. Importantly, all mAbs demonstrated a good safety profile compared with placebo.ConclusionConsidering the improvement in FEV1 and its safety, the development of mAbs for COPD still holds significant clinical potential.Systematic review registrationPROSPERO, CRD42023452714.

Staphylococcus aureus can cause localized infections such as abscesses and pneumonia, as well as systemic infections such as bacteremia and sepsis. Especially, methicillin-resistant S. aureus often presents multidrug resistance, which becomes a major clinical challenge. One of the most common reasons for methicillin-resistant S. aureus antibiotic resistance is the presence of biofilms. Natural antimicrobial peptides derived from different species have shown effectiveness in combating S. aureus biofilms. In this review, we summarize the inhibitory activity of antimicrobial peptides against S. aureus planktonic cells and biofilms. We also summarize the possible inhibitory mechanisms, involving cell adhesion inhibition, membrane fracture, biofilm disruption and DNA disruption. We believe this can provide the basis for further research against S. aureus biofilm-associated infections.

Heparan sulfate (HS) is a major component of cell surface glycocalyx with extensive negative charges and plays a protective role by preventing toxins, including small molecule drugs and anticancer cationic lytic peptides (ACLPs), from cells. However, this effect may compromise the treatment efficiency of anticancer drugs. To overcome the impedance of cancer cell glycocalyx, an HS-targeting ACLP PTP-7z was designed by fusion of an ACLP and a Zn2+-binding HS-targeting peptide. Upon Zn2+ ion binding, PTP-7z could self-assemble into uniform nanoparticles and show improved serum stability and reduced hemolysis, which enable it to self-deliver to tumor sites. The peptide PTP-7z showed a pH- and Zn2+ ion-dependent HS-binding ability, which triggers the HS-induced in situ self-assembling on the cancer cell surface in the acidic tumor microenvironment (TME). The self-assembled PTP-7z can overcome the impedance of cell glycocalyx by either disrupting cell membranes or translocating into cells through endocytosis and inducing cell apoptosis. Moreover, PTP-7z can also inhibit cancer cell migration. These results proved that HS-responsive in situ self-assembling is a practical strategy to overcome the cancer cell glycocalyx barrier for ACLPs and could be extended to the design of other peptide drugs to promote their in vivo application.

Secreted chemokines form concentration gradients in target tissues to control migratory directions and patterns of immune cells in response to inflammatory stimulation; however, how the gradients are formed is much debated. Heparan sulfate (HS) binds to chemokines and modulates their activities. In this study, we investigated the roles of HS in the gradient formation and chemoattractant activity of CCL5 that is known to bind to HS. CCL5 and heparin underwent liquid–liquid phase separation and formed gradient, which was confirmed using CCL5 immobilized on heparin-beads. The biological implication of HS in CCL5 gradient formation was established in CHO-K1 (wild-type) and CHO-677 (lacking HS) cells by Transwell assay. The effect of HS on CCL5 chemoattractant activity was further proved by Transwell assay of human peripheral blood cells. Finally, peritoneal injection of the chemokines into mice showed reduced recruitment of inflammatory cells either by mutant CCL5 (lacking heparin-binding sequence) or by addition of heparin to wild-type CCL5. Our experimental data propose that co-phase separation of CCL5 with HS establishes a specific chemokine concentration gradient to trigger directional cell migration. The results warrant further investigation on other heparin-binding chemokines and allows for a more elaborate insight into disease process and new treatment strategies.

The structural components of the thymus are essential for guiding T cell development, but a thorough spatial view is still absent. Here we develop the TSO-his tool, designed to integrate multimodal data from single-cell and spatial transcriptomics to decipher the intricate structure of human thymus. Specifically, we characterize dynamic changes in cell types and critical markers, identifying ELOVL4 as a mediator of CD4+ T cell positive selection in the cortex. Utilizing the mapping function of TSO-his, we reconstruct thymic spatial architecture at single-cell resolution and recapitulates classical cell types and their essential co-localization for T cell development; additionally, previously unknown co-localization relationships such as that of CD8 alpha alpha with memory B cells and monocytes are identified. Incorporating VDJ sequencing data, we also delineate distinct intermediate thymocyte states during alpha beta T cell development. Overall, these insights enhance our understanding of thymic biology and may inform therapeutic interventions targeting T cell-mediated immune responses. Thymus is important for shaping T cell immunity, but spatial insights at cellular and molecular level are still scarce. Here the author use multi-omics approaches and custom algorithms to reconstruct the spatial organization of human thymi for both confirming known features and unrevealing new components during thymocyte maturation.

Background Multiple myeloma (MM) is the most aggressive and prevalent primary malignant tumor within the blood system, and can be classified into grades RISS-I, II, and III. High-grade tumors are associated with decreased survival rates and increased recurrence rates. To better understand metabolic disorders and expand the potential targets for MM, we conducted large-scale untargeted metabolomics on plasma samples from MM patients and healthy controls (HC). Methods Our study included thirty-three HC, thirty-eight newly diagnosed MM patients (NDMM) categorized into three RISS grades (grade I: n = 5; grade II: n = 19; grade III: n = 8), and ninety-two MM patients post-targeted therapy with bortezomib-based regimens. Metabolites were analyzed and identified using ultra high liquid chromatography coupled with Q Orbitrap mass spectrometry (UPLC-HRMS), followed by verification through a self-built database. Results Compared with HC participants, seventy metabolites, primarily associated with the citrate cycle, amino acids and glycerophospholipid/sphingolipid metabolism, and nine metabolic pathways (citrate cycle, choline metabolism, glyceropholipid metabolism, sphingolipid metabolism, valine, leucine and isoleucine biosynthesis, etc.) exhibited significant changes in NDMM. Notably, lactic acid and leucine have emerged not only as diagnostic biomarkers but also as markers for tumor monitoring in staging and prognosis, respectively. Conclusion Our findings on key metabolites and metabolic pathways provide novel insights into the exploration of diagnostic and therapeutic targets for MM. A prospective study is essential to validate these discoveries for future MM patient care.

BackgroundPatients with Chronic Obstructive Pulmonary Disease (COPD) frequently face substantial medication burdens. Follow-up care on medication management is critical in achieving disease control. This study aimed to analyze the complexity of COPD-specific medication and determine how it impacted patients’ attendance on follow-up care.MethodsThis multicenter study includes patients with COPD from 1,223 hospitals across 29 provinces in China from January 2021 to November 2022. The medication Regimen Complexity Index (MRCI) score was used to measure COPD-specific medication complexity. The association between medication complexity and follow-up care attendance was evaluated using the Cox Proportional Hazard Model.ResultsAmong 16,684 patients, only 2,306 (13.8%) returned for follow-up medication management. 20.3% of the patients had high complex medication regimen (MRCI score >15.0). The analysis revealed that compared to those with less complex regimens, patients with more complex medication regimens were significantly less likely to attend the follow-up medication care, with a Hazard Ratio (HR) of 0.82 (95% Confidence Interval [CI], 0.74–0.91). Specifically, patients with more complex dosage forms were 51% less likely to attend the follow-up care (95% CI, 0.43–0.57). This pattern was especially marked among male patients, patients younger than 65 years, and those without comorbid conditions.ConclusionHigher medication complexity was associated with a decreased likelihood of attending follow-up care. To promote care continuity in chronic disease management, individuals with complex medication regimens should be prioritized for enhanced education. Furthermore, pharmacists collaborating with respiratory physicians to deprescribe and simplify dosage forms should be considered in the disease management process.

AbstractMounting clinical evidence suggests that a comprised intestinal barrier contributes to the progression of nonalcoholic steatohepatitis (NASH); nevertheless, the precise mechanism remains elusive. This study unveils a significant upregulation of nuclear receptor‐binding SET domain protein 2 (NSD2) in the intestines of obese humans and mice subjected to a high‐fat cholesterol diet (HFCD). Intestine‐specific NSD2 knockout attenuated the progression of intestinal barrier impairment and NASH, whereas NSD2 overexpression exacerbated this progression. Mechanistically, NSD2 directly regulates the transcriptional activation of Ern1 by demethylating histone H3 at lysine 36 (H3K36me2), thus activating the ERN1–JNK axis to intensify intestinal barrier impairment and subsequently foster NASH progression. These findings elucidate the crucial role of NSD2‐mediated H3K36me2 in intestinal barrier impairment, suggesting that targeting intestinal NSD2 can represent a novel therapeutic approach for NASH.

目的:研究奈玛特韦片/利托那韦片组合包装(以下简称"奈马特韦/利托那韦")与伏立康唑联合应用时,是否会影响伏立康唑的暴露量.方法:回顾性纳入国家呼吸医学中心2022年12月至2023年1月北京新型冠状病毒感染暴发期间同时使用伏立康唑和奈马特韦/利托那韦的患者,对药物剂量、联合用药情况、伏立康唑血药浓度测定和不良反应进行记录和分析.结果:共纳入14例患者的17个伏立康唑血药浓度监测结果.仅有1例患者伏立康唑血药浓度偏低,2例患者超过治疗上限的50％,多数患者的伏立康唑血药浓度均在治疗范围内;具有基线伏立康唑浓度数据的7例患者中,除1例患者因浓度过高减量外,其余患者联合用药时浓度均与基线浓度类似或略高.与同期其他伏立康唑血药浓度数据比较,联合治疗中伏立康唑血药浓度偏高的比例略有增加.未发现可归因于两药的不良反应.结论:与药品说明书标示不同,在我国人群中,伏立康唑与奈马特韦/利托那韦的联合应用是可行的,并建议监测血药浓度,以保证用药安全性和有效性.

Purpose:Pharmacists are key members of the pain management interdisciplinary team in many developed countries. However, the implementation of clinical pharmacy services in pain management is impeded by the imbalance between the pain physicians and clinical pharmacists specializing in pain management in China. The purpose of this study was to elucidate the perceptions, expectations and current experience of Chinese pain physicians regarding clinical pharmacy services.Patients and Methods:An anonymous, self-administered questionnaire was designed according to previously published studies with minor modifications and distributed online to 1100 pain physicians selected randomly in hospitals across all 31 provinces of mainland China in 2021. Data were analyzed using descriptive and inferential statistics.Results:A total of 1071 valid questionnaires were included for analysis. The pain physicians were from all 31 provinces of mainland China and most of them were from tertiary hospitals holding an undergraduate degree. Among listed kinds of clinical pharmacy services, pain physicians were less comfortable with pharmacists treating minor illnesses (p < 0.001). Pain physicians' experiences with clinical pharmacy services were far less than their expectations (p < 0.001), which is in line with the results that most of pain physicians (65.9%) interacted with pharmacists at a frequency of less than once a week. Significant differences in the experiences were found among ages (p < 0.01) and among years of work experience (p < 0.05) of pain physicians. Pain physicians' expectations of pharmacists were positively correlated with their experiences with clinical pharmacy services (p < 0.001).Conclusion:Pain physicians in China had positive perceptions and high expectations, but relatively low experiences regarding clinical pharmacy services. Expanding clinical pharmacist pain management credentialing and increasing pain physicians' exposure to clinical pharmacy services are favourable to support the interdisciplinary collaboration in pain management in China.

目的 为肺移植患者联用伏立康唑后他克莫司的剂量调整提供依据.方法 回顾性收集2020年1月至2022年12月在我院联合使用了伏立康唑和他克莫司的肺移植患者资料.采用SPSS 21.0软件分析伏立康唑对他克莫司谷浓度、日剂量和标准化血药浓度的影响,并对可能影响他克莫司标准化血药浓度的因素进行多元线性回归分析.结果 共纳入肺移植患者153例.联用伏立康唑后,患者使用的他克莫司平均日剂量从3.37 mg降至0.76 mg,谷浓度和标准化血药浓度均显著升高(P＜0.0001).伏立康唑日剂量与他克莫司标准化血药浓度呈显著负相关(P=0.0001,r=-0.224);伏立康唑谷浓度与他克莫司谷浓度(P＜0.0001,r=0.316)、标准化血药浓度(P＜0.0001,r=0.249)均呈显著正相关.联用伏立康唑后,单肺移植患者的他克莫司标准化血药浓度显著高于双肺移植患者,且口服伏立康唑后他克莫司的标准化血药浓度显著高于静脉滴注伏立康唑后(P＜0.05);大部分肝肾功能指标均无显著变化.多因素回归分析结果显示,伏立康唑谷浓度对他克莫司标准化血药浓度具有显著影响(P＜0.001).结论 伏立康唑谷浓度对他克莫司的血药浓度和剂量调整影响较大,是影响他克莫司血药浓度的独立因素.临床应在联合伏立康唑后对他克莫司减量,同时对两药进行治疗药物监测.

随着医疗器械审评审批制度改革的不断深化,医疗器械创新的不断发展,国家对于医疗器械临床试验的监管也更加科学和完善.本研究以医疗器械临床试验机构备案管理信息系统数据和国家政务公开网站数据为基础,从备案机构数量及地域分布、备案机构级别、备案专业、备案主要研究者以及医疗器械临床试验开展情况等方面进行系统分析,以展示我国医疗器械临床试验机构的发展现状.分析结果显示,医疗器械临床试验备案机构数量逐年上涨,反映出对医疗器械临床试验重视程度越来越高,但医疗器械临床试验机构地域分布和临床试验开展数量仍然存在分布不均衡的现象.随着利好政策密集出台,我国医疗器械临床试验未来势必向着全方位、广覆盖、多层级的方向发展.

The World Health Organization has recently published a list of 12 drug-resistant bacteria that posed a significant threat to human health, and Pseudomonas aeruginosa (P. aeruginosa) was among them. In China, P. aeruginosa is a common pathogen in hospital acquired pneumonia, accounting for 16.9-22.0%. It is a ubiquitous opportunistic pathogen that can infect individuals with weakened immune systems, leading to hospital-acquired acute and systemic infections. The excessive use of antibiotics has led to the development of various mechanisms in P. aeruginosa to resist conventional drugs. Thus, there is an emergence of multidrug-resistant strains, posing a major challenge to conventional antibiotics and therapeutic approaches. Antimicrobial peptides are an integral component of host defense and have been found in many living organisms. Most antimicrobial peptides are characterized by negligible host toxicity and low resistance rates, making them become promising for use as antimicrobial products. This review particularly focuses on summarizing the inhibitory activity of natural antimicrobial peptides against P. aeruginosa planktonic cells and biofilms, as well as the drug interactions when these peptides used in combination with conventional antibiotics. Moreover, the underlying mechanism of these antimicrobial peptides against P. aeruginosa strains was mainly related to destroy the membrane structure through interacting with LPS or increasing ROS levels, or targeting cellular components, leaded to cell lysis. Hopefully, this analysis will provide valuable experimental data on developing novel compounds to combat P. aeruginosa.