Proteomics analysis of lysine crotonylation and 2-hydroxyisobutyrylation reveals significant features of systemic lupus erythematosus

Introduction/objectives

To seek significant features of systemic lupus erythematosus (SLE) by utilizing bioinformatics analysis.

Method

Liquid chromatography-tandem mass spectrometry (LC–MS/MS) was used to quantify lysine crotonylation (Kcr) and lysine 2-hydroxyisobutyrylation (Khib) in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) patients and normal controls.

Results

Seventy-six differentially modified proteins (DMPs) dually modified by Kcr and Khib were identified between SLE patients and healthy people. GO enrichment analysis prompted significant enrichment of seventy-six DMPs in MHC class II protein complex binding and leukocyte migration. KEGG pathways were enriched in antigen processing and presentation pathway and leukocyte transendothelial migration pathway. Six DMPs (CLTC, HSPA1B, HSPA8, HSP90AB1, HSPD1, and PDIA3) were identified in antigen processing and presentation pathway, of which HSPA8 was the core protein. Significant changes of Kcr and Khib in HSPA8 may increase ATP hydrolysis and promote antigen binding to MHC II molecule. In leukocyte transendothelial migration pathway, 7 DMPs (ACTN1, ACTN4, EZR, MSN, RAC1, RHOA, and VCL) were identified. MSN was the protein with the most modification sites in this pathway. In amino terminal ferm region of MSN, Kcr and Khib expression change may lead to the adhesion between leukocytes and endothelial cells, which was an important step of leukocyte migration.

Conclusion

Kcr and Khib may promote the antigen presentation and jointly regulate the tissue damage mediated by leukocyte migration in SLE patients, which may play key roles in the pathogenesis of SLE probably.

DCE-MRI诊断原发性肝癌效能和TACE术后评估肿瘤活性应用价值研究*

目的 探讨动态对比增强磁共振成像(DCE-MRI)检查诊断原发性肝癌(PLC)患者的效能及评价疗效的价值。方法 2017年1月～2021年6月我院诊治的肝占位性病变患者68例,均接受DCE-MRI检查,并行穿刺细胞学检查诊断,应用临床流行病学基本技术评估MRI诊断的效能。所有PLC患者接受经皮肝动脉化疗栓塞术(TACE)治疗,术后再次接受MRI检查,评估疗效。结果 DCE-MRI检查显示PLC患者肝内特征性恶性肿瘤表现,T1WI序列为低信号,T2WI序列为高信号,动脉期明显强化,门脉期快速消退,偶见明显的肿瘤包膜;在68例肝占位性病变患者,经穿刺细胞学检查,诊断PLC患者64例,非肿瘤病变4例;DCE-MRI检查诊断的灵敏度、特异度、准确率、阳性和阴性预测值分别为95.2%、75.0%、89.7%、93.8%和25.0%;在TACE术后,MRI检查发现肿瘤被完全灭活18例(28.1%),部分灭活25例(39.1%),肿瘤稳定15例(23.4%),疾病进展6例(9.3%)。结论 DCE-MRI检查在诊断PLC和治疗后疗效判断方面有独特的作用,可指导临床制定治疗方案,价值很大。     

The China birth cohort study (CBCS)

European Journal of Epidemiology - The China birth cohort study (CBCS) is a prospective longitudinal, mega-cohort study and the first national-based birth cohort study, aiming to establish a birth...     

菊花脑芳樟醇合酶基因CnTPS1的克隆与原核表达分析＊

目的 克隆菊花脑芳樟醇合酶基因CnTPS1的全长编码序列，利用原核系统表达融合蛋白，为进一步研究该基因在菊花脑萜类合成中的功能提供理论依据。方法 以菊花脑基因组数据为基础，设计特异性引物，PCR扩增CnTPS1的全长编码序列，利用生物信息学分析软件分析序列特征。利用qRT-PCR技术分析CnTPS1基因在不同组织中的基因表达量。构建原核表达载体，体外诱导目的蛋白表达。结果 CnTPS1编码序列全长1749bp，编码582个氨基酸；基因表达模式分析表明该基因在茎和管状花中表达量较高；原核表达系统能诱导出67.58kDa大小的蛋白。结论 首次从菊花脑中克隆得到一个芳樟醇合酶基因CnTPS1，运用生物信息学方法对其编码蛋白的理化性质、结构特征等进行了分析预测，分析了该基因的组织表达模式，并在原核表达系统中成功诱导表达出目标蛋白，这些结果将为菊花脑萜类合酶基因的功能以及萜类物质生物合成途径的解析提供理论依据。     

First-line nivolumab plus chemotherapy vs chemotherapy in patients with advanced gastric,gastroesophageal junction and esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis

First-line chemotherapy for advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric/gastroesophageal junction cancer (GC/GEJC) has poor median overall survival (OS; <1 year). We report efficacy and safety results from Chinese patients in the phase III global CheckMate 649 study of nivolumab plus chemotherapy vs chemotherapy for the first-line treatment of GC/GEJC/esophageal adenocarcinoma (EAC). Chinese patients with previously untreated advanced or metastatic GC/GEJC/EAC were randomized to receive nivolumab (360 mg Q3W or 240 mg Q2W) plus chemotherapy (XELOX [capecitabine and oxaliplatin] Q3W or FOLFOX [oxaliplatin, leucovorin and 5-fluorouracil] Q2W), nivolumab plus ipilimumab (not reported) or chemotherapy alone. OS, blinded independent central review-assessed progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and safety are reported. Of 1581 patients enrolled and randomized, 208 were Chinese. In these patients, nivolumab plus chemotherapy resulted in clinically meaningful improvement in median OS (14.3 vs 10.2 months; HR 0.61 [95% CI: 0.44-0.85]), median PFS (8.3 vs 5.6 months; HR 0.57 [95% CI: 0.40-0.80]), ORR (66% vs 45%) and median DOR (12.2 vs 5.6 months) vs chemotherapy, respectively. The safety profile was acceptable, with no new safety signals observed. Consistent with results from the global primary analysis of CheckMate 649, nivolumab plus chemotherapy demonstrated a clinically meaningful improvement in OS and PFS and higher response rate vs chemotherapy and an acceptable safety profile in Chinese patients. Nivolumab plus chemotherapy represents a new standard first-line treatment for Chinese patients with non-HER2-positive advanced GC/GEJC/EAC.     

Chronic acidosis rewires cancer cell metabolism through PPARα signaling

The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that adaptation to growth at an extracellular pH (pH_e) mimicking acidic tumor niches is associated with upregulated net acid extrusion capacity and elevated intracellular pH at physiological pH_e, but not at acidic pH_e. Using metabolic profiling, shotgun lipidomics, imaging and biochemical analyses, we show that the acid adaptation-induced phenotype is characterized by a shift toward oxidative metabolism, increased lipid droplet-, triacylglycerol-, peroxisome content and mitochondrial hyperfusion. Peroxisome proliferator-activated receptor-α (PPARA, PPARα) expression and activity are upregulated, at least in part by increased fatty acid uptake. PPARα upregulates genes driving increased mitochondrial and peroxisomal mass and β-oxidation capacity, including mitochondrial lipid import proteins CPT1A, CPT2 and SLC25A20, electron transport chain components, peroxisomal proteins PEX11A and ACOX1, and thioredoxin-interacting protein (TXNIP), a negative regulator of glycolysis. This endows acid-adapted cancer cells with increased capacity for utilizing fatty acids for metabolic needs, while limiting glycolysis. As a consequence, the acid-adapted cells exhibit increased sensitivity to PPARα inhibition. We conclude that PPARα is a key upstream regulator of metabolic changes favoring cancer cell survival in acidic tumor niches.     

Perceived benefits of geriatric specialty telemedicine among rural patients and caregivers

Objective

Explore the perceived benefits of a Veterans Health Administration (VHA) geriatric specialty telemedicine service (GRECC Connect) among rural, older patients and caregivers to contribute to an assessment of its quality and value.

Data Sources

In Spring 2021, we interviewed a geographically diverse sample of rural, older patients and their caregivers who participated in GRECC Connect telemedicine visits.

Study Design

A cross-sectional qualitative study focused on patient and caregiver experiences with telemedicine, including perceived benefits and challenges.

Data Collection

We conducted 30 semi-structured qualitative interviews with rural, older (≥65) patients enrolled in the VHA and their caregivers via videoconference or phone. Interviews were recorded, transcribed, and analyzed using a rapid qualitative analysis approach.

Principal Findings

Participants described geriatric specialty telemedicine visits focused on cognitive assessments, tailored physical therapy, medication management, education on disease progression, support for managing multiple comorbidities, and suggestions to improve physical functioning. Participants reported that, in addition to prescribing medications and ordering tests, clinicians expedited referrals, coordinated care, and listened to and validated both patient and caregiver concerns. Perceived benefits included improved patient health; increased patient and caregiver understanding and confidence around symptom management; and greater feelings of empowerment, hopefulness, and support. Challenges included difficulty accessing some recommended programs and services, uncertainty related to instructions or follow-up, and not receiving as much information or treatment as desired. The content of visits was well aligned with the domains of the Age-Friendly Health Systems and Geriatric 5Ms frameworks (Medication, Mentation, Mobility, what Matters most, and Multi-complexity).

Conclusions

Alignment of patient and caregiver experiences with widely-used models of comprehensive geriatric care indicates that high-quality geriatric care can be provided through virtual modalities. Additional work is needed to develop strategies to address challenges and optimize and expand access to geriatric specialty telemedicine.