Pan-cancer proteomic map of 949 human cell lines

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A systematic review of the methodological quality of economic evaluations in genetic screening and testing for monogenic disorders

PurposeUnderstanding the value of genetic screening and testing for monogenic disorders requires high-quality, methodologically robust economic evaluations. This systematic review sought to assess the methodological quality among such studies and examined opportunities for improvement.MethodsWe searched PubMed, Cochrane, Embase, and Web of Science for economic evaluations of genetic screening/testing (2013-2019). Methodological rigor and adherence to best practices were systematically assessed using the British Medical Journal checklist.ResultsAcross the 47 identified studies, there were substantial variations in modeling approaches, reporting detail, and sophistication. Models ranged from simple decision trees to individual-level microsimulations that compared between 2 and >20 alternative interventions. Many studies failed to report sufficient detail to enable replication or did not justify modeling assumptions, especially for costing methods and utility values. Meta-analyses, systematic reviews, or calibration were rarely used to derive parameter estimates. Nearly all studies conducted some sensitivity analysis, and more sophisticated studies implemented probabilistic sensitivity/uncertainty analysis, threshold analysis, and value of information analysis.ConclusionWe describe a heterogeneous body of work and present recommendations and exemplar studies across the methodological domains of (1) perspective, scope, and parameter selection; (2) use of uncertainty/sensitivity analyses; and (3) reporting transparency for improvement in the economic evaluation of genetic screening/testing.     

PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity

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基于文本挖掘和生物医学数据库的新型冠状病毒肺炎药物发现

目的 基于文本挖掘技术和生物医学数据库对新型冠状病毒肺炎（COVID-19）相关文献进行数据挖掘分析，探究COVID-19及其主要症状发热、咳嗽、呼吸障碍相关基因靶点，筛选潜在有效的化学药和中药。方法 使用GenCLiP 3网站获取COVID-19和其主要症状咳嗽、发热、呼吸障碍共4个关键词的共有靶点，在METASCAPE数据库中对其进行基因本体（GO）和通路富集分析，再利用String数据库和Cytoscape软件构建共有靶点的蛋白质相互作用网络，筛选获得核心基因，运用DGIdb数据库、SymMap数据库针对核心基因进行中西医治疗药物预测。结果 获得COVID-19及其主要症状共有基因靶点28个，其中有IL2、IL1B、CCL2等核心基因16个，使用DGIdb数据库筛选获得与16个关键靶点相互作用的化学药包括沙利度胺、来氟米特、环孢素等28种，中药包括虎杖、黄芪、芦荟等70味。结论 COVID-19及其主要症状的病理机制可能和CD4、KNG1、VEGFA等28个共有基因相关，可能通过介导TNF、IL-17等信号通路参与COVID-19病理过程。潜在有效药物可能通过作用相关靶点通路起到治疗COVID-19的作用。     

Patient navigation across the cancer care continuum: An overview of systematic reviews and emerging literature

Patient navigation is a strategy for overcoming barriers to reduce disparities and to improve access and outcomes. The aim of this umbrella review was to identify, critically appraise, synthesize, and present the best available evidence to inform policy and planning regarding patient navigation across the cancer continuum. Systematic reviews examining navigation in cancer care were identified in the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, Cumulative Index of Nursing and Allied Health (CINAHL), Epistemonikos, and Prospective Register of Systematic Reviews (PROSPERO) databases and in the gray literature from January 1, 2012, to April 19, 2022. Data were screened, extracted, and appraised independently by two authors. The JBI Critical Appraisal Checklist for Systematic Review and Research Syntheses was used for quality appraisal. Emerging literature up to May 25, 2022, was also explored to capture primary research published beyond the coverage of included systematic reviews. Of the 2062 unique records identified, 61 systematic reviews were included. Fifty-four reviews were quantitative or mixed-methods reviews, reporting on the effectiveness of cancer patient navigation, including 12 reviews reporting costs or cost-effectiveness outcomes. Seven qualitative reviews explored navigation needs, barriers, and experiences. In addition, 53 primary studies published since 2021 were included. Patient navigation is effective in improving participation in cancer screening and reducing the time from screening to diagnosis and from diagnosis to treatment initiation. Emerging evidence suggests that patient navigation improves quality of life and patient satisfaction with care in the survivorship phase and reduces hospital readmission in the active treatment and survivorship care phases. Palliative care data were extremely limited. Economic evaluations from the United States suggest the potential cost-effectiveness of navigation in screening programs.     

Cribado de cáncer de pulmón: Supervivencia en un amplio programa de detección precoz en España (I-ELCAP)

IntroductionLung cancer (LC) is usually diagnosed at advanced stages with only a 12% 5-year survival. Trials as NLST and NELSON show a mortality decrease, which justifies implementation of lung cancer screening in risk population. Our objective was to show survival results of the largest LC screening program in Spain with low dosage computed tomography (LDCT).MethodsClinical records from International Early Lung Cancer Detection Program (IELCAP) at Valencia, Spain were analysed. This program recruited volunteers, ever-smokers aged 40-80 years, since 2008. Results are compared to those from other similar sizeable programs.ResultsA total of 8278 participants were screened with at least two-rounds until November 2020. A mean of 6 annual screening rounds were performed. We detected 239 tumours along 12-year follow-up. Adenocarcinoma was the most common histology, being 61.3% at stage I. The lung cancer prevalence and incidence proportion was 1.5% and 1.4%, respectively with an annual detection rate of 0.17. One-year survival and 10-year survival were 90% and 80.1%, respectively. Adherence was 96.84%.ConclusionLargest lung cancer screening in Spain shows that survival is improved when is performed in multidisciplinary team experienced in management of LC, and is comparable to similar screening programs.     

Glucose starvation induces resistance to metformin through the elevation of mitochondrial multidrug resistance protein 1

Metformin, a drug for type 2 diabetes mellitus, has shown therapeutic effects for various cancers. However, it had no beneficial effects on the survival rate of human malignant mesothelioma (HMM) patients. The present study was performed to elucidate the underlying mechanism of metformin resistance in HMM cells. Glucose‐starved HMM cells had enhanced resistance to metformin, demonstrated by decreased apoptosis and autophagy and increased cell survival. These cells showed abnormalities in mitochondria, such as decreased ATP synthesis, morphological elongation, altered mitochondrial permeability transition pore and hyperpolarization of mitochondrial membrane potential (MMP). Intriguingly, Mdr1 was significantly upregulated in mitochondria but not in cell membrane. The upregulated mitochondrial Mdr1 was reversed by treatment with carbonyl cyanide m‐chlorophenyl hydrazone, an MMP depolarization inducer. Furthermore, apoptosis and autophagy were increased in multidrug resistance protein 1 knockout HMM cells cultured under glucose starvation with metformin treatment. The data suggest that mitochondrial Mdr1 plays a critical role in the chemoresistance to metformin in HMM cells, which could be a potential target for improving its therapeutic efficacy.     

Marmoset cytochrome P450 2B6, a propofol hydroxylase expressed in liver

1. The common marmoset (Callithrix jacchus) is a useful experimental animal to evaluate the pharmacokinetics of drug candidates. Cytochrome P450 (P450) 2B enzyme in marmoset livers has been identified; however, only limited information on the enzymatic properties and distribution has been available.

2. Marmoset P450 2B6 amino acids showed high sequence identities (>86%) with those of primates including humans and cynomolgus monkeys. Phylogenetic analysis using amino acid sequences indicated that marmoset P450 2B6 was closer to human and cynomolgus monkey P450 2B6 than to P450 2B orthologs of other species, including pigs, dogs, rabbits and rodents.

3. Quantitative polymerase chain reaction analysis using specific primers showed P450 2B6 mRNA predominantly expressed in livers among the five marmoset tissues, similar to those of humans and cynomolgus monkeys.

4. Marmoset P450 2B6 heterologously expressed in Escherichia coli membranes oxidized 7-ethoxycoumarin, pentoxyresorufin, propofol and testosterone, at roughly similar rates to those of humans and/or cynomolgus monkeys. A high capacity of marmoset P450 2B6 with propofol 4-hydroxylation (at low ionic strength conditions) with a low K_m value was relatively comparable to that for marmoset livers.

5. These results collectively indicated a high propofol 4-hydroxylation activity of P450 2B6 expressed in marmoset livers.