Individualized medicine 2010

Molecular and cell biology have revolutionized not only diagnosis, therapy and prevention of human diseases but also greatly contributed to the understanding of their pathogenesis. Based on modern molecular and biochemical methods it is possible to identify on the one hand point mutations and single nucleotide polymorphisms. On the other hand, using high throughput array technologies, it is possible to analyse thousands of genes or gene products simultaneously, resulting in an individual gene or gene expression profile (signature). These data increasingly allow to define the individual risk for a given disease and to predict the individual prognosis of a disease as well as the efficacy of therapeutic strategies (individualized medicine). In the following sections some of the recent advances of predictive medicine and their clinical relevance will be addressed.     

Metastatic risk and resistance to BRAF inhibitors in melanoma defined by selective allelic loss of ATG5

Melanoma is a paradigm of aggressive tumors with a complex and heterogeneous genetic background. Still, melanoma cells frequently retain developmental traits that trace back to lineage specification programs. In particular, lysosome-associated vesicular trafficking is emerging as a melanoma-enriched lineage dependency. However, the contribution of other lysosomal functions such as autophagy to melanoma progression is unclear, particularly in the context of metastasis and resistance to targeted therapy. Here we mined a broad spectrum of cancers for a meta-analysis of mRNA expression, copy number variation and prognostic value of 13 core autophagy genes. This strategy identified heterozygous loss of ATG5 at chromosome band 6q21 as a distinctive feature of advanced melanomas. Importantly, partial ATG5 loss predicted poor overall patient survival in a manner not shared by other autophagy factors and not recapitulated in other tumor types. This prognostic relevance of ATG5 copy number was not evident for other 6q21 neighboring genes. Melanocyte-specific mouse models confirmed that heterozygous (but not homozygous) deletion of Atg5 enhanced melanoma metastasis and compromised the response to targeted therapy (exemplified by dabrafenib, a BRAF inhibitor in clinical use). Collectively, our results support ATG5 as a therapeutically relevant dose-dependent rheostat of melanoma progression. Moreover, these data have important translational implications in drug design, as partial blockade of autophagy genes may worsen (instead of counteracting) the malignant behavior of metastatic melanomas.     

新发缺血性脑卒中患者实施单病种质量管理的预后评价

目的 调查分析上海市某三甲医院缺血性脑卒中单病种质量管理实施情况并评价其效果。方法 采用回顾性调查的方法,以NIHSS评分为疗效评价依据,对新发缺血性脑卒中单病种质量管理实施组和未实施组的预后情况进行分析评估。结果 在2组基线资料均衡的情况下,缺血性脑卒中单病种质量管理实施组的疗效显著优于未实施组,尤其是发病初始疾病严重程度一般者的疗效最好。结论 缺血性脑卒中单病种质量管理通过对诊疗过程的质量控制,规范了诊疗行为,改善了新发缺血性脑卒中患者的预后。     

Prognostic significance of the systemic immune‐inflammation index in pancreatic carcinoma patients: a meta-analysis

Background: Systemic immune-inflammation index (SII) is a prognostic indicator for several malignancies, including pancreatic carcinoma; however, there is no consensus on its significance. In the current study, a systematic meta-analysis was used to explore the correlation between SII and prognosis in pancreatic carcinoma patients.Methods: PubMed, Embase and Cochrane Library databases were screened from inception to May 2020. Studies describing the prognostic role of SII in pancreatic carcinoma were then retrieved. The pooled hazard ratio (HR) and 95% confidence interval (CI) was calculated using random- or fixed-effects models to determine the correlation between SII and prognosis.Results: A total of four studies, comprising 1749 patients, met the inclusion criteria of the study and were therefore included in this meta-analysis. The meta-analysis showed that high SII indicated was correlated with worse overall survival (OS) in patients with pancreatic carcinoma (HR: 1.43, 95% CI: 1.24–1.65, P<0.001). These findings were validated through subgroup analyses, stratified by the American Joint Committee on Cancer (AJCC) stage. In addition, patients with high SII showed poorer cancer-specific survival (HR: 2.32, 95% CI: 1.55–3.48, P<0.001). However, analysis showed no significant correlations between SII and disease-free and relapse-free survival (RFS).Conclusion: These findings indicate that SII is a potential non-invasive and a promising tool for predicting clinical outcomes of pancreatic carcinoma patients. However, the current research did not explore whether neoadjuvant therapy has an effect on the prognostic value of SII. Further studies using adequate designs and larger sample sizes are required to validate these findings.     

Circulating and tissue microRNAs as a potential diagnostic biomarker in patients with thrombotic events

Venous and arterial thrombosis are conditions that have a considerable burden if left untreated. The hypoxia-induced by the occluded vessel can disrupt the circulation of any organ, the cornerstone of treating thrombosis is rapid diagnosis and appropriate treatment. Diagnosis of thrombosis may be made by using laboratory tests or imaging techniques in individuals who have clinical manifestations of a thrombotic event. The use of serum micro ribonucleic acids (RNAs) has recently been applied to the diagnosis of thrombosis. These small RNA molecules are emerging as new diagnostic markers but have had very limited applications in vascular disease. Most of the articles provided various microRNAs with different levels of accuracy. However, there remains a lack of an appropriate panel of the most specific microRNA in the literature. The purpose of the present review was to summarize the existing data on the use of microRNAs as a diagnostic biomarker for venous thrombosis.     

Development of a risk scoring system for patients with papillary thyroid cancer

As the importance of personalized therapeutics in aggressive papillary thyroid cancer (PTC) increases, accurate risk stratification is required. To develop a novel prognostic scoring system for patients with PTC (n = 455), we used mRNA expression and clinical data from The Cancer Genome Atlas. We performed variable selection using Network‐Regularized high‐dimensional Cox‐regression with gene network from pathway databases. The risk score was calculated using a linear combination of regression coefficients and mRNA expressions. The risk score and clinical variables were assessed by several survival analyses. The risk score showed high discriminatory power for the prediction of event‐free survival as well as the presence of metastasis. In multivariate analysis, the risk score and presence of metastasis were significant risk factors among the clinical variables that were examined together. In the current study, we developed a risk scoring system that will help to identify suitable therapeutic options for PTC.     

Skp2 is over-expressed in breast cancer and promotes breast cancer cell proliferation

The F box protein Skp2 is oncogenic. Skp2 and Skp2B, an isoform of Skp2 are overexpressed in breast cancer. However, little is known regarding the mechanism by which Skp2B promotes the occurrence and development of breast cancer. Here, we determined the expression and clinical outcomes of Skp2 in breast cancer samples and cell lines using breast cancer database, and investigated the role of Skp2 and Skp2B in breast cancer cell growth, apoptosis and cell cycle arrest. We obtained Skp2 is significantly overexpressed in breast cancer samples and cell lines, and high Skp2 expression positively correlated with poor prognosis of breast cancer. Both Skp2 and Skp2B could promote breast cancer cell proliferation, inhibit cell apoptosis, change the cell cycle distribution and induce the increased S phase cells and therefore induce cell proliferation in breast cancer cells. Moreover, the 2 isoforms could both suppress PIG3 expression via independent pathways in the breast cancer cells. Skp2 suppressed p53 and inhibited PIG3-induced apoptosis, while Skp2B attenuated the function of PIG3 by inhibiting PHB. Our results indicate that Skp2 and Skp2B induce breast cancer cell development and progression, making Skp2 and Skp2B potential molecular targets for breast cancer therapy.