Histone Methylation Marks on Circulating Nucleosomes as Novel Blood-Based Biomarker in Colorectal Cancer

Circulating nucleic acids (CNAs) are under investigation as a liquid biopsy in cancer as potential non-invasive biomarkers, as stable structure in circulation nucleosomes could be valuable sources for detection of cancer-specific alterations in histone modifications. Our interest is in histone methylation marks with a focus on colorectal cancer, one of the leading cancers respective the incidence and mortality. Our previous work included the analysis of trimethylations of lysine 9 on histone 3 (H3K9me3) and of lysine 20 on histone 4 (H4K20me3) by chromatin immuno- precipitation-related PCR in circulating nucleosomes. Here we asked whether global immunologic measurement of histone marks in circulation could be a suitable approach to show their potential as biomarkers. In addition to H3K9me3 and H4K20me3 we also measured H3K27me3 in plasma samples from CRC patients (n = 63) and cancer free individuals (n = 40) by ELISA-based methylation assays. Our results show that of three marks, the amounts of H3K27me3 (p = 0.04) and H4K20me3 (p < 0.001) were significantly lower in CRC patients than in healthy controls. For H3K9me3 similar amounts were measured in both groups. Areas under the curve (AUC) in receiver operating characteristic (ROC) curves indicating the power of CRC detection were 0.620 for H3K27me3, 0.715 for H4K20me3 and 0.769 for the combination of both markers. In conclusion, findings of this preliminary study reveal the potential of blood-based detection of CRC by quantification of histone methylation marks and the additive effect of the marker combination.     

胸腺五肽辅助治疗肺癌对免疫功能影响及其疗效的系统评价

为了系统地评价胸腺五肽作为辅助药物治疗各种肺癌的疗效及其对机体免疫功能的影响，利用电子检索收集有关胸腺五肽联合放疗或化疗方案治疗肺癌的临床随机对照试验文献，对符合纳入标准的文献，采用RevMan5.3 软件进行系统评价。最终共纳入文献 9 篇，总样本量 784 例。Meta 分析结果表明，胸腺五肽作为辅助药物治疗各种肺癌提高总有效率的差异无统计学意义[OR ＝ 1.44, 95%CI(0.99, 2.10), P ＝0.06 ＞ 0.05]。在对免疫功能的影响方面，胸腺五肽的使用显著增高外周血中的 CD3+ 细胞水平[OR ＝ 5.88, 95% CI(2.34, 9.42), P ＝0.001]，CD4+ 细胞水平也显著上升[OR ＝8.32, 95%CI(5.22, 11.42), P ＜ 0.00001] , CD4＋ /CD8＋比值也有明显的提高[OR ＝ 0.38, 95% CI(0.18, 0.59), P＝0.0002]，但 CD8+ 细胞水平的差异无统计学意义[OR ＝－3.12, 95% CI ( －9.02, 2.79), P ＞0.05]。总的来说，本研究在一定程度上反映了在辅助治疗肺癌方面，胸腺五肽能显著提高外周血中的 CD3+ 细胞水平、CD4+ 细胞水平、CD4+/CD8+ 比值。而对于治疗的有效率、CD8+ 细胞水平，差异无统计学意义。     

Preliminary Evidence on the Diagnostic and Molecular Role of Circulating Soluble EGFR in Non-Small Cell Lung Cancer

Assessment of biological diagnostic factors providing clinically-relevant information to guide physician decision-making are still needed for diseases with poor outcomes, such as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a promising molecule in the clinical management of NSCLC. While the EGFR transmembrane form has been extensively investigated in large clinical trials, the soluble, circulating EGFR isoform (sEGFR), which may have a potential clinical use, has rarely been considered. This study investigates the use of sEGFR as a potential diagnostic biomarker for NSCLC and also characterizes the biological function of sEGFR to clarify the molecular mechanisms involved in the course of action of this protein. Plasma sEGFR levels from a heterogeneous cohort of 37 non-advanced NSCLC patients and 54 healthy subjects were analyzed by using an enzyme-linked immunosorbent assay. The biological function of sEGFR was analyzed in vitro using NSCLC cell lines, investigating effects on cell proliferation and migration. We found that plasma sEGFR was significantly decreased in the NSCLC patient group as compared to the control group (median value: 48.6 vs. 55.6 ng/mL respectively; p = 0.0002). Moreover, we demonstrated that sEGFR inhibits growth and migration of NSCLC cells in vitro through molecular mechanisms that included perturbation of EGF/EGFR cell signaling and holoreceptor internalization. These data show that sEGFR is a potential circulating biomarker with a physiological protective role, providing a first approach to the functional role of the soluble isoform of EGFR. However, the impact of these data on daily clinical practice needs to be further investigated in larger prospective studies.     

Role of Extracellular Vesicles in Epithelial Ovarian Cancer: A Systematic Review

Extracellular vesicles (EVs) are a heterogeneous group of cell-derived submicron vesicles released under physiological or pathological conditions. EVs mediate the cellular crosstalk, thus contributing to defining the tumor microenvironment, including in epithelial ovarian cancer (EOC). The available literature investigating the role of EVs in EOC has been reviewed following PRISMA guidelines, focusing on the role of EVs in early disease diagnosis, metastatic spread, and the development of chemoresistance in EOC. Data were identified from searches of Medline, Current Contents, PubMed, and from references in relevant articles from 2010 to 1 April 2020. The research yielded 194 results. Of these, a total of 36 papers, 9 reviews, and 27 original types of research were retained and analyzed. The literature findings demonstrate that a panel of EV-derived circulating miRNAs may be useful for early diagnosis of EOC. Furthermore, it appears clear that EVs are involved in mediating two crucial processes for metastatic and chemoresistance development: the epithelial–mesenchymal transition, and tumor escape from the immune system response. Further studies, more focused on in vivo evidence, are urgently needed to clarify the role of EV assessment in the clinical management of EOC patients.     

Prediction of rock mass P wave velocity using blasthole drilling information

In this paper, the development of the models for the prediction of rock mass P wave velocity is presented. For model development, the database of 53 cases including widely used and recorded drilling parameters and P wave velocity was constructed from the field studies conducted in 13 open pit lignite mines. Both conventional linear, non-linear multiple regression and Adaptive Neuro Fuzzy Inference System (ANFIS) were used for model development. Prediction performance indicators showed that ANFIS model presented the best performance and it can successfully be used for the preliminary prediction of P wave velocities of rock masses.     

Visceral Obesity and Its Shared Role in Cancer and Cardiovascular Disease: A Scoping Review of the Pathophysiology and Pharmacological Treatments

The association between obesity, cancer and cardiovascular disease (CVD) has been demonstrated in animal and epidemiological studies. However, the specific role of visceral obesity on cancer and CVD remains unclear. Visceral adipose tissue (VAT) is a complex and metabolically active tissue, that can produce different adipokines and hormones, responsible for endocrine-metabolic comorbidities. This review explores the potential mechanisms related to VAT that may also be involved in cancer and CVD. In addition, we discuss the shared pharmacological treatments which may reduce the risk of both diseases. This review highlights that chronic inflammation, molecular aspects, metabolic syndrome, secretion of hormones and adiponectin associated to VAT may have synergistic effects and should be further studied in relation to cancer and CVD. Reductions in abdominal and visceral adiposity improve insulin sensitivity, lipid profile and cytokines, which consequently reduce the risk of CVD and some cancers. Several medications have shown to reduce visceral and/or subcutaneous fat. Further research is needed to investigate the pathophysiological mechanisms by which visceral obesity may cause both cancer and CVD. The role of visceral fat in cancer and CVD is an important area to advance. Public health policies to increase public awareness about VAT’s role and ways to manage or prevent it are needed.     

Inhibitory Monoclonal Antibodies and Their Recombinant Derivatives Targeting Surface-Exposed Carbonic Anhydrase XII on Cancer Cells

Monoclonal and recombinant antibodies are widely used for the diagnostics and therapy of cancer. They are generated to interact with cell surface proteins which are usually involved in the development and progression of cancer. Carbonic anhydrase XII (CA XII) contributes to the survival of tumors under hypoxic conditions thus is considered a candidate target for antibody-based therapy. In this study, we have generated a novel collection of monoclonal antibodies (MAbs) against the recombinant extracellular domain of CA XII produced in HEK-293 cells. Eighteen out of 24 MAbs were reactive with cellular CA XII on the surface of live kidney and lung cancer cells as determined by flow cytometry. One MAb 14D6 also inhibited the enzymatic activity of recombinant CA XII as measured by the stopped-flow assay. MAb 14D6 showed the migrastatic effect on human lung carcinoma A549 and renal carcinoma A498 cell lines in a ‘wound healing’ assay. It did not reduce the growth of multicellular lung and renal cancer spheroids but reduced the cell viability by the ATP Bioluminescence assay. Epitope mapping revealed the surface-exposed amino acid sequence (35-FGPDGENS-42) close to the catalytic center of CA XII recognized by the MAb 14D6. The variable regions of the heavy and light chains of MAb 14D6 were sequenced and their complementarity-determining regions were defined. The obtained variable sequences were used to generate recombinant antibodies in two formats: single-chain fragment variable (scFv) expressed in E. coli and scFv fused to human IgG1 Fc fragment (scFv-Fc) expressed in Chinese Hamster Ovary (CHO) cells. Both recombinant antibodies maintained the same specificity for CA XII as the parental MAb 14D6. The novel antibodies may represent promising tools for CA XII-related cancer research and immunotherapy.     

Microenvironment and related genes predict outcomes of patients with cervical cancer: evidence from TCGA and bioinformatic analysis

Cervical cancer (CESC) is one of the most common cancers and affects the female genital tract. Consistent HPV infection status has been determined to be a vital cause of tumorigenesis. HPV infection may induce changes to the immune system and limit the host’s immune response. Immunotherapy is therefore essential to improving the overall survival of both locally advanced and recurrent CESC patients. Using 304 relevant samples from TCGA, we assessed immune cell function in CESC patients to better understand the status of both tumor micro-environment cells and immune cells in CESC. Functional enrichment analysis, pathway enrichment analysis, and PPI network construction were performed to explore the differentially expressed genes (DEGs). The analysis identified 425 DEGs, which included 295 up-regulated genes and 130 down-regulated genes. We established that upregulation of CCL5 was correlated with significantly better survival, meaning that CCL5 expression could serve as a novel prognostic biomarker for CESC patients. We further focused on CCL5 as a hub gene in CESC, as it had significant correlations with increased numbers of several types of immune cells. Cell-type fractions of M1 macrophages were significantly higher in the high-immune-scores group, which was associated with better overall survival. Finally, we concluded that CCL5 is a promising prognostic biomarker for CESC, as well as a novel chemotherapeutic target.