Vitamin D Compounds PRI-2191 and PRI-2205 Enhance Anastrozole Activity in Human Breast Cancer Models

1,25-Dihydroxycholecalciferol, the hormonally active vitamin D₃ metabolite, is known to exhibit therapeutic effects against breast cancer, mainly by lowering the expression of estrogen receptors and aromatase activity. Previously, the safety of the vitamin D active metabolite (24R)-1,24-dihydroxycholecalciferol (PRI-2191) and 1,25(OH)₂D₃ analog PRI-2205 was tested, and the in vitro activity of these analogs against different cancer cell lines was studied. We determined the effect of the two vitamin D compounds on anastrozole (An) activity against breast cancer based on antiproliferative activity, ELISA, flow cytometry, enzyme inhibition potency, PCR, and xenograft study. Both the vitamin D active metabolite and synthetic analog regulated the growth of not only estrogen receptor-positive cells (T47D and MCF-7, in vitro and in vivo), but also hormone-independent cancer cells such as SKBR-3 (HER-2-positive) and MDA-MB-231 (triple-negative), despite their relatively low VDR expression. Combined with An, PRI-2191 and PRI-2205 significantly inhibited the tumor growth of MCF-7 cells. Potentiation of the antitumor activity in combined treatment of MCF-7 tumor-bearing mice is related to the reduced activity of aromatase by both An (enzyme inhibition) and vitamin D compounds (switched off/decreased aromatase gene expression, decreased expression of other genes related to estrogen signaling) and by regulation of the expression of the estrogen receptor ERα and VDR.     

Synthesis of Benzophenones and in vitro Evaluation of Their Anticancer Potential in Breast and Prostate Cancer Cells

Breast and prostate cancers are frequently treated with chemotherapy. Several novel chemicals are being reported for this purpose, particularly synthetic and natural benzophenones. This work reports the synthesis of substituted 2-hydroxybenzophenones through 1,4-conjugate addition/intramolecular cycloaddition/dehydration of nitromethane on key intermediate chromones. Structures were extensively studied by means of 2D NMR spectroscopy and single-crystal XRD. Their cytotoxicity was evaluated in vitro in two breast cancer cell lines (MDA-MB-231 and T47-D) and one prostate cancer cell line (PC3). The most potent compound exhibited good cytotoxic effects against the three cancer cell lines (IC₅₀ values ranging from 12.09 to 26.49 μm ) and induced cell-cycle retardation only on prostate cancer cells, which suggested that it might exert cell-type-specific effects.     

Deep Learning Based Process Analytics Model for Predicting Type 2 Diabetes Mellitus

Process analytics is one of the popular research domains that advanced in the recent years. Process analytics encompasses identification, monitoring, and improvement of the processes through knowledge extraction from historical data. The evolution of Artificial Intelligence (AI)-enabled Electronic Health Records (EHRs) revolutionized the medical practice. Type 2 Diabetes Mellitus (T2DM) is a syndrome characterized by the lack of insulin secretion. If not diagnosed and managed at early stages, it may produce severe outcomes and at times, death too. Chronic Kidney Disease (CKD) and Coronary Heart Disease (CHD) are the most common, long-term and life-threatening diseases caused by T2DM. Therefore, it becomes inevitable to predict the risks of CKD and CHD in T2DM patients. The current research article presents automated Deep Learning (DL)-based Deep Neural Network (DNN) with Adagrad Optimization Algorithm i.e., DNN-AGOA model to predict CKD and CHD risks in T2DM patients. The paper proposes a risk prediction model for T2DM patients who may develop CKD or CHD. This model helps in alarming both T2DM patients and clinicians in advance. At first, the proposed DNN-AGOA model performs data preprocessing to improve the quality of data and make it compatible for further processing. Besides, a Deep Neural Network (DNN) is employed for feature extraction, after which sigmoid function is used for classification. Further, Adagrad optimizer is applied to improve the performance of DNN model. For experimental validation, benchmark medical datasets were used and the results were validated under several dimensions. The proposed model achieved a maximum precision of 93.99%, recall of 94.63%, specificity of 73.34%, accuracy of 92.58%, and F-score of 94.22%. The results attained through experimentation established that the proposed DNN-AGOA model has good prediction capability over other methods.     

ACCUGRAM: A novel approach based on classification to frequency band selection for rotating machinery fault diagnosis

Frequency band selection (FBS) in rotating machinery fault diagnosis aims to recognize frequency band location including a fault transient out of a full band spectrum, and thus fault diagnosis can suppress noise influence from other frequency components. Impulsiveness and cyclostationarity have been recently recognized as two distinctive signatures of a transient. Thus, many studies have focused on developing quantification metrics of the two signatures and using them as indicators to guide FBS. However, most previous studies almost ignore another aspect of FBS, i.e. health reference, which significantly affect FBS performance. To address this issue, this paper investigates importance of a health reference and recognize it as the third critical aspect in FBS. With help of the health reference, the frequency band where the fault transient exists could be located. A novel approach based on classification is proposed to integrate all three aspects (impulsiveness, cyclostationarity, and health reference) for FBS. Classification accuracy is developed as a novel indicator to select the most sensitive frequency band for rotating machinery fault diagnosis. The proposed method (coined by accugram) has been validated on benchmark and experiment datasets. Comparison results show its effectiveness and robustness over conventional envelope analysis, the kurtogram, and the infogram.     

PROfound研究——前列腺癌精准治疗新希望

转移性去势抵抗性前列腺癌（metastatic castrate-resistant prostate cancer,mCRPC）是前列腺癌发展的终末阶段。患者生存预后很差。尽管不断地有新的治疗手段出现，比如新型内分泌治疗以及紫杉醇类化疗，mCRPC患者的生存期依然很有限。奥拉帕利是一款聚腺苷酸二磷酸核糖基聚合酶（poly ADP-ribose polymerase,PARP）抑制剂，PARP酶在DNA修复中扮演着重要的角色。奥拉帕利已经获批用于卵巢癌和乳腺癌的治疗。目前，奥拉帕利用于mCRPC治疗的III期临床研究PROfound的结果在2019年的欧洲肿瘤内科学会（ESMO）年会与2020年的美国临床肿瘤学会-泌尿生殖系统肿瘤研讨会（ASCO-GU）已经发布。本文将带来PROfound研究的结果以及最新的结果更新。     

The Gut Microbiota: A Potential Gateway to Improved Health Outcomes in Breast Cancer Treatment and Survivorship

Breast cancer is the most frequently diagnosed cancer in women worldwide. The disease and its treatments exert profound effects on an individual’s physical and mental health. There are many factors that impact an individual’s risk of developing breast cancer, their response to treatments, and their risk of recurrence. The community of microorganisms inhabiting the gastrointestinal tract, the gut microbiota, affects human health through metabolic, neural, and endocrine signaling, and immune activity. It is through these mechanisms that the gut microbiota appears to influence breast cancer risk, response to treatment, and recurrence. A disrupted gut microbiota or state of ‘dysbiosis’ can contribute to a biological environment associated with higher risk for cancer development as well as contribute to negative treatment side-effects. Many cancer treatments have been shown to shift the gut microbiota toward dysbiosis; however, the microbiota can also be positively manipulated through diet, prebiotic and probiotic supplementation, and exercise. The objective of this review is to provide an overview of the current understanding of the relationship between the gut microbiota and breast cancer and to highlight potential strategies for modulation of the gut microbiota that could lead to improved clinical outcomes and overall health in this population.     

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.