Formation of acrylamide in microwave-roasted sorghum and associated dietary risk

The effect of microwave roasting parameters (300, 450 and 600 W; 5, 10 and 15 min) on acrylamide content in sorghum grain was determined using High Pressure Liquid Chromatography (HPLC)-photo diode array (PDA) detector coupled with C-18 column. Samples roasted at 300 and 450 W did not possess acrylamide, whereas 600 W (15 min) favoured formation of 2740.19 µg/kg of acrylamide, levels far exceeding the defined European Union (EU) limits. The chronic daily intake (CDI) for acrylamide through consumption of such grain flour was 3.25–9.5-fold higher to Joint FAO/WHO Expert Committee on Food Additives (JECFA) defined high exposure limits. The margin of exposure (MOE) values ranged from 4.3 to 12.76 and from 11.07 to 32.27 for neoplastic and neurological effects, respectively, demonstrating high exposure and serious health concerns associated with dietary intake of this toxicant. This study assesses the risk for the Indian population and highlights the importance of optimising process parameters for food product to minimise such exposure risks.     

基于多通道的ICU脑血管疾病死亡风险预测模型

死亡风险预测指根据病人临床体征监测数据来预测未来一段时间的死亡风险。对于ICU病患，通过死亡风险预测可以有针对性地对病人做出临床诊断，以及合理安排有限的医疗资源。基于临床使用的MEWS和Glasgow昏迷评分量表，针对ICU病人临床监测的17项生理参数，提出一种基于多通道的ICU脑血管疾病死亡风险预测模型。引入多通道概念应用于BiLSTM模型，用于突出每个生理参数对死亡风险预测的作用。采用Attention机制用于提高模型预测精度。实验数据来自MIMIC [Ⅲ]数据库，从中提取3?080位脑血管疾病患者的16?260条记录用于此次研究，除了六组超参数实验之外，将所提模型与LSTM、Multichannel-BiLSTM、逻辑回归（logistic regression）和支持向量机（support vector machine, SVM）四种模型进行了对比分析，准确率Accuracy、灵敏度Sensitive、特异性Specificity、AUC-ROC和AUC-PRC作为评价指标，实验结果表明，所提模型性能优于其他模型，AUC值达到94.3%。     

Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

The low overall survival rate of patients with pancreatic cancer has driven research to seek a new therapeutic protocol. Radiotherapy (RT) is frequently an option in the neoadjuvant or palliative settings for pancreatic cancer treatment. This study explored the effect of RT protocols on the tumor microenvironment (TME) and their consequent impact on anti-programmed cell death ligand-1 (PD-L1) therapy. Using a murine orthotopic pancreatic tumor model, UN-KC-6141, RT-disturbed TME was examined by immunohistochemical staining. The results showed that ablative RT is more effective than fractionated RT at recruiting T cells. On the other hand, fractionated RT induces more myeloid-derived suppressor cell infiltration than ablative RT. The RT-disturbed TME presents a higher perfusion rate per vessel. The increase in vessel perfusion is associated with a higher amount of anti-PD-L1 antibody being delivered to the tumor. Animal survival is increased by anti-PD-L1 therapy after ablative RT, with 67% of treated animals surviving more than 30 days after tumor inoculation compared to a median survival time of 16.5 days for the control group. Splenocytes isolated from surviving animals were specifically cytotoxic for UN-KC-6141 cells. We conclude that the ablative RT-induced TME is more suited than conventional RT-induced TME to combination therapy with immune checkpoint blockade.     

Differences in PARP Inhibitors for the Treatment of Ovarian Cancer: Mechanisms of Action,Pharmacology, Safety,and Efficacy

Poly(ADP-ribose) polymerases (PARP) are proteins responsible for DNA damage detection and signal transduction. PARP inhibitors (PARPi) are able to interact with the binding site for PARP cofactor (NAD+) and trapping PARP on the DNA. In this way, they inhibit single-strand DNA damage repair. These drugs have been approved in recent years for the treatment of ovarian cancer. Although they share some similarities, from the point of view of the chemical structure and pharmacodynamic, pharmacokinetic properties, these drugs also have some substantial differences. These differences may underlie the different safety profiles and activity of PARPi.     

AQP3 Increases Intercellular Cohesion in NSCLC A549 Cell Spheroids through Exploratory Cell Protrusions

Tumor cell aggregation is critical for cell survival following the loss of extracellular matrix attachment and dissemination. However, the underlying mechanotransduction of clustering solitary tumor cells is poorly understood, especially in non-small cell lung cancers (NSCLC). Here, we examined whether cell surface protrusions played an important role in facilitating the physical contact between floating cells detached from a substrate. We employed poly-2-hydroxyethyl methacrylate-based 3D culture methods to mimic in vivo tumor cell cluster formation. The suprastructural analysis of human NSCLC A549 cell spheroids showed that finger-like protrusions clung together via the actin cytoskeleton. Time-lapse holotomography demonstrated that the finger-like protrusions of free-floating cells in 3D culture displayed exploratory coalescence. Global gene expression analysis demonstrated that the genes in the organic hydroxyl transport were particularly enriched in the A549 cell spheroids. Particularly, the knockdown of the water channel aquaporin 3 gene (AQP3) impaired multicellular aggregate formation in 3D culture through the rearrangement of the actomyosin cytoskeleton. Moreover, the cells with reduced levels of AQP3 decreased their transmigration. Overall, these data indicate that cell detachment-upregulated AQP3 contributes to cell surface protrusions through actomyosin cytoskeleton remodeling, causing the aggressive aggregation of free-floating cells dependent on the property of the substratum and collective metastasis.     

Reduced Claudin-12 Expression Predicts Poor Prognosis in Cervical Cancer

Background: Within the claudin (CLDN) family, CLDN12 mRNA expression is altered in various types of cancer, but its clinicopathological relevance has yet to be established due to the absence of specific antibodies (Abs) with broad applications. Methods: We generated a monoclonal Ab (mAb) against human/mouse CLDN12 and verified its specificity. By performing immunohistochemical staining and semiquantification, we evaluated the relationship between CLDN12 expression and clinicopathological parameters in tissues from 138 cases of cervical cancer. Results: Western blot and immunohistochemical analyses revealed that the established mAb selectively recognized the CLDN12 protein. Twenty six of the 138 cases (18.8%) showed low CLDN12 expression, and the disease-specific survival (DSS) and recurrence-free survival rates were significantly decreased compared with those in the high CLDN12 expression group. We also demonstrated, via univariable and multivariable analyses, that the low CLDN12 expression represents a significant prognostic factor for the DSS of cervical cancer patients (HR 3.412, p = 0.002 and HR 2.615, p = 0.029, respectively). Conclusions: It can be concluded that a reduced CLDN12 expression predicts a poor outcome for cervical cancer. The novel anti-CLDN12 mAb could be a valuable tool to evaluate the biological relevance of the CLDN12 expression in diverse cancer types and other diseases.     

The Role of microRNAs in Development of Colitis-Associated Colorectal Cancer

Colorectal cancer (CRC) is the third most deadly cancer worldwide, and inflammatory bowel disease (IBD) is one of the critical factors in CRC carcinogenesis. IBD is responsible for an unphysiological and sustained chronic inflammation environment favoring the transformation. MicroRNAs (miRNAs) belong to a class of highly conserved short single-stranded segments (18–25 nucleotides) non-coding RNA and have been extensively discussed in both CRC and IBD. However, the role of miRNAs in the development of colitis-associated CRC (CAC) is less clear. The aim of this review is to summarize the major upregulated (miR-18a, miR-19a, miR-21, miR-31, miR-155 and miR-214) and downregulated (miR-124, miR-193a-3p and miR-139-5p) miRNAs in CAC, and their roles in genes’ expression modulation in chronic colonic-inflammation-induced carcinogenesis, including programmed cell-death pathways. These miRNAs dysregulation could be applied for early CAC diagnosis, to predict therapy efficacy and for precision treatment.     

Nanovaccine-Mediated Cell Selective Delivery of Neoantigens Potentiating Adoptive Dendritic Cell Transfer for Personalized Immunization

Neoantigen vaccines and adoptive dendritic cell (DC) transfer are major clinical approaches to initiate personalized immunity in cancer patients. However, the immunization efficacy is largely limited by the in vivo trajectory including neoantigens’ access to resident DCs and DCs’ access to lymph nodes (LNs). Herein, an innovative strategy is proposed to improve personalized immunization through neoantigen-loaded nanovaccines synergized with adoptive DC transfer. It is found that it enables selective delivery of neoantigens to resident DCs and macrophages by coating cancer cell membranes onto neoantigen-loaded nanoparticles. In addition, the nanovaccines promote the secretion of chemokine C-C motif ligand 2 (CCL2), CCL3, and C-X-C motif ligand 10 from macrophages, thus potentiating the access of transferred DCs to LNs. This immunization strategy enables coordinated delivery of identified neoantigens and autologous tumor lysate-derived undefined antigens, leading to initiation of antitumor T cell immunity in a personalized manner. It significantly inhibits tumor growth in prophylactic and established mouse tumor models. The findings provide a new vision for potentiating adoptive cell transfer by nanovaccines, which may open the door to a transformative possibility for improving personalized immunization.