CD44基因多态性与宫颈癌及非小细胞肺癌的相关性

背景与目的：CD44分子是众多肿瘤细胞的标志分子，其表达水平与肿瘤细胞的恶性程度有关。该研究探讨CD44基因中的单核苷酸多态性（single nucleotide polymorphism，SNP）位点与云南汉族人群宫颈癌和非小细胞肺癌（nonsmall cell lung cancer，NSCLC）易感性的相关性。方法：选取了CD44基因中的两个SNP位点rs13347和rs8193，采用TagMan基因分型的方法，分析这两个多态性位点在497例宫颈癌患者和500例健康对照个体以及483例NSCLC患者和471例健康对照个体中的分布特征，并分析CD44基因中的多态性位点与云南汉族人群宫颈癌和NSCLC的相关性。结果：rs13347和rs8193位点等位基因和基因型在宫颈癌组和对照组中的分布频率的差异无统计学意义（P>0.05）。而在NSCLC组和对照组的比较中：rs13347和rs8193位点等位基因在NSCLC组和对照组中的分布频率的差异有统计学意义（P=0.020和P=0.004）；这两个位点基因型在NSCLC组和对照组中分布频率的差异有统计学意义（P=0.027和P=0.020）；其中rs13347位点等位基因C在NSCLC组中的分布频率显著高于对照组，可能是NSCLC发生的风险因素（OR=1.250，95% CI：1.035～1.509），rs8193位点等位基因C在对照组中的分布频率显著高于NSCLC组，可能是NSCLC发生的保护性因素（OR=0.768，95%CI：0.641～0.921）。单倍型分析结果显示，rs13347C-rs8193T和rs13347T-rs8193C在NSCLC组和对照组中的分布频率差异有统计学意义（P=0.003和0.022）；该结果说明单倍型rs13347C-rs8193T可能是云南汉族人群NSCLC发生的风险性因素（OR=1.316，95%CI：1.096～1.579）。结论：CD44基因中的两个SNP位点rs13347和rs8193可能与云南汉族人群宫颈癌发病风险无关，而可能与云南汉族人群NSCLC具有相关性。     

Low-dose all-trans retinoic acid enhances cytotoxicity of cisplatin and 5-fluorouracil on CD44+ cancer stem cells

Cis-diamminedichloridoplatinum(II)(CDDP)-based combination chemotherapy is frequently used in gastrointestinal cancer. The synergistic mechanism of all-trans retinoic acid (ATRA), cisplatin (CDDP) and 5-fluorouracil (5-FU) in combination remains unclear. Despite their potent antitumor properties, resistance to CDDP and 5-FU develops frequently in tumors. To clarify this mechanism, we determined the sensitivity to each drug and their combination in two gastrointestinal cancer stem cells (CSCs) subpopulation.Here, we report the identification and separation of CD44⁺ cells from human gastric carcinoma (AGS) and human esophageal squamous cell carcinoma (KYSE-30) cancer cell lines by magnetic activated cell sorting (MACS). We allowed the CD44^± cells to grow 6 days at a subtoxic concentration of ATRA and then treated with different concentration of CDDP and 5-FU for 24 h. The cytotoxicity was examined by cell proliferation MTT assay. Additionally, AO/EB staining was used for detection of apoptotic cells. In order to determine whether the growth inhibition was also associated with changes in cell cycle distribution, cell cycle analysis was performed using flow cytometry.Low concentration of ATRA (1 μM, 6days) followed by 5-FU and CDDP was found to be more effective than either drugs alone, thus resulting in synergistic cytotoxicity in Kyse-30 and AGSCD44^± cells. Furthermore, there was an indication that the combination of ATRA with 5FU and CDDP caused an increase in cell cycle arrest in G2/M and G0/G1.We conclude that low concentration of ATRA enhances the cytotoxicity of CDDP and 5FU by facilitating apoptosis and cell cycle arrest in gastrointestinal CSCs and provide a rational basis for the design of novel, well-tolerated CDDP- and 5FU-based chemotherapy in human gastrointestinal carcinoma.     

Molecular simplification of lipid A structure: TLR4-modulating cationic and anionic amphiphiles

A growing body of data suggests that therapies based on Toll-like receptors (TLR) targeting, in particular TLR4, holds promise in curing autoimmune and inflammatory pathologies still lacking specific treatment, included several rare diseases. While TLR4 activators (agonists) have already found successful clinical application as vaccine adjuvants, the use of TLR4 blockers (antagonists) as antisepsis agents or as agents against inflammatory diseases (including arthritis, multiple sclerosis, neuroinflammations) and cancer is still at a preclinical phase of development. This minireview focuses on recent achievements on the development of TLR4 modulators based on lipid A structure simplification, in particular on compounds having disaccharide or monosaccharide structures. As the TLR4 activity of natural TLR4 ligands (lipopolysaccharide, LPS and its biologically active part, the lipid A) depends on both the structure of endotoxin aggregates in solution and on single-molecule interaction with MD-2 and CD14 receptors, the rational design of TLR4 modulators should in principle take into account both these factors. In the light of the most recent advances in the field, in this minireview we discuss the structure–activity relationship in simplified lipid A analogs, with cationic or anionic amphiphilic structures.     

低密度脂蛋白在2型糖尿病骨质疏松中的作用研究进展

2型糖尿病及骨质疏松已成为我国最主要的慢性代谢性疾病。2型糖尿病常伴有血脂紊乱，常表现为低密度脂蛋白升高，而越来越多的研究表明血脂通过不同的方式影响骨代谢，其机制可能是通过抑制骨髓间充质干细胞成骨分化，通过RANK/RNAKL/OPG信号通路及炎症反应调节破骨细胞等方式调节骨代谢。     

Immune Checkpoint Inhibitor Toxicities

Immune checkpoint inhibitors are molecules that increase the endogenous immune response against tumors. They have revolutionized the field of oncology. Since their initial approval for the treatment of advanced melanoma, their use has expanded to the treatment of several other advanced cancers. Unfortunately, immune checkpoint inhibitors have also been associated with the emergence of a new subset of autoimmune-like toxicities, known as immune-related adverse events. These toxicities differ depending on the agent, malignancy, and individual susceptibilities. Although the skin and colon are most commonly involved, any organ may be affected, including the liver, lungs, kidneys, and heart. Most of these toxicities are diagnosed by excluding other secondary infectious or inflammatory causes. Corticosteroids are commonly used for treatment of moderate and severe immune-related adverse events, although additional immunosuppressive therapy may occasionally be required. The occurrence of immune-related toxicities may require discontinuation of immunotherapy, depending on the specific toxicity and its severity. In this article, we provide a focused review to familiarize practicing clinicians with this important topic given that the use of immune checkpoint inhibitors continues to increase.     

Anisotropic Bladder Planning Target Volume in Bladder Radiation Therapy

Purpose

This study aimed to investigate 3 planning target volume (PTV) margin expansions and determine the most appropriate volume to be used in bladder preservation therapy when using daily cone beam computed tomography (CBCT). We aimed to establish whether a smaller PTV expansion is feasible without risking geographical miss.

Engraftable neural crest stem cells derived from cynomolgus monkey embryonic stem cells

Neural crest stem cells (NCSCs), a population of multipotent cells that migrate extensively and give rise to diverse derivatives, including peripheral and enteric neurons and glia, craniofacial cartilage and bone, melanocytes and smooth muscle, have great potential for regenerative medicine. Non-human primates provide optimal models for the development of stem cell therapies. Here, we describe the first derivation of NCSCs from cynomolgus monkey embryonic stem cells (CmESCs) at the neural rosette stage. CmESC-derived neurospheres replated on polyornithine/laminin-coated dishes migrated onto the substrate and showed characteristic expression of NCSC markers, including Sox10, AP2α, Slug, Nestin, p75, and HNK1. CmNCSCs were capable of propagating in an undifferentiated state in vitro as adherent or suspension cultures, and could be subsequently induced to differentiate towards peripheral nervous system lineages (peripheral sympathetic neurons, sensory neurons, and Schwann cells) and mesenchymal lineages (osteoblasts, adipocytes, chondrocytes, and smooth muscle cells). CmNCSCs transplanted into developing chick embryos or fetal brains of cynomolgus macaques survived, migrated, and differentiated into progeny consistent with a neural crest identity. Our studies demonstrate that CmNCSCs offer a new tool for investigating neural crest development and neural crest-associated human disease and suggest that this non-human primate model may facilitate tissue engineering and regenerative medicine efforts.