Evaluation of Floxuridine Oligonucleotide Conjugates Carrying Potential Enhancers of Cellular Uptake

Conjugation of small molecules such as lipids or receptor ligands to anti-cancer drugs has been used to improve their pharmacological properties. In this work, we studied the biological effects of several small-molecule enhancers into a short oligonucleotide made of five floxuridine units. Specifically, we studied adding cholesterol, palmitic acid, polyethyleneglycol (PEG 1000), folic acid and triantennary N-acetylgalactosamine (GalNAc) as potential enhancers of cellular uptake. As expected, all these molecules increased the internalization efficiency with different degrees depending on the cell line. The conjugates showed antiproliferative activity due to their metabolic activation by nuclease degradation generating floxuridine monophosphate. The cytotoxicity and apoptosis assays showed an increase in the anti-cancer activity of the conjugates related to the floxuridine oligomer, but this effect did not correlate with the internalization results. Palmitic and folic acid conjugates provide the highest antiproliferative activity without having the highest internalization results. On the contrary, cholesterol oligomers that were the best-internalized oligomers had poor antiproliferative activity, even worse than the unmodified floxuridine oligomer. Especially relevant is the effect induced by palmitic and folic acid derivatives generating the most active drugs. These results are of special interest for delivering other therapeutic oligonucleotides.     

Genetic Contribution of Endometriosis to the Risk of Developing Hormone-Related Cancers

Endometriosis is a common gynecological disorder that has been associated with endometrial, breast and epithelial ovarian cancers in epidemiological studies. Since complex diseases are a result of multiple environmental and genetic factors, we hypothesized that the biological mechanism underlying their comorbidity might be explained, at least in part, by shared genetics. To assess their potential genetic relationship, we performed a two-sample mendelian randomization (2SMR) analysis on results from public genome-wide association studies (GWAS). This analysis confirmed previously reported genetic pleiotropy between endometriosis and endometrial cancer. We present robust evidence supporting a causal genetic association between endometriosis and ovarian cancer, particularly with the clear cell and endometrioid subtypes. Our study also identified genetic variants that could explain those associations, opening the door to further functional experiments. Overall, this work demonstrates the value of genomic analyses to support epidemiological data, and to identify targets of relevance in multiple disorders.     

Cumin Prevents 17β-Estradiol-Associated Breast Cancer in ACI Rats

Breast cancer (BC) is a leading cause of cancer deaths in women in less developed countries and the second leading cause of cancer death in women in the U.S. In this study, we report the inhibition of E2-mediated mammary tumorigenesis by Cuminum cyminum (cumin) administered via the diet as cumin powder, as well as dried ethanolic extract. Groups of female ACI rats were given either an AIN-93M diet or a diet supplemented with cumin powder (5% and 7.5%, w/w) or dried ethanolic cumin extract (1%, w/w), and then challenged with subcutaneous E2 silastic implants (1.2 cm; 9 mg). The first appearance of a palpable mammary tumor was significantly delayed by both the cumin powder and extract. At the end of the study, the tumor incidence was 96% in the control group, whereas only 55% and 45% animals had palpable tumors in the cumin powder and extract groups, respectively. Significant reductions in tumor volume (660 ± 122 vs. 138 ± 49 and 75 ± 46 mm³) and tumor multiplicity (4.21 ± 0.43 vs. 1.16 ± 0.26 and 0.9 ± 0.29 tumors/animal) were also observed by the cumin powder and cumin extract groups, respectively. The cumin powder diet intervention dose- and time-dependently offset E2-related pituitary growth, and reduced the levels of circulating prolactin and the levels of PCNA in the mammary tissues. Mechanistically, the cumin powder diet resulted in a significant reversal of E2-associated modulation in ERα, CYP1A1 and CYP1B1. Further, the cumin powder diet reversed the expression levels of miRNAs (miR-182, miR-375, miR-127 and miR-206) that were highly modulated by E2 treatment. We analyzed the composition of the extract by GC/MS and established cymene and cuminaldehyde as major components, and further detected no signs of gross or systemic toxicity. Thus, cumin bioactives can significantly delay and prevent E2-mediated mammary tumorigenesis in a safe and effective manner, and warrant continued efforts to develop these clinically translatable spice bioactives as chemopreventives and therapeutics against BC.     

How Cancer Cells Invade Bladder Epithelium and Form Tumors: The Mouse Bladder Tumor Model as a Model of Tumor Recurrence in Patients

Non-muscle-invasive bladder cancer is the most common form of bladder cancer. The main problem in managing bladder tumors is the high recurrence after the transurethral resection of bladder tumors (TURBT). Our study aimed to examine the fate of intravesically applied cancer cells as the implantation of cancer cells after TURBT is thought to be a cause of tumor recurrence. We established an orthotopic mouse bladder tumor model with MB49-GFP cancer cells and traced them during the first three days to define their location and contacts with normal urothelial cells. Data were obtained by Western blot, immunolabeling, and light and electron microscopy. We showed that within the first two hours, applied cancer cells adhered to the traumatized epithelium by cell projections containing α3β1 integrin on their tips. Cancer cells then migrated through the epithelium and on day 3, they reached the basal lamina or even penetrated it. In established bladder tumors, E-cadherin and desmoplakin 1/2 were shown as feasible immunohistochemical markers of tumor margins based on the immunolabeling of various junctional proteins. Altogether, these results for the first time illustrate cancer cell implantation in vivo mimicking cellular events of tumor recurrence in bladder cancer patients.     

pHEMA: An Overview for Biomedical Applications

Poly(2-hydroxyethyl methacrylate) (pHEMA) as a biomaterial with excellent biocompatibility and cytocompatibility elicits a minimal immunological response from host tissue making it desirable for different biomedical applications. This article seeks to provide an in-depth overview of the properties and biomedical applications of pHEMA for bone tissue regeneration, wound healing, cancer therapy (stimuli and non-stimuli responsive systems), and ophthalmic applications (contact lenses and ocular drug delivery). As this polymer has been widely applied in ophthalmic applications, a specific consideration has been devoted to this field. Pure pHEMA does not possess antimicrobial properties and the site where the biomedical device is employed may be susceptible to microbial infections. Therefore, antimicrobial strategies such as the use of silver nanoparticles, antibiotics, and antimicrobial agents can be utilized to protect against infections. Therefore, the antimicrobial strategies besides the drug delivery applications of pHEMA were covered. With continuous research and advancement in science and technology, the outlook of pHEMA is promising as it will most certainly be utilized in more biomedical applications in the near future. The aim of this review was to bring together state-of-the-art research on pHEMA and their applications.     

An Autophagy-Disrupting Small Molecule Promotes Cancer Cell Death via Caspase Activation

A novel autophagy inhibitor, autophazole (Atz), which promoted cancer cell death via caspase activation, is described. This compound was identified from cell-based high-content screening of an imidazole library. The results showed that Atz was internalized into lysosomes of cells where it induced lysosomal membrane permeabilization (LMP). This process generated nonfunctional autolysosomes, thereby inhibiting autophagy. In addition, Atz was found to promote LMP-mediated apoptosis. Specifically, LMP induced by Atz caused release of cathepsins from lysosomes into the cytosol. Cathepsins in the cytosol cleaved Bid to generate tBid, which subsequently activated Bax to induce mitochondrial outer membrane permeabilization (MOMP). This event led to cancer cell death via caspase activation. Overall, the findings suggest that Atz will serve as a new chemical probe in efforts aimed at gaining a better understanding of the autophagic process.     

半导体TiO2的光催化性能及其应用

TiO₂作为一种优秀的光催化材料，其在环境保护等领域的应用研究十分活跃，主要是在废水处理、空气净化、癌症治疗以及杀菌消毒等方面。介绍了新颖的光诱导超亲水性及其应用。     

6,7-二氢-6-甲基-3-甲硫基吡喃[4,3-c]吡唑-4-(2H)-酮衍生物的合成及生物活性

6-甲基-5,6-二氢吡喃-2,4-二酮和二硫化碳、碘甲烷缩合得到5,6-二氢吡喃-2,4-二酮的二硫缩醛化合物,然后和取代肼反应得到1位取代和2位取代6,7-二氢-6-甲基-3-甲硫基吡喃[4,3-c]吡唑-4-(2H)-酮衍生物。其化学结构通过单晶X衍射、1HNMR、13CNMR、元素分析证实。生物活性测试结果初步表明,该类化合物表现出一定的杀菌和对前列腺癌细胞PC3的抑制活性。     

Modelling the effects of human papillomavirus in cervical cells

Worldwide, cervical cancer is the second most common cancer in women, after breast cancer. The prevalence of this malignant disease is estimated at 1.4 million cases worldwide, causing about 290,000 deaths and 500,000 new cases per year, of which 80% correspond to women living in developing countries. In this work we propose a family of ordered models for basal cells of the cervix corresponding to different stages ranging from normal cells to the formation of precancerous lesions. We analyse the first member of the family analytically and for the second member we developed a non-standard numerical method in order to extract some biological information.