Abstract Introduction: Neuroblastomas (NB) are the most common solid tumor in children and infants, and are frequently resistant to all standard therapies. Patients are accordingly vulnerable to acute and long-term systemic effects of toxic chemotherapy. These drugs target rapidly dividing cells throughout the body, leading to severe side effects. One strategy to reduce off-target toxicities is to selectively increase drug uptake in the tumor. In pilot studies, we found that microbubbles containing liposomal doxorubicin, an agent that is effective against NB, and focused ultrasound (sonoporation) increased doxorubicin uptake in NB xenografts. However, NB is typically treated with multidrug chemotherapy, raising the importance of testing additional agents. In these studies, we evaluated a novel liposomal formulation of topotecan, an agent used in NB treatment which is both effective and associated with significant systemic toxicities. In vitro studies are needed to determine the IC50 (concentration of the drug needed to reduce the number of live cells by half). A required esterase cleavage at the delivery site can inhibit liposome encapsulated drug release. Therefore, we hypothesized that liposomal topotecan (2T-T) would have a higher IC50 than free topotecan. Methods: We tested the effect of 2T-T on nine different NB cell lines:LA1-55n, LA-1-5S, LAN-5, NGP, SK-N-AS, BE2, SHEP, NBL-WN, and SH-SY5Y;five N-type (invasive), three S-type (noninvasive), seven MYCN-amplified (poor prognosis). We have tested free topotecan in 3 of these (LA-1-5S, NBL-WN, SH-SY5Y). Cells were plated in full RPMI at 80% confluence. 2T-T or topotecan (0 to 50 uM) were added to cells 24 hours later for 72 hours. Viable cells were estimated using a WST cell counting kit. 50uM empty liposomes and lysis buffer were used as controls. Experiments were performed in triplicate, with p≥0.05deemed significant (student t-test or ratio-paired t-test using PRISM). Results: 2T-T had a mean IC50 of 0.37±0.58uM(mean R2=0.9±0.07).Empty liposomes caused no cytotoxicity in any cell line. We found no difference in IC50 according to S or N type (0.50±0.65vs 0.35±0.58(p=ns)). The mean IC50 of MYCN-amplified cells was 0.47±0.63,while that of non-MYCN-amplified was 0.031±0.029(n=2), suggesting no difference in cytotoxicity based on MYCN status. 2T-T had a 2 fold lower IC50 than free topotecan (1.14±1.19vs 0.48±0.82,p=0.046), suggesting liposomes did not inhibit topotecan release. Conclusion: These findings suggest that liposomal topotecan (T2-T) has a lower IC50 than free topotecan in NB, and that MYCN amplification and phenotype do not modify 2T-T cytotoxicity. Our results suggest that liposomal encapsulation does not inhibit topotecan release, but could increase its cytotoxicity by increasing topotecan half-life. We predict that, in vivo 2T-T could reduce toxicities and side effects, warranting the investigation of 2T-T sonoporation in NB xenografts. Citation Format: Paula Viza Gomes, Stephanie Shen, Meghan Hill, Kilkee Flynn, Mendi Marquez, Liliya Frolova, Jessica J. Kandel, Michaelann Tartis, Sonia L. Hernandez. Novel liposomal topotecan formulation has a lower IC50 than the free form on neuroblastoma cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1729.
Colorectal cancer (CRC) is the third leading cause of cancer death in the U.S., and early detection and diagnosis are essential for effective treatment. Current methods are inadequate for rapid detection of early disease, revealing flat lesions, and delineating tumor margins with accuracy and molecular specificity. Fluorescence endoscopy can generate wide field-of-view images enabling detection of CRC lesions and margins; increased signal intensity and improved signal-to-noise ratios can increase both speed and sensitivity of cancer detection. For this purpose, we developed targeted near-infrared (NIR) fluorescent silica nanoparticles (FSNs). We tuned their size to 50–200 nm and conjugated their surface with an antibody to carcinoembryonic antigen (CEA) to prepare CEA-FSNs. The physicochemical properties and biodegradable profiles of CEA-FSN were characterized, and molecular targeting was verified in culture using HT29 (CEA positive) and HCT116 (CEA negative) cells. CEA-FSNs bound to the HT29 cells to a greater extent than to the HCT116 cells, and smaller CEA-FSNs were internalized into HT29 cells more efficiently than larger CEA-FSNs. After intravenous administration of CEA-FSNs, a significantly greater signal was observed from the CEA-positive HT29 than the CEA-negative HCT116 tumors in xenografted mice. In F344-PIRC rats, polyps in the intestine were detected by white-light endoscopy, and NIR fluorescent signals were found in the excised intestinal tissue after topical application of CEA-FSNs. Immunofluorescence imaging of excised tissue sections demonstrated that the particle signals coregistered with signals for both CRC and CEA. These results indicate that CEA-FSNs have potential as a molecular imaging marker for early diagnosis of CRC.
To assess the genetic association between secretor status and ankylosing spondylitis (AS).A restriction digest method for determining secretor status was developed; 166 patients with AS and 216 healthy British white controls were typed for secretor status using this method.The frequency of nonsecretors among patients with AS (47/166, 28%) was not significantly different from controls (72/216, 33%).Secretor status does not influence susceptibility to AS.
Background Trauma in pregnancy can lead to life-threatening hemorrhage. Conventional treatments of hemorrhage include medical and surgical management. However, if these measures fail uterine compression is an option to control bleeding. We present a case where this management was employed. Case A patient presented at 36 weeks of gestation with multiple injuries after a motor vehicle collision and experienced disseminated intravascular coagulation (DIC). The use of a Bakri balloon in combination with external compression with Coban, a sterile self-adherent bandage, after delivery temporized her bleeding and allowed her to become stable for further management. Conclusion When other measures fail and a hysterectomy is considered unsafe, the combination of internal and external uterine compression is an option.
Photodynamic therapy (PDT) has been extensively explored as a minimally invasive treatment strategy for malignant cancers. It works with the help of a photosensitizer located within cancer cells that is irradiated by near-infrared light to produce potent toxins and singlet oxygen (1O2) and induce cell death. However, reactive oxygen species can be overexpressed in tumor tissue because of the rapid metabolic activity in cancer cells, and the insufficient oxygenation (hypoxia) can lead to low production of singlet oxygen (1O2) during PDT. In this study, we developed nanocomposites composed of a hollow manganese silicate (HMnOSi) nanoparticle and a photosensitizer (Ce6) that can generate significant amounts of O2 to relieve tumor hypoxia and enhance the therapeutic efficacy of PDT. Our nanocomposites were characterized by UV-vis, fluorescence spectroscopy, transmission electron microscopy (TEM), energy-dispersive X-ray, and dynamic light scattering. Our particles' hollow mesoporous structures were shown to retain large amounts of Ce6 on the particle surface with high loading capacity (33%). TEM imaging showed that the nanoparticles could be biodegradable over time in simulated body fluid, which can imply clinical potentials. Significant H2O2 quenching capabilities to alleviate hypoxic conditions in a solid tumor were also presented. For breast cancer cells, the nanocomposite-treated group revealed that 91% of cells were dead under laser activation compared to 51% for the control group (free Ce6). In an animal study, our nanocomposites showed almost fourfold tumor growth inhibition versus the control and more than twofold over free Ce6 in orthotopic tumor xenografts. In addition, the oxygen saturation contrast inside tumors was evaluated by photoacoustic imaging to demonstrate the alleviated hypoxia in vivo. Our works provide a smart nanosystem to ameliorate the hypoxic tumor microenvironment and augment the efficacy of PDT in a targeted cancer treatment.
Part IIA of the Environmental Protection Act 1990 sets out a regulatory regime for the identification and remediation of land where contamination is causing unacceptable risks to defined receptors. The Environment Agency has a number of regulatory roles under this regime. Where land is designated as a Special Site, as defined in the Contaminated Land (England) Regulations 2000, the Agency will act as the enforcing authority. It is expected that a similar regime will be introduced in Wales during 2001, but the reader should check whether definitions of Special Sites in the Welsh regulations are the same as in the English ones. The Environment Agency's approach to carrying out its regulatory responsibilities is set out in its Part RA Process Documentation,, available on the Agency website (www.environment-agency. gov.uk). This documentation sets out how the Agency intends to carry out its responsibilities under Part IIA of the Environmental Protection Act 1990, which came into force in England on 1 April 2000.
Rheumatoid arthritis (RA) is an autoimmune disease that affects 1-2% of the human population worldwide, and effective therapies with targeted delivery for local immune suppression have not been described. We address this problem by developing a novel theranostic nanoparticle for RA and assessed its therapeutic and targeting effects under image-guidance.
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