Combinatorial resveratrol and quercetin polymeric micelles mitigate doxorubicin induced cardiotoxicity in vitro and in vivo

Doxorubicin hydrochloride (ADR) is an anthracycline antibiotic used to treat various cancers. However, due to its extensive cardiotoxic side effects a lifetime cumulative dose limit of 450–550 mg/m2 exists. The postulated mechanism of the cardiotoxicity is generation of reactive oxygen and nitrogen species. Natural products like resveratrol (RES), and quercetin (QUE) are known free radical scavengers and have shown cardioprotective effects. However, concurrent dosing of these natural products with ADR is limited due to their low solubility, and low oral bioavailability. We hypothesize that the combination of RES and QUE in Pluronic® F127 micelles (mRQ) when co-administered with ADR, will be cardioprotective in vitro and in vivo, while maintaining or increasing the efficacy of ADR against cancer cell lines in vitro. We prepared mRQ micelles capable of retaining 1.1 mg/mL and 1.42 mg/mL of RES and QUE respectively. The in vitro release of RES and QUE from the micelles followed first order kinetics over 48 h. In vitro cell viability and combination index analysis studies in human ovarian cancer cells (SKOV-3) and rat cardiomyocytes (H9C2) showed that RES:QUE: ADR at 10:10:1 ratio was synergistic in SKOV-3 cells and antagonistic in H9C2 cells. Caspase 3/7 activity studies indicated that mRQ did not interfere with ADR caspase activity in SKOV-3 cells but significantly decreased it in H9C2 cells. The generation of reactive oxygen species (ROS) in SKOV-3 and H9C2 cells in the presence of mRQ also indicated no changes in ROS activity in SKOV-3 cells but significant scavenging in H9C2 cells. Healthy mice were exposed to acute doses of ADR and ADR with mRQ. Based on biochemical estimations the presence of mRQ with ADR conferred full cardioprotection in these mice. Concurrent administration of mRQ with ADR at 10:10:1 ratio provides a viable strategy to mitigate acute ADR induced cardiotoxicity.Keywords: Natural products, Cardiotoxicity, Polymeric micelles, Doxorubicin, Chemosensitizatio

Dont Mess with Texas: Getting the Lone Star State to Net-Zero by 2050

The world is decarbonizing. Many countries, companies, and financial institutions have committed to cutting their emissions. Decarbonization commitments have been issued by: 136 countries including Canada, China, and the UK, at least 16 U.S. states including New York, Louisiana, and Virginia, and a third of the largest 2,000 publicly traded companies in the world, including Apple, Amazon, and Walmart, and numerous Texas companies like ExxonMobil, American and Southwest Airlines, Baker Hughes, and AT&T.1–9 These decarbonizing countries, states, cities, and companies are Texas's energy customers. If Texas ignores the challenge to decarbonize its economy, it may eventually face the more difficult challenge of selling carbon-intensive products to customers around the world who do not want them. We are already seeing this scenario beginning to play out with France canceling a liquified natural gas deal from Texas gas producers and both U.S. and international automakers announcing shifts to electric vehicles. Proactive net-zero emissions strategies might allow Texas to maintain energy leadership and grow the economy within a rapidly decarbonizing global marketplace.Thankfully, Texas is uniquely positioned to lead the world in the transition to a carbon-neutral energy economy. With the second highest Gross State Product in the US, the Texas economy is on par with countries like Canada, Italy, or Brazil. Thus, Texas's decisions have global implications. Texas also has an abundant resource of low-carbon energy sources to harness and a world-class workforce with technical capabilities to implement solutions at a large-scale quickly and safely. Texas has a promising opportunity to lead the world towards a better energy system in a way that provides significant economic benefits to the state by leveraging our renewable resources, energy industry expertise, and strong manufacturing and export markets for clean electricity, fuels, and products. The world is moving, with or without Texas, but it is likely to move faster--and Texas will be more prosperous--if Texans lead the way.There are many ways to fully decarbonize the Texas economy across all sectors by 2050. In this analysis, we present a Business as Usual (BAU) scenario and four possible pathways to Texas achieving state-wide net-zero emissions by 2050. Figure ES-1 provides a visual comparison of scenario conditions

Nanomedicine Drug Delivery for the Treatment of Lymphatically Metastasizing Cancers

Nearly 80% of solid tumors, such as melanoma, metastasize via the lymphatic system. The most common form of melanoma is BRAF-mutant melanoma, and additional mutations, such as a PTEN mutation in the PI3K pathway, is required for metastases to occur. Standard therapy includes treatment with small molecules dabrafenib (DAB) and trametinib (TRAM). Pictilisib (PIC) targets PI3K and is in clinical trials. Small molecules have limited lymphatic uptake, leaving cancer in the lymphatic system undertreated. Therefore, the aim of this work is to develop a platform for delivering drugs to lymphatic melanoma metastases in therapeutic concentrations. First, a review of lymphatic anatomy and physiology, changes in the presence of cancer, and experimental techniques used for targeting drugs to the lymphatics is presented. Then, a drug-loaded nanoparticle platform for delivering DAB and TRAM in 1:1 molar ratios (DT-NP) or DAB, TRAM, and PIC in 1:1:1 molar ratios (DTP-NP) to treat lymphatic BRAF- and PTEN-mutant melanoma metastases is presented. Nanoparticles were assessed for in vitro cytotoxicity in two melanoma cell lines. Dose limiting toxicity (DLT) and maximum tolerated dose (MTD) were determined in mice, and efficacy was examined in a BRaf- and Pten-mutant melanoma transgenic mouse model. Findings show that DT-NPs and DTP-NPs are more potent in cell lines than individually dosed drugs. The MTD for both formulations is 12.5 mg/kg/dose administered subcutaneously once weekly for three weeks in mice. Nanoparticles are more efficacious in the transgenic mouse model than orally administered targeted therapy, indicating enhanced lymphatic drug delivery in vivo. Therefore, this work demonstrates that drug-loaded nanoparticles are synergistic in vitro and are efficacious both in vitro and in vivo in a clinically relevant transgenic melanoma mouse model. This platform may have utility in targeting other lymphatically metastasizing cancers that are treated with systemically administered small molecules

Walking the Talk: Moving Indigenous Studies from the Classroom to the Community

In this session students will showcase their final assignments from the course Anthropology 4050: Canadian Status/Treaty Indian Reserve Communities. Throughout the course we have discussed the complexities of the history of the reserve system in Canada, the nuances of the Treaty process, the rigidity of the Indian Act, the traumas of residential schools and lived implications of forced relocations on Indigenous communities. We have examined how colonial relations are spatialized and how this spacialization translates into lived social relations. This showcase represents our desire to share what we have learned and why it matters with our TRU community in the hopes of nurturing a space of understanding, compassion, and mutually respectful conversation