Cancer Cachexia: Traditional Therapies and Novel Molecular Mechanism-Based Approaches to Treatment

The complex syndrome of cancer cachexia (CC) that occurs in 50% to 80% cancer patients has been identified as an independent predictor of shorter survival and increased risk of treatment failure and toxicity, contributing to the mortality and morbidity in this population. CC is a pathological state including a symptom cluster of loss of muscle (skeletal and visceral) and fat, manifested in the cardinal feature of emaciation, weakness affecting functional status, impaired immune system, and metabolic dysfunction. The most prominent feature of CC is its non-responsiveness to traditional treatment approaches; randomized clinical trials with appetite stimulants, 5-HT3 antagonists, nutrient supplementation, and Cox-2 inhibitors all have failed to demonstrate success in reversing the metabolic abnormalities seen in CC. Interventions based on a clear understanding of the mechanism of CC, using validated markers relevant to the underlying metabolic abnormalities implicated in CC are much needed. Although the etiopathogenesis of CC is poorly understood, studies have proposed that NFkB is upregulated in CC, modulating immune and inflammatory responses induce the cellular breakdown of muscle, resulting in sarcopenia. Several recent laboratory studies have shown that n-3 fatty acid may attenuate protein degradation, potentially by preventing NFkB accumulation in the nucleus, preventing the degradation of muscle proteins. However, clinical trials to date have produced mixed results potentially attributed to timing of interventions (end stage) and utilizing outcome markers such as weight which is confounded by hydration, cytotoxic therapies, and serum cytokines. We propose that selective targeting of proteasome activity with a standardized dose of omega-3-acid ethyl esters, administered to cancer patients diagnosed with early stage CC, in addition to a standard intervention with nutritionally adequate diet and appetite stimulants, will alter metabolic abnormalities by downregulating NFkB, preventing the breakdown of myofibrillar proteins and resulting in increasing serum protein markers, lean body mass, and functional status

Dendrocerus mexicali (Hymenoptera, Ceraphronoidea, Megaspilidae): Novel antennal morphology, first description of female, and expansion of known range into the U.S.

Dendrocerus mexicali has been described by Paul Dessart from a single male specimen collected in Mexico. Using 87 newly identified specimens we expand the known range to include the Southwestern United States and Florida, provide an expanded description of the species, and provide the first record of the female. We also use confocal laser scanning microscopy and in vitro hydrostatic pressure changes to investigate the functional morphology of apparently unique basally flexible antennal branches

Dendrocerus mexicali images and semantic statements

Figures and OWL files for Burks et al 2016. Dendrocerus mexicali (Hymenoptera, Ceraphronoidea, Megaspilidae): Novel antennal morphology, first description of female, and expansion of known range into the U.S.<br

A Two-Photon Microimaging-Microdevice System for Four-Dimensional Imaging of Local Drug Delivery in Tissues

Advances in the intratumor measurement of drug responses have included a pioneering biomedical microdevice for high throughput drug screening in vivo, which was further advanced by integrating a graded-index lens based two-dimensional fluorescence micro-endoscope to monitor tissue responses in situ across time. While the previous system provided a bulk measurement of both drug delivery and tissue response from a given region of the tumor, it was incapable of visualizing drug distribution and tissue responses in a three-dimensional (3D) way, thus missing the critical relationship between drug concentration and effect. Here we demonstrate a next-generation system that couples multiplexed intratumor drug release with continuous 3D spatial imaging of the tumor microenvironment via the integration of a miniaturized two-photon micro-endoscope. This enables optical sectioning within the live tissue microenvironment to effectively profile the entire tumor region adjacent to the microdevice across time. Using this novel microimaging-microdevice (MI-MD) system, we successfully demonstrated the four-dimensional imaging (3 spatial dimensions plus time) of local drug delivery in tissue phantom and tumors. Future studies include the use of the MI-MD system for monitoring of localized intra-tissue drug release and concurrent measurement of tissue responses in live organisms, with applications to study drug resistance due to nonuniform drug distribution in tumors, or immune cell responses to anti-cancer agents

A Miniaturized Platform for Multiplexed Drug Response Imaging in Live Tumors

By observing the activity of anti-cancer agents directly in tumors, there is potential to greatly expand our understanding of drug response and develop more personalized cancer treatments. Implantable microdevices (IMD) have been recently developed to deliver microdoses of chemotherapeutic agents locally into confined regions of live tumors; the tissue can be subsequently removed and analyzed to evaluate drug response. This method has the potential to rapidly screen multiple drugs, but requires surgical tissue removal and only evaluates drug response at a single timepoint when the tissue is excised. Here, we describe a “lab-in-a-tumor” implantable microdevice (LIT-IMD) platform to image cell-death drug response within a live tumor, without requiring surgical resection or tissue processing. The LIT-IMD is inserted into a live tumor and delivers multiple drug microdoses into spatially discrete locations. In parallel, it locally delivers microdose levels of a fluorescent cell-death assay, which diffuses into drug-exposed tissues and accumulates at sites of cell death. An integrated miniaturized fluorescence imaging probe images each region to evaluate drug-induced cell death. We demonstrate ability to evaluate multi-drug response over 8 h using murine tumor models and show correlation with gold-standard conventional fluorescence microscopy and histopathology. This is the first demonstration of a fully integrated platform for evaluating multiple chemotherapy responses in situ. This approach could enable a more complete understanding of drug activity in live tumors, and could expand the utility of drug-response measurements to a wide range of settings where surgery is not feasible

A Miniaturized Platform for Multiplexed Drug Response Imaging in Live Tumors

By observing the activity of anti-cancer agents directly in tumors, there is potential to greatly expand our understanding of drug response and develop more personalized cancer treatments. Implantable microdevices (IMD) have been recently developed to deliver microdoses of chemotherapeutic agents locally into confined regions of live tumors; the tissue can be subsequently removed and analyzed to evaluate drug response. This method has the potential to rapidly screen multiple drugs, but requires surgical tissue removal and only evaluates drug response at a single timepoint when the tissue is excised. Here, we describe a “lab-in-a-tumor” implantable microdevice (LIT-IMD) platform to image cell-death drug response within a live tumor, without requiring surgical resection or tissue processing. The LIT-IMD is inserted into a live tumor and delivers multiple drug microdoses into spatially discrete locations. In parallel, it locally delivers microdose levels of a fluorescent cell-death assay, which diffuses into drug-exposed tissues and accumulates at sites of cell death. An integrated miniaturized fluorescence imaging probe images each region to evaluate drug-induced cell death. We demonstrate ability to evaluate multi-drug response over 8 h using murine tumor models and show correlation with gold-standard conventional fluorescence microscopy and histopathology. This is the first demonstration of a fully integrated platform for evaluating multiple chemotherapy responses in situ. This approach could enable a more complete understanding of drug activity in live tumors, and could expand the utility of drug-response measurements to a wide range of settings where surgery is not feasible

Relationship between the COVID-19 pandemic and structural inequalities within the pediatric trauma population

Abstract Background The COVID-19 pandemic disrupted social, political, and economic life across the world, shining a light on the vulnerability of many communities. The objective of this study was to assess injury patterns before and after implementation of stay-at-home orders (SHOs) between White children and children of color and across varying levels of vulnerability based upon children’s home residence. Methods A multi-institutional retrospective study was conducted evaluating patients < 18 years with traumatic injuries. A “Control” cohort from an averaged March-September 2016–2019 time period was compared to patients injured after SHO initiation-September 2020 (“COVID” cohort). Interactions between race/ethnicity or social vulnerability index (SVI), a marker of neighborhood vulnerability and socioeconomic status, and the COVID-19 timeframe with regard to the outcomes of interest were assessed using likelihood ratio Chi-square tests. Differences in injury intent, type, and mechanism were then stratified and explored by race/ethnicity and SVI separately. Results A total of 47,385 patients met study inclusion. Significant interactions existed between race/ethnicity and the COVID-19 SHO period for intent (p < 0.001) and mechanism of injury (p < 0.001). There was also significant interaction between SVI and the COVID-19 SHO period for mechanism of injury (p = 0.01). Children of color experienced a significant increase in intentional (COVID 16.4% vs. Control 13.7%, p = 0.03) and firearm (COVID 9.0% vs. Control 5.2%, p < 0.001) injuries, but no change was seen among White children. Children from the most vulnerable neighborhoods suffered an increase in firearm injuries (COVID 11.1% vs. Control 6.1%, p = 0.001) with children from the least vulnerable neighborhoods having no change. All-terrain vehicle (ATV) and bicycle crashes increased for children of color (COVID 2.0% vs. Control 1.1%, p = 0.04 for ATV; COVID 6.7% vs. Control 4.8%, p = 0.02 for bicycle) and White children (COVID 9.6% vs. Control 6.2%, p < 0.001 for ATV; COVID 8.8% vs. Control 5.8%, p < 0.001 for bicycle). Conclusions In contrast to White children and children from neighborhoods of lower vulnerability, children of color and children living in higher vulnerability neighborhoods experienced an increase in intentional and firearm-related injuries during the COVID-19 pandemic. Understanding inequities in trauma burden during times of stress is critical to directing resources and targeting intervention strategies