Assessment of KRASG12C inhibitors for colorectal cancer.

Colorectal cancer (CRC) is a highly prevalent and lethal cancer worldwide. Approximately 45% of CRC patients harbor a gain-in-function mutation in KRAS. KRAS is the most frequently mutated oncogene accounting for approximately 25% of all human cancers. Gene mutations in KRAS cause constitutive activation of the KRAS protein and MAPK/AKT signaling, resulting in unregulated proliferation and survival of cancer cells and other aspects of malignant transformation, progression, and metastasis. While KRAS has long been considered undruggable, the FDA recently approved two direct acting KRAS inhibitors, Sotorasib and Adagrasib, that covalently bind and inactivate KRASG12C. Both drugs showed efficacy for patients with non-small cell lung cancer (NSCLC) diagnosed with a KRASG12C mutation, but for reasons not well understood, were considerably less efficacious for CRC patients diagnosed with the same mutation. Thus, it is imperative to understand the basis for resistance to KRASG12C inhibitors, which will likely be the same limitations for other mutant specific KRAS inhibitors in development. This review provides an update on clinical trials involving CRC patients treated with KRASG12C inhibitors as a monotherapy or combined with other drugs. Mechanisms that contribute to resistance to KRASG12C inhibitors and the development of novel RAS inhibitors with potential to escape such mechanisms of resistance are also discussed.

A comprehensive preanalytical protocol for fresh solid tumor biospecimens.

Nearly seventy percent of diagnostic lab test errors occur due to variability in preanalytical factors. These are the parameters involved with all aspects of tissue processing, starting from the time tissue is collected from the patient in the operating room, until it is received and tested in the laboratory. While there are several protocols for transporting fixed tissue, organs, and liquid biopsies, such protocols are lacking for transport and handling of live solid tumor tissue specimens. There is a critical need to establish preanalytical protocols to reduce variability in biospecimen integrity and improve diagnostics for personalized medicine. Here, we provide a comprehensive protocol for the standard collection, handling, packaging, cold-chain logistics, and receipt of solid tumor tissue biospecimens to preserve tissue viability.

Preanalytical protocol for fresh solid tumor biospecimens.

Nearly seventy percent of diagnostic lab test errors occur due to variability in preanalytical factors. 1-4 These are the parameters involved with all aspects of tissue processing, starting from the time tissue is collected from the patient in the operating room, until it is received and tested in the laboratory. While there are several protocols for transporting fixed tissue, organs, and liquid biopsies, such protocols are lacking for transport and handling of live solid tumor tissue specimens. There is a critical need to establish preanalytical protocols to reduce variability in biospecimen integrity and improve diagnostics for personalized medicine. 2,5 Here, we provide a comprehensive protocol for the standard collection, handling, packaging, cold-chain logistics, and receipt of solid tumor tissue biospecimens to preserve tissue viability.

A hitchhiker's guide to cancer models.

Cancer is a complex and uniquely personal disease. More than 1.7 million people in the United States are diagnosed with cancer every year. As the burden of cancer grows, so does the need for new, more effective therapeutics and for predictive tools to identify optimal, personalized treatment options for every patient. Cancer models that recapitulate various aspects of the disease are fundamental to making advances along the continuum of cancer treatment from benchside discoveries to bedside delivery. In this review, we use a thought experiment as a vehicle to arrive at four broad categories of cancer models and explore the strengths, weaknesses, opportunities, and threats for each category in advancing our understanding of the disease and improving treatment strategies.

Evaluating Population Density as a Parameter for Optimizing COVID-19 Testing: Statistical Analysis.

BACKGROUND: SARS-CoV-2 transmission risk generally increases with the proximity of those shedding the virus to those susceptible to infection. Thus, this risk is a function of both the number of people and the area they occupy. However, the latter continues to evade the COVID-19 testing policy. OBJECTIVE: The aim of this study is to analyze per capita COVID-19 testing data reported for Alabama to evaluate whether testing realignment along population density, rather than density agnostic per capita, would be more effective. METHODS: Descriptive statistical analyses were performed for population, density, COVID-19 tests administered, and positive cases for all 67 Alabama counties. RESULTS: Tests reported per capita appeared to suggest widespread statewide testing. However, there was little correlation (r=0.28, P=.02) between tests per capita and the number of cases. In terms of population density, new cases were higher in areas with a higher population density, despite relatively lower test rates as a function of density. CONCLUSIONS: Increased testing in areas with lower population density has the potential to induce a false sense of security even as cases continue to rise sharply overall.

Measuring Surface and Interfacial Tension In Situ in Microdripping Mode for Electrohydrodynamic Applications.

Walking on water is made possible, at least for tiny insects, by molecular interaction at the interfaces of dissimilar materials. Impact of these interactions-surface tension (SFT) and, more broadly, interfacial tension (IFT)-is particularly evident at micro and nano sizescales. Thus, implications of walking on water can be significant for SFT or IFT (S/IFT)-driven nanofabrication technologies, such as electrohydrodynamic atomization (EHDA), in developing next generation biomimetic microphysiological systems (MPS) and drug delivery systems (DDS). However, current methods for estimating S/IFT, based on sessile drops or new surface formation on a ring or plate, are unsuitable for integration with EHDA assemblies used in electrospinning and electrospraying. Here, we show an in situ method for estimating S/IFT specifically devised for EHDA applications using signal processing algorithms that correlate the frequency and periodicity of liquid dispensed in EHDA microdripping mode with numerical solutions from computational fluid dynamics (CFD). Estimated S/IFT was generally in agreement with published ranges for water-air, 70% ethanol-air, chloroform-air, and chloroform-water. SFT for solutions with surfactants decreased with increasing concentrations of surfactant, but at relatively higher than published values. This was anticipated, considering that established methods measure SFT at boundaries with asymmetrically high concentrations of surfactants which lower SFT.

Novel Biomimetic Microphysiological Systems for Tissue Regeneration and Disease Modeling.

Biomaterials engineered to closely mimic morphology, architecture, and nanofeatures of naturally occurring in vivo extracellular matrices (ECM) have gained much interest in regenerative medicine and in vitro biomimetic platforms. Similarly, microphysiological systems (MPS), such as lab-chip, have drummed up momentum for recapitulating precise biomechanical conditions to model the in vivo microtissue environment. However, porosity of in vivo scaffolds regulating barrier and interface functions is generally absent in lab-chip systems, or otherwise introduces considerable cost, complexity, and an unrealistic uniformity in pore geometry. We address this by integrating electrospun nanofibrous porous scaffolds in MPS to develop the lab-on-a-brane (LOB) MPS for more effectively modeling transport, air-liquid interface, and tumor progression and for personalized medicine applications.

Wet-laid soy fiber reinforced hydrogel scaffold: Fabrication, mechano-morphological and cell studies.

Among materials used in biomedical applications, hydrogels have received consistent linear growth in interest over the past decade due to their large water volume and saliency to the natural extracellular matrix. These materials are often limited due to their sub-optimal mechanical properties which are typically improved via chemical or physical crosslinking. Chemical crosslinking forms strong inter-polymer bonds but typically uses reagents that are cytotoxic while physical crosslinking is more temperamental to environmental changes but can be formed without these toxic reagents. In this study, we added a fiber-reinforcement phase to a poly(vinyl alcohol) (PVA) hydrogel formed through successive freezing-thawing cycles by incorporating a non-woven microfiber mat formed by the wet-lay process. By reinforcing the hydrogel with a wet-laid fibrous mat, the ultimate tensile strength and modulus increased from 0.11 ± 0.01 MPa and 0.17 ± 0.02 kPa to 0.24 ± 0.02 MPa and 5.76 ± 1.12 kPa, respectively. An increase in toughness and elongation was also found increasing from 2.52 ± 0.37 MPa to 25.6 ± 3.84 and 51.89 ± 5.16% to 111.16 ± 9.68%, respectively. The soy fibers were also found to induce minimal cytotoxicity with endothelial cell viability showing 96.51% ± 1.91 living cells after a 48 h incubation. This approach to hydrogel-reinforcement presents a rapid, tunable method by which hydrogels can attain increased mechanical properties without sacrificing their inherent biologically favorable properties.