Development of Novel Epoxyketone-Based Proteasome Inhibitors as a Strategy To Overcome Cancer Resistance to Carfilzomib and Bortezomib.

Over the past 15 years, proteasome inhibitors (PIs), namely bortezomib, carfilzomib (Cfz) and ixazomib, have significantly improved the overall survival and quality-of-life for multiple myeloma (MM) patients. However, a significant portion of MM patients do not respond to PI therapies. Drug resistance is present either de novo or acquired after prolonged therapy through mechanisms that remain poorly defined. The lack of a clear understanding of clinical PI resistance has hampered the development of next-generation PI drugs to treat MM patients who no longer respond to currently available therapies. Here, we designed and synthesized novel epoxyketone-based PIs by structural modifications at the P1' site. We show that a Cfz analog, 9, harboring a hydroxyl substituent at its P1' position was highly cytotoxic against cancer cell lines displaying de novo or acquired resistance to Cfz. These results suggest that peptide epoxyketones incorporating P1'-targeting moieties may have the potential to bypass resistance mechanisms associated with Cfz and to provide additional clinical options for patients resistant to Cfz.

Temperature and Alternative Hosts Influence Aceria tosichella Infestation and Wheat Streak Mosaic Virus Infection.

Wheat streak mosaic, caused by Wheat streak mosaic virus (WSMV; family Potyviridae), is the most important and common viral disease of wheat (Triticum aestivum L.) in the Great Plains of North America. WSMV is transmitted by the wheat curl mite (WCM; Aceria tosichella). We evaluated how mean daily temperatures, cumulative growing degree-days, day of the year, and surrounding alternative host identity affected WCM infestation and WSMV infection of wheat from late summer through early autumn in Montana, United States. Cumulative growing degree-days, warm mean daily temperatures (i.e., >10°C), and surrounding alternative hosts interacted to alter risk of WCM infestation and WSMV infection. Wheat surrounded by Bromus tectorum L. and preharvest volunteer wheat had WCM infestation and WSMV infection rates of 88% in years when the mean daily temperature was 15°C in October, compared with 23% when surrounded by bare ground, and <1% when the temperature was 0°C regardless of surrounding alternative host. Mean daily temperatures in the cereal-growing regions of Montana during autumn are marginally conducive to WCM population growth and movement. As the region continues to warm, the period of WCM movement will become longer, potentially increasing the frequency of WSMV outbreaks.

Imaging of the high-risk carotid plaque: magnetic resonance imaging.

The emergence of the concept of high-risk atherosclerotic plaque has led to considerable interest in noninvasive imaging techniques to identify high-risk features before clinical sequelae. For plaques in the carotid arteries, magnetic resonance imaging has undergone considerable histologic validation to link imaging features to indicators of plaque instability, including plaque burden, intraplaque hemorrhage, fibrous cap disruption, lipid rich necrotic core, and calcification. Recently introduced imaging technologies, especially those focused on three-dimensional imaging sequences, are now poised for integration into the clinical workup of patients with suspected carotid atherosclerosis. The purpose of this article is to review the carotid plaque magnetic resonance imaging techniques that are most ready for integration into the clinic.

Impact of Cropping Systems, Soil Inoculum, and Plant Species Identity on Soil Bacterial Community Structure.

Farming practices affect the soil microbial community, which in turn impacts crop growth and crop-weed interactions. This study assessed the modification of soil bacterial community structure by organic or conventional cropping systems, weed species identity [Amaranthus retroflexus L. (redroot pigweed) or Avena fatua L. (wild oat)], and living or sterilized inoculum. Soil from eight paired USDA-certified organic and conventional farms in north-central Montana was used as living or autoclave-sterilized inoculant into steam-pasteurized potting soil, planted with Am. retroflexus or Av. fatua and grown for two consecutive 8-week periods to condition soil nutrients and biota. Subsequently, the V3-V4 regions of the microbial 16S rRNA gene were sequenced by Illumina MiSeq. Treatments clustered significantly, with living or sterilized inoculum being the strongest delineating factor, followed by organic or conventional cropping system, then individual farm. Living inoculum-treated soil had greater species richness and was more diverse than sterile inoculum-treated soil (observed OTUs, Chao, inverse Simpson, Shannon, P < 0.001) and had more discriminant taxa delineating groups (linear discriminant analysis). Living inoculum soil contained more Chloroflexi and Acidobacteria, while the sterile inoculum soil had more Bacteroidetes, Firmicutes, Gemmatimonadetes, and Verrucomicrobia. Organically farmed inoculum-treated soil had greater species richness, more diversity (observed OTUs, Chao, Shannon, P < 0.05), and more discriminant taxa than conventionally farmed inoculum-treated soil. Cyanobacteria were higher in pots growing Am. retroflexus, regardless of inoculum type, for three of the four organic farms. Results highlight the potential of cropping systems and species identity to modify soil bacterial communities, subsequently modifying plant growth and crop-weed competition.

Prevention of biofilm formation by methacrylate-based copolymer films loaded with rifampin, clarithromycin, doxycycline alone or in combination.

PURPOSE: This study reports the incorporation of the antibiotics rifampin, doxycycline and clarithromycin in poly(styrene-co-methyl methacrylate films and their effect on biofilm prevention. BACKGROUND: Invasive procedures in patients such as surgical device, or intravenous or urinary catheter implantation, often results in complicated hospital-acquired nosocomial infections. Biofilm formation is essential to establish these infections on these devices and novel antibiotic delivery approaches are needed for more effective management. METHODS: The films were evaluated in vitro for drug release and for their ability to prevent biofilm formation by methicillin susceptible and methicillin resistant Staphylococcus aureus. Surface tension components, obtained from contact angle measurements, and the morphology of the films evaluated by scanning electron microscopy were also investigated. RESULTS: In this study, antibiotic-loaded methacrylic copolymer films that effectively released rifampin, clarithromycin and doxycycline for up to 21 days prevented biofilm formation when tested in an in vitro bioreactor model. These drug loaded copolymer films provided the advantage by coating materials with a novel surface that was unsuitable for resettling of biofilms once the antibiotic was dissolved from the polymer surface. A combination of rifampin and clarithromycin released from the polymer film provided >99.9% kill of an MRSA inoculate for up to 72 h. CONCLUSION: Results showed that combining multiple drugs in copolymer films with unique surface properties, initial hydrophilicity and increase in roughness, can be an effective way to prevent biofilm formation.

Carotid magnetic resonance imaging. A window to study atherosclerosis and identify high-risk plaques.

Despite recent advances in the understanding and etiology of cardiovascular disease, it remains the leading cause of morbidity and mortality worldwide. A great deal of research has been dedicated to investigating and identifying plaque instability: the so-called "vulnerable plaque". A reliable, in vivo, imaging method capable of identifying plaque characteristics associated with high-risk plaque will be immensely useful for evaluating plaque status and predicting future events. With excellent soft-tissue contrast and resolution, magnetic resonance imaging (MRI) has the ability to visualize features of vulnerable plaques, as well as perform longitudinal studies on the etiology, progression, and regression of atherosclerotic plaque. This review will cover the current state-of-the-art and new developments in carotid MRI to characterize atherosclerosis and its use in clinical diagnoses and longitudinal studies to understand mechanisms of lesion progression and regression.