Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways

The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKβ independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.</p

Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways

The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKβ independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.</p

Review of \u3ci\u3e Groundwater Management in the West\u3c/i\u3e by Jeffrey S. Ashley and Zachary A. Smith

Groundwater is becoming an increasingly important water source throughout the United States, especially in the West where surface supplies are limited and usually over-committed. An assessment of groundwater in the West is needed, and this book fills an important gap in providing useful information in a well-organized and accessible fashion. Ashley and Smith discuss the West, incorporating nineteen states, within four subregions: Pacific Coast, Rocky Mountains, Great Plains, and the Southwest. Each state is addressed in an individual chapter observing the same format: after a brief introduction, the authors describe the state\u27s physical characteristics and demographics, the laws, politics, and policy governing water use, and prospects for the future. The chapters range in length from seventeen pages for California and fourteen for Arizona and Nebraska to seven for South Dakota and Idaho and eight for Utah

Groundwater Exploitation in the High Plains

The High Plains region was once called the Great American Desert and thought to be, in the words of explorer Stephen Long, “wholly unfit for cultivation.” Now we know that beneath the surface, unbeknownst to the explorers and early settlers, lies the Ogallala aquifer, an underground formation that stretches for 800 miles from the Texas panhandle to South Dakota. It holds more water than Lake Huron. Indeed, the Ogallala has been referred to as the sixth Great Lake. It is the water pumped for irrigation from the Ogallala that has enabled a naturally dry region to produce up to 40 percent of America’s beef and 20 to 25 percent of its food and fiber, an output worth about $20 billion. In the forty years since the invention of center pivot irrigation, the High Plains aquifer system has been depleted at an astonishing rate. In 1978 the volume of water pumped from the aquifer exceeded the annual flow of the Colorado River. In Texas, water levels are down 200 feet in some areas. In Kansas, 700 miles of rivers that once flowed year round no longer flow at all. In short, the High Plains may be becoming the desert it was once thought to be. Is it too late to solve the problem? Geographers David Kromm and Stephen White assembled nine of the most knowledgeable scholars and water professionals in the Great Plains to help answer that question. The result is a collection of essays that insightfully examine the dilemmas of groundwater use. From a variety of perspectives they address both the technical problems and the politics of water management to provide a badly needed analysis of the implications of large-scale irrigation. They have included three case studies: the Nebraska Sand Hills, Northwestern Kansas, and West Texas. Kromm and White provide an introduction and conclusion to the volume. Description David Kromm is professor emeritus of geography at Kansas State University. He is the author of World Regional Geography, numerous articles on water management. Stephen White was professor of geography at Kansas State University. He published more than 75 book chapters and scholarly articles and, with Kromm, two widely distributed KSU reports, Conserving the Ogallala: What Next? and Conserving Water in the High Plains. Gilbert F. White was the author or coauthor of more than two dozen books on flooding and water management, including Drawers of Water: Domestic Water Use in East Africa and Water for Life: Water Management and Environmental Policy. With a New Preface by David E. Kromm. Edited by David E. Kromm and Stephen E. White, Contributors include Wayne A. Bossert, Steve Gaul, Donald E. Green, David E. Kromm, J. T. Musick, M. Duane Nellis, Rebecca S. Roberts, B. A. Stewart, Otis W. Templer, Lloyd V. Urban, and Stephen E. White. This Kansas Open Books title is funded by a grant from the National Endowment for the Humanities and the Andrew W. Mellon Foundation Humanities Open Book Program.https://digitalcommons.pittstate.edu/kansas_open_books/1037/thumbnail.jp

Milking the plains: movement of large dairy operations into southwestern Kansas

Western Kansas has an historical identification with cattle, with a focus on cattle ranching and more specifically since the 1950s, beef-cattle feedlots. Since the mid-1990s large dairy operations have moved into southwestern Kansas. Today more than twenty large dairies house more than 70,000 milk cows. These operate as confined feeding operations similar to beef-cattle feedlots. Regional advantages for the dairy industry include affordable land with wide-open space, local residents’ cattle- and dairy-friendly attitudes, and other factors. Regional promoters have actively recruited dairies, and a dairy-business support system has emerged. The prospects for continued expansion of dairies in southwestern Kansas are unclear; despite the locational advantages and the possibility that the industry may continue to relocate here, as did the cattle-feeding industry several decades ago, further moves into the area may depend on continued resources availability and additional infrastructure development

An active learning framework for enhancing identification of non-artifactual intracranial pressure waveforms

Objective: Intracranial pressure (ICP) is an important and established clinical measurement that is used in the management of severe acute brain injury. ICP waveforms are usually triphasic and are susceptible to artifact because of transient catheter malfunction or routine patient care. Existing methods for artifact detection include threshold-based, stability-based, or template matching, and result in higher false positives (when there is variability in the ICP waveforms) or higher false negatives (when the ICP waveforms lack complete triphasic components but are valid). Approach: We hypothesized that artifact labeling of ICP waveforms can be optimized by an active learning approach which includes interactive querying of domain experts to identify a manageable number of informative training examples. Main results: The resulting active learning based framework identified non-artifactual ICP pulses with a superior AUC of 0.96 + 0.012, compared to existing methods: template matching (AUC: 0.71 + 0.04), ICP stability (AUC: 0.51 + 0.036) and threshold-based (AUC: 0.5 + 0.02). Significance: The proposed active learning framework will support real-time ICP-derived analytics by improving precision of artifact-labelling

Ketamine to treat super-refractory status epilepticus

Objective To test ketamine infusion efficacy in the treatment of super-refractory status epilepticus (SRSE), we studied patients with SRSE who were treated with ketamine retrospectively. We also studied the effect of high doses of ketamine on brain physiology as reflected by invasive multimodality monitoring (MMM). Methods We studied a consecutive series of 68 patients with SRSE who were admitted between 2009 and 2018, treated with ketamine, and monitored with scalp EEG. Eleven of these patients underwent MMM at the time of ketamine administration. We compared patients who had seizure cessation after ketamine initiation to those who did not. Results Mean age was 53 +/- 18 years and 46% of patients were female. Seizure burden decreased by at least 50% within 24 hours of starting ketamine in 55 (81%) patients, with complete cessation in 43 (63%). Average dose of ketamine infusion was 2.2 +/- 1.8 mg/kg/h, with median duration of 2 (1-4) days. Average dose of midazolam was 1.0 +/- 0.8 mg/kg/h at the time of ketamine initiation and was started at a median of 0.4 (0.1-1.0) days before ketamine. Using a generalized linear mixed effect model, ketamine was associated with stable mean arterial pressure (odds ratio 1.39, 95% confidence interval 1.38-1.40) and with decreased vasopressor requirements over time. We found no effect on intracranial pressure, cerebral blood flow, or cerebral perfusion pressure. Conclusion Ketamine treatment was associated with a decrease in seizure burden in patients with SRSE. Our data support the notion that high-dose ketamine infusions are associated with decreased vasopressor requirements without increased intracranial pressure. Classification of evidence This study provides Class IV evidence that ketamine decreases seizures in patients with SRSE