STX-478, a Mutant-Selective, Allosteric PI3Kα Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3Kα-Mutant Xenografts.

Phosphoinositide 3-kinase α (PIK3CA) is one of the most mutated genes across cancers, especially breast, gynecologic, and head and neck squamous cell carcinoma tumors. Mutations occur throughout the gene, but hotspot mutations in the helical and kinase domains predominate. The therapeutic benefit of isoform-selective PI3Kα inhibition was established with alpelisib, which displays equipotent activity against the wild-type and mutant enzyme. Inhibition of wild-type PI3Kα is associated with severe hyperglycemia and rash, which limits alpelisib use and suggests that selectively targeting mutant PI3Kα could reduce toxicity and improve efficacy. Here we describe STX-478, an allosteric PI3Kα inhibitor that selectively targets prevalent PI3Kα helical- and kinase-domain mutant tumors. STX-478 demonstrated robust efficacy in human tumor xenografts without causing the metabolic dysfunction observed with alpelisib. Combining STX-478 with fulvestrant and/or cyclin-dependent kinase 4/6 inhibitors was well tolerated and provided robust and durable tumor regression in ER+HER2- xenograft tumor models. SIGNIFICANCE: These preclinical data demonstrate that the mutant-selective, allosteric PI3Kα inhibitor STX-478 provides robust efficacy while avoiding the metabolic dysfunction associated with the nonselective inhibitor alpelisib. Our results support the ongoing clinical evaluation of STX-478 in PI3Kα-mutated cancers, which is expected to expand the therapeutic window and mitigate counterregulatory insulin release. See related commentary by Kearney and Vasan, p. 2313. This article is featured in Selected Articles from This Issue, p. 2293.

Review Paper: Residual Stresses in Deposited Thin-Film Material Layers for Micro- and Nano-Systems Manufacturing.

This review paper covers a topic of significant importance in micro- and nano-systems development and manufacturing, specifically the residual stresses in deposited thin-film material layers and methods to control or mitigate their impact on device behavior. A residual stress is defined as the presence of a state of stress in a thin-film material layer without any externally applied forces wherein the residual stress can be compressive or tensile. While many material properties of deposited thin-film layers are dependent on the specific processing conditions, the residual stress often exhibits the most variability. It is not uncommon for residual stresses in deposited thin-film layers to vary over extremely large ranges of values (100% percent or more) and even exhibit changes in the sign of the stress state. Residual stresses in deposited layers are known to be highly dependent on a number of factors including: processing conditions used during the deposition; type of material system (thin-films and substrate materials); and other processing steps performed after the thin-film layer has been deposited, particularly those involving exposure to elevated temperatures. The origins of residual stress can involve a number of complex and interrelated factors. As a consequence, there is still no generally applicable theory to predict residual stresses in thin-films. Hence, device designers usually do not have sufficient information about the residual stresses values when they perform the device design. Obviously, this is a far less than ideal situation. The impact of this is micro- and nano-systems device development takes longer, is considerably more expensive, and presents higher risk levels. The outline of this paper is as follows: a discussion of the origins of residual stresses in deposited thin-film layers is given, followed by an example demonstrating the impact on device behavior. This is followed by a review of thin-film deposition methods outlining the process parameters known to affect the resultant residual stress in the deposited layers. Then, a review of the reported methods used to measure residual stresses in thin-films are described. A review of some of the literature to illustrate the level of variations in residual stresses depending on processing conditions is then provided. Methods which can be used to control the stresses and mitigate the impact of residual stresses in micro- and nano-systems device design and fabrication are then covered, followed by some recent development of interest.

Spatial equity implications and neighborhood indicators of ridehailing trip frequency and vehicle miles traveled in the phoenix metro region.

Early optimism for ridehailing services to complement existing public transit services and offer individuals another shared mobility service with reduced travel costs and improved travel times have largely proven to be unsubstantiated. This unwelcomed outcome, in part due to the popularity of ridehailing services among wealthier populations and restrictions on the less-expensive ridesharing service in some urban settings, has likely instead resulted in heightened disparities in access to this on-demand mobility option for historically-marginalized populations and under-resourced communities. This hypothesis is examined by estimating the macro-level socioeconomic and built environment determinants of ridehailing pick-ups and drop-offs in the Phoenix metro region with spatial lag of X modeling. A geographically weighted regression (GWR) model of vehicle miles traveled was then estimated using route-level ridehailing data from a third-party mileage tracking app to identify zonal attributes associated with this measure of vehicle-based exposure. Together, study findings highlight the benefits and drawbacks of greater ridehailing service activity, identifying a need for programs and interventions that safeguard and improve access to affordable high-quality mobility options for transportation disadvantaged neighborhoods.

Recent Advances in Reactive Ion Etching and Applications of High-Aspect-Ratio Microfabrication.

This paper reviews the recent advances in reaction-ion etching (RIE) for application in high-aspect-ratio microfabrication. High-aspect-ratio etching of materials used in micro- and nanofabrication has become a very important enabling technology particularly for bulk micromachining applications, but increasingly also for mainstream integrated circuit technology such as three-dimensional multi-functional systems integration. The characteristics of traditional RIE allow for high levels of anisotropy compared to competing technologies, which is important in microsystems device fabrication for a number of reasons, primarily because it allows the resultant device dimensions to be more accurately and precisely controlled. This directly leads to a reduction in development costs as well as improved production yields. Nevertheless, traditional RIE was limited to moderate etch depths (e.g., a few microns). More recent developments in newer RIE methods and equipment have enabled considerably deeper etches and higher aspect ratios compared to traditional RIE methods and have revolutionized bulk micromachining technologies. The most widely known of these technologies is called the inductively-coupled plasma (ICP) deep reactive ion etching (DRIE) and this has become a mainstay for development and production of silicon-based micro- and nano-machined devices. This paper will review deep high-aspect-ratio reactive ion etching technologies for silicon, fused silica (quartz), glass, silicon carbide, compound semiconductors and piezoelectric materials.

Coho salmon spawner mortality in western US urban watersheds: bioinfiltration prevents lethal storm water impacts.

Adult coho salmon Oncorhynchus kisutch return each autumn to freshwater spawning habitats throughout western North America. The migration coincides with increasing seasonal rainfall, which in turn increases storm water run-off, particularly in urban watersheds with extensive impervious land cover. Previous field assessments in urban stream networks have shown that adult coho are dying prematurely at high rates (>50%). Despite significant management concerns for the long-term conservation of threatened wild coho populations, a causal role for toxic run-off in the mortality syndrome has not been demonstrated.We exposed otherwise healthy coho spawners to: (i) artificial storm water containing mixtures of metals and petroleum hydrocarbons, at or above concentrations previously measured in urban run-off; (ii) undiluted storm water collected from a high traffic volume urban arterial road (i.e. highway run-off); and (iii) highway run-off that was first pre-treated via bioinfiltration through experimental soil columns to remove pollutants.We find that mixtures of metals and petroleum hydrocarbons - conventional toxic constituents in urban storm water - are not sufficient to cause the spawner mortality syndrome. By contrast, untreated highway run-off collected during nine distinct storm events was universally lethal to adult coho relative to unexposed controls. Lastly, the mortality syndrome was prevented when highway run-off was pretreated by soil infiltration, a conventional green storm water infrastructure technology.Our results are the first direct evidence that: (i) toxic run-off is killing adult coho in urban watersheds, and (ii) inexpensive mitigation measures can improve water quality and promote salmon survival. Synthesis and applications. Coho salmon, an iconic species with exceptional economic and cultural significance, are an ecological sentinel for the harmful effects of untreated urban run-off. Wild coho populations cannot withstand the high rates of mortality that are now regularly occurring in urban spawning habitats. Green storm water infrastructure or similar pollution prevention methods should be incorporated to the maximal extent practicable, at the watershed scale, for all future development and redevelopment projects, particularly those involving transportation infrastructure.

The role of elective perioperative dialysis in nondialysis renal failure patients.

BACKGROUND: Patients with renal insufficiency represent a difficult group. They show an increased morbidity and mortality after heart surgery. Nondialysis chronic kidney disease patients show higher mortality than patients receiving chronic dialysis. Their management is not standardized. This study was undertaken to determine whether elective perioperative dialysis in these patients improved outcomes. METHOD: A retrospective review of records of nondialysis chronic kidney disease patients was carried out. Patients who were not dialyzed before surgery (group A, n = 28) were compared with a propensity-matched group of patients (group B, n = 28) who received elective dialysis preoperatively for their baseline characteristics and outcomes of their heart surgery. RESULTS: Patients who received elective dialysis in the perioperative period (group B) showed fewer neurologic complications (p = 0.004), shorter postoperative length of stay (p = 0.053), fewer gastrointestinal complications (p = 0.051), and fewer major adverse events (p = 0.013). Multiorgan failure and discharge to an extended care facility were also less frequent in group B, although this did not reach statistical significance. CONCLUSIONS: Nondialysis renal failure patients, particularly those with higher creatinine concentrations, may benefit from elective perioperative dialysis in terms of decreased rates of complications and shorter postoperative length of stay.

Effect of mannose chain length on targeting of glucocerebrosidase for enzyme replacement therapy of Gaucher disease.

Recombinant human glucocerebrosidase (imiglucerase, Cerezyme) is used in enzyme replacement therapy for Gaucher disease. Complex oligosaccharides present on Chinese hamster ovary cell-expressed glucocerebrosidase (GCase) are enzymatically remodeled into a mannose core, facilitating mannose receptor-mediated uptake into macrophages. Alternative expression systems could be used to produce GCase containing larger oligomannose structures, offering the possibility of an improvement in targeting to macrophages. A secondary advantage of these expression systems would be to eliminate the need for carbohydrate remodeling. Here, multiple expression systems were used to produce GCase containing primarily terminal oligomannose, from Man2 to Man9. GCase from these multiple expression systems was compared to Cerezyme with respect to affinity for mannose receptor and serum mannose-binding lectin (MBL), macrophage uptake, and intracellular half-life. In vivo studies comparing clearance and targeting of Cerezyme and the Man9 form of GCase were carried out in a Gaucher mouse model (D409V/null). Mannose receptor binding, macrophage uptake, and in vivo targeting were similar for all forms of GCase. Increased MBL binding was observed for all forms of GCase having larger mannose structures than those of Cerezyme, which could influence pharmacokinetic behavior. These studies demonstrate that although alternative cell expression systems are effective for producing oligomannose-terminated glucocerebrosidase, there is no biochemical or pharmacological advantage in producing GCase with an increased number of mannose residues. The display of alternative carbohydrate structures on GCase expressed in these systems also runs the risk of undesirable consequences, such as an increase in MBL binding or a possible increase in immunogenicity due to the presentation of non-mammalian glycans.

AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease.

Niemann-Pick A disease (NPA) is a fatal lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. The lack of functional ASM results in cellular accumulation of sphingomyelin and cholesterol within distended lysosomes throughout the brain. In this study, we investigated the potential of AAV-mediated expression of ASM to correct the brain pathology in an ASM knockout (ASMKO) mouse model of NPA. An AAV serotype 2 vector encoding human ASM (AAV2-hASM) was injected directly into the adult ASMKO hippocampus of one hemisphere. This resulted in expression of human ASM in all major cell layers of the ipsilateral hippocampus for at least 15 weeks postinjection. Transduced cells were also present in the entorhinal cortex, medial septum, and contralateral hippocampus in a pattern consistent with retrograde axonal transport of AAV2. There was a substantial reduction of distended lysosomes and an almost complete reversal of cholesterol accumulation in all areas of the brain that were targeted by AAV2-hASM. These findings show that the ASMKO brain is responsive to ASM replacement and that retrograde transport of AAV2 functions as a platform for widespread gene delivery and reversal of pathology in affected brain.