Showing papers by "Kettering University published in 2018"

CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade.

Abstract: Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL) 1 . Although a majority of patients will achieve a complete response following a single infusion of CD19-targeted CAR-modified T cells (CD19 CAR T cells)2–4, the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterized by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines, including interleukin-6 (IL-6)2,5. CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumor burden2–4. CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity2–9. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. Here we report a murine model of CRS that develops within 2–3 d of CAR T cell infusion and that is potentially lethal and responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell–derived cytokines, but by IL-6, IL-1 and nitric oxide (NO) produced by recipient macrophages, which enables new therapeutic interventions. Blocking IL-1 and iNOS prevents CAR T cell–induced cytokine release syndrome.

Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer

Abstract: PurposeTreatment with programmed cell death-1 or programmed death ligand 1 (PD-(L)1) inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of corticosteroid...

Hydrogen production from biomass using dark fermentation

Abstract: Hydrogen applicability in the power, chemical and petrochemical industries is constantly growing. Efficient methods of hydrogen generation from renewable sources, including waste products, are currently being developed, even though hydrogen is mainly produced through steam reforming or thermal cracking of natural gas or petroleum fractions. In paper alternative methods of hydrogen production with a particular emphasis on dark fermentation are discussed. The review compiles essential information on strains of bacteria used in the production of hydrogen from waste products in the agroindustry and from lignocellulosic biomass. The effect of such parameters as kind of raw material, method of processing, temperature, pH, substrate concentration, partial pressure of hydrogen, hydraulic retention time, method of inoculum preparation and the type and operating parameters of a reactor on the yield of dark fermentation is discussed. The review aims at presentation of current state of knowledge on the dark fermentation process utilizing waste materials as substrates. The results of investigations with emphasis on the most important issues regarding operating parameters of dark fermentation are also included.

Ubiquitin-like Protein Conjugation: Structures, Chemistry, and Mechanism

Abstract: Ubiquitin-like proteins (Ubl’s) are conjugated to target proteins or lipids to regulate their activity, stability, subcellular localization, or macromolecular interactions. Similar to ubiquitin, conjugation is achieved through a cascade of activities that are catalyzed by E1 activating enzymes, E2 conjugating enzymes, and E3 ligases. In this review, we will summarize structural and mechanistic details of enzymes and protein cofactors that participate in Ubl conjugation cascades. Precisely, we will focus on conjugation machinery in the SUMO, NEDD8, ATG8, ATG12, URM1, UFM1, FAT10, and ISG15 pathways while referring to the ubiquitin pathway to highlight common or contrasting themes. We will also review various strategies used to trap intermediates during Ubl activation and conjugation.

Optimized base editors enable efficient editing in cells, organoids and mice.

Abstract: CRISPR base editing enables the creation of targeted single-base conversions without generating double-stranded breaks. However, the efficiency of current base editors is very low in many cell types. We reengineered the sequences of BE3, BE4Gam, and xBE3 by codon optimization and incorporation of additional nuclear-localization sequences. Our collection of optimized constitutive and inducible base-editing vector systems dramatically improves the efficiency by which single-nucleotide variants can be created. The reengineered base editors enable target modification in a wide range of mouse and human cell lines, and intestinal organoids. We also show that the optimized base editors mediate efficient in vivo somatic editing in the liver in adult mice.

Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins.

Abstract: Advanced, metastatic melanomas frequently grow in subcutaneous tissues and portend a poor prognosis. Though subcutaneous tissues are largely composed of adipocytes, the mechanisms by which adipocytes influence melanoma are poorly understood. Using in vitro and in vivo models, we find that adipocytes increase proliferation and invasion of adjacent melanoma cells. Additionally, adipocytes directly transfer lipids to melanoma cells, which alters tumor cell metabolism. Adipocyte-derived lipids are transferred to melanoma cells through the FATP/SLC27A family of lipid transporters expressed on the tumor cell surface. Among the six FATP/SLC27A family members, melanomas significantly overexpress FATP1/SLC27A1. Melanocyte-specific FATP1 expression cooperates with BRAFV600E in transgenic zebrafish to accelerate melanoma development, an effect that is similarly seen in mouse xenograft studies. Pharmacologic blockade of FATPs with the small-molecule inhibitor Lipofermata abrogates lipid transport into melanoma cells and reduces melanoma growth and invasion. These data demonstrate that stromal adipocytes can drive melanoma progression through FATP lipid transporters and represent a new target aimed at interrupting adipocyte-melanoma cross-talk.Significance: We demonstrate that stromal adipocytes are donors of lipids that mediate melanoma progression. Adipocyte-derived lipids are taken up by FATP proteins that are aberrantly expressed in melanoma. Inhibition of FATPs decreases melanoma lipid uptake, invasion, and growth. We provide a mechanism for how stromal adipocytes drive tumor progression and demonstrate a novel microenvironmental therapeutic target. Cancer Discov; 8(8); 1006-25. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 899.

A Double-Scale, Particle-Filtering, Energy State Prediction Algorithm for Lithium-Ion Batteries

Abstract: In order for the battery management system (BMS) in an electric vehicle to function properly, accurate and robust indication of the energy state of the lithium-ion batteries is necessary. This robustness requires that the energy state can be estimated accurately even when the working conditions of batteries change dramatically. This paper implements battery remaining available energy prediction and state-of-charge (SOC) estimation against testing temperature uncertainties, as well as inaccurate initial SOC values. A double-scale particle filtering method has been developed to estimate or predict the system state and parameters on two different time scales. The developed method considers the slow time-varying characteristics of the battery parameter set and the quick time-varying characteristics of the battery state set. In order to select the preferred battery model, the Akaike information criterion (AIC) is used to make a tradeoff between the model prediction accuracy and complexity. To validate the developed double-scale particle filtering method, two different kinds of lithium-ion batteries were tested at three temperatures. The experimental results show that, with 20% initial SOC deviation, the maximum remaining available energy prediction and SOC estimation errors are both within 2%, even when the wrong temperature is indicated. In this case, the developed double-scale particle filtering method is expected to be robust in practice.

Individual meaning-centered psychotherapy for the treatment of psychological and existential distress: A randomized controlled trial in patients with advanced cancer.

Abstract: Background Patients with advanced cancer have high rates of psychological distress, including depression, anxiety, and spiritual despair. This study examined the effectiveness of individual meaning-centered psychotherapy (IMCP) in comparison with supportive psychotherapy (SP) and enhanced usual care (EUC) in improving spiritual well-being and quality of life and reducing psychological distress in patients with advanced cancer. Methods Patients (n = 321) were randomly assigned to IMCP (n = 109), SP (n = 108), or EUC (n = 104). Assessments were conducted at 4 time points: before intervention, midtreatment (4 weeks), 8 weeks after treatment, and 16 weeks after treatment. Results Significant treatment effects (small to medium in magnitude) were observed for IMCP, in comparison with EUC, for 5 of 7 outcome variables (quality of life, sense of meaning, spiritual well-being, anxiety, and desire for hastened death), with Cohen's d ranging from 0.1 to 0.34; no significant improvement was observed for patients receiving SP (d .05 for all variables). The effect of IMCP was significantly greater than the effect of SP for quality of life and sense of meaning (d = 0.19) but not for the remaining study variables. Conclusions This study provides further support for the efficacy of IMCP as a treatment for psychological and existential/spiritual distress in patients with advanced cancer. Significant treatment effects (small to moderate effect sizes) were observed in comparison with usual care, and somewhat more modest differences in improvement (small effect sizes) were observed in comparison with SP. Thus, the benefits of meaning-centered psychotherapy appear to be unique to the intervention and highlight the importance of addressing existential issues with patients approaching the end of life. Cancer 2018. © 2018 American Cancer Society.

Nanotechnology Strategies To Advance Outcomes in Clinical Cancer Care

Abstract: Ongoing research into the application of nanotechnology for cancer treatment and diagnosis has demonstrated its advantages within contemporary oncology as well as its intrinsic limitations. The National Cancer Institute publishes the Cancer Nanotechnology Plan every 5 years since 2005. The most recent iteration helped codify the ongoing basic and translational efforts of the field and displayed its breadth with several evolving areas. From merely a technological perspective, this field has seen tremendous growth and success. However, an incomplete understanding of human cancer biology persists relative to the application of nanoscale materials within contemporary oncology. As such, this review presents several evolving areas in cancer nanotechnology in order to identify key clinical and biological challenges that need to be addressed to improve patient outcomes. From this clinical perspective, a sampling of the nano-enabled solutions attempting to overcome barriers faced by traditional therapeutics and di...

TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells.

Abstract: TET enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which can lead to DNA demethylation. However, direct connections between TET-mediated DNA demethylation and transcriptional output are difficult to establish owing to challenges in distinguishing global versus locus-specific effects. Here we show that TET1, TET2 and TET3 triple-knockout (TKO) human embryonic stem cells (hESCs) exhibit prominent bivalent promoter hypermethylation without an overall corresponding decrease in gene expression in the undifferentiated state. Focusing on the bivalent PAX6 locus, we find that increased DNMT3B binding is associated with promoter hypermethylation, which precipitates a neural differentiation defect and failure of PAX6 induction during differentiation. dCas9-mediated locus-specific demethylation and global inactivation of DNMT3B in TKO hESCs partially reverses the hypermethylation at the PAX6 promoter and improves differentiation to neuroectoderm. Taking these findings together with further genome-wide methylation and TET1 and DNMT3B ChIP-seq analyses, we conclude that TET proteins safeguard bivalent promoters from de novo methylation to ensure robust lineage-specific transcription upon differentiation.

How to Build a Patient-Specific Hybrid Simulator for Orthopaedic Open Surgery: Benefits and Limits of Mixed-Reality Using the Microsoft HoloLens

Abstract: Orthopaedic simulators are popular in innovative surgical training programs, where trainees gain procedural experience in a safe and controlled environment. Recent studies suggest that an ideal simulator should combine haptic, visual, and audio technology to create an immersive training environment. This article explores the potentialities of mixed-reality using the HoloLens to develop a hybrid training system for orthopaedic open surgery. Hip arthroplasty, one of the most common orthopaedic procedures, was chosen as a benchmark to evaluate the proposed system. Patient-specific anatomical 3D models were extracted from a patient computed tomography to implement the virtual content and to fabricate the physical components of the simulator. Rapid prototyping was used to create synthetic bones. The Vuforia SDK was utilized to register virtual and physical contents. The Unity3D game engine was employed to develop the software allowing interactions with the virtual content using head movements, gestures, and voice commands. Quantitative tests were performed to estimate the accuracy of the system by evaluating the perceived position of augmented reality targets. Mean and maximum errors matched the requirements of the target application. Qualitative tests were carried out to evaluate workload and usability of the HoloLens for our orthopaedic simulator, considering visual and audio perception and interaction and ergonomics issues. The perceived overall workload was low, and the self-assessed performance was considered satisfactory. Visual and audio perception and gesture and voice interactions obtained a positive feedback. Postural discomfort and visual fatigue obtained a nonnegative evaluation for a simulation session of 40 minutes. These results encourage using mixed-reality to implement a hybrid simulator for orthopaedic open surgery. An optimal design of the simulation tasks and equipment setup is required to minimize the user discomfort. Future works will include Face Validity, Content Validity, and Construct Validity to complete the assessment of the hip arthroplasty simulator.

Cryo-EM structures of fungal and metazoan mitochondrial calcium uniporters.

Abstract: The mitochondrial calcium uniporter (MCU) is a highly selective calcium channel and a major route of calcium entry into mitochondria How the channel catalyses ion permeation and achieves ion selectivity are not well understood, partly because MCU is thought to have a distinct architecture in comparison to other cellular channels Here we report cryo-electron microscopy reconstructions of MCU channels from zebrafish and Cyphellophora europaea at 85 A and 32 A resolutions, respectively In contrast to a previous report of pentameric stoichiometry for MCU, both channels are tetramers The atomic model of C europaea MCU shows that a conserved WDXXEP signature sequence forms the selectivity filter, in which calcium ions are arranged in single file Coiled-coil legs connect the pore to N-terminal domains in the mitochondrial matrix In C europaea MCU, the N-terminal domains assemble as a dimer of dimers; in zebrafish MCU, they form an asymmetric crescent The structures define principles that underlie ion permeation and calcium selectivity in this unusual channel

Ultrasmall targeted nanoparticles with engineered antibody fragments for imaging detection of HER2-overexpressing breast cancer

Abstract: Controlling the biodistribution of nanoparticles upon intravenous injection is the key to achieving target specificity. One of the impediments in nanoparticle-based tumor targeting is the inability to limit the trafficking of nanoparticles to liver and other organs leading to smaller accumulated amounts in tumor tissues, particularly via passive targeting. Here we overcome both these challenges by designing nanoparticles that combine the specificity of antibodies with favorable particle biodistribution profiles, while not exceeding the threshold for renal filtration as a combined vehicle. To that end, ultrasmall silica nanoparticles are functionalized with anti-human epidermal growth factor receptor 2 (HER2) single-chain variable fragments to exhibit high tumor-targeting efficiency and efficient renal clearance. This ultrasmall targeted nanotheranostics/nanotherapeutic platform has broad utility, both for imaging a variety of tumor tissues by suitably adopting the targeting fragment and as a potentially useful drug delivery vehicle.

Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma.

Abstract: Importance Identification of patients with hereditary renal cell carcinoma (RCC) is important for cancer screening and, in patients with advanced disease, for guiding treatment. The prevalence of cancer-related germline mutations in patients with advanced RCC and the phenotypes associated with some rare mutations are unknown. Objectives To examine the prevalence of germline mutations in both known RCC predisposition genes and other cancer-associated genes and to identify clinical and pathologic factors associated with germline mutations. Design, Setting, and Participants In this cohort study conducted from October 1, 2015, to July 31, 2017, 254 of 267 patients with advanced (American Joint Committee on Cancer stage III or IV) RCC who were seen in medical oncology or urology clinics agreed to germline sequencing and disclosure of results under an institutional protocol of matched tumor-germline DNA sequencing. Main Outcomes and Measures Mutation prevalence and spectrum in patients with advanced RCC were determined. Clinical characteristics were assessed by mutation status. Results Of the 254 patients (median age [range], 56 [13-79] years; 179 [70.5%] male; 211 [83.1%] non-Hispanic white), germline mutations were identified in 41 (16.1%); 14 (5.5%) had mutations in syndromic RCC-associated genes (7 inFH, 3 inBAP1, and 1 each inVHL,MET,SDHA,andSDHB). The most frequent mutations wereCHEK2(n = 9) andFH(n = 7). Of genes not previously associated with RCC risk,CHEK2was overrepresented in patients compared with the general population, with an odds ratio of RCC of 3.0 (95% CI, 1.3-5.8;P = .003). Patients with non–clear cell RCC were significantly more likely to have an RCC-associated gene mutation (9 [11.7%] of 74 vs 3 [1.7%] of 177;P = .001), and 8 (10.0%) had a mutation in a gene that could guide therapy. Of patients with mutations in RCC-associated genes, 5 (35.7%) failed to meet current clinical guidelines for genetic testing. Conclusions and Relevance Of patients with non–clear cell RCC, more than 20% had a germline mutation, of which half had the potential to direct systemic therapy. Current referral criteria for genetic testing did not identify a substantial portion of patients with mutations, supporting the role of a more inclusive sequencing approach.

A Modular-Designed Three-Phase High-Efficiency High-Power-Density EV Battery Charger Using Dual/Triple-Phase-Shift Control

Abstract: In this paper, an enhancement-mode GaN high-electron mobility transistor (HEMT)-based 7.2-kW single-phase charger was built. Connecting three such single-phase modules to the three-phase grid, respectively, generates a three-phase ∼22-kW charger with the $>{\text{97}}\% $ efficiency and $>{\text{3.3}}-{\rm{kW}/ \rm{L}}$ power density, superior to present Si-device-based chargers. In addition to GaN HEMTs with fast-switching transitions yielding high efficiency, the proposed charger employs the dc/dc stage to control the power factor and power delivery simultaneously, yielding little dc-bus capacitance and thereby high power density. To secure the soft switching for all switches within full voltage and power ranges, a variable switching frequency control with dual phase shifts was adopted at high power, and a triple phase shift was employed to improve the power factor at low power. Both control strategies accommodated the wide input range (80–260 VAC) and output range (200–450 VDC). A closed-loop control for the three-phase charger was realized to minimize the output current ripple and balance the power among three single-phase modules. Experimental results validated this design.

Effective method of treatment of industrial effluents under basic pH conditions using acoustic cavitation – A comprehensive comparison with hydrodynamic cavitation processes

Abstract: The use of acoustic cavitation in advanced oxidation processes (AOPs) is a promising trend in research for treatment of industrial effluents. The paper presents the results of investigations on the use of acoustic cavitation aided by additional oxidation processes (ozonation/H2O2 oxidation/Peroxone/UV-C) for the treatment of effluents from the production of bitumens. Under these conditions, the total contaminant load, expressed as chemical oxygen demand (COD), could be lowered by 51%. In addition, changes in concentrations of volatile organic compounds identified in the effluents following the treatment are discussed. The investigations revealed that by using acoustic cavitation combined with the Peroxone process, the majority of oxygenated organic compounds were oxidized. The paper also compares AOPs based on acoustic cavitation with hydrodynamic cavitation-aided processes. This study revealed that the use of acoustic cavitation results in a higher effectiveness of degradation of organic compounds using AOPs based on hydrogen peroxide. On the other hand, hydrodynamic cavitation is generally a slightly more effective method for degradation of organic compounds for ozone-based AOPs. Furthermore, furfural and 2-methylcyclohexanone were discovered as secondary pollutants whose concentration increased during the treatment.

A Survey of Calibration Methods for Optical See-Through Head-Mounted Displays

Abstract: Optical see-through head-mounted displays (OST HMDs) are a major output medium for Augmented Reality, which have seen significant growth in popularity and usage among the general public due to the growing release of consumer-oriented models, such as the Microsoft Hololens. Unlike Virtual Reality headsets, OST HMDs inherently support the addition of computer-generated graphics directly into the light path between a user's eyes and their view of the physical world. As with most Augmented and Virtual Reality systems, the physical position of an OST HMD is typically determined by an external or embedded 6-Degree-of-Freedom tracking system. However, in order to properly render virtual objects, which are perceived as spatially aligned with the physical environment, it is also necessary to accurately measure the position of the user's eyes within the tracking system's coordinate frame. For over 20 years, researchers have proposed various calibration methods to determine this needed eye position. However, to date, there has not been a comprehensive overview of these procedures and their requirements. Hence, this paper surveys the field of calibration methods for OST HMDs. Specifically, it provides insights into the fundamentals of calibration techniques, and presents an overview of both manual and automatic approaches, as well as evaluation methods and metrics. Finally, it also identifies opportunities for future research.

Margins in breast cancer: How much is enough?

Abstract: The appropriate negative margin width for women undergoing breast-conserving surgery for both ductal carcinoma in situ (DCIS) and invasive carcinoma is controversial. This review examines the available data on the margin status for invasive breast cancer and DCIS, and highlights the similarities and differences in tumor biology and standard treatments that affect the local recurrence (LR) risk and, therefore, the optimal surgical margin. Consensus guidelines support a negative margin, defined as no ink on tumor, for invasive carcinoma treated with breast-conserving therapy. Because of differences in the growth pattern and utilization of systemic therapy, a margin of 2 mm has been found to minimize the LR risk for women with DCIS undergoing lumpectomy and radiation therapy (RT). Wider negative margins do not improve local control for DCIS or invasive carcinoma when they are treated with lumpectomy and RT. Re-excision for negative margins should be individualized, and the routine practice of performing additional surgery to obtain a wider negative margin is not supported by the literature. Cancer 2018;124:1335-41. © 2018 American Cancer Society.

In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R )-4-Fluoroglutamine

Abstract: Preclinical and trial data support fluorine 18–(2S,4R)-4-fluoroglutamine (FGln) avidity as a PET biomarker of glutamine flux and metabolism and suggest possible correlations between tumor FGln PET phenotype, oncometabolic genotype, and tumor aggressiveness.