Sound-induced stapes velocity (Vs) was measured intraoperatively in 14 patients undergoing cochlear implantation. All 14 patients had no history of middle-ear pathology, and their ossicular chains ...appeared normal on intraoperative inspection and palpation. The magnitude of the mean Vs (normalized by simultaneously-measured ear-canal sound pressure) was stiffness-dominated at frequencies below 1
kHz, increased up to ∼4
kHz, and then decreased at higher frequencies. The phase of the mean velocity was +0.2 periods at 0.3
kHz, and gradually became a phase lag at higher frequencies. The mean Vs measured in this study was similar to that of seven ears reported in the only other published study of live human measurements (
Huber et al., 2001). We also made measurements of Vs in fresh cadaveric temporal bones using a technique identical to that used in live ears, including similar measurement angles and location. The mean Vs measured in the cadaveric ears under these conditions was similar to the mean Vs measurements in the 14 live ears. This indicates that middle-ear mechanics are similar in live and cadaveric ears. In addition, interspecies comparisons were made between our live human Vs and the Vs reported in different animal studies. There were some clear similarities in Vs across species, as well as differences. The primary interspecies differences were in the magnitude of the Vs as well as in the frequency of transitions in the magnitudes’ frequency dependence from rising to flat or falling.
Cloud-type classification based on multispectral satellite imagery data has been widely researched and demonstrated to be useful for distinguishing a variety of classes using a wide range of methods. ...The research described here is a comparison of the classifier output from two very different algorithms applied to Geostationary Operational Environmental Satellite (GOES) data over the course of one year. The first algorithm employs spectral channel thresholding and additional physically based tests. The second algorithm was developed through a supervised learning method with characteristic features of expertly labeled image samples used as training data for a 1-nearest-neighbor classification. The latter’s ability to identify classes is also based in physics, but those relationships are embedded implicitly within the algorithm. A pixel-to-pixel comparison analysis was done for hourly daytime scenes within a region in the northeastern Pacific Ocean. Considerable agreement was found in this analysis, with many of the mismatches or disagreements providing insight to the strengths and limitations of each classifier. Depending upon user needs, a rule-based or other postprocessing system that combines the output from the two algorithms could provide the most reliable cloud-type classification.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Plexiform neurofibromas (PNF) represent a major source of morbidity in persons with neurofibromatosis type 1 (NF1). There remains an unmet need to develop new and effective treatment strategies for ...PNF given that a significant proportion of patients do not exhibit durable responses to currently available therapies. Using an integrated multi-omic approach, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Concordantly, combined CDK4/6 and ERK1/2 inhibition demonstrated robust synergism and enhanced anti-tumor activity in a mouse model of NF1-associated PNF that has demonstrated high fidelity in forecasting therapeutic responses in clinical trials. Collectively, these results demonstrate the utility of systems biology coupled with preclinical modeling to rationally inform novel single agent and combination therapies in the treatment of rare diseases.
Abstract
Malignant Peripheral Nerve Sheath Tumor (MPNST) is a rare soft tissue sarcoma that can arise from patients with NF1 (neurofibromatosis type 1). These patients are at a much greater risk of ...developing MPNST than the general population (10% vs. 0.01%, respectively). Existing chemotherapeutic and targeted agents have thus far not been successful in MPNST treatment, with a 5-year patient survival rate of just 35%-50%. Recent research implicates Signal Transducer and Activator of Transcription-3 (STAT3) and Hypoxia Inducible Factor 1 (HIF1) in driving MPNST. STAT3 is a transcription factor implicated in several cancers, and phosphorylated STAT3 (p-STAT3) expression indicates aggressive disease at disease onset in MPNST. STAT3 is activated upon phosphorylation by Janus Kinase (JAK), but its DNA binding and transcriptional activity is regulated by Apurinic/apyrimidinic endonuclease/redox factor-1 (APE1/Ref-1 or Ref-1) redox function. Ref-1 is a multifunctional protein involved in repairing DNA damage via endonuclease activity and in redox regulation of various transcription factors including STAT3, HIF-1α, and NFκB. High expression levels of Ref-1 indicate decreased survival in several cancers. We characterized Ref-1 and p-STAT3 expression in several MPNST samples including: the IN Pediatric BioBank, and established MPNST cell lines, new patient-derived tumor cells, and genetically engineered mouse models. We observed strong Ref-1 and phospho-STAT3 staining in the majority of these samples. We examined the expression of p-STAT3 and Ref-1 in mice that have conditional ablation in the Schwann cells of Nf1-/-; Arf+/- and Nf1-/-; Arf-/- mice and found a significant increase in positivity of p-STAT3 and Ref-1 expression in the sections containing MPNST. It also appears that there may be differences in staining intensity based on Arf genotype as the Nf1-/-; Arf-/- have stronger staining than the Nf1-/-; Arf+/-. Knocking down Ref-1 or STAT3 impairs MPNST growth in vitro. Inhibiting the redox activity of Ref-1 using the redox-specific APE1 inhibitor, APX3330 (and its next generation analogs), or inhibiting STAT3 activity using Napabucasin also resulted in reduced in vitro growth. Investigation into the apoptotic pathways that are activated following treatment demonstrate activation of caspase 3/7. Several biomarkers downstream of Ref-1 and STAT3 were downregulated following Ref-1 redox or STAT3 inhibition. We also performed RNA-sequencing to identify differentially expressed genes (DEGs) following Ref-1 or STAT3 knockdown and implicate new targets associated with clinical response in MPNST. In vivo experiments performed on mice implanted with ST88-14 cells using either APX2009 (APX3330 analog) or Napabucasin both resulted in significantly reduced tumor growth and additional combination studies are underway. Obtaining these results with clinically-tested Ref-1 and STAT3 inhibitors make the translation of this work highly plausible for pediatric patients with MPNST in the future. We will use both PDX and genetically engineered models of MPNST to test and validate these novel targets.
Citation Format: Fenil Shah, Olivia Babb, Chi Zhang, Silpa Gampala, Emily Zhang, Steven D Rhodes, Andrew R. Tee, Brian Calver, Ellie Rad, Verena Staedtke, Karen E Pollok, D. Wade Clapp, Mark R. Kelley, Melissa L. Fishel. Signaling through Ref-1 and STAT3 in soft tissue sarcoma (MPNST) and the effects of perturbing this pathway on tumor cell survival and gene expression abstract. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C017. doi:10.1158/1535-7163.TARG-19-C017
NexSat Miller, Steven D.; Hawkins, Jeffrey D.; Kent, John ...
Bulletin of the American Meteorological Society,
04/2006, Letnik:
87, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Under the auspices of the National Polar-orbiting Operational Environmental Satellite System’s (NPOESS) Integrated Program Office (IPO), the Naval Research Laboratory (NRL) has developed “NexSat” ...(www.nrlmry.navy.mil/nexsat_pages/nexsat_home.html)—a public-access online demonstration over the continental United States (CONUS) of near-real-time environmental products highlighting future applications from the Visible/Infrared Imager/Radiometer Suite (VIIRS). Based on a collection of operational and research-grade satellite observing systems, Nex-Sat products include the detection, enhancement, and where applicable, physical retrieval of deep convection, low clouds, light sources at night, rainfall, snow cover, aircraft contrails, thin cirrus layers, dust storms, and cloud/ aerosol properties, all presented in the context of value-added imagery. The purpose of NexSat is threefold: 1) to communicate the advanced capabilities anticipated from VIIRS, 2) to present this information in near–real time for use by forecasters, resource managers, emergency response teams, civic planners, the aviation community, and various government agencies, and 3) to augment the NRL algorithm development multisensor/model-fusion test bed for accelerated transitions to operations during the NPOESS era. This paper presents an overview of NexSat, highlighting selected products from the diverse meteorological phenomenology over the CONUS.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Malignant Peripheral Nerve Sheath Tumor (MPNST) is a rare soft tissue sarcoma common in patients with NF1 (neurofibromatosis type 1). MPNSTs respond poorly to most chemotherapeutics due to ...molecular heterogeneity and altered signal transduction pathways. Ref-1 and STAT3 are highly expressed in MPNST patient samples offering druggable pathways. Inhibition of one singular protein, like Ref-1 to block the activity of many important transcription factors (TFs), STAT3, HIF1a, and NFkB is key to improving success in MPNST therapy. Inhibition of both Ref-1 and STAT3 in MPNST lines resulted in decreased proliferation, wound healing, tumor signaling, and deactivation of MPNST survival genes. Further, knockdown of Ref-1 or STAT3 resulted in a concordant decrease in NFkB activity. Ref-1 redox inhibitor, APX3330 that completed Phase I clinical trial (NCT03375086), potently inhibited in vitro growth of a panel of MPNST cells. We have also been developing new more potent analogs of APX3330 for inhibition of Ref-1 redox function and potent cell killing in our panel of MPNST cells. Several of these analogs significantly and potently reduced NFkB and HIF1a activity at concentrations where cell killing was minimal, pointing toward an on-target effect. Based on the role of Ref-1 in transcriptional regulation of MPNST, RNA sequencing after knockdown of Ref-1 was used to determine mechanistic effects on MPNST gene expression. We have identified 443 genes up-regulated and 758 genes down-regulated in two MPNST cell lines with siRef-1. The pathways enriched by the commonly up-regulated genes included RNA polymerase, P53 downstream, glycerophospholipid, and other lipid metabolism pathways; the pathways enriched by the commonly down-regulated genes included cell cycle, adaptive immune response, and VEGF signaling pathways. From this data, we also found that OXPHOS (Oxidative Phosphorylation) pathway genes (like NDUFS2, SURF1, COX15) were down with siRef-1 along with others like AURKA, RNASEH2A, CDC20, GINS4, TIMELESS that were identified in our previous publication to be MPNST survival genes. Based on our published observations that Ref-1 inhibition dramatically affects metabolic pathways, we used OXPHOS deficient and proficient osteosarcoma cells and confirmed the impact of Ref-1 redox activity on metabolism. Furthermore, if we combine Ref-1 inhibition with a-ketoglutarate (aKG) and target the tumor cells’ dependence on aspartate biosynthesis, the tumor cell death was dramatic (p < 0.0001). Two new xenolines were established from patient PDXs and are being validated for growth inhibition and downregulation of MPNST survival genes with Ref-1 knockdown and redox inhibition using APX analogs both in vitro and in vivo. Successful derailing of MPNST survival pathways by targeting Ref-1 redox function is our aim to treat this rare but deadly cancer.
Citation Format: Silpa Gampala, Olivia Babb, Nikkitha Umesh Ganesh, Steven D. Rhodes, Reza M. Saadatzadeh, Kai Pollard, Christine Pratilas, Jing-Ruey Joanna Yeh, Karen E. Pollok, Wade D. Clapp, Mark R. Kelley, Chi Zhang, Melissa L. Fishel. Elucidating the mechanistic effect of targeting Ref-1 redox function on MPNST survival signaling using patient-derived xenolines abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2009.
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