Publications by authors named "Wade Aaron"

12 Publications

  • Page 1 of 1

The effect of wavelength on the variability of the flash visual evoked potential P2: A potential biomarker for mild cognitive impairment and Alzheimer's dementia.

Int J Psychophysiol 2021 06 18;164:23-29. Epub 2021 Feb 18.

Department of Physics, University of West Florida, United States.

As the number of individuals diagnosed with amnestic mild cognitive impairment (aMCI) and Alzheimer's dementia (AD) increases, a need exists for early detection and treatment of the disorders. A recent review of the literature conducted by Arruda et al. (2020) revealed that the latency of the flash visual-evoked potential-P2 (FVEP-P2) may possess pathognomic information that may assist in the early detection and treatment of each disease. Unfortunately, while group differences in latency are robust, the ability to discriminate between individuals remains difficult due to the natural variability associated with the FVEP-P2 latency. In the current investigation, we examine the role of wavelength of light in the production of the FVEP-P2, with the goal of reducing the variability associated with the FVEP-P2 latency and improving the diagnostic accuracy of the FVEP-P2 evaluation.

Method: Twenty-four healthy individuals (11 males and 13 females), ages 18 to 36 years (M = 25.00, SD = 5.60), participated in this investigation. Each participant experienced five blocks of 100 strobe flashes (or trials) under two different light conditions (blue filtered light and polychromatic white light) with their eyes closed. The FVEP-P2 associated with each trial was identified and the latency and amplitude of each component was calculated.

Result: The results of several repeated measures analysis of variance revealed no statistically significant differences in intra- and inter-individual variability associated with the P2 latency or amplitude. However, there was a significant difference in the amplitude of the P2 produced by the two lights, with blue filtered light producing significantly lower amplitudes than the polychromatic white light.

Conclusion: The results of the present investigation suggest that while imperfect, the current practice of employing polychromatic white light in the production of the FVEP-P2 remains the gold standard and that additional methods of reducing the natural variability of the P2 need to be developed if the FVEP-P2 latency is to be used as a biomarker.
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http://dx.doi.org/10.1016/j.ijpsycho.2021.02.011DOI Listing
June 2021

Preclinical Characterization of HPN536, a Trispecific, T-Cell-Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors.

Clin Cancer Res 2021 03 1;27(5):1452-1462. Epub 2020 Dec 1.

Harpoon Therapeutics, South San Francisco, California.

Purpose: Mesothelin (MSLN) is a glycophosphatidylinositol-linked tumor antigen overexpressed in a variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast cancer. Early signs of clinical efficacy with MSLN-targeting agents have validated MSLN as a promising target for therapeutic intervention, but therapies with improved efficacy are still needed to address the significant unmet medical need posed by MSLN-expressing cancers.

Experimental Design: We designed HPN536, a 53-kDa, trispecific, T-cell-activating protein-based construct, which binds to MSLN-expressing tumor cells, CD3ε on T cells, and to serum albumin. Experiments were conducted to assess the potency, activity, and half-life of HPN536 in assays, rodent models, and in nonhuman primates (NHP).

Results: HPN536 binds to MSLN-expressing tumor cells and to CD3ε on T cells, leading to T-cell activation and potent redirected target cell lysis. A third domain of HPN536 binds to serum albumin for extension of plasma half-life. In cynomolgus monkeys, HPN536 at doses ranging from 0.1 to 10 mg/kg demonstrated MSLN-dependent pharmacologic activity, was well tolerated, and showed pharmacokinetics in support of weekly dosing in humans.

Conclusions: HPN536 is potent, is well tolerated, and exhibits extended half-life in NHPs. It is currently in phase I clinical testing in patients with MSLN-expressing malignancies (NCT03872206).
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3392DOI Listing
March 2021

TriTACs, a Novel Class of T-Cell-Engaging Protein Constructs Designed for the Treatment of Solid Tumors.

Mol Cancer Ther 2021 01 17;20(1):109-120. Epub 2020 Nov 17.

Harpoon Therapeutics, South San Francisco, California.

T cells have a unique capability to eliminate cancer cells and fight malignancies. Cancer cells have adopted multiple immune evasion mechanisms aimed at inhibiting T cells. Dramatically improved patient outcomes have been achieved with therapies genetically reprogramming T cells, blocking T-cell inhibition by cancer cells, or transiently connecting T cells with cancer cells for redirected lysis. This last modality is based on antibody constructs that bind a surface antigen on cancer cells and an invariant component of the T-cell receptor. Although high response rates were observed with T-cell engagers specific for CD19, CD20, or BCMA in patients with hematologic cancers, the treatment of solid tumors has been less successful. Here, we developed and characterized a novel T-cell engager format, called TriTAC (for Trispecific T-cell Activating Construct). TriTACs are engineered with features to improve patient safety and solid tumor activity, including high stability, small size, flexible linkers, long serum half-life, and highly specific and potent redirected lysis. The present study establishes the structure/activity relationship of TriTACs and describes the development of HPN424, a PSMA- (FOLH1-) targeting TriTAC in clinical development for patients with metastatic castration-resistant prostate cancer.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0061DOI Listing
January 2021

Photomodulated rayleigh scattering of single semiconductor nanowires: probing electronic band structure.

Nano Lett 2011 Oct 16;11(10):4329-36. Epub 2011 Sep 16.

Department of Physics, University of Cincinnati , Cincinnati, Ohio 45221-0011, United States.

The internal electronic structures of single semiconductor nanowires can be resolved using photomodulated Rayleigh scattering spectroscopy. The Rayleigh scattering from semiconductor nanowires is strongly polarization sensitive which allows a nearly background-free method for detecting only the light that is scattered from a single nanowire. While the Rayleigh scattering efficiency from a semiconductor nanowire depends on the dielectric contrast, it is relatively featureless as a function of energy. However, if the nanowire is photomodulated using a second pump laser beam, the internal electronic structure can be resolved with extremely high signal-to-noise and spectral resolution. The photomodulated Rayleigh scattering spectra can be understood theoretically as a first derivative of the scattering efficiency that results from a modulation of the band gap and depends sensitively on the nanowire diameter. Fits to spectral lineshapes provide both the band structure and the diameter of individual GaAs and InP nanowires under investigation.
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http://dx.doi.org/10.1021/nl202433gDOI Listing
October 2011

Discovery of amide replacements that improve activity and metabolic stability of a bis-amide smoothened antagonist hit.

Bioorg Med Chem Lett 2011 Sep 23;21(18):5206-9. Epub 2011 Jul 23.

Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.

A bis-amide antagonist of Smoothened, a seven-transmembrane receptor in the Hedgehog signaling pathway, was discovered via high throughput screening. In vitro and in vivo experiments demonstrated that the bis-amide was susceptible to N-acyl transferase mediated amide scission. Several bioisosteric replacements of the labile amide that maintained in vitro potency were identified and shown to be metabolically stable in vitro and in vivo.
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http://dx.doi.org/10.1016/j.bmcl.2011.07.052DOI Listing
September 2011

Addressing PXR liabilities of phthalazine-based hedgehog/smoothened antagonists using novel pyridopyridazines.

Bioorg Med Chem Lett 2010 Aug 8;20(15):4607-10. Epub 2010 Jun 8.

Amgen, Inc., South San Francisco, CA 94080, USA.

Pyridopyridazine antagonists of the hedgehog signaling pathway are described. Designed to optimize our previously described phthalazine smoothened antagonists, a representative compound eliminates a PXR liability while retaining potency and in vitro metabolic stability. Moreover, the compound has improved efficacy in a hedgehog/smoothened signaling mouse pharmacodynamic model.
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http://dx.doi.org/10.1016/j.bmcl.2010.06.006DOI Listing
August 2010

Design of 1-piperazinyl-4-arylphthalazines as potent Smoothened antagonists.

Bioorg Med Chem Lett 2010 Jun 28;20(12):3618-22. Epub 2010 Apr 28.

Department of Medicinal Chemistry, AMGEN, S. San Francisco, CA 94080, USA.

The Hedgehog (Hh) signaling pathway regulates cell proliferation and differentiation in developing tissues, and abnormal activation of the Hh pathway has been linked to several tumor subsets. As a transducer of Hh signaling, the GPCR-like protein Smoothened (Smo) is a promising target for disruption of unregulated Hh signaling. A series of 1-amino-4-arylphthalazines was developed as potent and orally bioavailable inhibitors of Smo. A representative compound from this class demonstrated significant tumor volume reduction in a mouse medulloblastoma model.
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http://dx.doi.org/10.1016/j.bmcl.2010.04.110DOI Listing
June 2010

Hepatocyte growth factor is a preferred in vitro substrate for human hepsin, a membrane-anchored serine protease implicated in prostate and ovarian cancers.

Biochem J 2005 Aug;390(Pt 1):125-36

Department of Biology, Amgen San Francisco, 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.

Hepsin is a membrane-anchored, trypsin-like serine protease with prominent expression in the human liver and tumours of the prostate and ovaries. To better understand the biological functions of hepsin, we identified macromolecular substrates employing a tetrapeptide PS-SCL (positional scanning-synthetic combinatorial library) screen that rapidly determines the P1-P4 substrate specificity. Hepsin exhibited strong preference at the P1 position for arginine over lysine, and favoured threonine, leucine or asparagine at the P2, glutamine or lysine at the P3, and proline or lysine at the P4 position. The relative activity of hepsin toward individual AMC (7-amino-4-methylcoumarin)-tetrapeptides was generally consistent with the overall peptide profiling results derived from the PC-SCL screen. The most active tetrapeptide substrate Ac (acetyl)-KQLR-AMC matched with the activation cleavage site of the hepatocyte growth factor precursor sc-HGF (single-chain HGF), KQLR downward arrowVVNG (where downward arrow denotes the cleavage site), as identified by a database analysis of trypsin-like precursors. X-ray crystallographic studies with KQLR chloromethylketone showed that the KQLR peptide fits well into the substrate-binding cleft of hepsin. This hepsin-processed HGF induced c-Met receptor tyrosine phosphorylation in SKOV-3 ovarian cancer cells, indicating that the hepsin-cleaved HGF is biologically active. Activation cleavage site mutants of sc-HGF with predicted non-preferred sequences, DPGR downward arrowVVNG or KQLQ downward arrowVVNG, were not processed, illustrating that the P4-P1 residues can be important determinants for substrate specificity. In addition to finding macromolecular hepsin substrates, the extracellular inhibitors of the HGF activator, HAI-1 and HAI-2, were potent inhibitors of hepsin activity (IC50 4+/-0.2 nM and 12+/-0.5 nM respectively). Together, our findings suggest that the HGF precursor is a potential in vivo substrate for hepsin in tumours, where hepsin expression is dysregulated and may influence tumorigenesis through inappropriate activation and/or regulation of HGF receptor (c-Met) functions.
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http://dx.doi.org/10.1042/BJ20041955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1184568PMC
August 2005

Regulation of ACTH levels in anterior pituitary cells during stimulated secretion: evidence for aspartyl and cysteine proteases in the cellular metabolism of ACTH.

Peptides 2003 May;24(5):717-25

Department of Neurosciences and Medicine, University of California, San Diego, La Jolla, CA, USA.

The regulation of cellular levels of adrenocorticotropin hormone (ACTH) in response to stimulated secretion was investigated to define the extent of cellular depletion of ACTH and subsequent increases to replenish ACTH levels in anterior pituitary cells (in primary culture). Treatment of cells with secretagogues for short-term incubation times (hours) resulted in extensive depletion of cellular ACTH. Corticotropin releasing factor (CRF) induced depletion of cellular levels of ACTH by 60-70% of control levels. The CRF-induced reduction of cellular ACTH was inhibited by the glucocorticoid dexamethasone. Phorbol myristate acetate (PMA), which stimulates protein kinase C (PKC), reduced ACTH levels by 50-60%. Forskolin, a stimulator of cAMP production, produced a moderate reduction in cellular ACTH. During prolonged incubation of cells (2 days) with these secretagogues, further reduction of ACTH levels by 70-80% was observed. However, increased cellular levels of ACTH occurred with continued treatment of cells with secretagogues, which provided nearly complete replenishment of cellular ACTH after 5 days treatment with secretagogues. Notably, the rising levels of cellular ACTH were inhibited by the aspartyl protease inhibitor acetyl-pepstatin A, and by the cysteine protease inhibitor E64d. These results demonstrate that depletion and recovery of ACTH levels are coordinately regulated, and that the increases in cellular levels of ACTH during the recovery phase involves participation of aspartyl and cysteine proteases. Thus, aspartyl and cysteine proteases may be involved in the cellular metabolism of ACTH.
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http://dx.doi.org/10.1016/s0196-9781(03)00126-8DOI Listing
May 2003

Obliteration of alpha-melanocyte-stimulating hormone derived from POMC in pituitary and brains of PC2-deficient mice.

J Neurochem 2003 Aug;86(3):556-63

Buck Institute for Age Research, Novato, California 94945, USA.

Alpha-melanocyte-stimulating hormone (alpha-MSH) is a neuropeptide expressed in pituitary and brain that is known to regulate energy balance, appetite control, and neuroimmune functions. The biosynthesis of alpha-MSH requires proteolytic processing of the proopiomelanocortin (POMC) precursor. Therefore, this study investigated the in vivo role of the prohormone convertase 2 (PC2) processing enzyme for production of alpha-MSH in PC2-deficient mice. Specific detection of alpha-MSH utilized radioimmunoassay (RIA) that does not crossreact with the POMC precursor, and which does not crossreact with other adrenocorticotropin hormone (ACTH) and beta-endorphin peptide products derived from POMC. alpha-MSH in PC2-deficient mice was essentially obliterated in pituitary, hypothalamus, cortex, and other brain regions (collectively), compared to wild-type controls. These results demonstrate the critical requirement of PC2 for the production of alpha-MSH. The absence of alpha-MSH was accompanied by accumulation of ACTH, ACTH-containing imtermediates, and POMC precursor. ACTH was increased in pituitary and hypothalamus of PC2-deficient mice, evaluated by RIA and reversed-phase high pressure liquid chromatography (RP-HPLC). Accumulation of ACTH demonstrates its role as a PC2 substrate that can be converted for alpha-MSH production. Further analyses of POMC-derived intermediates in pituitary, conducted by denaturing western blot conditions, showed accumulation of ACTH-containing intermediates in pituitaries of PC2-deficient mice, which implicate participation of such intermediates as PC2 substrates. Moreover, accumulation of POMC was observed in PC2-deficient mice by western blots with anti-ACTH and anti-beta-endorphin. In addition, increased beta-endorphin1-31 was observed in pituitary and hypothalamus of PC2-deficient mice, suggesting beta-endorphin1-31 as a substrate for PC2 in these tissues. Overall, these studies demonstrated that the PC2 processing enzyme is critical for the in vivo production of alpha-MSH in pituitary and brain.
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http://dx.doi.org/10.1046/j.1471-4159.2003.01856.xDOI Listing
August 2003

Regulation of cellular alpha-MSH and beta-endorphin during stimulated secretion from intermediate pituitary cells: involvement of aspartyl and cysteine proteases in the control of cellular levels of alpha-MSH and beta-endorphin.

Peptides 2002 Aug;23(8):1409-18

Department of Medicine, University of California, San Diego, La Jolla, CA, USA.

The regulation of cellular levels of alpha-melanocyte stimulating factor (alpha-MSH) and beta-endorphin in response to stimulated secretion from intermediate pituitary cells in primary culture was investigated in this study. Regulation of the cell content of alpha-MSH and beta-endorphin occurred in two phases consisting of (a) initial depletion of cellular levels of these peptide hormones during short-term secretion (3 h) induced by isoproterenol, forskolin, or phorbol myristate acetate (PMA) which was followed by (b) long-term (24 h) increases in cellular levels of alpha-MSH and beta-endorphin in response to stimulated secretion induced by isoproterenol and PMA. In short-term experiments (3 h), cellular levels of alpha-MSH and beta-endorphin were reduced by 30-50% during stimulated secretion of these peptide hormones by isoproterenol (agonist for the beta-adrenergic receptor), forskolin that activates protein kinase A (PKA), and PMA that activates protein kinase C (PKC). Moreover, dopamine inhibited isoproterenol-induced depletion of cellular alpha-MSH and beta-endorphin. During long-term incubation of cells (24 h) with isoproterenol, cellular alpha-MSH and beta-endorphin were increased to twice that of controls (unstimulated cells). Treatment with PMA for 24 h also increased cellular levels of alpha-MSH and beta-endorphin. Moreover, cellular levels of alpha-MSH and beta-endorphin were decreased during long-term treatment of cells with an aspartyl protease inhibitor, pepstatin A, and with the cysteine protease inhibitor E64c. These results implicate aspartyl and cysteine proteases in the cellular production of alpha-MSH and beta-endorphin that requires proteolytic processing of their common precursor proopiomelanocortin (POMC). These findings demonstrate the parallel regulation of cellular levels of alpha-MSH and beta-endorphin during their cosecretion, which may involve aspartyl and cysteine proteases in the metabolism of these peptide hormones.
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http://dx.doi.org/10.1016/s0196-9781(02)00079-7DOI Listing
August 2002

Beta-amyloid peptide in regulated secretory vesicles of chromaffin cells: evidence for multiple cysteine proteolytic activities in distinct pathways for beta-secretase activity in chromaffin vesicles.

J Neurochem 2002 Apr;81(2):237-56

Buck Institute for Age Research, Novato, California 94945, USA.

A key factor in Alzheimer's disease (AD) is the beta-secretase activity that is required for the production of beta-amyloid (Abeta) peptide from its amyloid precursor protein (APP) precursor. In this study, the majority of Abeta secretion from neuronal chromaffin cells was found to occur via the regulated secretory pathway, compared with the constitutive secretory pathway; therefore, beta-secretase activity in the regulated secretory pathway was examined for the production and secretion of Abeta in chromaffin cells obtained from in vivo adrenal medullary tissue. The presence of Abeta(1-40) in APP-containing chromaffin vesicles, which represent regulated secretory vesicles, was demonstrated by radioimmunoassay (RIA) and reverse-phase high-performance liquid chromatography. These vesicles also contain Abeta(1-42), measured by RIA. Significantly, regulated secretion of Abeta(1-40) from chromaffin cells represented the majority of secreted Abeta (> 95% of total secreted Abeta), compared with low levels of constitutively secreted Abeta(1-40). These results indicate the importance of Abeta production and secretion in the regulated secretory pathway as a major source of extracellular Abeta. Beta-secretase activity in isolated chromaffin vesicles was detected with the substrate Z-Val-Lys-Met-/MCA (methylcoumarinamide) that contains the beta-secretase cleavage site. Optimum beta-secretase activity in these vesicles required reducing conditions and acidic pH (pH 5-6), consistent with the in vivo intravesicular environment. Evidence for cysteine protease activity was shown by E64c inhibition of Z-Val-Lys-Met-MCA-cleaving activity, and E64c inhibition of Abeta(1-40) production in isolated chromaffin vesicles. Chromatography resolved the beta-secretase activity into two distinct proteolytic pathways consisting of: (i) direct cleavage of the beta-secretase site at Met-/Asp by two cysteine proteolytic activities represented by peaks Il-A and Il-B, and (ii) an aminopeptidase-dependent pathway represented by peak I cysteine protease activity that cleaves between Lys-/Met, followed by Met-aminopeptidase that would generate the beta-secretase cleavage site. Treatment of chromaffin cells in primary culture with the cysteine protease inhibitor E64d reduced the production of the beta-secretase product, a 12-14 kDa C-terminal APP fragment. In addition, BACE 1 and BACE 2 were detected in chromaffin vesicles; BACE 1 represented a small fraction of total beta-secretase activity in these vesicles. These results illustrate that multiple cysteine proteases, in combination with BACE 1, contribute to beta-secretase activity in the regulated secretory pathway. These results complement earlier findings for BACE 1 as beta3-secretase for Abeta production in the constitutive secretory pathway that provides basal secretion of Abeta into conditioned media. These findings suggest that drug inhibition of several proteases may be required for reducing Abeta levels as a potential therapeutic approach for AD.
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http://dx.doi.org/10.1046/j.1471-4159.2002.00794.xDOI Listing
April 2002
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