Ahmed Chenna

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Data from Molecular and Clinical Activity of CDX-3379, an Anti-ErbB3 Monoclonal Antibody, in Head and Neck Squamous Cell Carcinoma Patients

Purpose:ErbB3 and its ligand neuregulin-1 (NRG1) are widely expressed in head and neck squamous c... more Purpose:ErbB3 and its ligand neuregulin-1 (NRG1) are widely expressed in head and neck squamous cell carcinoma (HNSCC) and associated with tumor progression. A “window-of-opportunity” study (NCT02473731) was conducted to evaluate the pharmacodynamic effects of CDX-3379, an anti-ErbB3 mAb, in patients with HNSCC.Patients and Methods:Twelve patients with newly diagnosed, operable HNSCC received two infusions of CDX-3379 (1,000 mg) at a 2-week interval prior to tumor resection. The primary study objective was to achieve ≥50% reduction in tumor ErbB3 signaling (phosphorylation of ErbB3; pErbB3) in ≥30% of patients. Other potential tumor biomarkers, pharmacokinetics, safety, and tumor measurements were also assessed.Results:pErbB3 was detectable in all tumors prior to treatment and decreased for 10 of 12 (83%) patients following CDX-3379 dosing, with ≥50% reduction in 7 of 12 (58%; P = 0.04; 95% confidence interval, 27.7%–84.8%). Target trough CDX-3379 serum levels were achieved in all patients. CDX-3379 treatment–related toxicity was grade 1–2 and included diarrhea, fatigue, and acneiform dermatitis. Five of 12 (42%) patients had shrinkage in tumor burden, including a marked clinical response in a patient with human papillomavirus–negative oral cavity HNSCC. All patients with tumor shrinkage had tumors that expressed both NRG1 and ErbB3 and demonstrated reduced pErbB3 with CDX-3379 treatment.Conclusions:This study demonstrates that CDX-3379 can inhibit tumor ErbB3 phosphorylation in HNSCC. CDX-3379 was well tolerated and associated with measurable tumor regression. A phase II study (NCT03254927) has been initiated to evaluate CDX-3379 in combination with cetuximab for patients with advanced HNSCC.

Synthesis of 8-(Hydroxymethyl)-3,<i>N</i><sup>4</sup>-etheno-2‘-deoxycytidine, a Potential Carcinogenic Glycidaldehyde Adduct, and Its Site-Specific Incorporation into DNA Oligonucleotides

Chemical Research in Toxicology, Feb 25, 2000

The previously unreported glycidaldehyde adduct, 8-(hydroxymethyl)-3,N 4 -etheno-2&amp;amp;am... more The previously unreported glycidaldehyde adduct, 8-(hydroxymethyl)-3,N 4 -etheno-2&amp;amp;amp;#x27;-deoxycytidine (8-HM-εdC), has been synthesized for the first time by reaction of 2&amp;amp;amp;#x27;-deoxycytidine with bromoacetaldehyde at pH 4.5, followed by reduction with sodium borohydride. The adduct was characterized ...

NNA-DNA adducts as biomarkers for detecting exposure to thirdhand smoke

OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information), Jan 21, 2020

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NNA, a thirdhand smoke constituent, induces DNA damage in vitro and in human cells

Supplementary Table 1 from p95HER2 Methionine 611 Carboxy-Terminal Fragment Is Predictive of Trastuzumab Adjuvant Treatment Benefit in the FinHer Trial

Supplementary Table 1

Quantitative p95HER2 and HER2 correlations with outcome in the FinHer trial

Cancer Research, 2015

Supplementary Figure S1 from p95HER2 Methionine 611 Carboxy-Terminal Fragment Is Predictive of Trastuzumab Adjuvant Treatment Benefit in the FinHer Trial

Supplementary Figure 1

Supplementary Data from Molecular and Clinical Activity of CDX-3379, an Anti-ErbB3 Monoclonal Antibody, in Head and Neck Squamous Cell Carcinoma Patients

Table S1. Pharmacokinetic Parameters Figure S1. Ki67 Expression by IHC. Figure S2: ErbB3 RNA and ... more

ChemInform Abstract: Functionalised Benzocyclooctenones: Synthesis and Chemistry

ChemInform, May 22, 1990

Ring expansion of the tetralone derivative (I) is only achieved with the carboxylate (I), giving ... more Ring expansion of the tetralone derivative (I) is only achieved with the carboxylate (I), giving the benzocyclooctene (III) in poor yield. Various interconversions of benzo(5,6)cycloocta(1,2-c)furanones are described. The structure of the keto lactone (VI), a key intermediate for the production of lactam structures, such as (X), is investigated by X-ray crystallography (space group P21/n with Z = 8). Similarly to the hydrazine derivative (XIII), a series of benzo(5,6)cycloocta(1,2-c)pyrrole-1,3-diones are prepared from (XI).

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The ATN Puzzle: Piecing Together an Alzheimer’s Plasma Panel (P7-9.010)

Neurology, Apr 9, 2024

Markers of Immune Activation and Inflammation in Individuals With Postacute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 Infection

The Journal of Infectious Diseases, Sep 27, 2021

Background. The biological processes associated with postacute sequelae of severe acute respirato... more Background. The biological processes associated with postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) are unknown. Methods. We measured soluble markers of inflammation in a SARS-CoV-2 recovery cohort at early (<90 days) and late (>90 days) timepoints. We defined PASC as the presence of 1 or more coronavirus disease 2019 (COVID-19)-attributed symptoms beyond 90 days. We compared fold-changes in marker values between those with and without PASC using mixed-effects models with terms for PASC and early and late recovery time periods. Results. During early recovery, those who went on to develop PASC generally had higher levels of cytokine biomarkers including tumor necrosis factor-α (1.14-fold higher mean ratio [95% confidence interval {CI}, 1.01-1.28]; P = .028) and interferon-γ-induced protein 10 (1.28-fold higher mean ratio [95% CI, 1.01-1.62]; P = .038). Among those with PASC, there was a trend toward higher interleukin 6 levels during early recovery (1.29-fold higher mean ratio [95% CI, .98-1.70]; P = .07), which became more pronounced in late recovery (1.44-fold higher mean ratio [95% CI, 1.11-1.86]; P < .001). These differences were more pronounced among those with a greater number of PASC symptoms. Conclusions. Persistent immune activation may be associated with ongoing symptoms following COVID-19. Further characterization of these processes might identify therapeutic targets for those experiencing PASC.

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Supplementary Figure S2 from p95HER2 Methionine 611 Carboxy-Terminal Fragment Is Predictive of Trastuzumab Adjuvant Treatment Benefit in the FinHer Trial

Supplementary Figure 2 from Quantitative Measurements of Tumoral p95HER2 Protein Expression in Metastatic Breast Cancer Patients Treated with Trastuzumab: Independent Validation of the p95HER2 Clinical Cutoff

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Supplementary Figure 1 from Quantitative Measurements of Tumoral p95HER2 Protein Expression in Metastatic Breast Cancer Patients Treated with Trastuzumab: Independent Validation of the p95HER2 Clinical Cutoff

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Data from Quantitative Measurements of Tumoral p95HER2 Protein Expression in Metastatic Breast Cancer Patients Treated with Trastuzumab: Independent Validation of the p95HER2 Clinical Cutoff

Purpose: P95HER2 (p95) is a truncated form of the HER2, which lacks the trastuzumab-binding site ... more Purpose: P95HER2 (p95) is a truncated form of the HER2, which lacks the trastuzumab-binding site and contains a hyperactive kinase domain. Previously, an optimal clinical cutoff of p95 expression for progression-free survival (PFS) and overall survival (OS) was defined using a quantitative VeraTag assay (Monogram Biosciences) in a training set of trastuzumab-treated metastatic breast cancer (MBC) patients.Experimental Design: In the current study, the predictive value of the p95 VeraTag assay cutoff established in the training set was retrospectively validated for PFS and OS in an independent series of 240 trastuzumab-treated MBC patients from multiple institutions.Results: In the subset of 190 tumors assessed as HER2-total (H2T)-positive using the quantitative HERmark assay (Monogram Biosciences), p95 VeraTag values above the predefined cutoff correlated with shorter PFS (HR = 1.43; P = 0.039) and shorter OS (HR = 1.94; P = 0.0055) where both outcomes were stratified by hormone receptor status and tumor grade. High p95 expression correlated with shorter PFS (HR = 2.41; P = 0.0003) and OS (HR = 2.57; P = 0.0025) in the hormone receptor-positive subgroup of patients (N = 78), but not in the hormone receptor-negative group. In contrast with the quantitative p95 VeraTag measurements, p95 immunohistochemical expression using the same antibody was not significantly correlated with outcomes.Conclusions: The consistency in the p95 VeraTag cutoff across different cohorts of patients with MBC treated with trastuzumab justifies additional studies using blinded analyses in larger series of patients. Clin Cancer Res; 20(10); 2805–13. ©2014 AACR.

Analytical and Clinical Assessment of Plasma Phospho-Tau Isoforms in Alzheimer’s Disease (AD) (S15.006)

Abstract 10570: Inflammation During Early Post-Acute Covid-19 is Associated With Reduced Exercise Capacity and Long Covid Symptoms After 1 Year

Circulation, Nov 8, 2022

Reduced Exercise Capacity, Chronotropic Incompetence, and Early Systemic Inflammation in Cardiopulmonary Phenotype Long Coronavirus Disease 2019

The Journal of Infectious Diseases, May 11, 2023

Background. Mechanisms underlying persistent cardiopulmonary symptoms after severe acute respirat... more Background. Mechanisms underlying persistent cardiopulmonary symptoms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (postacute sequelae of coronavirus disease 2019 [COVID-19; PASC] or "long COVID") remain unclear. This study sought to elucidate mechanisms of cardiopulmonary symptoms and reduced exercise capacity. Methods. We conducted cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring among adults >1 year after SARS-CoV-2 infection, compared those with and those without symptoms, and correlated findings with previously measured biomarkers. Results. Sixty participants (median age, 53 years; 42% female; 87% nonhospitalized; median 17.6 months after infection) were studied. At CPET, 18/37 (49%) with symptoms had reduced exercise capacity (<85% predicted), compared with 3/19 (16%) without symptoms (P = .02). The adjusted peak oxygen consumption (VO 2) was 5.2 mL/kg/min lower (95% confidence interval, 2.1-8.3; P = .001) or 16.9% lower percent predicted (4.3%-29.6%; P = .02) among those with symptoms. Chronotropic incompetence was common. Inflammatory markers and antibody levels early in PASC were negatively correlated with peak VO 2. Late-gadolinium enhancement on CMR and arrhythmias were absent. Conclusions. Cardiopulmonary symptoms >1 year after COVID-19 were associated with reduced exercise capacity, which was associated with earlier inflammatory markers. Chronotropic incompetence may explain exercise intolerance among some with "long COVID.

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Abstract 3029: Profiling HER3/ErbB3 activation in formalin-fixed, paraffin-embedded (FFPE) breast tumor samples that express high and low HER2/ErbB2 levels using proximity-based immunoassays

Background: HER3 is widely accepted as a potent heterodimerization partner for HER2 tyrosine kina... more Background: HER3 is widely accepted as a potent heterodimerization partner for HER2 tyrosine kinase. HER3 activation may promote intrinsic and/or acquired resistance to HER2-targeted therapies. Therapeutic strategies that target HER3 directly or in combination with HER2 are being evaluated both preclinically and clinically. Historically, such strategies have focused exclusively on tumors that exhibit HER2 gene-amplification and/or over-expression (HER2 high/positive). Recent studies suggest distinct or additional utility in non-amplified, low HER2 tumor settings (HER2 low/negative). Attempts to identify appropriate HER2-positive patient populations that are likely to benefit from HER3-targeted therapies have revealed an important need for more quantitative, sensitive methods of measuring HER2 and HER3 protein expression other than traditional IHC, and also for quantitative, directed measurements of HER3 activation. Methods: Dual-antibody proximity-binding assays (VeraTag) were used to measure HER2 total (HERmark®), HER3 total, HER2-HER3 heterodimer, phospho-HER3 and HER3-PI3 kinase (p85) protein expression across a broad dynamic range in a group of HER2-(low) and HER2+ (high) FFPE breast tumors (HER2 status determined by IHC and verified by HERmark). Dual-antibody proximity-binding assays developed for use in high HER2 FFPE tumor specimens (PloS ONE: 28 Jan 2011 10.1371/journal.pone.0016443) were optimized for use in low HER2 samples. Results: HER2 expression spanned nearly a 2-log10 dynamic range in the HER2 breast tumor set. HER3 expression spanned a 1.5-log10 dynamic range in these tumors and trended with HER2 expression levels. HER2-HER3 heterodimerization correlated more closely with HER2 expression than HER3 expression in both low and high HER2 breast tumors, suggesting that HER2 may be the primary driver of heterodimerization. Correlations between phospho-HER3, HER3-PI3K, and HER2-HER3 heterodimer measurements were observed, with each analyte spanning a ∼1-log10 dynamic range for the corresponding measurement. HER3 signaling patterns in low and high HER2 breast tumors were compared to assess the level of HER3 activation relative to HER2 expression levels. Conclusions: We have developed multiple assays for quantitative measurements of HER3 activation in FFPE breast tumors samples that express low and high levels of the HER2 receptor. These assays are presently being investigated preclinically to define mechanism of drug action, and in clinical trials to predict response to targeted therapies. Citation Format: Jerry Wallweber, Ahmed Chenna, Roy Ravanera, Weidong Huang, David Stathas, Gayle Marshall, Chris Womack, Alison Pritchard, Ken Thress, Carl Barrett, Christos Petropoulos, Lisa DeFazio Eli, John Winslow. Profiling HER3/ErbB3 activation in formalin-fixed, paraffin-embedded (FFPE) breast tumor samples that express high and low HER2/ErbB2 levels using proximity-based immunoassays. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3029. doi:10.1158/1538-7445.AM2013-3029

Role of antibodies, inflammatory markers, and echocardiographic findings in post-acute cardiopulmonary symptoms after SARS-CoV-2 infection

medRxiv (Cold Spring Harbor Laboratory), Nov 26, 2021

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by pee... more

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