Publications by authors named "J C S Harding"

1,447 Publications

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A Phase 1 Dose-Escalation and Expansion Study of Telaglenastat in Patients With Advanced or Metastatic Solid Tumors.

Clin Cancer Res 2021 Jul 20. Epub 2021 Jul 20.

Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center.

Purpose: Glutamine is a critical fuel for solid tumors. Interference with glutamine metabolism is deleterious to neoplasia in preclinical models. A Phase 1 study of the oral, first-in-class, glutaminase inhibitor telaglenastat was conducted in treatment-refractory solid tumor patients to define recommended phase 2 dose (RP2D) and evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity.

Experimental Design: Dose escalation by 3 +3 design was followed by exploratory tumor-/biomarker-specific cohorts.

Results: Among 120 patients, fatigue (23%) and nausea (19%) were the most common toxicity. Maximum tolerated dose was not reached. Correlative analysis indicated >90% glutaminase inhibition in platelets at plasma exposures >300 nM; >75% tumoral glutaminase inhibition; and significant increase in circulating glutamine. RP2D was defined at 800mg twice-daily. Disease control rate (DCR) was 43% across expansion cohorts (overall response rate 5%, DCR 50% in renal cell carcinoma).

Conclusions: Telaglenastatis safe with a favorable PK/PD profile and signal of antitumor activity supporting further clinical development.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1204DOI Listing
July 2021

AN EVALUATION OF RESURGENCE DURING FUNCTIONAL COMMUNICATION TRAINING.

Psychol Rec 2013 Jan 23;63(1):3-20. Epub 2017 May 23.

The University of Iowa.

Three children who displayed destructive behavior maintained by negative reinforcement received functional communication training (FCT). During FCT, the children were required to complete a demand and then to mand (touch a card attached to a microswitch, sign, or vocalize) to receive brief play breaks. Prior to and 1 to 3 times following the initiation of FCT, extinction probes were conducted to evaluate the resurgence of destructive behavior when the microswitch without the mand card was present or the microswitch and the mand card were absent to determine if different patterns of resurgence occurred when the microswitch was present or absent and, for 2 of the children, if changes in resurgence occurred at different points in treatment. Results showed that FCT led to relatively rapid reductions in destructive behavior. During all extinction sessions, resurgence of destructive behavior occurred with only minimal differences across the switch/no card and no-switch conditions.
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http://dx.doi.org/10.11133/j.tpr.2013.63.1.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281923PMC
January 2013

Investigating the genetic architecture of disease resilience in pigs by genome-wide association studies of complete blood count traits collected from a natural disease challenge model.

BMC Genomics 2021 Jul 13;22(1):535. Epub 2021 Jul 13.

Livestock Gentec, Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, Canada.

Background: Genetic improvement for disease resilience is anticipated to be a practical method to improve efficiency and profitability of the pig industry, as resilient pigs maintain a relatively undepressed level of performance in the face of infection. However, multiple biological functions are known to be involved in disease resilience and this complexity means that the genetic architecture of disease resilience remains largely unknown. Here, we conducted genome-wide association studies (GWAS) of 465,910 autosomal SNPs for complete blood count (CBC) traits that are important in an animal's disease response. The aim was to identify the genetic control of disease resilience.

Results: Univariate and multivariate single-step GWAS were performed on 15 CBC traits measured from the blood samples of 2743 crossbred (Landrace × Yorkshire) barrows drawn at 2-weeks before, and at 2 and 6-weeks after exposure to a polymicrobial infectious challenge. Overall, at a genome-wise false discovery rate of 0.05, five genomic regions located on Sus scrofa chromosome (SSC) 2, SSC4, SSC9, SSC10, and SSC12, were significantly associated with white blood cell traits in response to the polymicrobial challenge, and nine genomic regions on multiple chromosomes (SSC1, SSC4, SSC5, SSC6, SSC8, SSC9, SSC11, SSC12, SSC17) were significantly associated with red blood cell and platelet traits collected before and after exposure to the challenge. By functional enrichment analyses using Ingenuity Pathway Analysis (IPA) and literature review of previous CBC studies, candidate genes located nearby significant single-nucleotide polymorphisms were found to be involved in immune response, hematopoiesis, red blood cell morphology, and platelet aggregation.

Conclusions: This study helps to improve our understanding of the genetic basis of CBC traits collected before and after exposure to a polymicrobial infectious challenge and provides a step forward to improve disease resilience.
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http://dx.doi.org/10.1186/s12864-021-07835-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278769PMC
July 2021

Noninvasive Detection of Polyclonal Acquired Resistance to FGFR Inhibition in Patients With Cholangiocarcinoma Harboring FGFR2 Alterations.

JCO Precis Oncol 2021 8;5. Epub 2021 Jan 8.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Fibroblast growth factor receptor (FGFR) 2 alterations, present in 5%-15% of intrahepatic cholangiocarcinomas (IHC), are targets of FGFR-directed therapies. Acquired resistance is common among patients who respond. Biopsies at the time of acquired resistance to targeted agents may not always be feasible and may not capture the genetic heterogeneity that could exist within a patient. We studied circulating tumor DNA (ctDNA) as a less invasive means of potentially identifying genomic mechanisms of resistance to FGFR-targeted therapies.

Materials And Methods: Serial blood samples were collected from eight patients with FGFR-altered cholangiocarcinoma for ctDNA isolation and next-generation sequencing (NGS) throughout treatment and at resistance to anti-FGFR-targeted therapy. ctDNA was sequenced using a custom ultra-deep coverage NGS panel, incorporating dual index primers and unique molecular barcodes to enable high-sensitivity mutation detection.

Results: Thirty-one acquired mutations in , 30/31 located in the kinase domain, were identified at resistance in six of eight patients with detectable ctDNA. Up to 13 independent mutations were detected per patient, indicative of striking genomic concordance among resistant subclones.

Conclusion: ctDNA could be an effective means to longitudinally monitor for acquired resistance in FGFR2-altered IHC. The numerous acquired genetic alterations in suggest frequent polyclonal mechanisms of resistance that cannot be detected from single-site tissue biopsies.
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http://dx.doi.org/10.1200/PO.20.00178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232836PMC
January 2021

Targeting NF-κB with Nanotherapy in a Mouse Model of Adult T-Cell Leukemia/Lymphoma.

Nanomaterials (Basel) 2021 Jun 16;11(6). Epub 2021 Jun 16.

USF Health Heart Institute, University of South Florida, Tampa, FL 33602, USA.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive, clonal malignancy of mature T cells caused by human T-cell leukemia virus type 1. Although it is a rare tumor type, it serves as an excellent model of a virus driven process that transforms cells and engenders a highly malignant tumor that is extraordinarily difficult to treat. The viral transcriptional transactivator (Tax) in the HTLV-1 genome directly promotes tumorigenesis, and Tax-induced oncogenesis depends on its ability to constitutively activate NF-κB signaling. Accordingly, we developed and evaluated a nano-delivery system that simultaneously inhibits both canonical (p65) and noncanonical (p100) NF-κB signaling pathways locally in tumors after systemic administration. Our results demonstrate that siRNA is delivered rapidly to ATLL tumors after either i.p. or i.v. injection. The siRNA treatment significantly reduced both p65 and p100 mRNA and protein expression. Anti-NF-κB nanotherapy significantly inhibited tumor growth in two distinct tumor models in mice: a spontaneous Tax-driven tumor model, and a Tax tumor cell transplant model. Moreover, siRNA nanotherapy sensitized late-stage ATLL tumors to the conventional chemotherapeutic agent etoposide, indicating a pleiotropic benefit for localized siRNA nanotherapeutics.
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http://dx.doi.org/10.3390/nano11061582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234599PMC
June 2021