A5066879227- Biblical Studies and Interpretation
- Historical and Linguistic Studies
- Archaeology and Historical Studies
- Historical, Religious, and Philosophical Studies
- Christian Theology and Mission
- Pentecostalism and Christianity Studies
- Religion, Society, and Development
- Monoclonal and Polyclonal Antibodies Research
- CAR-T cell therapy research
- PI3K/AKT/mTOR signaling in cancer
- Classical Antiquity Studies
- Theology and Canon Law Studies
- Lung Cancer Treatments and Mutations
- American Constitutional Law and Politics
- Cancer Immunotherapy and Biomarkers
- Byzantine Studies and History
- Immune Cell Function and Interaction
- Religion and Society Interactions
- Reformation and Early Modern Christianity
- Religious Studies and Spiritual Practices
- Linguistics and language evolution
- Ancient Egypt and Archaeology
- African history and culture analysis
- Historical and Religious Studies of Rome
- Cancer, Hypoxia, and Metabolism
University of Edinburgh
2012-2023
University of Divinity
2008-2022
University of Iowa Hospitals and Clinics
2022
University of Birmingham
2021
UK Biobank
2019
University of the West Indies
2019
University of Newcastle Australia
2010-2018
Exelixis (United States)
2007-2017
Xencor (United States)
2017
Hunter Medical Research Institute
2010-2017
<h3>Importance</h3> The humanized monoclonal antibody atezolizumab targets programmed death-ligand 1 and has demonstrated durable single-agent activity in a subset of metastatic triple-negative breast cancers. To extend the observed activity, combinatorial approaches are being tested with standard cytotoxic chemotherapies known to induce immunogenic tumor cell death. <h3>Objective</h3> examine safety, tolerability, preliminary clinical plus nab-paclitaxel <h3>Design, Setting,...
As the first structural elucidation of a modular polyketide synthase (PKS) domain, crystal structure macrocycle-forming thioesterase (TE) domain from 6-deoxyerythronolide B (DEBS) was solved by combination multiple isomorphous replacement and multiwavelength anomalous dispersion refined to an R factor 24.1% 2.8-Å resolution. Its overall tertiary architecture belongs α/β-hydrolase family, with two unusual features unprecedented in this family: hydrophobic leucine-rich dimer interface...
Azepino[4,5-b]indoles have been identified as potent agonists of the farnesoid X receptor (FXR). In vitro and in vivo optimization has led to discovery 6m (XL335, WAY-362450) a potent, selective, orally bioavailable FXR agonist (EC(50) = 4 nM, Eff 149%). Oral administration LDLR(-/-) mice results lowering cholesterol triglycerides. Chronic an atherosclerosis model significant reduction aortic arch lesions.
3502 Background: Atezolizumab (atezo; MPDL3280A) is an engineered antibody that inhibits binding of PD-L1 to its receptors, PD-1 and B7.1. Atezo has demonstrated monotherapy activity in a multitude human tumor types. However, response rates microsatellite stable (MSS) CRCs have been lower than other indications. In preclinical models, targeted inhibition MEK leads upregulation MHC I on cells, induces intratumoral T-cell infiltration enhances anti-PDL1 activity. We therefore conducted Phase...
BackgroundCabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part a phase 2 randomized discontinuation trial nine tumor-type cohorts.Patients methodsEligible had Child-Pugh A liver function ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose 100 mg daily. After initial 12-week treatment period, stable disease (SD) per...
441 Background: ccRCC, the most common histologic subtype of renal cancer, is universally associated with dysregulation VHL pathway, leading to HIF-2α accumulation and upregulation multiple oncogenic pathways. Cas an orally bioavailable, small-molecule inhibitor that potently inhibits transcription HIF-2α-dependent genes. Methods: ARC-20 (NCT05536141) a phase 1, open-label study evaluating monotherapy in pts (age ≥18) ccRCC who are naïve previously treated anti-PD-(L)1 VEGFR-TKI therapies....
Activation of the PI3K (phosphoinositide 3-kinase) pathway is a frequent occurrence in human tumors and thought to promote growth, survival, resistance diverse therapies. Here, we report pharmacologic characterization pyridopyrimidinone derivative XL765 (SAR245409), potent highly selective pan inhibitor class I PI3Ks (α, β, γ, δ) with activity against mTOR. Broad kinase selectivity profiling >130 protein kinases revealed that for mTOR over other kinases. In cellular assays, inhibits...
673 Background: Blockade of the PD-L1/PD-1 axis is a proven immunologic approach for treatment many cancers; however, not all pts respond to monotherapy. Bev, an anti–VEGF-A antibody, has demonstrated clinical efficacy in mCRC and enhanced T-cell infiltration tumors preclinical studies. Thus, we postulated that combining atezo (anti-PD-L1) with bev would augment anti-tumor immune responses, resulting improved more durable benefit. We report results from first study anti-PD-L1 agent + VEGF-A...
A series of novel, highly potent, selective, and ATP-competitive mammalian target rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery with low nanomolar activity greater than 1000-fold selectivity over closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation mTOR complex 1 (p-p70S6K, pS6, p-4E-BP1) 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics oral...
Abstract Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed various cancers and correlates with tumor growth survival. Resistance to a variety anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors chemotherapeutic agents, has been attributed the absence or attenuation downregulating signals along pathway. Thus, have therapeutic potential as single agents combination other therapies for cancer indications....
9009 Background: Alectinib has proven systemic and CNS efficacy in patients (pts) with ALK+ aNSCLC (ALEX study). Tumor cell death caused by alectinib may release antigens broadening the potential anti-tumor T response. The monoclonal antibody atezolizumab (atezo) releases suppression inhibiting PD-L1 binding improves OS second-line NSCLC treatment. We hypothesized atezo combination would lead to enhanced efficacy. Methods: This phase Ib enrolled treatment-naïve pts regardless of status,...
560 Background: The majority of pts with mCRC have microsatellite stable (MSS) tumors minimal response to PD-L1/PD-1 blockade. MEK inhibition upregulates tumor major histocompatibility complex-I expression, promotes intratumoral T-cell accumulation and improves anti–PD-L1 responses (Ebert, Immunity. 2016), supporting clinical evaluation combined (A) plus MEKi (C) in mCRC. Methods: Pts chemotherapy-refractory or locally advanced were evaluated. A was administered IV q2w at 800 mg. C dosed PO...
The dihydrofolate reductase (fol) gene in Escherichia coli has been deleted and replaced by a selectable marker. Verification of the delta fol::kan strain accomplished using genetic biochemical criteria, including Southern analysis chromosomal DNA. mutation is stable E. K549 [thyA polA12 (Ts)] can be successfully transduced to other strains providing they have mutations their thymidylate synthetase (thyA) genes. A preliminary investigation relationship between fol thyA expression suggests...
The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment disease. A large body evidence has PI3Kγ modulation autoimmune and inflammatory processes it intriguing target drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated further optimization studies. in vitro activity first HTS hit, designated as sulfonylpiperazine scaffold, was...
Objectives: Casdatifan (AB521), an orally bioavailable small-molecule inhibitor of HIF-2α, potently inhibits transcription HIF-2α-dependent genes in cell lines and preclinical species. The objective this analysis was to develop a population plasma urine PK model describing the relationship between dose casdatifan PK, conduct simulations compare exposure subjects with normal renal function those moderate impairment, support inclusion renally impaired patients future clinical trials.METHODS:...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMechanism-Based Inhibition of Thymidylate Synthase by 5-(Trifluoromethyl)-2'-deoxyuridine 5'-MonophosphateJens W. Eckstein, Paul G. Foster, Janet Finer-Moore, Yusuke Wataya, and Daniel V. SantiCite this: Biochemistry 1994, 33, 50, 15086–15094Publication Date (Print):December 1, 1994Publication History Published online1 May 2002Published inissue 1 December...