Comparison of Plasma p-tau217 and [F]FDG-PET for Identifying Alzheimer Disease in People With Early-Onset or Atypical Dementia.

Background And Objectives: To compare the diagnostic performance of an immunoassay for plasma concentrations of phosphorylated tau (p-tau) 217 with visual assessments of fluorine-18 fluorodeoxyglucose [F]FDG-PET in individuals who meet appropriate use criteria for Alzheimer dementia (AD) biomarker assessments.

Methods: We performed a retrospective analysis of individuals with early-onset (age <65 years at onset) and/or atypical dementia (features other than memory at onset), who were evaluated at a tertiary care memory clinic. All participants underwent measurements of CSF biomarkers (Aβ42, p-tau181, and total tau levels), as well as [F]FDG-PET scans, amyloid-PET scans, and plasma p-tau217 quantifications.

Plasma phosphorylated tau181 outperforms [F] fluorodeoxyglucose positron emission tomography in the identification of early Alzheimer disease.

Background And Purpose: This study was undertaken to compare the performance of plasma p-tau181 with that of [F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in the identification of early biological Alzheimer disease (AD).

Methods: We included 533 cognitively impaired participants from the Alzheimer's Disease Neuroimaging Initiative. Participants underwent PET scans, biofluid collection, and cognitive tests.

Pro-Oxidant Auranofin and Glutathione-Depleting Combination Unveils Synergistic Lethality in Glioblastoma Cells with Aberrant Epidermal Growth Factor Receptor Expression.

Glioblastoma (GBM) is the most prevalent and advanced malignant primary brain tumor in adults. GBM frequently harbors epidermal growth factor receptor (EGFR) wild-type () gene amplification and/or activating mutation. EGFR-driven GBM relies on the thioredoxin (Trx) and/or glutathione (GSH) antioxidant systems to withstand the excessive production of reactive oxygen species (ROS).

A Nuclear Magnetic Resonance (NMR)- and Mass Spectrometry (MS)-Based Saturation Kinetics Model of a Decoction as a Treatment for Kidney Stones.

(BP) is a medicinal plant used to treat many conditions when taken as a leaf juice, leaves in capsules, as an ethanolic extract, and as herbal tea. These preparations have been chemically analyzed except for decoctions derived from boiled green leaves. In preparation for a clinical trial to validate BP tea as a treatment for kidney stones, we used NMR and MS analyses to characterize the saturation kinetics of the release of metabolites.

Molecular Profiling of Peanut under Raw, Roasting, and Autoclaving Conditions Using High-Resolution Magic Angle Spinning and Solution H NMR Spectroscopy.

Higher rates of peanut allergy have been observed in countries that commonly roast peanuts prior to consumption. Despite the importance of understanding the role of thermal processing in allergy and on peanut composition, studies toward generating signatures that identify molecular contents following processing are scant. Here, we identified spectral signatures to track changes and differences in the molecular composition of peanuts under raw, roasted, and high-pressure and high-temperature autoclaved conditions.

Molecular Analysis of the Superior Efficacy of a Dual Epidermal Growth Factor Receptor (EGFR)-DNA-Targeting Combi-Molecule in Comparison with Its Putative Prodrugs 6-Mono-Alkylamino- and 6,6-Dialkylaminoquinazoline in a Human Osteosarcoma Xenograft Model.

: ZR2002 is a dual EGFR-DNA-targeting combi-molecule that carries a chloroethyl group at the six-position of the quinazoline ring designed to alkylate DNA. Despite its good pharmacokinetics, ZR2002 is metabolized in vivo into dechlorinated metabolites, losing the DNA-alkylating function required to damage DNA. To increase the DNA damage activity in tumor cells in vivo, we compared ZR2002 with two of its 6-N,N-disubstituted analogs: "JS61", with a nitrogen mustard function at the six-position of the quinazoline ring, and "JS84", with an N-methyl group.

Discordance and Concordance Between Cerebrospinal and [F]FDG-PET Biomarkers in Assessing Atypical and Early-Onset AD Dementia Cases.

Background And Objectives: To assess the concordance and discordance between the core Alzheimer disease (AD) CSF biomarkers and [F]fluorodeoxyglucose (FDG)-PET patterns evaluated clinically in memory clinic patients who meet appropriate use criteria for AD biomarker investigations.

Methods: We retrospectively assessed participants with atypical and/or early-onset dementia evaluated at a tertiary care memory clinic. All individuals underwent CSF evaluations for Aβ42, phosphorylated tau (P-tau181) and total tau, and brain [F]FDG-PET.

Quantitative Analysis of the Potency of Equimolar Two-Drug Combinations and Combi-Molecules Involving Kinase Inhibitors In Vitro: The Concept of Balanced Targeting.

The median-effect principle proposed by Chou and Talalay is the most effective approach to parameterize interactions between several agents in combination. However, this method cannot be used to evaluate the effectiveness of equimolar drug combinations, which are comparative references for dual-targeting molecular design. Here, using data acquired through the development of "combi-molecules" blocking two kinases (e.

Design and Mechanism of Action of a New Prototype of Combi-Molecule "Programed" to Release Bioactive Species at a pH Range Akin to That of the Tumor Microenvironment.

The clinical use of cytotoxic agents is plagued by systemic toxicity. We report a novel approach that seeks to design a "combi-molecule" to behave as an alkylating agent on its own and to undergo acid-catalyzed conversion to two bioactive species at a pH range akin to that of a tumor microenvironment: an AL530 prototype was synthesized and we studied its ability to release a chlorambucil analogue (CBL-A) plus a potent mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor (PD98059) at different pHs in buffered solutions, plasma and tumors. Its potency was compared in vitro with CBL+PD98059 (SRB assay) and in vivo in a xenograft model.

Subcellular distribution and mechanism of action of AL906, a novel and potent EGFR inhibitor rationally designed to be green fluorescent.

To enhance the potency of EGFR inhibitors, we developed a novel strategy that seeks to conjugate EGFR to a bioactive moiety leading to a molecule termed "combi-molecule". In order to mimic the penetration of this type of molecules, based upon previously reported structure activity relationship studies, we designed a new molecule containing a quinazoline moiety tethered to a p-nitrobenzoxadiazole (NBD) moiety [molecular weight (MW) 700]. Despite its size, AL906 growth inhibitory activity was superior to that of the clinical drug gefitinib.

Design and Synthesis of a Trifunctional Molecular System "Programmed" to Block Epidermal Growth Factor Receptor Tyrosine Kinase, Induce High Levels of DNA Damage, and Inhibit the DNA Repair Enzyme (Poly(ADP-ribose) Polymerase) in Prostate Cancer Cells.

Resistance to chemotherapy in advanced cancers can be mediated by different factors such as epidermal growth factor receptor (EGFR) overexpression and DNA repair enzymes. Therefore, current standards of care usually involve combinations of multiple treatments. Here, to reduce the adverse effects of multiple drug combinations and improve outcome, we proposed a single drug approach to block multiple overlapping effects that characterize chemoresistance.

Comparative analysis of the dual EGFR-DNA targeting and growth inhibitory properties of 6-mono-alkylamino- and 6,6-dialkylaminoquinazoline-based type II combi-molecules.

Over the past decade, we described a novel tumour targeted approach that sought to design "combi-molecules" to hit two distinct targets in tumour cells. Here, to generate small combi-molecules with strong DNA damaging potential while retaining EGFR inhibitory potency, we developed the first synthetic strategy to access the 6-N, N-disubstituted quinazoline scaffold and designed JS61 to possess a nitrogen mustard function directly attached to the 6-position of the quinazoline ring. We compared its biological activity with that of structures containing either a hemi mustard or a non-alkylating substituent.

Temporal Effects of Quercetin on Tight Junction Barrier Properties and Claudin Expression and Localization in MDCK II Cells.

Kidney stones affect 10% of the population. Yet, there is relatively little known about how they form or how to prevent and treat them. The claudin family of tight junction proteins has been linked to the formation of kidney stones.

Mechanisms and Antitumor Activity of a Binary EGFR/DNA-Targeting Strategy Overcomes Resistance of Glioblastoma Stem Cells to Temozolomide.

Purpose: Glioblastoma (GBM) is a fatal primary malignant brain tumor. GBM stem cells (GSC) contribute to resistance to the DNA-damaging chemotherapy, temozolomide. The epidermal growth factor receptor (EGFR) displays genomic alterations enabling DNA repair mechanisms in half of GBMs.

Radiomics in Glioblastoma: Current Status and Challenges Facing Clinical Implementation.

Radiomics analysis has had remarkable progress along with advances in medical imaging, most notability in central nervous system malignancies. Radiomics refers to the extraction of a large number of quantitative features that describe the intensity, texture and geometrical characteristics attributed to the tumor radiographic data. These features have been used to build predictive models for diagnosis, prognosis, and therapeutic response.

Temozolomide Induced Hypermutation in Glioma: Evolutionary Mechanisms and Therapeutic Opportunities.

Glioma are the most common type of malignant brain tumor, with glioblastoma (GBM) representing the most common and most lethal type of glioma. Surgical resection followed by radiotherapy and chemotherapy using the alkylating agent Temozolomide (TMZ) remain the mainstay of treatment for glioma. While this multimodal regimen is sufficient to temporarily eliminate the bulk of the tumor mass, recurrence is inevitable and often poses major challenges for clinical management due to treatment resistance and failure to respond to targeted therapies.

Dasatinib sensitises triple negative breast cancer cells to chemotherapy by targeting breast cancer stem cells.

Background: Patients with triple negative breast cancer (TNBC) exhibit poor prognosis and are at high risk of tumour relapse, due to the resistance to chemotherapy. These aggressive phenotypes are in part attributed to the presence of breast cancer stem cells (BCSCs). Therefore, targeting BCSCs is a priority to overcoming chemotherapy failure in TNBCs.

Molecular analysis of the dual targeting of the epidermal growth factor receptor and the O-methylguanine-DNA methyltransferase with a double arm hybrid molecule.

Disordered expression of the epidermal growth factor receptor (EGFR) has been associated with induction of DNA repair genes (e.g. XRCC1, ERCC1) and resistance to radiation and genotoxic drugs.

Examination of VDR/RXR/DRIP205 Interaction, Intranuclear Localization, and DNA Binding in Ras-Transformed Keratinocytes and Its Implication for Designing Optimal Vitamin D Therapy in Cancer.

Retinoid X receptor (RXR) occupies a central position within the nuclear receptor superfamily, serving as an obligatory partner to numerous other nuclear receptors, including vitamin D receptor (VDR). In the current study, we examined whether phosphorylation of RXRα at serine 260 affects VDR/RXR and VDR interacting protein (DRIP) 205 coactivator recruitment, interactions, and binding of the VDR/human RXRα (hRXRα)/DRIP205 complex to chromatin. Serine 260 is a critical amino acid on the hRXRα that is located in close spatial proximity to regions of coactivator and corepressor interactions.

Performance of Knowledge-Based Radiation Therapy Planning for the Glioblastoma Disease Site.

Purpose: The presence of multiple serial organs at risk (OARs) in close proximity to the tumor makes treatment planning for glioblastoma (GBM) complex and time consuming. The present study aimed to create a knowledge-based (KB) radiation therapy model for GBM patients using RapidPlan.

Methods And Materials: An initial model was trained using 82 glioblastoma patients treated with 60 Gy in 30 fractions.

A type I combi-targeting approach for the design of molecules with enhanced potency against BRCA1/2 mutant- and O6-methylguanine-DNA methyltransferase (mgmt)- expressing tumour cells.

Background: Mutations of the DNA repair proteins BRCA1/2 are synthetically lethal with the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), which when inhibited, leads to cell death due to the absence of compensatory DNA repair mechanism. The potency of PARP inhibitors has now been clinically proven. However, disappointingly, acquired resistance mediated by the reactivation of wild type BRCA1/2 has been reported.

Dasatinib + Gefitinib, a non platinum-based combination with enhanced growth inhibitory, anti-migratory and anti-invasive potency against human ovarian cancer cells.

Background: Ovarian cancer is the leading cause of death for gynecological cancers and the 6th cause of women cancer death in developed countries. The late stage detection, the peritoneal dissemination and the acquisition of resistance against carboplatin are the main reasons to explain this poor prognosis and strengthen the need of alternative treatments to improve the management of ovarian cancer and/or to sensitize tumors to platinum salts. Epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (Met) and cellular Src kinase (c-Src) are crucial kinases implied in ovarian tumor growth, survival, invasion and resistance to carboplatin.

Modifiable Risk Factors for Delirium in Critically Ill Trauma Patients: A Multicenter Prospective Study.

Objective:: Intensive care unit (ICU)-acquired delirium has been associated with increased morbidity and mortality. Prevention strategies including modification of delirium risk factors are emphasized by practice guidelines. No study has specifically evaluated modifiable delirium risk factors in trauma ICU patients.