A Hybrid Alloying Nanozyme-Glutathione Inhibitor Co-Delivery System Initiates a Dual-Disruption on Cancer Redox Homeostasis.

Altered redox homeostasis has long been observed in cancer cells, which can be exploited for therapeutic benefits. However, reactive oxygen species (ROS) pleiotropy coupling with reductive adaptation in cancer cells poses a formidable challenge for redox dyshomeostasis-based cancer therapy. Herein, a AuPd alloying nanozyme-glutathione (GSH) biosynthesis inhibitor co-delivery system (B-BMES) is developed using dendritic SiO as a matrix to target cancer redox homeostasis.

A Poly(amino acid)-Based Nanomedicine Strategy: Telomere-Telomerase Axis Targeting and Magnetic Resonance Imaging in Hepatocellular Carcinoma Treatment.

Targeting telomere maintenance has emerged as a promising strategy for hepatocellular carcinoma (HCC) treatment. However, given the duality of the telomere-telomerase axis in telomere maintenance, a comprehensive strategy is urgently needed. Herein, we develop a poly(amino acid) (D-PAAs)-based strategy for spatiotemporal codelivery of telomerase inhibitor, BIBR1523, and AKT inhibitor, isobavachalcone.

Incidence rate of hospitalization and mortality in the first year following initial diagnosis of cardiac amyloidosis in the US claims databases.

Objective: This study aimed to determine rates of hospitalization and in-hospital mortality in the first year following amyloidosis diagnosis with cardiac involvement using observational databases.

Methods: Three administrative claims databases, IBM MarketScan Commercial Claims and Encounters (CCAE), IBM MarketScan Multi-State Medicare Database (MDCR), and Optum's de-identified Clinformatics Data Mart Database (Optum) were analyzed. Adults ≥18 years old, with a diagnosis of amyloidosis and evidence of cardiac involvement (i.

Direct conversion of wet sewage sludge to carbon catalyst for sulfamethoxazole degradation through peroxymonosulfate activation.

The high moisture content of wet sewage sludge generated from wastewater treatment process not only brings high cost of sewage disposal, but also limits its utilization as resource. In this study, an efficient strategy of directly utilizing wet sludge to develop advanced carbocatalyst via a hydrothermal coupled pyrolysis process was proposed. The possible application of as-synthesized carbocatalyst was evaluated by activating peroxymonosulfate (PMS) to degrade a model pollutant of sulfamethoxazole (SMX).

Structure-guided design fine-tunes pharmacokinetics, tolerability, and antitumor profile of multispecific frizzled antibodies.

Aberrant activation of Wnt/β-catenin signaling occurs frequently in cancer. However, therapeutic targeting of this pathway is complicated by the role of Wnt in stem cell maintenance and tissue homeostasis. Here, we evaluated antibodies blocking 6 of the 10 human Wnt/Frizzled (FZD) receptors as potential therapeutics.

Influence of age on the pharmacokinetics, pharmacodynamics, efficacy, and safety of rivaroxaban.

Objective: Atrial fibrillation, peripheral and coronary artery disease, and venous thromboembolism are major risk factors for stroke, disability, and death in the rapidly growing older (≥ 65 years.) population. In the absence of clear guidelines on the appropriate use of the newer non-vitamin K antagonist oral anticoagulants in this population, this study specifically reviews the available literature for rivaroxaban and the impact of age that may affect the pharmacokinetics, pharmacodynamics, efficacy, and safety of this anticoagulant.

Angelicin inhibits liver cancer growth in vitro and in vivo.

Previous studies have reported that angelicin exerted antiproliferative effects on several types of tumor cell. However, to the best of our knowledge, the effects of angelicin monotherapy on human liver cancer remain to be investigated. In the present study, the antitumor activity of angelicin was evaluated in vitro and in vivo, and the molecular mechanisms underlying its effects were investigated.

Risk Prediction for Ischemic Stroke and Transient Ischemic Attack in Patients Without Atrial Fibrillation: A Retrospective Cohort Study.

Background: Stroke mainly occurs in patients without atrial fibrillation (AF). This study explored risk prediction models for ischemic stroke and transient ischemic attack (TIA) in patients without AF.

Methods: Three US-based healthcare databases (Truven MarketScan Commercial Claims and Encounters [CCAE], Medicare Supplemental [MDCR], and Optum Clinformatics [Optum]) were used to establish patient cohorts without AF during the index period of 2008-2012.

Design and optimization of (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones as potent PLK4 inhibitors with oral antitumor efficacy.

Previous efforts from our laboratory demonstrated that (E)-3-((3-(E)-vinylaryl)-1H-indazol-6-yl)methylene)-indolin-2-ones are potent PLK4 inhibitors with in vivo anticancer efficacy upon IP dosing. As part of a continued effort to develop selective and orally efficacious inhibitors, we examined variations on this theme wherein 'directly-linked' aromatics, pendant from the indazole core, replace the arylvinyl moiety. Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones.

A proposed statistical framework for the management of subgroup analyses for large clinical trials.

Planned and unplanned subgroup analyses of large clinical trials are frequently performed and the results are sometimes difficult to interpret. The source of a nominal significant finding may come from a true signal, variation of the clinical trial outcome or the observed data structure. Quantitative assessment is critical to the interpretation of the totality of the clinical data.

The discovery of Polo-like kinase 4 inhibitors: identification of (1R,2S).2-(3-((E).4-(((cis).2,6-dimethylmorpholino)methyl)styryl). 1H.indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (CFI-400945) as a potent, orally active antitumor agent.

Previous publications from our laboratory have introduced novel inhibitors of Polo-like kinase 4 (PLK4), a mitotic kinase identified as a potential target for cancer therapy. The search for potent and selective PLK4 inhibitors yielded (E)-3-((1Hindazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones, e.g.

Synthetic antibodies with a human framework that protect mice from lethal Sudan ebolavirus challenge.

The ebolaviruses cause severe and rapidly progressing hemorrhagic fever. There are five ebolavirus species; although much is known about Zaire ebolavirus (EBOV) and its neutralization by antibodies, little is known about Sudan ebolavirus (SUDV), which is emerging with increasing frequency. Here we describe monoclonal antibodies containing a human framework that potently inhibit infection by SUDV and protect mice from lethal challenge.

Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent.

PLK4 was identified as a promising therapeutic target through a systematic approach that combined RNAi screening with gene expression analysis in human breast cancers and cell lines. A drug discovery program culminated in CFI-400945, a potent and selective PLK4 inhibitor. Cancer cells treated with CFI-400945 exhibit effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication, mitotic defects, and cell death.

Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides.

TTK kinase was identified by in-house siRNA screen and pursued as a tractable, novel target for cancer treatment. A screening campaign and systematic optimization, supported by computer modeling led to an indazole core with key sulfamoylphenyl and acetamido moieties at positions 3 and 5, respectively, establishing a novel chemical class culminating in identification of 72 (CFI-400936). This potent inhibitor of TTK (IC50=3.

The discovery of Polo-like kinase 4 inhibitors: design and optimization of spiro[cyclopropane-1,3'[3H]indol]-2'(1'H).ones as orally bioavailable antitumor agents.

Polo-like kinase 4 (PLK4), a unique member of the polo-like kinase family of serine-threonine kinases, is a master regulator of centriole duplication that is important for maintaining genome integrity. Overexpression of PLK4 is found in several human cancers and is linked with a predisposition to tumorigenesis. Previous efforts to identify potent and efficacious PLK4 inhibitors resulted in the discovery of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which are superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones reported herein.

Nanocage structure derived from sulfonated β-cyclodextrin intercalated layered double hydroxides and selective adsorption for phenol compounds.

Nanocage structures derived from decasulfonated β-cyclodextrin (SCD) intercalated ZnAl- and MgAl- layered double hydroxides (LDHs) were prepared through calcination-rehydration reactions. The ZnAl- and MgAl-LDH layers revealed different basal spacings (1.51 nm for SCD-ZnAl-LDH and 1.

Enhancing the electromagnetic performance of Co through the phase-controlled synthesis of hexagonal and cubic Co nanocrystals grown on graphene.

Cobalt is a promising soft metallic magnetic material used for important applications in the field of absorbing stealth technology, especially for absorbing centimeter waves. However, it frequently presents a weak dielectric property because of its instability, aggregation, and crystallographic form. A method for enhancing the electromagnetic property of metal Co via phase-controlled synthesis of Co nanostructures grown on graphene (GN) networks has been developed.

Targeting HER2+ breast cancer cells: lysosomal accumulation of anti-HER2 antibodies is influenced by antibody binding site and conjugation to polymeric nanoparticles.

Humanized monoclonal antibodies (mAb) against HER2 are being engineered to treat cancer. We utilized phage-display technology to generate a novel anti-HER2 mAb (named 73JIgG) that binds an epitope of HER2 distinct from that of trastuzumab. Although these mAbs bind to the same cell surface receptor, they have different cell distribution profiles.

The discovery of PLK4 inhibitors: (E)-3-((1H-Indazol-6-yl)methylene)indolin-2-ones as novel antiproliferative agents.

The family of Polo-like kinases is important in the regulation of mitotic progression; this work keys on one member, namely Polo-like kinase 4 (PLK4). PLK4 has been identified as a candidate anticancer target which prompted a search for potent and selective inhibitors of PLK4. The body of the paper describes lead generation and optimization work which yielded nanomolar PLK4 inhibitors.

Rivaroxaban: a novel oral anticoagulant for the prevention and treatment of several thrombosis-mediated conditions.

The development of rivaroxaban (XARELTO®) is an important new medical advance in the field of oral anticoagulation. Thrombosis-mediated conditions constitute a major burden for patients, healthcare systems, and society. For more than 60 years, the prevention and treatment of these conditions have been dominated by oral vitamin K antagonists (such as warfarin) and the injectable heparins.

Impact of global geographic region on time in therapeutic range on warfarin anticoagulant therapy: data from the ROCKET AF clinical trial.

Background: Vitamin K antagonist (VKA) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (TTR) is a widely cited measure of the quality of VKA therapy. We sought to identify factors associated with TTR in a large, international clinical trial.

Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.

Background: The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin.

Methods: In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin.

Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress.

Tumor cells gain a survival/growth advantage by adapting their metabolism to respond to environmental stress, a process known as metabolic transformation. The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells up-regulate glycolysis under aerobic conditions. However, other mechanisms mediating metabolic transformation remain undefined.

Bias and variance evaluation of QT interval correction methods.

There is an increasing regulatory emphasis on assessing drug-induced QT interval prolongation. Since QT interval is correlated with heart rate (HR), assessment of drug-induced QT interval prolongation should be made at a standardized HR, resulting in the need to correct QT interval (QTc) for HR. This study investigates the statistical properties of QTc intervals using individual based correction (IBC), population based correction (PBC), or fixed correction (FC) methods under both the linear and log-linear regression models for the QT-RR relationship where RR is the time elapsing between two consecutive heart beats (inversely related to HR through RR = 60/HR).