Discovery of A-910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor.

TAM receptor tyrosine kinases have emerged as promising therapeutic targets for cancer treatment due to their roles in both tumor intrinsic survival mechanisms and suppression of antitumor immunity within the tumor microenvironment. Inhibiting MerTK and Axl selectively is believed to hinder cancer cell survival, reverse the protumor myeloid phenotype, and suppress efferocytosis, thereby eliciting an antitumor immune response. In this study, we present the discovery of , a highly potent and selective dual MerTK/Axl inhibitor, achieved through a structure-based medicinal chemistry campaign.

Water quality evaluation and ecological-health risk assessment on trace elements in surface water of the northeastern Qinghai-Tibet Plateau.

The Qinghai-Tibet Plateau is a unique area with water sources for approximately 40 % of the population in the world. Water resources and water quality are closely associated with ecological security and human health. Fifty-one trace elements in surface water samples (n = 40) were measured, and water quality, health and ecological risks were assessed.

RETRACTED: MicroRNA-204-GSDMD interaction regulates pyroptosis of fibroblast-like synoviocytes in ankylosing spondylitis.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).

Backers investment behavior on explicit and implicit factors in reward-based crowdfunding based on ELM theory.

The aim of this study is to identify the dynamic explicit and implicit information factors which displayed on the webpage of platforms that influence backers' investment decision-making behavior. We analyze the connections among these factors by collecting the longitudinal dataset from reward-based crowdfunding platform. Based on ELM model, we establish Fixed Estimation Panel Data Model respectively according to explicit and implicit factors and take Funding Status (crowdfunding results) as the moderating variable to observe the goal gradient effect.

Effects of surgical approaches and morphological characteristics on the follow up outcomes of patients with posterolateral tibial plateau fractures.

This study aimed to study the effects of surgical approaches and identify the morphological characteristics associated with the 1-year follow-up outcome of patients with posterolateral tibial plateau fractures after successful surgery.We followed 200 postoperative patients for 1 year. The modified Hospital for Special Knee Surgery score (HSS score) was used to evaluate the functional recovery of the knee.

Essential role of the family-dosage in DiGeorge-like anomaly and metabolic homeostasis.

and () encode adapter proteins with similar biochemical properties. Here, we show that a 50% reduction of the family-combined dosage generates developmental defects, including aspects of DiGeorge/del22q11 syndrome in mice. Like the mouse homologs of two 22q11.

Distribution of Black Carbon in Topsoils of the Northeastern Qinghai-Tibet Plateau Under Natural and Anthropogenic Influences.

Black carbon (BC), ubiquitous in soils, plays an important role in global carbon cycles, the radiative heat balance of the Earth, pollutant fate, emissions of greenhouse gas, soil fertility, soil microbial community, and ecosystem stability. However, information on BC in topsoils of the northeastern Qinghai-Tibet Plateau is limited. Therefore, this study performed field sampling and analyzed contents of total BC and soot BC in topsoils.

Distribution, pollution, bioaccumulation, and ecological risks of trace elements in soils of the northeastern Qinghai-Tibet Plateau.

Environmental quality of the northeastern Qinghai-Tibet Plateau has attracted more attention due to increasing anthropogenic disturbance. Therefore, this study investigated the distribution, pollution, ecological risks, and bioaccumulation of 12 target heavy metals and 16 rare earth elements (REEs) in soils of this area. The average concentrations of target trace elements in soils ranged from 0.

Targeting lysine specific demethylase 4A (KDM4A) tandem TUDOR domain - A fragment based approach.

The tandem TUDOR domains present in the non-catalytic C-terminal half of the KDM4A, 4B and 4C enzymes play important roles in regulating their chromatin localizations and substrate specificities. They achieve this regulatory role by binding to different tri-methylated lysine residues on histone H3 (H3-K4me3, H3-K23me3) and histone H4 (H4-K20me3) depending upon the specific chromatin environment. In this work, we have used a 2D-NMR based fragment screening approach to identify a novel fragment (1a), which binds to the KDM4A-TUDOR domain and shows modest competition with H3-K4me3 binding in biochemical as well as in vitro cell based assays.

Discovery and optimization of novel constrained pyrrolopyridone BET family inhibitors.

Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.

Pollution, ecological-health risks, and sources of heavy metals in soil of the northeastern Qinghai-Tibet Plateau.

The Qinghai-Tibet Plateau, especially the northeastern region, is not a pure land any more due to recently increasing anthropogenic activities. This study collected soil samples from 70 sites of the northeastern Qinghai-Tibet Plateau to evaluate pollution, ecological-health risks, and possible pollution sources of heavy metals. The concentrations of heavy metals in soil were relatively high.

Discovery of N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor.

The development of bromodomain and extraterminal domain (BET) bromodomain inhibitors and their examination in clinical studies, particularly in oncology settings, has garnered substantial recent interest. An effort to generate novel BET bromodomain inhibitors with excellent potency and drug metabolism and pharmacokinetics (DMPK) properties was initiated based upon elaboration of a simple pyridone core. Efforts to develop a bidentate interaction with a critical asparagine residue resulted in the incorporation of a pyrrolopyridone core, which improved potency by 9-19-fold.

Preclinical Characterization of BET Family Bromodomain Inhibitor ABBV-075 Suggests Combination Therapeutic Strategies.

ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered phase I clinical trials. Comprehensive preclinical characterization of ABBV-075 demonstrated broad activity across cell lines and tumor models, representing a variety of hematologic malignancies and solid tumor indications. In most cancer cell lines derived from solid tumors, ABBV-075 triggers prominent G cell-cycle arrest without extensive apoptosis.

Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors.

Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, K = 160 μM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays.

Methylpyrrole inhibitors of BET bromodomains.

An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further modifications to the methylpyrrole core provided compounds with improved properties and enhanced activity in a mouse model of multiple myeloma.

CX-5461 induces autophagy and inhibits tumor growth via mammalian target of rapamycin-related signaling pathways in osteosarcoma.

Osteosarcoma (OS) is the most common primary bone tumor, but molecular mechanisms of the disease have not been well understood, and treatment of metastatic OS remains a challenge. Rapid ribosomal RNA synthesis in cancer is transcribed by RNA polymerase I, which results in unbridled cell growth. The recent discovery of CX-5461, a selective RNA polymerase I inhibitor, exerted its inhibitory effect of ribosomal RNA synthesis and antiproliferative potency.

Silencing of carboxypeptidase E inhibits cell proliferation, tumorigenicity, and metastasis of osteosarcoma cells.

Carboxypeptidase E (CPE), a prohormone processing enzyme, has been implicated in the progression of multiple malignancies. However, the biological role and molecular mechanisms of CPE in osteosarcoma remain elusive. In this study, we assessed the effects of CPE on cell proliferation, tumorigenicity, migration, and invasion in osteosarcoma.

Intramedullary nail versus plate treatments for distal tibial fractures: a meta-analysis.

Introduction: Controversy remained on whether the optimal treatment for distal tibial fractures is intramedullary nail (IMN) or plate.

Methods: Databases including PubMed, Embase, Cochrane library, Wanfang and CNKI were retrieved up to May 31, 2014 for eligible studies. Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool was used to evaluate literature qualities.

Developing lipid nanoparticle-based siRNA therapeutics for hepatocellular carcinoma using an integrated approach.

Successful siRNA therapeutics requires the optimal integration of multiple components, including an efficient delivery system, a disease indication that is appropriate for siRNA-based therapy, and a potent and nontoxic siRNA against a robust therapeutic target. Although all currently available delivery systems have limitations, it is important to recognize that a careful selection of the disease indication, therapeutic target, and siRNA molecule could partially compensate for deficiencies associated with the delivery system and makes it possible to advance a therapeutic siRNA regimen. In this study, we present the development of siRNA therapeutics for hepatocellular carcinoma using an integrated approach, including the development of an efficient lipid nanoparticle delivery system, the identification of a robust therapeutic target that does not trigger liver toxicity upon target knockdown, and the selection of potent and nonimmunogenic siRNA molecules against the target.

RNA interference-mediated knockdown of Livin suppresses cell proliferation and invasion and enhances the chemosensitivity to cisplatin in human osteosarcoma cells.

Livin is a novel member of the inhibitor of apoptosis protein (IAP) family that has been reported to be overexpressed in a variety of human malignancies, including osteosarcoma. However, the potential roles of Livin in tumorigenesis have not been elucidated. In the present study, we employed RNA interference (RNAi) technology to suppress endogenous Livin expression in osteosarcoma cells and successfully generated a U2-OS cell line with stably knockdown of Livin.

Cationic lipids percentage and processing temperature are critical in designing siRNA lipid nanoparticles.

To design a clinically viable small interfering RNA (siRNA) formulation, it is essential to understand the in vivo siRNA delivery mechanism during the product development. However, majority of reported siRNA delivery studies are based on testing only isolated factors, with ambiguous interpretation of often in vitro transfection results. Correlating physicochemical properties with in vivo transfection efficiency thus represents an important step towards rational design of siRNA delivery systems.

A robust in vivo positive-readout system for monitoring siRNA delivery to xenograft tumors.

Delivering small interfering RNA (siRNA) to tumors is the major technical hurdle that prevents the advancement of siRNA-based cancer therapy. One of the difficulties associated with the development of clinically relevant delivery systems is the lack of reliable tools for monitoring siRNA delivery to tumors in vivo. We describe here a novel, positive-readout system where siRNA-mediated target knockdown elicits a rapid and robust increase of reporter activity.

Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization.

Aurora kinase B inhibitors induce apoptosis secondary to polyploidization and have entered clinical trials as an emerging class of neocytotoxic chemotherapeutics. We demonstrate here that polyploidization neutralizes Mcl-1 function, rendering cancer cells exquisitely dependent on Bcl-XL/-2. This "addiction" can be exploited therapeutically by combining aurora kinase inhibitors and the orally bioavailable BH3 mimetic, ABT-263, which inhibits Bcl-XL, Bcl-2, and Bcl-w.

Overcoming obstacles to develop effective and safe siRNA therapeutics.

Background: RNA interference (RNAi) is a promising new therapeutic modality. By acting at the mRNA level, RNAi circumvents the druggability issue associated with many disease-driven genes. The lack of safe and effective methods to deliver RNAi therapeutics remains the primary technical hurdle that prevents full utilization of the potential of RNAi therapy.