Targeting TAG-72 in cutaneous T cell lymphoma.

Purpose: Current monoclonal antibody-based treatment approaches for cutaneous T cell lymphoma (CTCL) rely heavily on the ability to identify a tumor specific target that is essentially absent on normal cells. Herein, we propose tumor associated glycoprotein-72 (TAG-72) as one such target. TAG-72 is a mucin-associated, truncated O-glycan that has been identified as a chimeric antigen receptor (CAR)-T cell target in solid tumor indications.

The glucocorticoid receptor acts locally to protect dystrophic muscle and heart during disease.

Absence of dystrophin results in muscular weakness, chronic inflammation and cardiomyopathy in Duchenne muscular dystrophy (DMD). Pharmacological corticosteroids are the DMD standard of care; however, they have harsh side effects and unclear molecular benefits. It is uncertain whether signaling by physiological corticosteroids and their receptors plays a modifying role in the natural etiology of DMD.

Engineering T cell receptor fusion proteins using nonviral CRISPR/Cas9 genome editing for cancer immunotherapy.

Manufacture of chimeric antigen receptor (CAR)-T cells usually involves the use of viral delivery systems to achieve high transgene expression. However, it can be costly and may result in random integration of the CAR into the genome, creating several disadvantages including variation in transgene expression, functional gene silencing and potential oncogenic transformation. Here, we optimized the method of nonviral, CRISPR/Cas9 genome editing using large donor DNA delivery, knocked-in an anti-tumor single chain variable fragment (scFv) into the N-terminus of CD3ε and efficiently generated fusion protein (FP) T cells.

Angiogenic Hyaluronic Acid Hydrogels with Curcumin-Coated Magnetic Nanoparticles for Tissue Repair.

Angiogenic magnetic hydrogels are attractive for tissue engineering applications because their integrated properties can improve angiogenesis while providing magnetic guidance and stimulation for tissue healing. In this study, we synthesized magnetic nanoparticles (MNPs) with curcumin as an angiogenic agent, referred to as CMNPs, via a one-pot coprecipitation method. We dispersed CMNPs in hyaluronic acid (HyA) to create angiogenic magnetic hydrogels.

Engineered CAR-T cells targeting TAG-72 and CD47 in ovarian cancer.

Chimeric antigen receptor (CAR) T cells have revolutionized blood cancer immunotherapy; however, their efficacy against solid tumors has been limited. A common mechanism of tumor escape from single target therapies is downregulation or mutational loss of the nominal epitope. Targeting multiple antigens may thus improve the effectiveness of CAR immunotherapies.

Antimicrobial Bioresorbable Mg-Zn-Ca Alloy for Bone Repair in a Comparison Study with Mg-Zn-Sr Alloy and Pure Mg.

Magnesium-zinc-calcium (Mg-Zn-Ca) alloys have attracted increasing attention for biomedical implant applications, especially for bone repair, because of their biocompatibility, biodegradability, and similar mechanical properties to human bone. The objectives of this study were to characterize Mg-2 wt % Zn-0.5 wt % Ca (named ZC21) alloy pins microstructurally and mechanically, and determine their degradation and interactions with host cells and pathogenic bacteria in vitro and in vivo in comparison with the previously studied Mg-4 wt % Zn-1 wt % strontium (named ZSr41) alloy and Mg control.

Multi-Omics Identifies Circulating miRNA and Protein Biomarkers for Facioscapulohumeral Dystrophy.

The development of therapeutics for muscle diseases such as facioscapulohumeral dystrophy (FSHD) is impeded by a lack of objective, minimally invasive biomarkers. Here we identify circulating miRNAs and proteins that are dysregulated in early-onset FSHD patients to develop blood-based molecular biomarkers. Plasma samples from clinically characterized individuals with early-onset FSHD provide a discovery group and are compared to healthy control volunteers.

Antimicrobial Properties of MgO Nanostructures on Magnesium Substrates.

Magnesium (Mg) and its alloys have attracted increasing attention in recent years as medical implants for repairing musculoskeletal injuries because of their promising mechanical and biological properties. However, rapid degradation of Mg and its alloys in physiological fluids limited their clinical translation because the accumulation of hydrogen (H) gas and fast release of OH ions could adversely affect the healing process. Moreover, infection is a major concern for internally implanted devices because it could lead to biofilm formation, prevent host cell attachment on the implants, and interfere osseointegration, resulting in implant failure or other complications.

Allelopathic Potential of Rice and Identification of Published Allelochemicals by Cloud-Based Metabolomics Platform.

The methanol extracts of nine popular cultivated Vietnamese rice cultivars ( L.cv. OM 2395, 5451, 6976, 380, 5930, 4498, 3536, N406, and 7347) were used to explore their allelopathic potential on barnyardgrass ( L.

Androgens stimulate erythropoiesis through the DNA-binding activity of the androgen receptor in non-hematopoietic cells.

Background: Androgens function through DNA and non-DNA binding-dependent signalling of the androgen receptor (AR). How androgens promote erythropoiesis is not fully understood.

Design And Methods: To identify the androgen signalling pathway, we treated male mice lacking the second zinc finger of the DNA-binding domain of the AR (AR ) with non-aromatizable 5α-dihydrotestosterone (5α-DHT) or aromatizable testosterone.

Photo-assisted green synthesis of silver doped silk fibroin/carboxymethyl cellulose nanocomposite hydrogels for biomedical applications.

Silver nanoparticles (AgNPs) and regenerated silk fibroin (RSF) have recently attracted significant interests for their potential applications in preventing wound-related infections and in tissue engineering. Indeed, nano-silver has long been recognized as one of the most effective antimicrobial agents, and silk fibroin is well known for its capability of stimulating cell activities and facilitating tissue regeneration. In this study, a green synthesis approach was used to create a composite hydrogel (CoHy) of RSF stabilized with CarboxymethylCellulose-Na (CMC-Na) and loaded with AgNPs.

Ketogenic diet in combination with voluntary exercise impacts markers of hepatic metabolism and oxidative stress in male and female Wistar rats.

Ketogenic diets (KDs) are shown to benefit hepatic metabolism; however, their effect on the liver when combined with exercise is unknown. We investigated the effects of a KD versus a "western" diet (WD) on markers of hepatic lipid metabolism and oxidative stress in exercising rats. Male and female Wistar rats with access to voluntary running wheels were randomized to 3 groups ( = 8-14 per group): standard chow (SC; 17% fat), WD (42% fat), or KD (90.

Antimicrobial Activities and Mechanisms of Magnesium Oxide Nanoparticles (nMgO) against Pathogenic Bacteria, Yeasts, and Biofilms.

Magnesium oxide nanoparticle (nMgO) is a light metal based antimicrobial nanoparticle that can be metabolized and fully resorbed in the body. To take advantage of the antimicrobial properties of nMgO for medical use, it is necessary to determine the minimal inhibitory, bactericidal and fungicidal concentrations (MIC, MBC and MFC) of nMgO against prevalent infectious bacteria and yeasts. The objective of this study was to use consistent methods and conditions to reveal and directly compare the efficacy of nMgO against nine prevalent pathogenic microorganisms, including two gram-negative bacteria, three gram-positive bacteria with drug-resistant strains, and four yeasts with drug-resistant strains.

Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population.

Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo.

The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia.

Resistance to chemotherapy is a major problem in cancer treatment, and it is frequently associated with failure of tumor cells to undergo apoptosis. Birinapant, a clinical SMAC mimetic, had been designed to mimic the interaction between inhibitor of apoptosis proteins (IAPs) and SMAC/Diablo, thereby relieving IAP-mediated caspase inhibition and promoting apoptosis of cancer cells. We show that acute myeloid leukemia (AML) cells are sensitive to birinapant-induced death and that the clinical caspase inhibitor emricasan/IDN-6556 augments, rather than prevents, killing by birinapant.

Drug Delivery: Microneedles Integrated with Pancreatic Cells and Synthetic Glucose-Signal Amplifiers for Smart Insulin Delivery (Adv. Mater. 16/2016).

A bio-responsive microneedle-based patch, integrated with a rhodamine-stained glucose-signal amplifier and calcein-AM-stained pancreatic β-cell capsules, is developed by Z. Gu and co-workers. This "smart cell patch", described on page 3115, effectively regulates the blood glucose level of type-1 diabetic mice, achieving a reduction for over 10 h.

Microneedles Integrated with Pancreatic Cells and Synthetic Glucose-Signal Amplifiers for Smart Insulin Delivery.

An innovative microneedle (MN)-based cell therapy is developed for glucose-responsive regulation of the insulin secretion from exogenous pancreatic β-cells without implantation. One MN patch can quickly reduce the blood-sugar levels (BGLs) of chemically induced type-1 diabetic mice and stabilize BGLs at a reduced level for over 10 h.

Concentration-dependent behaviors of bone marrow derived mesenchymal stem cells and infectious bacteria toward magnesium oxide nanoparticles.

Unlabelled: This article reports the quantitative relationship between the concentration of magnesium oxide (MgO) nanoparticles and its distinct biological activities towards mammalian cells and infectious bacteria for the first time. The effects of MgO nanoparticles on the viability of bone marrow derived mesenchymal stem cells (BMSCs) and infectious bacteria (both gram-negative Escherichia coli and gram-positive Staphylococcus epidermidis) showed a concentration-dependent behavior in vitro. The critical concentrations of MgO nanoparticles identified in this study provided valuable guidelines for biomaterial design toward potential clinical translation.

Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics.

Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells.

Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML.

Phosphoinositide signaling regulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5)P3 and PtdIns(3,4)P2, leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5)P3 3-phosphatase (PTEN), PtdIns(3,4,5)P3 5-phosphatases (eg, SHIP), and PtdIns(3,4)P2 4-phosphatases (eg, INPP4B).

An updated systematic review of the role of host genetics in susceptibility to influenza.

The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted in June 2011 to summarise the evidence on the role of host genetics in susceptibility to influenza, and this report updates that previously published review. Animal studies suggest that genetic control of susceptibility to severe influenza in mice is complex and not controlled by a single locus, but there is encouraging evidence that some of the host genetic determinants of susceptibility to severe disease may be common across influenza subtypes.

Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription.

Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). A screen for compounds that downregulate Mcl-1 identified the kinase inhibitor, PIK-75, which demonstrates marked proapoptotic activity against a panel of cytogenetically diverse primary human AML patient samples.

The role of host genetics in susceptibility to influenza: a systematic review.

Background: The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted to summarize the current state of evidence on the role of host genetics in susceptibility to influenza (PROSPERO registration number: CRD42011001380).

Methods And Findings: PubMed, Web of Science, the Cochrane Library, and OpenSIGLE were searched using a pre-defined strategy for all entries up to the date of the search.