Preclinical Therapeutic Efficacy of RAF/MEK/ERK and IGF1R/AKT/mTOR Inhibition in Neuroblastoma.

Activating mutations in the RAS/MAPK pathway are observed in relapsed neuroblastoma. Preclinical studies indicate that these tumors have an increased sensitivity to inhibitors of the RAS/MAPK pathway, such as MEK inhibitors. MEK inhibitors do not induce durable responses as single agents, indicating a need to identify synergistic combinations of targeted agents to provide therapeutic benefit.

Polar Organic Charge-Transfer Complex of the Asymmetrical Component for Flexible Piezoelectric Energy Harvesting and Self-Powered Wearable Sensors.

Organic piezomaterials have attracted much attention because of their easy processing, lightweight, and mechanic flexibility properties. Developing new smart organic piezomaterials is highly required for new-generation electronic applications. Here, we found a novel organic piezomaterial of organic charge-transfer complex (CTC) consisting of dibenzcarbazole analogue (DBCz) and tetracyanoquinodimethane (TCNQ) in the molecular-level heterojunction stacking mode.

Tuning the Dynamic Properties of Epoxy Vitrimers via Bioinspired Polymer-Nanoparticle Bond Dynamics.

In this work, FeO nanoparticles anchored with dopamine molecules were developed via bioinspired iron-catechol coordination interactions, and the dopamine-modified FeO surface was linked to the matrix through strong interfacial interactions between the nanoparticles and the epoxy vitrimer. Results showed that the typical dynamic parameters of vitrimer could be readily adjusted in the epoxy vitrimer composites. These findings demonstrate that it is efficient to adjust the dynamic properties of vitrimers by introducing the metal-coordination bonds into epoxy vitrimer networks.

Mpox vaccine and infection-driven human immune signatures: an immunological analysis of an observational study.

Background: Monkeypox virus has recently infected more than 88 000 people, raising concerns about our preparedness against this emerging viral pathogen. Licensed and approved for mpox, the JYNNEOS vaccine has fewer side-effects than previous smallpox vaccines and has shown immunogenicity against monkeypox in animal models. This study aims to elucidate human immune responses to JYNNEOS vaccination compared with mpox-induced immunity.

Mpox vaccine and infection-driven human immune signatures.

Background: Mpox (formerly known as monkeypox) outbreaks outside endemic areas peaked in July 2022, infecting > 85,000 people and raising concerns about our preparedness against this emerging viral pathogen. Licensed and approved for mpox, the JYNNEOS vaccine has fewer side effects than previous smallpox vaccines and demonstrated efficacy against mpox infection in humans. Comparing JYNNEOS vaccine- and mpox-induced immunity is imperative to evaluate JYNNEOS' immunogenicity and inform vaccine administration and design.

Polarization-induced nanohelixes of organic cocrystals from asymmetric components with dopant-induced chirality inversion.

Supramolecular chirality is essential for the development of functional materials. In this study, we report the synthesis of twisted nanobelts based on charge-transfer (CT) complexes using self-assembly cocrystallization starting from asymmetric components. An asymmetric donor, DBCz, and a typical acceptor, tetracyanoquinodimethane, were used to construct a chiral crystal architecture.

Bivalent intra-spike binding provides durability against emergent Omicron lineages: Results from a global consortium.

The SARS-CoV-2 Omicron variant of concern (VoC) and its sublineages contain 31-36 mutations in spike and escape neutralization by most therapeutic antibodies. In a pseudovirus neutralization assay, 66 of the nearly 400 candidate therapeutics in the Coronavirus Immunotherapeutic Consortium (CoVIC) panel neutralize Omicron and multiple Omicron sublineages. Among natural immunoglobulin Gs (IgGs), especially those in the receptor-binding domain (RBD)-2 epitope community, nearly all Omicron neutralizers recognize spike bivalently, with both antigen-binding fragments (Fabs) simultaneously engaging adjacent RBDs on the same spike.

Energy Level, Crystal Morphology and Fluorescence Emission Tuning in Cocrystals via Molecular-Level Engineering.

Organic donor-acceptor complexes as new organic semiconductor class have attracted wide attention, due to their potential applications in functional optoelectronics. Herein, we present two new charge transfer cocrystals of di-cyanodiazafluorene -perylene (DCPE) and di-cyanodiazaflfluorene-pyrene (DCPY) through a rational cocrystal-engineering strategy. Although they are both 1 : 1 mixed stacking cocrystals with similar chemical structures, the DCPE cocrystal possesses a non-centrosymmetric space group and narrower band gap compared to DCPY cocrystal, because of the non-covalent bonding variation.

The Combination of Trametinib and Ganitumab is Effective in RAS-Mutated PAX-Fusion Negative Rhabdomyosarcoma Models.

Purpose: PAX-fusion negative rhabdomyosarcoma (FN RMS) is driven by alterations in the RAS/MAP kinase pathway and is partially responsive to MEK inhibition. Overexpression of IGF1R and its ligands is also observed in FN RMS. Preclinical and clinical studies have suggested that IGF1R is itself an important target in FN RMS.

Erratum: KLF10 inhibits cell growth by regulating PTTG1 in multiple myeloma under the regulation of microRNA-106b-5p: Erratum.

[This corrects the article DOI: 10.7150/ijbs.45999.

Two-Dimensional Membranes with Highly Charged Nanochannels for Osmotic Energy Conversion.

Inadequate mass transportation of semipermeable membranes causes poor osmotic energy conversion from salinity-gradient. Here, the lamellar graphene oxide membranes (GOMs) constructed with numerous fusiform-like nanochannels, that are pre-filled with negatively charged polyanion electrolytes, to both enhance the ion permeability and ion selectivity of the membrane for energy harvest from the salinty gradient, were developed. The as-prepared membrane achieved the maximum output power density of ∼4.

Chlorine-Substituted N-Heteroacene Analogues Acting as Organic Semiconductors for Solution-Processed n-type Organic Field-Effect Transistors.

High performance solution processable n-type organic semiconductor is an essential element to realize low-cost, all organic and flexible composite logic circuits. In the design of n-type semiconducting materials, tuning the LUMO level of compounds is a key point. As a strong electron withdrawing unit, the introduction of chlorine atom into the chemical structure can increase the electron affinity of the material and reduce the LUMO energy level.

Helical mesoscopic crystals based on an achiral charge-transfer complex with controllable untwisting/breaking.

The development of synthetic helical structures from achiral molecules and stimulus-responsive shape transformations are vital for biomimetics and mechanical actuators. A stimulus regarded as the force to induce chirality modulation plays a significant role in the helical supramolecular structure design through symmetry breaking. Herein, we synthesized a metastable complex Form 1 crystal composed of pyrene and (4,8-bis(dicyanomethylene)-4,8-dihydrobenzo[1,2-:4,5-']-dithiophen-e) DTTCNQ components with a torsional backbone by C-H⋯N hydrogen bonds a quick cooling method.

Identification and functional study of novel oligonucleotides: CpG Seq 13 and CpG Seq 19.

This study explored new immunoadjuvants with stronger immune activity to enhance therapeutic effects against leukemia. Whole blood and bone marrow of acute myeloid leukemia (AML) patients and healthy volunteers were collected. Isolated mononuclear cells were treated with two newly designed CpG oligodeoxynucleotides, CpG sequence 13 and 19, and known CpG oligodeoxynucleotides and analyzed via flow cytometry.

Hypomorphic mTOR Downregulates CDK6 and Delays Thymic Pre-T LBL Tumorigenesis.

PI3K/AKT/mTOR pathway hyperactivation is frequent in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL). To model inhibition of mTOR, pre-T-cell lymphoblastic leukemia/lymphoma (pre-T LBL) tumor development was monitored in mice with T lymphocyte-specific, constitutively active AKT (Lck-MyrAkt2) that were either crossed to mTOR knockdown (KD) mice or treated with the mTOR inhibitor everolimus. Lck-MyrAkt2;mTOR KD mice lived significantly longer than Lck-MyrAkt2;mTOR wild-type (WT) mice, although both groups ultimately developed thymic pre-T LBL.

KLF10 inhibits cell growth by regulating PTTG1 in multiple myeloma under the regulation of microRNA-106b-5p.

Krüppel-like factor 10 (KLF10) has been identified as an important regulator in carcinogenesis and cancer progression. However, the role of KLF10 in multiply myeloma (MM) development and progression remains unknown. In present study, we found that KLF10 mRNA and protein were down-regulated in MM tissues and cell lines.

Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice.

Background And Aims: Glypican 3 (GPC3) is an oncofetal antigen involved in Wnt-dependent cell proliferation that is highly expressed in hepatocellular carcinoma (HCC). We investigated whether the functions of chimeric antigen receptors (CARs) that target GPC3 are affected by their antibody-binding properties.

Methods: We collected peripheral blood mononuclear cells from healthy donors and patients with HCC and used them to create CAR T cells, based on the humanized YP7 (hYP7) and HN3 antibodies, which have high affinities for the C-lobe and N-lobe of GPC3, respectively.

The Outcome of TGFβ Antagonism in Metastatic Breast Cancer Models Reflects a Complex Balance between Tumor-Suppressive and Proprogression Activities of TGFβ.

Purpose: TGFβs are overexpressed in many advanced cancers and promote cancer progression through mechanisms that include suppression of immunosurveillance. Multiple strategies to antagonize the TGFβ pathway are in early-phase oncology trials. However, TGFβs also have tumor-suppressive activities early in tumorigenesis, and the extent to which these might be retained in advanced disease has not been fully explored.

The role of nonmuscle myosin 2A and 2B in the regulation of mesenchymal cell contact guidance.

Contact guidance refers to the ability of cells to sense the geometrical features of the microenvironment and respond by changing their shape and adopting the appropriate orientation. Inhibition and ablation of nonmuscle myosin 2 (NM2) paralogues have demonstrated their importance for contact guidance. However, the specific roles of the NM2 paralogues have not been systematically studied.

T-Cell Deletion of MyD88 Connects IL17 and IκBζ to RAS Oncogenesis.

Cancer development requires a favorable tissue microenvironment. By deleting in keratinocytes or specific bone marrow subpopulations in oncogenic RAS-mediated skin carcinogenesis, we show that IL17 from infiltrating T cells and IκBζ signaling in keratinocytes are essential to produce a permissive microenvironment and tumor formation. Both normal and RAS-transformed keratinocytes respond to tumor promoters by activating canonical NF-κB and IκBζ signaling, releasing specific cytokines and chemokines that attract Th17 cells through MyD88-dependent signaling in T cells.

Cbl interacts with multiple E2s in vitro and in cells.

Many receptor tyrosine kinases (RTKs, such as EGFR, MET) are negatively regulated by ubiquitination and degradation mediated by Cbl proteins, a family of RING finger (RF) ubiquitin ligases (E3s). Loss of Cbl protein function is associated with malignant transformation driven by increased RTK activity. RF E3s, such as the Cbl proteins, interact with a ubiquitin-conjugating enzyme (E2) to confer specificity to the ubiquitination process and direct the transfer of ubiquitin from the E2 to one or more lysines on the target proteins.

Genome-Wide RNAi Screen Identifies PMPCB as a Therapeutic Vulnerability in EpCAM Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a genetically heterogeneous disease for which a dominant actionable molecular driver has not been identified. Patients with the stem cell-like EpCAMAFP HCC subtype have poor prognosis. Here, we performed a genome-wide RNAi screen to identify genes with a synthetic lethal interaction with EpCAM as a potential therapeutic target for the EpCAMAFP HCC subtype.

INTERNAL LIMITING MEMBRANE PEELING AND AIR TAMPONADE FOR STAGE III AND STAGE IV IDIOPATHIC MACULAR HOLE.

Purpose: To evaluate the effect of internal limiting membrane peeling and air tamponade for idiopathic macular hole, and explore reasons and interventions for persistent holes.

Methods: One hundred and thirty-five eyes with Stage III and IV idiopathic macular hole that underwent 23-gauge vitrectomy, internal limiting membrane peeling, and air tamponade were reviewed. Eyes with persistent holes underwent a second surgery.

MP-3 measurement of retinal sensitivity in macular hole area and its predictive value on visual prognosis.

Purpose: To explore a measuring method for retinal sensitivity in macular hole area by Microperimeter-3 (MP-3) and evaluate its predictive value on visual prognosis.

Methods: This was a case series study including 44 eyes of 44 patients with idiopathic macular hole. Retinal sensitivity inside and 0.

Immunological effects of a low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor priming regimen on a mouse leukemia model.

The low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor (G-CSF) (CAG) priming regimen is an effective treatment for patients with relapsed or refractory acute myeloid leukemia (AML) and advanced myelodysplastic syndrome (MDS). G-CSF influences the bone marrow microenvironment (BMM) by mobilizing regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), as well as by reducing the expression of stromal cell-derived factor-1α (SDF-1α). In the present study, a WEHI-3-grafted BALB/c mouse AML model (AML-M4) was employed to determine how the BMM was altered by different treatment regimens.