ZP4: A novel target for CAR-T cell therapy in triple negative breast cancer.

Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat due to a lack of effective targeted therapies. Chimeric antigen receptor (CAR)-T cells hold promise, but their efficacy in solid tumors is often limited by on-target/off-tumor toxicities. Through comprehensive bioinformatic analysis of public RNA and proteomic data, we identified zona pellucida glycoprotein 4 (ZP4) as a novel target for TNBC.

A checkpoint reversal receptor mediates bipartite activation and enhances CAR T-cell function.

The efficacy of CAR T-cells (CART) in solid tumors is limited by immune inhibition. In our study, we observed that effector cytokines mediated the upregulation of the PD-L1 immune-checkpoint in primary glioblastoma (GBM). To offset the PD-L1 inhibitory signal, we engineered PD-1 checkpoint reversal receptors (CPR) with a CD28 or 41BB co-stimulatory endodomain and co-expressed them with a first-generation or a CD28-containing second-generation HER2-specific CAR (CPR/CART) using bicistronic vectors.

Cardiovascular Complications of Immune Effector Cell Therapies in Pediatric Hematological and Solid Tumors.

Background: Immune effector cell (IEC) therapies, including chimeric antigen receptor (CAR)-modified T-cell therapy, have shown efficacy in pediatric B-cell acute lymphoblastic leukemia (B-ALL) and are being investigated for other malignancies. A common toxicity associated with IEC therapy is cytokine release syndrome (CRS), which can lead to cardiovascular decompensation due to systemic inflammation. Data are limited regarding cardiovascular adverse effects in children.

Molecular dynamics at immune synapse lipid rafts influence the cytolytic behavior of CAR T cells.

Chimeric antigen receptor T cells (CART) targeting CD19 through CD28.ζ signaling induce rapid lysis of leukemic blasts, contrasting with persistent tumor control exhibited by 4-1BB.ζ-CART.

Therapeutic effects of mesenchymal stem cell conditioned media on streptozotocin-induced diabetes in Wistar rats.

Cell-based therapy is a new direction of treatment of diseases such as type 1 diabetes mellitus (T1DM); but unfortunately, its severe side effects include immunogenicity and tumor development. Using Mesenchymal stem cells conditioned medium (MSCs-CM) may be an alternative therapy to avoid stem cell risks, preserving effectiveness and demonstrating noticeably increased levels of cytokines, angiogenic factors, and growth factors that encourage and support regenerative processes. In the current work, we examined the effects of MSCs-CM injected in tail vein and pancreas directly compared with the standard antidiabetic drug, glimepiride in streptozotocin-induced type 1 diabetic rats.

KIRA6 is an Effective and Versatile Mast Cell Inhibitor of IgE-mediated Activation.

Mast cell (MC)-driven allergic diseases are constantly expanding and require the development of novel pharmacological MC stabilizers. Allergen/antigen (Ag)-triggered activation via crosslinking of the high-affinity receptor for IgE (FcεRI) is fundamentally regulated by SRC family kinases, for example, LYN and FYN, exhibiting positive and negative functions. We report that KIRA6, an inhibitor for the endoplasmic reticulum stress sensor IRE1α, suppresses IgE-mediated MC activation by inhibiting both LYN and FYN.

Anti-hepatocellular carcinoma activities of novel hydrazone derivatives downregulation of interleukin-6.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related morbidity worldwide. Sorafenib is a first-line drug for the treatment of HCC, however, it is reported to cause serious adverse effects and may lead to resistance in many patients. In this study, 20 hydrazone derivatives incorporating triazoles, pyrazolone, pyrrole, pyrrolidine, imidazoline, quinazoline, and oxadiazine moieties were designed, synthesized, and characterized.

Early rhombic lip Protogenin stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma.

We identify a population of Protogenin-positive (PRTG) MYC NESTIN stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RL). Oncogenic transformation of early Prtg rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG stem cells grow adjacent to a human-specific interposed vascular plexus in the RL, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma.

Prolonged cytopenias after immune effector cell therapy and lymphodepletion in patients with leukemia, lymphoma and solid tumors.

Background Aims: The success of chimeric antigen receptor (CAR) T-cell therapy in treating B-cell malignancies has led to the evaluation of CAR T-cells targeting a variety of other malignancies. Although the efficacy of CAR T-cells is enhanced when administered post-lymphodepleting chemotherapy, this can trigger bone marrow suppression and sustained cytopenia after CD19.CAR T-cell therapy.

A Comparative Study of "Grafting to" and "Grafting from" Conjugation Methods for the Preparation of Antibody-Temperature-Responsive Polymer Conjugates.

Early diagnosis of infectious diseases is still challenging particularly in a nonlaboratory environment or limited resources areas. Thus, sensitive, inexpensive, and easily handled diagnostic approaches are required. The lateral flow immunoassay (LFIA) is commonly used in the screening of infectious diseases despite its poor sensitivity, especially with low pathogenic loads (early stages of infection).

Protocol for preclinical evaluation of locoregionally delivered CAR T cells in patient-derived xenograft models of brain tumors.

Here, we present a protocol for preclinical evaluation of locoregionally delivered CAR T cells in patient-derived xenograft models of primary, metastatic, and recurrent brain tumors. We provide instructions for isolating peripheral blood mononuclear cells (PBMCs), producing CAR T cells in conjunction with locoregional delivery, and preclinical trial design and analysis involving CAR T cells. Additionally, we describe comprehensive preclinical readouts and guidelines for critical endpoint sample collections.

Identification of a clinically efficacious CAR T cell subset in diffuse large B cell lymphoma by dynamic multidimensional single-cell profiling.

Chimeric antigen receptor (CAR) T cells used for the treatment of B cell malignancies can identify T cell subsets with superior clinical activity. Here, using infusion products of individuals with large B cell lymphoma, we integrated functional profiling using timelapse imaging microscopy in nanowell grids with subcellular profiling and single-cell RNA sequencing to identify a signature of multifunctional CD8 T cells (CD8-fit T cells). CD8-fit T cells are capable of migration and serial killing and harbor balanced mitochondrial and lysosomal volumes.

TurboID-Based IRE1 Interactome Reveals Participants of the Endoplasmic Reticulum-Associated Protein Degradation Machinery in the Human Mast Cell Leukemia Cell Line HMC-1.2.

The unfolded protein response is an intricate system of sensor proteins in the endoplasmic reticulum (ER) that recognizes misfolded proteins and transmits information via transcription factors to either regain proteostasis or, depending on the severity, to induce apoptosis. The main transmembrane sensor is IRE1α, which contains cytoplasmic kinase and RNase domains relevant for its activation and the mRNA splicing of the transcription factor XBP1. Mast cell leukemia (MCL) is a severe form of systemic mastocytosis.

The renoprotective activity of amikacin-gamma-amino butyric acid-chitosan nanoparticles: a comparative study.

The development of nanoparticles (NPs) with active components with upgraded stability, and prolonged release helps in enhanced tissue regeneration. In addition, NPs are feasible strategy to boost antibiotic effectiveness and reduce drug side effects. Our study focuses on the use of amikacin (AMK) and gamma amino butyric acid (GABA) unloaded combinations or loaded on chitosan nanoparticles (CSNPs) for kidney protection.

Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma: a phase 1 trial.

In this prospective, interventional phase 1 study for individuals with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T cells (HER2 CAR T cells) after lymphodepletion with fludarabine (Flu) ± cyclophosphamide (Cy): 1 × 10 T cells per m after Flu (cohort A) or Flu/Cy (cohort B) and 1 × 10 CAR T cells per m after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2 CAR T cells after lymphodepletion. Determination of antitumor responses was the secondary outcome.

Does lateral extra-articular tenodesis affect knee stability in cases with isolated anterior cruciate ligament reconstruction?

Objective: The purpose of this randomised controlled trial was to assess the effect on knee function and stabilising effectiveness of lateral extra-articular tenodesis (LET) in anterior cruciate ligament (ACL) restoration.

Methods: A prospective randomised clinical study that compared the functional outcomes of two groups-one undergoing anatomic single bundle ACL reconstruction (ASB-ACLR) with ilio-tibial band tenodesis (LET) for 20 patients, and the other undergoing ASB-ACLR-was carried out between February 2020 and August 2022.

Results: By combining Lateral Extra-articular Tenodesis (LET) with intra-articular Anterior Cruciate Ligament Reconstruction (ACLR), our study observed a significant reduction in the occurrence of high-grade pivot-shift phenomena.

Design of an apoptotic cell-mimetic wound dressing using phosphoserine-chitosan hydrogels.

Inflammatory M1 macrophages create a hostile environment that impedes wound healing. Phosphoserine (PS) is a naturally occurring immunosuppressive molecule capable of polarizing macrophages from an inflammatory phenotype (M1) to an anti-inflammatory phenotype (M2). In this study, we designed, fabricated, and characterized PS-immobilized chitosan hydrogels as potential wound dressing materials.

Eobania vermiculata whole-body muscle extract-loaded chitosan nanoparticles enhanced skin regeneration and decreased pro-inflammatory cytokines in vivo.

Background: Usually, wounds recover in four to six weeks. Wounds that take longer time than this to heal are referred to as chronic wounds. Impaired healing can be caused by several circumstances like hypoxia, microbial colonization, deficiency of blood flow, reperfusion damage, abnormal cellular reaction and deficiencies in collagen production.

A facile, flexible, and multifunctional thermo-chemotherapy system for customized treatment of drug-resistant breast cancer.

Anticancer drug resistance invariably emerges and poses a significant barrier to curative therapy for various breast cancers. This results in a lack of satisfactory therapeutic medicine for cancer treatment. Herein, a universal vector system for drug-resistance breast cancer was designed to meet the needs of reversed multidrug resistance, thermo-chemotherapy, and long-term drug release behavior.

Targeting GBM with an Oncolytic Picornavirus SVV-001 alone and in combination with fractionated Radiation in a Novel Panel of Orthotopic PDX models.

Background: Animal models representing different molecular subtypes of glioblastoma multiforme (GBM) is desired for developing new therapies. SVV-001 is an oncolytic virus selectively targeting cancer cells. It's capacity of passing through the blood brain barrier makes is an attractive novel approach for GBM.

Cord blood transplantation for nonmalignant disorders: early functional immunity and high survival.

There is no consensus on the best donor for children with nonmalignant disorders and immune deficiencies in the absence of a matched related donor (MRD). We evaluated the 2-year overall survival (OS) after umbilical cord blood transplantation (UCBT) in patients with nonmalignant disorders from 2009 to 2020 enrolled in a prospective clinical trial using either 5/6 or 6/6 UCB as the cell source. Patients receive a fully ablative busulfan, cyclophosphamide, and fludarabine without serotherapy.

Silver nanoparticles induced testicular damage targeting NQO1 and APE1 dysregulation, apoptosis via Bax/Bcl-2 pathway, fibrosis via TGF-β/α-SMA upregulation in rats.

In medicine, silver nanoparticles (AgNPs) are employed often. They do, however, have negative impacts, particularly on the reproductive organs. This research aimed to assess AgNP impact on the testis and the possible intracellular mechanisms to induce testicular deteriorations in rats at various concentrations and different time intervals.