Anti-CLL1 liposome loaded with miR-497-5p and venetoclax as a novel therapeutic strategy in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a lethal hematologic malignancy. Chemotherapy resistance results in a dismal survival rate of 1-2 years in older adults with AML. Therefore, novel therapies are urgently required.

A Multicenter Phase II Trial of Ruxolitinib for Treatment of Corticosteroid Refractory Sclerotic Chronic Graft-Versus-Host Disease.

Purpose: Sclerotic chronic graft-versus-host disease (cGVHD) represents a highly morbid and refractory form of cGVHD, and novel therapies for sclerotic cGVHD are critically needed. This study aimed to determine the efficacy of ruxolitinib in patients with corticosteroid refractory sclerotic cGVHD.

Patients And Methods: In a single-arm multicenter phase II trial (N = 47), adults with sclerotic cGVHD refractory to corticosteroids and ≥one additional line of systemic therapy for cGVHD received ruxolitinib for ≥six months (ClinicalTrials.

A novel phosphodiesterase inhibitor for the treatment of chronic liver injury and metabolic diseases.

Background And Aims: Chronic liver disease leads to ~2 million deaths annually. Cyclic AMP (cAMP) signaling has long been studied in liver injury, particularly in the regulation of fatty acid (FA) β-oxidation and pro-inflammatory polarization of tissue-resident lymphocytes. Phosphodiesterase 4B inhibition has been explored as a therapeutic modality, but these drugs have had limited success and are known to cause significant adverse effects.

Therapeutic perspectives on PDE4B inhibition in adipose tissue dysfunction and chronic liver injury.

Introduction: Chronic liver disease (CLD) is a complex disease associated with profound dysfunction. Despite an incredible burden, the first and only pharmacotherapy for metabolic-associated steatohepatitis was only approved in March of this year, indicating a gap in the translation of preclinical studies. There is a body of preclinical work on the application of phosphodiesterase 4 inhibitors in CLD, none of these molecules have been successfully translated into clinical use.

Gemcitabine-Lipid Conjugate and ONC201 Combination Therapy Effectively Treats Orthotopic Pancreatic Tumor-Bearing Mice.

Gemcitabine (GEM) is a nucleoside analogue approved as a first line of therapy for pancreatic ductal adenocarcinoma (PDAC). However, rapid metabolism by plasma cytidine deaminase leading to the short half-life, intricate intracellular metabolism, ineffective cell uptake, and swift development of chemoresistance downgrades the clinical efficacy of GEM. ONC201 is a small molecule that inhibits the Akt and ERK pathways and upregulates the TNF-related apoptosis-inducing ligand (TRAIL), which leads to the reversal of both intrinsic and acquired GEM resistance in PDAC treatment.

Gemcitabine elaidate and ONC201 combination therapy for inhibiting pancreatic cancer in a KRAS mutated syngeneic mouse model.

Approximately 90% of pancreatic cancer (PC) contain KRAS mutations. Mutated KRAS activates the downstream oncogenic PI3K/AKT and MEK signaling pathways and induces drug resistance. However, targeting both pathways with different drugs can also lead to excessive toxicity.

Recent advances in drug delivery and targeting for the treatment of pancreatic cancer.

Despite significant treatment efforts, pancreatic ductal adenocarcinoma (PDAC), the deadliest solid tumor, is still incurable in the preclinical stages due to multifacet stroma, dense desmoplasia, and immune regression. Additionally, tumor heterogeneity and metabolic changes are linked to low grade clinical translational outcomes, which has prompted the investigation of the mechanisms underlying chemoresistance and the creation of effective treatment approaches by selectively targeting genetic pathways. Since targeting upstream molecules in first-line oncogenic signaling pathways typically has little clinical impact, downstream signaling pathways have instead been targeted in both preclinical and clinical studies.

Natural killer cells for pancreatic cancer immunotherapy: Role of nanoparticles.

Advanced pancreatic cancer patients have a dismal prognosis despite advances in integrative therapy. The field of tumor immunology has witnessed significant advancements for cancer treatment. However, immunotherapy for pancreatic cancer is not very effective due to its highly complex tumor microenvironment (TME).

Anti-miR-96 and Hh pathway inhibitor MDB5 synergistically ameliorate alcohol-associated liver injury in mice.

Alcohol-associated liver disease (ALD) and its complications are significant health problems worldwide. Several pathways in ALD are influenced by alcohol that drives inflammation, fatty acid metabolism, and fibrosis. Although miR-96 has become a key regulator in several liver diseases, its function in ALD remains unclear.

Targeting BRD4 and PI3K signaling pathways for the treatment of medulloblastoma.

Medulloblastoma (MB) is a malignant pediatric brain tumor which shows upregulation of MYC and sonic hedgehog (SHH) signaling. SHH inhibitors face acquired resistance, which is a major cause of relapse. Further, direct MYC oncogene inhibition is challenging, inhibition of MYC upstream insulin-like growth factor/ phosphatidylinositol-4,5-bisphosphate 3-kinase (IGF/PI3K) is a promising alternative.

Nanoparticle Delivery of Novel PDE4B Inhibitor for the Treatment of Alcoholic Liver Disease.

The incidence of alcoholic liver disease (ALD) is increasing worldwide while no effective treatment has been approved. The progression of ALD has proven to be related to the upregulation of phosphodiesterase 4 (PDE4) expression, and PDE4 inhibitors showed potential to improve ALD. However, the application of PDE4 inhibitors is limited by the gastrointestinal side effects due to PDE4D inhibition.

Recent advances in drug delivery and targeting to the brain.

Our body keeps separating the toxic chemicals in the blood from the brain. A significant number of drugs do not enter the central nervous system (CNS) due to the blood-brain barrier (BBB). Certain diseases, such as tumor growth and stroke, are known to increase the permeability of the BBB.

pH-sensitive nanomedicine of novel tubulin polymerization inhibitor for lung metastatic melanoma.

Microtubule binding agents such as paclitaxel and vincristine have activity in metastatic melanoma. However, even responsive tumors develop resistance, highlighting the need to investigate new drug molecules. Here, we showed that a new compound, CH-2-102, developed by our group, has high anti-tumor efficacy in human and murine melanoma cells.

Integrating geriatric assessment and genetic profiling to personalize therapy selection in older adults with acute myeloid leukemia.

Introduction: Survival benefit associated with intensive over low-intensity chemotherapy in older adults with acute myeloid leukemia (AML) is controversial. Geriatric assessment and genetic risk categories correlate with survival following intensive chemotherapy in older adults with AML and can guide treatment selection.

Materials And Methods: In a single-center trial, we integrated both geriatric assessment, and genetic risk categories to personalize selection of intensive versus low-intensity chemotherapy in older adults ≥60 years with AML (NCT03226418).

Effect of magnesium stearate surface coating method on the aerosol performance and permeability of micronized fluticasone propionate.

In this study, we evaluated the aerodynamic performance, dissolution, and permeation behavior of micronized fluticasone propionate (FP) and magnesium stearate (MgSt) binary mixtures. Micronized FP was dry mixed with 2% w/w MgSt using a tumble mixer and a resonant acoustic mixer (RAM) with and without heating. The mixing efficacy was determined by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analysis.

Polymeric nanomedicine for overcoming resistance mechanisms in hedgehog and Myc-amplified medulloblastoma.

Chemoresistance and inadequate therapeutics transport across the blood brain barrier (BBB) remain the major barriers to treating medulloblastoma (MB). Hedgehog (Hh) and IGF/PI3K pathways regulate tumor cell proliferation and resistance in MB. Current Hh inhibitors are effective initially to treat SHH-MB but acquire resistance.

Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis.

Type 2 diabetes mellitus (T2DM) associated non-alcoholic fatty liver disease (NAFLD) is the fourth-leading cause of death. Hyperglycemia induces various complications, including nephropathy, cirrhosis and eventually hepatocellular carcinoma (HCC). There are several etiological factors leading to liver disease development, which involve insulin resistance and oxidative stress.

2,2-Bis(hydroxymethyl) propionic acid based cyclic carbonate monomers and their (co)polymers as advanced materials for biomedical applications.

Designing grafted biodegradable polymers with tailored multi-functional properties is one of the most researched fields with extensive biomedical applications. Among many biodegradable polymers, polycarbonates have gained much attention due to their ease of synthesis, high drug loading, and excellent biocompatibility profiles. Among various monomers, 2,2-bis(hydroxymethyl) propionic acid (bis-MPA) derived cyclic carbonate monomers have been extensively explored in terms of their synthesis as well as their polymerization.

Lipid based nanocarriers for effective drug delivery and treatment of diabetes associated liver fibrosis.

Non-alcoholic fatty liver disease (NAFLD) is a cluster of several liver diseases like hepatic steatosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver (NAFL), liver fibrosis, and cirrhosis which may eventually progress to liver carcinoma. One of the primary key factors associated with the development and pathogenesis of NAFLD is diabetes mellitus. The present review emphasizes on diabetes-associated development of liver fibrosis and its treatment using different lipid nanoparticles such as stable nucleic acid lipid nanoparticles, liposomes, solid lipid nanoparticles, nanostructured lipid carriers, self-nanoemulsifying drug delivery systems, and conjugates including phospholipid, fatty acid and steroid-based.

Opportunities and challenges of fatty acid conjugated therapeutics.

Instability, poor cellular uptake and unfavorable pharmacokinetics and biodistribution of many therapeutic molecules require modification in their physicochemical properties. The conjugation of these APIs with fatty acids has demonstrated an enhancement in their lipophilicity and stability. The improvement in the formulations that resulted from the conjugation of a drug with a fatty acid includes increased half-life, enhanced cellular uptake and retention, targeted tumor delivery, reduced chemoresistance in cancer, and improved blood-brain-barrier (BBB) penetration.

Activation of dsRNA-Dependent Protein Kinase R by miR-378 Sustains Metabolic Inflammation in Hepatic Insulin Resistance.

MicroRNAs (miRNAs) are noncoding small RNAs that regulate various pathophysiological cellular processes. Here, we report that expression of the miR-378 family was significantly induced by metabolic inflammatory inducers, a high-fructose diet, and inflammatory cytokine tumor necrosis factor-α. Hepatic miRNA profiling revealed that expression of miR-378a was highly upregulated, which, in turn, targeted the 3'-untranslated region of PPARα mRNA, impaired mitochondrial fatty acid β-oxidation, and induced mitochondrial and endoplasmic reticulum stress.

Activation of dsRNA-Dependent Protein Kinase R by MicroRNA-378 Sustains Metabolic Inflammation in Hepatic Insulin Resistance.

MicroRNAs (miRNAs) are noncoding small RNAs that regulate various pathophysiological cellular processes. Here we reported that expression of the miR-378 family was significantly induced by metabolic inflammatory inducers, a high-fructose diet, and inflammatory cytokine TNFα. Hepatic miRNA profiling revealed that expression of miR-378a was highly upregulated which, in turn, targeted the 3'-UTR of PPARα mRNA, impaired mitochondrial fatty acid β-oxidation and induced mitochondrial and ER stress.