Liposomal Formulation of Hydroxychloroquine Can Inhibit Autophagy In Vivo.

Preclinical studies have shown that the anti-malarial drug hydroxychloroquine (HCQ) improves the anti-cancer effects of various therapeutic agents by impairing autophagy. These findings are difficult to translate in vivo as reaching an effective HCQ concentration at the tumor site for extended times is challenging. Previously, we found that free HCQ in combination with gefitinib (Iressa, ZD1839) significantly reduced tumor volume in immunocompromised mice bearing gefitinib-resistant JIMT-1 breast cancer xenografts.

The bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice.

Bile acids are liver-derived signaling molecules that can be found in the brain, but their role there remains largely unknown. We found increased brain chenodeoxycholic acid (CDCA) in mice with absent 12α-hydroxylase (Cyp8b1), a bile acid synthesis enzyme. In these Cyp8b1, and in Wt mice administered CDCA, stroke infarct area was reduced.

ETx-22, a Novel Nectin-4-Directed Antibody-Drug Conjugate, Demonstrates Safety and Potent Antitumor Activity in Low-Nectin-4-Expressing Tumors.

ETx-22, a novel ADC combining a tumor nectin-4-specific antibody and an innovative linker to exatecan, demonstrates significant and durable responses in low-target-expressing tumor models that are resistant to MMAE-based EV and has a better toxicity profile. This new ADC has the potential to benefit additional patient populations beyond its current indication.

Synergistic Dual Antibacterial Activity of Magnetite Hydrogels Doped with Silver.

In this work, we utilized poly--isopropylacrylamide (NIPAM), magnetic nanoparticles (MNPs), and silver nitrate to prepare magnetic hydrogel microparticles doped with silver, which exhibited a dual antimicrobial effect. The antibacterial effect of these composites was mediated by the antimicrobial activity of silver and the magnetic hyperthermic induction, which we believe increased biofilm disruption and silver release into the surrounding bacterial biofilms. The prepared particles were characterized by using several analytical techniques.

Nanoparticle Retinoic Acid-Inducible Gene I Agonist for Cancer Immunotherapy.

Pharmacological activation of the retinoic acid-inducible gene I (RIG-I) pathway holds promise for increasing tumor immunogenicity and improving the response to immune checkpoint inhibitors (ICIs). However, the potency and clinical efficacy of 5'-triphosphate RNA (3pRNA) agonists of RIG-I are hindered by multiple pharmacological barriers, including poor pharmacokinetics, nuclease degradation, and inefficient delivery to the cytosol where RIG-I is localized. Here, we address these challenges through the design and evaluation of ionizable lipid nanoparticles (LNPs) for the delivery of 3p-modified stem-loop RNAs (SLRs).

Multiparametric Single-Vesicle Flow Cytometry Resolves Extracellular Vesicle Heterogeneity and Reveals Selective Regulation of Biogenesis and Cargo Distribution.

Mammalian cells release a heterogeneous array of extracellular vesicles (EVs) that contribute to intercellular communication by means of the cargo that they carry. To resolve EV heterogeneity and determine if cargo is partitioned into select EV populations, we developed a method named "EV Fingerprinting" that discerns distinct vesicle populations using dimensional reduction of multiparametric data collected by quantitative single-EV flow cytometry. EV populations were found to be discernible by a combination of membrane order and EV size, both of which were obtained through multiparametric analysis of fluorescent features from the lipophilic dye Di-8-ANEPPS incorporated into the lipid bilayer.

Modeling the Thermodynamic Properties of Saturated Lactones in Nonideal Mixtures with the SAFT-γ Mie Approach.

The prediction of the thermodynamic properties of lactones is an important challenge in the flavor, fragrance, and pharmaceutical industries. Here, we develop a predictive model of the phase behavior of binary mixtures of lactones with hydrocarbons, alcohols, ketones, esters, aromatic compounds, water, and carbon dioxide. We extend the group-parameter matrix of the statistical associating fluid theory SAFT-γ Mie group-contribution method by defining a new cyclic ester group, denoted cCOO.

Limb shaking transient ischemic attack secondary to innominate artery stenosis.

Limb shaking transient ischemic attack is a rare disease manifestation typically caused by carotid stenosis but rarely caused by flow-limiting lesions involving more proximal vasculature. We demonstrate a case of limb shaking transient ischemic attack secondary to innominate stenosis in a 69-year-old woman who presented after a left leg shaking spell that caused her to fall and fracture her ipsilateral tibia. She did not experience changes in mentation and did not show any evidence of a postictal period.

Electrospun Metal-Organic Framework-Fabric Nanocomposites as Efficient Bactericides.

In this work, we utilized electrospinning to develop advanced composite membranes of polyvinyl chloride (PVC) loaded with postmetalated metal-organic frameworks (MOFs), specifically UiO-66(COOH)-Ag and ZIF-8-Ag. This innovative technique led to the creation of highly stable PVC/MOFs-Ag membrane composites, which were thoroughly characterized using various analytical techniques, including scanning electron microscopy, powder X-ray diffraction, thermogravimetric analysis, X-ray photoelectron spectroscopy, porosity analysis, and water contact angle measurement. The results verified the successful integration of MOF crystals within the nanofibrous PVC membranes.

STING-activating nanoparticles normalize the vascular-immune interface to potentiate cancer immunotherapy.

The tumor-associated vasculature imposes major structural and biochemical barriers to the infiltration of effector T cells and effective tumor control. Correlations between stimulator of interferon genes (STING) pathway activation and spontaneous T cell infiltration in human cancers led us to evaluate the effect of STING-activating nanoparticles (STANs), which are a polymersome-based platform for the delivery of a cyclic dinucleotide STING agonist, on the tumor vasculature and attendant effects on T cell infiltration and antitumor function. In multiple mouse tumor models, intravenous administration of STANs promoted vascular normalization, evidenced by improved vascular integrity, reduced tumor hypoxia, and increased endothelial cell expression of T cell adhesion molecules.

Nanoparticle STING Agonist Reprograms the Bone Marrow to an Antitumor Phenotype and Protects Against Bone Destruction.

Unlabelled: When breast cancer metastasizes to bone, treatment options are limited. Failure to treat bone metastases is thought to be due to therapy-resistant features of the bone marrow microenvironment. Using a murine model of bone metastatic mammary carcinoma, we demonstrate that systemic delivery of polymer nanoparticles loaded with cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) inhibited tumor growth and bone destruction after 7 days of treatment.

The German Cardiosurgery Atrial Fibrillation Registry: 1-Year Follow-up Outcomes.

Objectives: This study of German Cardiosurgery Atrial Fibrillation (CASE-AF) registry aims to describe the 1-year outcomes of patients undergoing ablative procedures for atrial fibrillation (AF) in a cardiosurgical setting.

Methods: Between January 2017 and April 2020, 17 German cardiosurgical units enrolled 1,000 consecutive patients undergoing concomitant or stand-alone ablation for AF. In-hospital and 1-year follow-up data were collected on web-based electronic case report forms.

The GermAn Laser Lead Extraction RegistrY: GALLERY.

Aims: The GermAn Laser Lead Extraction RegistrY: GALLERY is a retrospective, national multicentre registry, investigating the safety and efficacy of laser lead extraction procedures in Germany.

Methods And Results: Twenty-four German centres that are performing laser lead extraction have participated in the registry. All patients, treated with a laser lead extraction procedure between January 2013 and March 2017, were consecutively enrolled.

Association Between High-Density Lipoprotein Cholesterol Levels and Adverse Cardiovascular Outcomes in High-risk Populations.

Importance: Previous studies have shown lower cardiovascular risk with higher high-density lipoprotein cholesterol (HDL-C) levels. However, recent data in the general population have shown increased risk of adverse outcomes at very high HDL-C concentrations.

Objective: To study the association between very high HDL-C levels (>80 mg/dL) and mortality in patients with coronary artery disease (CAD) and to investigate the association of known HDL-C genotypes with high HDL-C level outcomes.

Usefulness of Restless Legs Symptoms to Predict Adverse Cardiovascular Outcomes in Men With Coronary Artery Disease.

The relationship between restless legs syndrome (RLS) and cardiovascular disease remains enigmatic in the general population, and its prognostic value in patients with coronary artery disease (CAD) is unknown. In this study, the frequency of RLS-like symptoms was assessed using a validated instrument in 3,266 patients undergoing cardiac catheterization (mean age 64 years, 62% male, 23% Black, and 74% with obstructive CAD). Patients were followed for primary end points of cardiovascular death or incident myocardial infarction.

The German CArdioSurgEry Atrial Fibrillation Registry: In-Hospital Outcomes.

Background: The aim of this study was to describe outcomes of patients undergoing surgical ablation for atrial fibrillation (AF) as either stand-alone or concomitant cardiosurgical procedures in Germany.

Methods: Patients with AF undergoing concomitant or stand-alone surgical ablation were included in the registry. Cardiac surgery centers across Germany were invited to participate and sought to enroll 1,000 consecutive patients.

Educational benefits of the online journal club: A systematic review.

Introduction: Online journal clubs (JCs) have increased during the COVID-19 pandemic with the resulting social distancing and popularity of online platforms. This systematic review aims to explore current evidence of their use/benefits for clinicians and compare their value to face-to-face (F2F) JCs.

Methods: PubMed, Web of Science, and Scopus were searched systematically, adhering to PRISMA guidelines.

Predictors of Mortality in Primary Surgical Repair of Postinfarction Ventricular Septal Defects: The Leipzig Experience.

Background: A postinfarction ventricular septal defect (pVSD) as a complication of acute myocardial infarction (AMI) is associated with high mortality. This retrospective, single-center study aimed to identify predictors of early and long-term outcomes in patients undergoing primary surgical repair of pVSD managed by various surgical techniques.

Methods: We reviewed data from 77 consecutive patients who underwent primary surgical repair after pVSD in our institution.

Repurposing Ivermectin for COVID-19: Molecular Aspects and Therapeutic Possibilities.

As of January 2021, SARS-CoV-2 has killed over 2 million individuals across the world. As such, there is an urgent need for vaccines and therapeutics to reduce the burden of COVID-19. Several vaccines, including mRNA, vector-based vaccines, and inactivated vaccines, have been approved for emergency use in various countries.

Colo-colic intussusception secondary to colon lipoma: A case report.

Introduction And Importance: Intestinal intussusception is rare in adults and it is associated with lead points affecting the colon in around 17% of patients. Lipomas are very rare benign tumors which may act as lead points for intestinal intussusception. Indeed, the incidence of intestinal intussusception is much rare when caused by lipomas.

Neurological and Neuropsychological Changes Associated with SARS-CoV-2 Infection: New Observations, New Mechanisms.

SARS-CoV-2 infects cells through angiotensin-converting enzyme 2 (ACE2), a ubiquitous receptor that interacts with the virus' surface S glycoprotein. Recent reports show that the virus affects the central nervous system (CNS) with symptoms and complications that include dizziness, altered consciousness, encephalitis, and even stroke. These can immerge as indirect immune effects due to increased cytokine production or via direct viral entry into brain tissue.

Amphiphilic Polyelectrolyte Graft Copolymers Enhance the Activity of Cyclic Dinucleotide STING Agonists.

Cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) hold great therapeutic potential, but their activity is hindered by poor drug-like properties that restrict cytosolic bioavailability. Here, this challenge is addressed through the synthesis and evaluation of a novel series of PEGMA-co-DEAEMA-co-BMA copolymers with pH-responsive, membrane-destabilizing activity to enhance intracellular delivery of the CDN, cGAMP. Copolymers are synthesized with PEGMA of two different molecular weights (300 and 950 Da) and over a range of PEG mass fraction and polymer molecular weight, and relationships between copolymer structure, self-assembly, endosomal escape, and cGAMP activity are elucidated.

Nanoparticle delivery improves the pharmacokinetic properties of cyclic dinucleotide STING agonists to open a therapeutic window for intravenous administration.

The stimulator of interferon genes (STING) pathway plays an important role in the immune surveillance of cancer and, accordingly, agonists of STING signaling have recently emerged as promising therapeutics for remodeling of the immunosuppressive tumor microenvironment (TME) and enhancing response rates to immune checkpoint inhibitors. 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) is the endogenous ligand for STING, but is rapidly metabolized and poorly membrane permeable, restricting its use to intratumoral administration. Nanoencapsulation has been shown to allow for systemic administration of cGAMP and other cyclic dinucleotides (CDN), but little is known about how nanocarriers affect important pharmacological properties that impact the efficacy and safety of CDNs.