Cephalopod-inspired jetting devices for gastrointestinal drug delivery.

Needle-based injections currently enable the administration of a wide range of biomacromolecule therapies across the body, including the gastrointestinal tract, through recent developments in ingestible robotic devices. However, needles generally require training, sharps management and disposal, and pose challenges for autonomous ingestible systems. Here, inspired by the jetting systems of cephalopods, we have developed and evaluated microjet delivery systems that can deliver jets in axial and radial directions into tissue, making them suitable for tubular and globular segments of the gastrointestinal tract.

Plasma Glial Fibrillary Acid Protein and Phosphorated Tau 181 Association with Presynaptic Density-Dependent Tau Pathology at F-SynVesT-1 Brain PET Imaging.

Background Synaptic loss is an important factor in Alzheimer disease (AD); however, blood assays that conveniently and rapidly reflect changes in synaptic density are lacking. Purpose To correlate multiple potential synaptic blood markers with synaptic density measured using F-SynVesT-1, a fluorine 18 (F)-labeled radiotracer, brain PET and to explore the independent associations between these markers and synaptic density. Materials and Methods This prospective study included 50 cognitively unimpaired (mean age, 65.

Variability in Lipid Profiles During Young Adulthood and the Risk of Coronary Artery Calcium Incidence in Midlife: Insights From the CARDIA Study.

Background: Intraindividual variability in lipid profiles is recognized as a potential predictor of cardiovascular events. However, the influence of early adulthood lipid profile variability along with mean lipid levels on future coronary artery calcium (CAC) incidence remains unclear.

Methods: A total of 2395 participants (41.

Orthogonal Hydroxyl Functionalization of cGAMP Confers Metabolic Stability and Enables Antibody Conjugation.

cGAMP is a signaling molecule produced by the cGAS-DNA complex to establish antimicrobial and antitumor immunity through STING. Whereas STING activation holds potential as a new strategy to treat cancer, cGAMP is generally considered unsuitable for in vivo use because of the rapid cleavage of its phosphodiester linkages and the limited cellular uptake under physiological conditions. Consequently, phosphorothioation and fluorination are commonly used to improve the metabolic stability and permeability of cGAMP and its synthetic analogues.

A Phase Ib Study of the DNA-PK Inhibitor Peposertib Combined with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer.

Purpose: Peposertib-an orally administered DNA-dependent protein kinase inhibitor-has shown potent radiosensitization in preclinical models. This dose-escalation study (NCT03770689) aimed to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of peposertib plus capecitabine-based chemoradiotherapy (CRT) and assessed its safety and efficacy in locally advanced rectal cancer.

Patients And Methods: Patients were treated for 5 to 5.

Phase I crossover study of DNA-protein kinase inhibitor peposertib in healthy volunteers: Effect of food and pharmacokinetics of an oral suspension.

Peposertib is an orally administered inhibitor of DNA-dependent protein kinase. We evaluated the effect of food on its pharmacokinetics, and examined the pharmacokinetics of an oral suspension (OS) of disintegrated tablets, in a phase I, open-label, crossover three-period study (NCT04702698). Twelve healthy volunteers were randomized to one of six treatment sequences.

A Phase 1 Study of the DNA-PK Inhibitor Peposertib in Combination With Radiation Therapy With or Without Cisplatin in Patients With Advanced Head and Neck Tumors.

Purpose: DNA-dependent protein kinase (DNA-PK) plays a key role in the repair of DNA double strand breaks via nonhomologous end joining. Inhibition of DNA-PK can enhance the effect of DNA double strand break inducing anticancer therapies. Peposertib (formerly "M3814") is an orally administered, potent, and selective small molecule DNA-PK inhibitor that has demonstrated radiosensitizing and antitumor activity in xenograft models and was well-tolerated in monotherapy.

Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathy.

Background: Hypertension can lead to podocyte damage and subsequent apoptosis, eventually resulting in glomerulosclerosis. Although alleviating podocyte apoptosis has clinical significance for the treatment of hypertensive nephropathy, an effective therapeutic target has not yet been identified. The function of septin4, a proapoptotic protein and an important marker of organ damage, is regulated by post-translational modification.

Urine Complement Factor Ba Is Associated with AKI in Critically Ill Children.

Key Points: Complement activation, specifically factor B, is implicated in AKI pathogenesis in animal models. Urine Ba (an activation fragment of factor B) was significantly higher in critically ill children with stage 3 AKI and sepsis-AKI. If larger studies show similar association between urine Ba and AKI severity, clinical trials of factor B inhibition are warranted.

Numerical investigation for optimization of spark-ignition internal combustion engine knock by Taguchi-Grey method.

This article carried out a numerical investigation of knock, using the Taguchi method and the grey relational analysis method to determine the importance and the contribution rate of multiple parameters on the peak pressure in the cylinder and the knock tendency under heavy load conditions. Four parameters, namely, compression ratio, spark timing, EGR rate, and inlet temperature, were set at four levels. The simulation was designed using a design of experiment method based on Taguchi's L orthogonal array.

Different Metabolic Phenotypes of Obesity and Risk of Coronary Artery Calcium Progression and Incident Cardiovascular Disease Events: The CARDIA Study.

Background: To investigate whether obesity with or without metabolic syndrome is prospectively associated with coronary artery calcium (CAC) progression and incident cardiovascular disease events.

Methods: A total of 1730 participants from the CARDIA study (Coronary Artery Risk Development in Young Adults) were included (age, 40.1±3.

Long-term Effect of Permanent Demyelination on Axonal Survival in Multiple Sclerosis.

Background And Objectives: To investigate the long-term effect of permanent demyelination on axonal attrition by examining an association between intereye asymmetry of the multifocal visual evoked potential (mfVEP) latency delay and subsequent thinning of retinal ganglion cell axons in patients with a long-standing history of unilateral optic neuritis (ON).

Methods: Only patients with a significant degree of chronic demyelination (intereye latency asymmetry >5 ms) were included in this study. The level of optic nerve demyelination was estimated at baseline by the latency delay of mfVEP, while the degree of axonal loss was assessed by thinning of the retinal nerve fiber layer (RNFL) thickness between baseline and follow-up visits.

Natural antibody and complement activation characterize patients with idiopathic nephrotic syndrome.

Focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are common forms of idiopathic nephrotic syndrome. The causes of these diseases are incompletely understood, but the response of patients to immunosuppressive therapies suggests that their pathogenesis is at least in part immune mediated. Preclinical and clinical research indicates that activation of the classical pathway of complement contributes to glomerular injury in FSGS.

Commensal bacteria and fungi differentially regulate tumor responses to radiation therapy.

Studies suggest that the efficacy of cancer chemotherapy and immunotherapy is influenced by intestinal bacteria. However, the influence of the microbiome on radiation therapy is not as well understood, and the microbiome comprises more than bacteria. Here, we find that intestinal fungi regulate antitumor immune responses following radiation in mouse models of breast cancer and melanoma and that fungi and bacteria have opposite influences on these responses.

Interferon-β Is Less Effective Than Other Drugs in Controlling the Rate of Retinal Ganglion Cell Loss in MS.

Objective: To investigate the association between disease-modifying therapies (DMTs) and the rate of progressive retinal ganglion cell (RGC) and nerve fiber loss in MS.

Methods: One hundred five relapsing-remitting patients with MS were followed annually for a median of 4.0 years using optical coherence tomography.

Metformin and Gastrointestinal Cancer Development in Newly Diagnosed Type 2 Diabetes: A Population-Based Study in Korea.

Introduction: Clinical studies have produced conflicting results on the effects of metformin on gastrointestinal cancer development. We aimed to investigate the association between metformin use and stomach, colon, liver, and pancreatic cancer development among patients with newly diagnosed, drug-naïve type 2 diabetes.

Methods: This retrospective study evaluated propensity score-matched patients with newly diagnosed type 2 diabetes from the Korean National Health Insurance Service database.

Determination of Strong-Phase Parameters in D→K_{S,L}^{0}π^{+}π^{-}.

We report the most precise measurements to date of the strong-phase parameters between D^{0} and D[over ¯]^{0} decays to K_{S,L}^{0}π^{+}π^{-} using a sample of 2.93  fb^{-1} of e^{+}e^{-} annihilation data collected at a center-of-mass energy of 3.773 GeV with the BESIII detector at the BEPCII collider.

[Endoscopic features and clinical correlation analysis of 24 patients with Cronkhite-Canada syndrome].

To clarify the endoscopic changes prior to corticosteroid therapy in Cronkhite-Canada syndrome (CCS) patients and to explore the correlation between endoscopic features and clinical characteristics. A total of 24 CCS patients who were hospitalized in Peking Union Medical College Hospital from January 1999 to June 2019 and underwent gastroscopy and colonoscopy before corticosteroid therapy were retrospectively enrolled. The endoscopic images were re-interpreted.

Sorting Nexin 10 Mediates Metabolic Reprogramming of Macrophages in Atherosclerosis Through the Lyn-Dependent TFEB Signaling Pathway.

Rationale: SNX10 (sorting nexin 10) has been reported to play a critical role in regulating macrophage function and lipid metabolism.

Objective: To investigate the precise role of SNX10 in atherosclerotic diseases and the underlying mechanisms.

Methods And Results: SNX10 expression was compared between human healthy vessels and carotid atherosclerotic plaques.

Chronic demyelination exacerbates neuroaxonal loss in patients with MS with unilateral optic neuritis.

Objective: To examine the effect of chronic demyelination in the optic nerve of patients with MS on progressive loss of retinal ganglion cell (RGC) axons.

Methods: Progressive retinal nerve fiber layer (RNFL) loss, as measured by optical coherence tomography, was longitudinally examined in 51 patients with MS with a history of unilateral optic neuritis (ON) and 25 normal controls. Patients were examined annually with a median of 4-year follow-up.

Structural Analysis of Rabies Virus Glycoprotein Reveals pH-Dependent Conformational Changes and Interactions with a Neutralizing Antibody.

Rabies virus (RABV), the etiological agent for the lethal disease of rabies, is a deadly zoonotic pathogen. The RABV glycoprotein (RABV-G) is a key factor mediating virus entry and the major target of neutralizing antibodies. Here, we report the crystal structures of RABV-G solved in the free form at ∼pH-8.

Risk of Recurrent Bleeding Events in Nonvalvular Atrial Fibrillation Treated with Vitamin K Antagonists: A Clinical Practice Research Datalink Study.

 There is little evidence on how the occurrence of a bleed in individuals on vitamin K antagonists (VKAs) impacts the risk of subsequent bleeds, and thromboembolic and ischemic events. Such information would help to inform treatment decisions following bleeds.  To estimate the impact of bleeding events on the risk of subsequent bleeds, venous thromboembolism (VTE), stroke, and myocardial infarction (MI) among patients initiating VKA treatment for new-onset nonvalvular atrial fibrillation (NVAF).