Characterization of the TLR9-Activating Potential of LNA-Modified Antisense Oligonucleotides.

Early characterization of the immunostimulatory potential of therapeutic antisense oligonucleotides (ASOs) is crucial. At present, little is known about the toll-like receptor 9 (TLR9)-mediated immunostimulatory potential of third-generation locked nucleic acid (LNA)-modified ASOs. In this study, we have systematically investigated the TLR9-activating potential of LNA-modified oligonucleotides using different mouse and human cell culture systems.

Human angiotensin-converting enzyme 2-specific antisense oligonucleotides reduce infection with SARS-CoV-2 variants.

Background: The Spike protein mutation severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to decreased protective effect of various vaccines and mAbs, suggesting that blocking SARS-CoV-2 infection by targeting host factors would make the therapy more resilient against virus mutations. Angiotensin-converting enzyme 2 (ACE2) is the host receptor of SARS-CoV-2 and its variants, as well as many other coronaviruses. Downregulation of ACE2 expression in the respiratory tract may prevent viral infection.

Antisense Oligonucleotide Therapy Decreases IL-1β Expression and Prolongs Survival in Mutant Nlrp3 Mice.

Antisense oligonucleotides (ASOs) are a novel therapeutic strategy that targets a specific gene and suppresses its expression. The cryopyrin-associated periodic syndromes (CAPS) are a spectrum of autoinflammatory diseases characterized by systemic and tissue inflammation that is caused by heterozygous gain-of-function mutations in the nucleotide-binding and oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) gene. The aim of this study was to investigate the efficacy of an Nlrp3-specific ASO treatment in CAPS.

Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity.

Background: Although immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses in a significant fraction of patients. This lack of long-term efficacy may be due to a poor pre-existing network linking innate and adaptive immunity. Here, we present an antisense oligonucleotide (ASO)-based strategy that dually targets toll-like receptor 9 (TLR9) and programmed cell death ligand 1 (PD-L1), aiming to overcome resistance to anti-PD-L1 monoclonal therapy.

Protocol for a Randomized Crossover Trial to Evaluate the Effect of Soft Brace and Rigid Orthosis on Performance and Readiness to Return to Sport Six Months Post-ACL-Reconstruction.

A randomized crossover trial was designed to investigate the influence of muscle activation and strength on functional stability/control of the knee joint, to determine whether bilateral imbalances still occur six months after successful anterior cruciate ligament reconstruction (ACLR), and to analyze whether the use of orthotic devices changes the activity onset of these muscles. Furthermore, conclusions on the feedforward and feedback mechanisms are highlighted. Therefore, twenty-eight patients will take part in a modified Back in Action (BIA) test battery at an average of six months after a primary unilateral ACLR, which used an autologous ipsilateral semitendinosus tendon graft.

Reproducibility of the German and Slovakian Versions of the Dietary Habits and Nutrition Beliefs Questionnaire (KomPAN).

Purpose: The aim of this study was to assess the reproducibility and reliability of the KomPAN questionnaire among two groups of university students from Germany and Slovakia.

Methods: A total of 422 individuals (mean age 21.4 years, SD 4.

ANGPTL4 silencing via antisense oligonucleotides reduces plasma triglycerides and glucose in mice without causing lymphadenopathy.

Angiopoietin-like 4 (ANGPTL4) is an important regulator of plasma triglyceride (TG) levels and an attractive pharmacological target for lowering plasma lipids and reducing cardiovascular risk. Here, we aimed to study the efficacy and safety of silencing ANGPTL4 in the livers of mice using hepatocyte-targeting GalNAc-conjugated antisense oligonucleotides (ASOs). Compared with injections with negative control ASO, four injections of two different doses of ANGPTL4 ASO over 2 weeks markedly downregulated ANGPTL4 levels in liver and adipose tissue, which was associated with significantly higher adipose LPL activity and lower plasma TGs in fed and fasted mice, as well as lower plasma glucose levels in fed mice.

CHOP-ASO Ameliorates Glomerular and Tubular Damage on Top of ACE Inhibition in Diabetic Kidney Disease.

Background: Maladaptive endoplasmic reticulum stress signaling in diabetic kidney disease (DKD) is linked to increased glomerular and tubular expression of the cell-death-promoting transcription factor C/EBP homologous protein (CHOP). Here, we determined whether locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) targeting CHOP ameliorate experimental DKD.

Methods: We determined the efficacy of CHOP-ASO in the early and late stages of experimental DKD (in 8- or 16-week-old db/db mice, respectively) alone or with an angiotensin-converting enzyme inhibitor (ACEi), after an in vivo dose-escalation study.

Investigation of the Activity of Antisense Oligonucleotides Targeting Multiple Genes by RNA-Sequencing.

Locked nucleic acid-modified antisense oligonucleotides (ASOs) can achieve strongly different degrees of target knockdown despite having similar biophysical properties and 100% homology with their target. The determinants for this observation remain largely unknown. We used multi-specific ASOs that have 100% sequence complementarity with a common target () and a different number of diverse targets and investigated their effect on gene expression in a cell line by RNA-sequencing.

No correlation between symmetry-based performance measures and patient-related outcome prior to and after total knee arthroplasty.

Purpose: Standardized outcome measures are crucial for the evaluation of different treatment and rehabilitation regimes in patients after total knee arthroplasty (TKA). Performance-based measures are necessary to capture different aspects of physical function. High reliability and agreement of five performance-based measures were hypothesized to differentiate between measurement error and change in test performance.

Using RNA-seq to Assess Off-Target Effects of Antisense Oligonucleotides in Human Cell Lines.

Background: The field of antisense oligonucleotide therapeutics is rapidly growing and in addition to small molecules and therapeutic antibodies, oligonucleotide-based gene expression modifiers have been developed as fully accepted therapeutics. Antisense oligonucleotides are designed to modify gene expression of their specific target genes. However, as their effect relies on Watson-Crick base pairing, they could also bind to other unintended complementary RNAs showing sufficient sequence homology, which in turn could lead to off-target effects.

Diet Quality Compared to the Nutritional Knowledge of Polish, German, and Slovakian University Students-Preliminary Research.

The eating habits of students differ significantly from those recommended by health practitioners. The aim of this study was to find differences related to diet quality and knowledge on nutrition among Polish, German, and Slovakian students as well as to examine which factors differentiate the diet quality of students from these three countries. The study was conducted on a group of 394 university students from Poland, Germany, and Slovakia.

Therapeutic Targeting of Metadherin Suppresses Colorectal and Lung Cancer Progression and Metastasis.

Colorectal and lung cancers account for one-third of all cancer-related deaths worldwide. Previous studies suggested that metadherin (MTDH) is involved in the development of colorectal and lung cancers. However, how MTDH regulates the pathogenesis of these cancers remains largely unknown.

Preventing ATP Degradation by ASO-Mediated Knockdown of CD39 and CD73 Results in A2aR-Independent Rescue of T Cell Proliferation.

The adenosine axis contributes to the suppression of antitumor immune responses. The ectonucleotidase CD39 degrades extracellular adenosine triphosphate (ATP) to adenosine monophosphate (AMP), which is degraded to adenosine by CD73. Adenosine binds to, e.

Patient, physiotherapist and surgeon endorsement of the core domain set for total hip and total knee replacement in Germany: a study protocol for an OMERACT initiative.

Introduction: There is a lack of harmonising measures for clinical trials on total joint replacement (TJR) that would allow for results from TJR studies to be compared or pooled. The Outcome Measures in Rheumatology (OMERACT) TJR core domain set is already endorsed among patients and physicians in the USA and Australia. Physiotherapists use different types of measurements compared to orthopaedic surgeons while both make substantial contributions to research in the field of TJR.

A highly efficient modality to block the degradation of tryptophan for cancer immunotherapy: locked nucleic acid-modified antisense oligonucleotides to inhibit human indoleamine 2,3-dioxygenase 1/tryptophan 2,3-dioxygenase expression.

Tumors can utilize a diverse repertoire of immunosuppressive mechanisms to evade attack by the immune system. Despite promising success with blockade of immune checkpoints like PD-1 the majority of patients does not respond to current immunotherapies. The degradation of tryptophan into immunosuppressive kynurenine is an important immunosuppressive pathway.

Publisher Correction: ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Anti-Niemann Pick C1 Single-Stranded Oligonucleotides with Locked Nucleic Acids Potently Reduce Ebola Virus Infection In Vitro.

Ebola virus is the causative agent of Ebola virus disease, a severe, often fatal illness in humans. So far, there are no US Food and Drug Administration (FDA)-approved therapeutics directed against Ebola virus. Here, we selected the host factor Niemann-Pick C1 (NPC1), which has been shown to be essential for Ebola virus entry into host cytoplasm, as a therapeutic target for suppression by locked nucleic acid-modified antisense oligonucleotides.

Nocturnal asthma is affected by genetic interactions between RORA and NPSR1.

Background: Neuropeptide S Receptor 1 ( NPSR1) and Retinoid Acid Receptor-Related Orphan Receptor Alpha (RORA ) interact biologically, are both known candidate genes for asthma, and are involved in controlling circadian rhythm. Thus, we assessed (1) whether interactions between RORA and NPSR1 specifically affect the nocturnal asthma phenotype and (2) how this may differ from other asthma phenotypes.

Methods: Interaction effects between 24 single-nucleotide polymorphisms (SNPs) in RORA and 35 SNPs in NPSR1 on asthma and nocturnal asthma symptoms were determined in 1432 subjects (763 asthmatics [192 with nocturnal asthma symptoms]; 669 controls) from the Multicenter Asthma Genetic in Childhood/International Study of Asthma and Allergies in Childhood studies.

ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression.

Understanding the intrinsic mediators that render CD8 T cells dysfunctional in the tumor microenvironment is a requirement to develop more effective cancer immunotherapies. Here, we report that C/EBP homologous protein (Chop), a downstream sensor of severe endoplasmic reticulum (ER) stress, is a major negative regulator of the effector function of tumor-reactive CD8 T cells. Chop expression is increased in tumor-infiltrating CD8 T cells, which correlates with poor clinical outcome in ovarian cancer patients.

Antisense oligonucleotide targeting CD39 improves anti-tumor T cell immunity.

Background: Cancer cells are known to develop mechanisms to circumvent effective anti-tumor immunity. The two ectonucleotidases CD39 and CD73 are promising drug targets, as they act in concert to convert extracellular immune-stimulating ATP to adenosine. CD39 is expressed by different immune cell populations as well as cancer cells of different tumor types and supports the tumor in escaping immune recognition and destruction.

Body Composition and Strength Parameters in Elite Judo Athletes 5 Years after Anterior Cruciate Ligament Reconstruction.

The purpose of this study was to investigate if there are still deficits in muscle mass or strength capabilities in elite judo athletes with a history of anterior cruciate ligament reconstruction (ACLR) after their return to the sport. Therefore, bioimpedance analysis, 3D-laser thigh circumference measurement and isokinetic dynamometry in a closed kinetic chain were used. The side-to-side differences were investigated in a group of judo athletes 5 years after ACLR (n=17) and compared with a group of healthy judo athletes (n=27).

Tissue flossing: a new short-term compression therapy for reducing exercise-induced delayed-onset muscle soreness. A randomized, controlled and double-blind pilot crossover trial.

Background: The symptomatic reduction of exercise-induced delayed-onset muscle soreness (DOMS) is of great interest in the fields of Sports Medicine and Physical Therapy. At this time, few therapeutic interventions have proven their effectiveness. One of the most promising interventions is compression therapy.

Development and characterization of DNAzyme candidates demonstrating significant efficiency against human rhinoviruses.

Background: Infections with human rhinoviruses (RVs) are responsible for millions of common cold episodes and the majority of asthma exacerbations, especially in childhood. No drugs specifically targeting RVs are available.

Objective: We sought to identify specific anti-RV molecules based on DNAzyme technology as candidates to a clinical study.