Effective Disease-modifying Treatment Research Articles

Disease-Modifying Symptomatic Treatment (DMST) Potential of Cannabinoids in Patients with Multiple Sclerosis.

With the recent introduction of a number of highly effective disease-modifying treatments (DMTs) and the resulting almost complete prevention of acute relapses in many patients with multiple sclerosis (MS), the interest of MS clinicians has gradually shifted from relapse prevention to counteraction of disease progression and the treatment of residual symptoms. Targeting the cannabinoid system with nabiximols is an approved and effective strategy for the treatment of spasticity secondary to MS. Recently, the concept of spasticity plus syndrome (SPS) was introduced to account for the evidence that spasticity often appears in MS patients in clusters with other symptoms (such as pain, bladder dysfunction, sleep, and mood disorders), where cannabinoids can also be effective due to their broader action on many immune and neuronal functions. Interestingly, outside these symptomatic benefits, extensive pre-clinical and clinical research indicated how the modulation of the cannabinoid system results in significant anti-inflammatory and neuroprotective effects, all potentially relevant for MS disease control. This evidence makes nabiximols a potential disease modifying symptomatic treatment (DMST), a concept introduced in an attempt to overcome the often artificial distinction between DMTs and symptomatic therapies (STs).

Genome-Wide Mendelian Randomization Identifies Ferroptosis-Related Drug Targets for Alzheimer's Disease.

Alzheimer's disease (AD) currently lacks effective disease-modifying treatments. Recent research suggests that ferroptosis could be a potential therapeutic target. Mendelian randomization (MR) is a widely used method for identifying novel therapeutic targets. Employ genetic information to evaluate the causal impact of ferroptosis-related genes on the risk of AD. 564 ferroptosis-related genes were obtained from FerrDb. We derived genetic instrumental variables for these genes using four brain quantitative trait loci (QTL) and two blood QTL datasets. Summary-data-based Mendelian randomization (SMR) and two-sample MR methods were applied to estimate the causal effects of ferroptosis-related genes on AD. Using extern transcriptomic datasets and triple-transgenic mouse model of AD (3xTg-AD) to further validate the gene targets identified by the MR analysis. We identified 17 potential AD risk gene targets from GTEx, 13 from PsychENCODE, and 22 from BrainMeta (SMR p < 0.05 and HEIDI test p > 0.05). Six overlapping ferroptosis-related genes associated with AD were identified, which could serve as potential therapeutic targets (PEX10, CDC25A, EGFR, DLD, LIG3, and TRIB3). Additionally, we further pinpointed risk genes or proteins at the blood tissue and pQTL levels. Notably, EGFR demonstrated significant dysregulation in the extern transcriptomic datasets and 3xTg-AD models. This study provides genetic evidence supporting the potential therapeutic benefits of targeting the six druggable genes for AD treatment, especially for EGFR (validated by transcriptome and 3xTg-AD), which could be useful for prioritizing AD drug development in the field of ferroptosis.

Intranasal administration of a synthetic TLR4 agonist INI-2004 significantly reduces allergy symptoms following therapeutic administration in a murine model of allergic sensitization.

Atopic diseases have been steadily increasing over the past decades and effective disease-modifying treatment options are urgently needed. These studies introduce a novel synthetic Toll-like receptor 4 (TLR4) agonist, INI-2004, with remarkable efficacy as a therapeutic intranasal treatment for seasonal allergic rhinitis. Using a murine airway allergic sensitization model, the impact of INI-2004 on allergic responses was assessed. One or two intranasal doses of INI-2004 significantly reduced airway resistance, eosinophil influx, and Th2 cytokine production - providing strong evidence of allergic desensitization. Further investigations revealed that a liposomal formulation of INI-2004 exhibited better safety and efficacy profiles compared to aqueous formulations. Importantly, the liposomal formulation demonstrated a 1000-fold increase in the maximum tolerated intravenous dose in pigs. Pre-clinical GLP toxicology studies in rats and pigs confirmed the safety of liposomal INI-2004, supporting its selection for human clinical trials. These findings lay the groundwork for the ongoing clinical evaluation of INI-2004 in allergic rhinitis as a stand-alone therapy for individuals poly-sensitized to multiple seasonal allergens. The study underscores the significance of innovative immunotherapy approaches in reshaping the landscape of allergic rhinitis management.

IL-6 Inhibition as a Therapeutic Target in Aged Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) onset at an advanced age is associated with a higher risk of developing progressive forms and a greater accumulation of disability for which there are currently no effective disease-modifying treatments. Immunosenescence is associated with the production of the senescence-associated secretory phenotype (SASP), with IL-6 being one of the most prominent cytokines. IL-6 is a determinant for the development of autoimmunity and neuroinflammation and is involved in the pathogenesis of MS. Herein, we aimed to preclinically test the therapeutic inhibition of IL-6 signaling in experimental autoimmune encephalomyelitis (EAE) as a potential age-specific treatment for elderly MS patients. Young and aged mice were immunized with myelin oligodendrocyte protein (MOG)35-55 and examined daily for neurological signs. Mice were randomized and treated with anti-IL-6 antibody. Inflammatory infiltration was evaluated in the spinal cord and the peripheral immune response was studied. The blockade of IL-6 signaling did not improve the clinical course of EAE in an aging context. However, IL-6 inhibition was associated with an increase in the peripheral immunosuppressive response as follows: a higher frequency of CD4 T cells producing IL-10, and increased frequency of inhibitory immune check points PD-1 and Tim-3 on CD4+ T cells and Lag-3 and Tim-3 on CD8+ T cells. Our results open the window to further studies aimed to adjust the anti-IL-6 treatment conditions to tailor an effective age-specific therapy for elderly MS patients.

Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target

Amyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease and lacks effective disease-modifying treatments. This study utilizes a comprehensive multiomic approach to investigate the early and sex-specific molecular mechanisms underlying ALS. By analyzing the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, alongside four transgenic mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS), we have uncovered significant molecular alterations associated with the disease. Here, we show that males exhibit more pronounced changes in molecular pathways compared to females. Our integrated analysis of transcriptomes, (phospho)proteomes, and miRNAomes also identified distinct ALS subclusters in humans, characterized by variations in immune response, extracellular matrix composition, mitochondrial function, and RNA processing. The molecular signatures of human subclusters were reflected in specific mouse models. Our study highlighted the mitogen-activated protein kinase (MAPK) pathway as an early disease mechanism. We further demonstrate that trametinib, a MAPK inhibitor, has potential therapeutic benefits in vitro and in vivo, particularly in females, suggesting a direction for developing targeted ALS treatments.

Drugs Targeting CD20 in Multiple Sclerosis: Pharmacology, Efficacy, Safety, and Tolerability.

Currently, there are four monoclonal antibodies (mAbs) that target the cluster of differentiation (CD) 20 receptor available to treat multiple sclerosis (MS): rituximab, ocrelizumab, ofatumumab, and ublituximab. B-cell depletion therapy has changed the therapeutic landscape of MS through robust efficacy on clinical manifestations and MRI lesion activity, and the currently available anti-CD20 mAb therapies for use in MS are a cornerstone of highly effective disease-modifying treatment. Ocrelizumab is currently the only therapy with regulatory approval for primary progressive MS. There are currently few data regarding the relative efficacy of these therapies, though several clinical trials are ongoing. Safety concerns applicable to this class of therapeutics relate primarily to immunogenicity and mechanism of action, and include infusion-related or injection-related reactions, development of hypogammaglobulinemia (leading to increased infection and malignancy risk), and decreased vaccine response. Exploration of alternative dose/dosing schedules might be an effective strategy for mitigating these risks. Future development of biosimilar medications might make these therapies more readily available. Although anti-CD20 mAb therapies have led to significant improvements in disease outcomes, CNS-penetrant therapies are still needed to more effectively address the compartmentalized inflammation thought to play an important role in disability progression.

Some Novel Therapies in Parkinson's Disease: A Promising Path Forward or Not Yet? A Systematic Review of the Literature.

In light of the unsuccessful traditional therapies for Parkinson's disease (PD) overmany years, there is an unmet need for the development of novel therapies to alleviate the symptoms of PD retardation or halt the progression of the disease itself. This systematic review aims to critically update some of the most promising novel treatments including gene therapy, cell-based therapies, targeted drug delivery, and neuroprotective agents, focusing on their challenges, limitations and future directions in PD research. Gene therapy in PD is encouraging, with AAV-based approaches targeting neurotrophic factors, dopamine production, and neuronal circuits in animal and clinical trials. A promising approach to targeted drug delivery for PD involves the use of nanotechnology to create drug delivery vehicles that can traverse the blood-brain barrier and deliver medications specifically to the regions of the brain affected by PD. Neuroprotective agents are compounds that have the ability to protect neurons from degeneration and death, and they hold great promise for the evolution of disease-modifying treatments for PD. Magnetic field therapy is a promising non-invasive method that promotes neural plasticity in PD. The establishment of standardized protocols for animal and human studies, safety, ethical considerations, and cost-effectiveness are the major challenges for the future research of novel PD therapies. The development of novel therapies for PD represents a promising path toward to effective personalized disease-modifying treatments for PD.

MicroRNAs are differentially expressed in equine plasma of horses with osteoarthritis and osteochondritis dissecans versus control horses.

Osteoarthritis (OA) is a leading cause of lameness in horses with no effective disease-modifying treatment and challenging early diagnosis. OA is considered a disease of the joint involving the articular cartilage, subchondral bone, synovial membrane, and ligaments. Osteochondritis dissecans (OCD) is a joint disease consisting of focal defects in the osteochondral unit which may progress to OA later in life. MicroRNAs (miRNAs) have been recognized as small non-coding RNAs that regulate a variety of biological processes and have been detected in biological fluids. MiRNAs are currently investigated for their utility as biomarkers and druggable targets for a variety of diseases. The current study hypothesizes that miRNA profiles can be used to actively monitor joint health and differences in miRNA profiles will be found in healthy vs diseased joints and that differences will be detectable in blood plasma of tested horses. Five horses with OA, OCD, and 4 controls (C) had blood plasma and synovial fluid collected. Total RNA, including miRNA was isolated before generating miRNA libraries from the plasma of the horses. Libraries were sequenced at the Schroeder Arthritis Institute (Toronto). Differential expression analysis was done using DESeq2 and validated using ddPCR. KEGG pathway analysis was done using mirPath v.3 (Diana Tools). 57 differentially expressed miRNAs were identified in OA vs C plasma, 45 differentially expressed miRNAs in OC vs C plasma, and 21 differentially expressed miRNAs in OA vs OCD plasma. Notably, miR-140-5p expression was observed to be elevated in OA synovial fluid suggesting that miR-140-5p may serve as a protective marker early on to attenuate OA progression. KEGG pathway analysis of differentially expressed plasma miRNAs showed relationships with glycan degradation, glycosaminoglycan degradation, and hippo signaling pathway. Interestingly, ddPCR was unable to validate the NGS data suggesting that isomiRs may play an integral role in miRNA expression when assessed using NGS technologies.

Hydrogel-Based Strategies for Intervertebral Disc Regeneration: Advances, Challenges and Clinical Prospects.

Millions of people worldwide suffer from low back pain and disability associated with intervertebral disc (IVD) degeneration. IVD degeneration is highly correlated with aging, as the nucleus pulposus (NP) dehydrates and the annulus fibrosus (AF) fissures form, which often results in intervertebral disc herniation or disc space collapse and related clinical symptoms. Currently available options for treating intervertebral disc degeneration are symptoms control with therapy modalities, and/or medication, and/or surgical resection of the IVD with or without spinal fusion. As such, there is an urgent clinical demand for more effective disease-modifying treatments for this ubiquitous disorder, rather than the current paradigms focused only on symptom control. Hydrogels are unique biomaterials that have a variety of distinctive qualities, including (but not limited to) biocompatibility, highly adjustable mechanical characteristics, and most importantly, the capacity to absorb and retain water in a manner like that of native human nucleus pulposus tissue. In recent years, various hydrogels have been investigated in vitro and in vivo for the repair of intervertebral discs, some of which are ready for clinical testing. In this review, we summarize the latest findings and developments in the application of hydrogel technology for the repair and regeneration of intervertebral discs.

Legal Representation of Patients with Dementia in Long Term Care Settings

Introduction: Dementia is a neurodegenerative disease which affects cognitive, physical, and behavioural abilities. To date there is no effective disease-modifying treatment, so the course of disease is progressive [1]. Worsening cognition in advanced stages can impair the person’s mental capacity to make decisions. Consequently, advanced care planning (ACP) is an important aspect in dementia management [2]. Guardianship is an integral part of ACP where the patient legally appoints a trusted person to make best interest decisions for them should they lose capacity. As a result, this study aims to assess the legal representation of patients suffering from dementia. Method: Patients residing in all the nine dementia wards at Saint Vincent De Paul Residence (SVPR), were recruited (203 patients). A diagnosis of dementia is a requirement for admission to these wards. A data collection sheet was designed and included data on the patient’s demographics, MMSE scores and guardianship statuses. Data was collected retrospectively from the patient’s medical records and their caring medical team where documentation was lacking. The data collection period included September to October 2022. Results: Only 7 patients had a guardianship present (3%). The patients’ children (57.1%) were more likely to apply for guardianship, followed by the patients’ spouses (28.6%). The guardianship status was clearly documented in the doctors’ notes and next of kin (NOK) paper, together with the name and contact details of the guardians. 196 patients (97%) did not have guardianship. 5 of these had a power of attorney (POA) but the type was not specified. 190 patients had a relative or friend listed as the next of kin (NOK) and a patient had no legal guardian or NOK. Conclusion: Most patients with Dementia did not have formal legal representation like guardianship or valid POAs. However, the majority of NOK documented were in line with the legal definition of the responsible carer according to the MHA

A novel class of oral, non-immunosuppressive, beta cell-targeting, TXNIP-inhibiting T1D drugs is emerging.

Diabetes treatment options have improved dramatically over the last 100 years, however, close to 2 million individuals in the U.S. alone live with type 1 diabetes (T1D) and are still dependent on multiple daily insulin injections and/or continuous insulin infusion with a pump to stay alive and no oral medications are available. After decades of focusing on immunosuppressive/immunomodulatory approaches for T1D, it has now become apparent that at least after disease onset, this by itself may not be sufficient, and in order to be effective, therapies need to also address beta cell health. This Perspective article discusses the emergence of such a beta cell-targeting, novel class of oral T1D drugs targeting thioredoxin-interacting protein (TXNIP) and some very recent advances in this field that start to address this unmet medical need. It thereby focuses on repurposing of the antihypertensive drug, verapamil found to non-specifically inhibit TXNIP and on TIX100, a new chemical entity specifically developed as an oral anti-diabetic drug to inhibit TXNIP. Both have shown striking anti-diabetic effects in preclinical studies. Verapamil has also proven to be beneficial in adults and children with recent onset T1D, while TIX100 has just been cleared by the U.S. Food and Drug Administration (FDA) to proceed to clinical trials. Taken together, we propose that such non-immunosuppressive, adjunctive therapies to insulin, alone or in combination with immune modulatory approaches, are critical in order to achieve effective and durable disease-modifying treatments for T1D.

Role of Indian Classical Music in Treating Alzheimer’s Disease and Related Dementias

The prevalence of Alzheimer’s disease (AD) and Alzheimer’s disease related dementias (ADRD) is on rise all around the globe with limited treatment options. Current symptomatic pharmacological treatments are modestly effective and are associated with adverse side effects. Therefore, there is an increased interest in validating non-pharmacological alternatives to treat AD/ADRD. One of such alternatives is music therapy which has recently picked up an upsurge not only in treating mental disorders but also other disparities. Many systematic reviews and meta-analyses using PubMed/Medline, Web of Science, Scopus, Google Scholar, and Cochrane database searches have revealed that music-based interventions successfully improved mood, depression, anxiety, verbal fluency, gait/motor abnormalities, autobiographic and episodic memory, and cognition, in neurological disorders including AD/ADRD and other dementias. In that regard, targeted effects of Indian Classical Music (Raga) are worth deciphering. In contrast to general emotional upliftment induced by other musical genres, Raga has an ability to evoke specific emotions based on its defined notational structure arranged in a specific ascending/descending order, and these effects are further magnified when the Raga is sung/performed at a designated time of the day based on its circadian specificity. Ragas containing the predominance of major notes are known to activate default mode network via induction of dopaminergic pathways and evoke cheerful/ happy emotions, causing mind-wandering and self-referential mental activity. On the other hand, the Raga becomes incrementally sentimental as the proportion of minor notes increase in a Raga structure. Ragas can affect brain activity, emotions, and autonomic functions. This review elucidates enhanced therapeutic potential of Indian Classical Music (Raga) as an advanced music therapy, that has an ability to exert Raga-specific health-effects in a circadian-specific manner. Raga therapy may be an effective disease-modifying treatment for treating AD and other dementias.

Pharmacological Targeting of Senescence with Senolytics as a New Therapeutic Strategy for Neurodegeneration.

Cellular senescence is a state of permanent cell-cycle arrest. Early in life, senescence has a physiologic role in tumor suppression and wound healing. However, gradually, as these senescent cells accumulate over the lifespan of an organism, they contribute to inflammation and the progression of age-related diseases, including neurodegeneration. Targeting senescent cells using a class of drugs known as "senolytics" holds great promise for the management of Alzheimer's and Parkinson's disease. Already, several senolytic compounds have been shown to ameliorate cognitive deficits across several preclinical models of neurodegeneration. Most of these senolytics (e.g., dasatinib) are repurposed clinical or experimental anticancer drugs, which trigger apoptosis of senescent cells by interfering with pro-survival pathways. However, outside of their senolytic function, many first-generation senolytics also have other less appreciated neuroprotective effects, such as potent antioxidant and anti-inflammatory activity. In addition, some senolytic drugs may also have negative dose-limiting toxicities, including thrombocytopenia. In this review, we discuss the various biologic pathways targeted by the leading senolytic drugs, namely dasatinib, quercetin, fisetin, and navitoclax. We further evaluate the clinical transability of these compounds for neurodegeneration, assessing their adverse effects, pharmacokinetic properties, and chemical structure. SIGNIFICANCE STATEMENT: Currently, there are no effective disease-modifying treatments for the most prevalent neurodegenerative disorders, including Alzheimer's and Parkinson's disease. Some of the drugs currently available for treating these diseases are associated with unwanted side-effects and/or become less efficacious with time. Therefore, researchers have begun to explore new innovative treatments for these belligerent diseases, including senolytic drugs. These agents lead to the apoptosis of senescent cells thereby preventing their deleterious role in neurodegeneration.

Baricitinib and β-Cell Function in Patients with New-Onset Type 1 Diabetes

BackgroundJanus kinase (JAK) inhibitors, including baricitinib, block cytokine signaling and are effective disease-modifying treatments for several autoimmune diseases. Whether baricitinib preserves β-cell function in type 1 diabetes is unclear.MethodsIn this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with type 1 diabetes diagnosed during the previous 100 days to receive baricitinib (4 mg once per day) or matched placebo orally for 48 weeks. The primary outcome was the mean C-peptide level, determined from the area under the concentration–time curve, during a 2-hour mixed-meal tolerance test at week 48. Secondary outcomes included the change from baseline in the glycated hemoglobin level, the daily insulin dose, and measures of glycemic control assessed with the use of continuous glucose monitoring.ResultsA total of 91 patients received baricitinib (60 patients) or placebo (31 patients). The median of the mixed-meal–stimulated mean C-peptide level at week 48 was 0.65 nmol per liter per minute (interquartile range, 0.31 to 0.82) in the baricitinib group and 0.43 nmol per liter per minute (interquartile range, 0.13 to 0.63) in the placebo group (P=0.001). The mean daily insulin dose at 48 weeks was 0.41 U per kilogram of body weight per day (95% confidence interval [CI], 0.35 to 0.48) in the baricitinib group and 0.52 U per kilogram per day (95% CI, 0.44 to 0.60) in the placebo group. The levels of glycated hemoglobin were similar in the two trial groups. However, the mean coefficient of variation of the glucose level at 48 weeks, as measured by continuous glucose monitoring, was 29.6% (95% CI, 27.8 to 31.3) in the baricitinib group and 33.8% (95% CI, 31.5 to 36.2) in the placebo group. The frequency and severity of adverse events were similar in the two trial groups, and no serious adverse events were attributed to baricitinib or placebo.ConclusionsIn patients with type 1 diabetes of recent onset, daily treatment with baricitinib over 48 weeks appeared to preserve β-cell function as estimated by the mixed-meal–stimulated mean C-peptide level. (Funded by JDRF International and others; BANDIT Australian New Zealand Clinical Trials Registry number, ACTRN12620000239965.)

Decision making in clinical trials: Interim analyses, innovative design, and biomarkers.

The efficient and accurate execution of clinical trials testing novel treatments for Alzheimer's disease (AD) is a critical component of the field's collective efforts to develop effective disease-modifying treatments for AD. The lengthy and heterogeneous nature of clinical progression in AD contributes to the challenges inherent in demonstrating a clinically meaningful benefit of any potential new AD therapy. The failure of many large and expensive clinical trials to date has prompted a focus on optimizing all aspects of decision making, to not only expedite the development of new treatments, but also maximize the value of the information that each clinical trial yields, so that all future clinical trials (including those that are negative) will contribute toward advancing the field. To address this important topic the Alzheimer's Association Research Roundtable convened December 1-2, 2020. The goals focused around identifying new directions and actionable steps to enhance clinical trial decision making in planned future studies.

The Role of CCL24 in Systemic Sclerosis.

Systemic sclerosis (SSc) is a chronic immune-mediated disease characterized by microangiopathy, immune dysregulation, and progressive fibrosis of the skin and internal organs. Though not fully understood, the pathogenesis of SSc is dominated by microvascular injury, endothelial dysregulation, and immune response that are thought to be associated with fibroblast activation and related fibrogenesis. Among the main clinical subsets, diffuse SSc (dSSc) is a progressive form with rapid and disseminated skin thickening accompanied by internal organ fibrosis and dysfunction. Despite recent advances and multiple randomized clinical trials in early dSSc patients, an effective disease-modifying treatment for progressive skin fibrosis is still missing, and there is a crucial need to identify new targets for therapeutic intervention. Eotaxin-2 (CCL24) is a chemokine secreted by immune cells and epithelial cells, which promotes trafficking of immune cells and activation of pro-fibrotic cells through CCR3 receptor binding. Higher levels of CCL24 and CCR3 were found in the skin and sera of patients with SSc compared with healthy controls; elevated levels of CCL24 and CCR3 were associated with fibrosis and predictive of greater lung function deterioration. Growing evidence supports the potency of a CCL24-blocking antibody as an anti-inflammatory and anti-fibrotic modulating agent in multiple preclinical models that involve liver, skin, and lung inflammation and fibrosis. This review highlights the role of CCL24 in orchestrating immune, vascular, and fibrotic pathways, and the potential of CCL24 inhibition as a novel treatment for SSc.

Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption.

Peripheral B cell depletion via anti-CD20 treatment is a highly effective disease-modifying treatment for reducing new relapses in multiple sclerosis (MS) patients. A drawback of rituximab (RTX) and other anti-CD20 antibodies is a poor immune response to vaccination. While this can be mitigated by treatment interruption of at least six months prior to vaccination, the timing to resume treatment while maintaining subsequent vaccine responses remains undetermined. Here, we characterized SARS-CoV-2 S-directed antibody and B cell responses throughout three BNT162b2 mRNA vaccine doses in RTX-treated MS patients, with the first two doses given during treatment interruption. We examined B-cell mediated immune responses in blood samples from patients with RTX-treated MS throughout three BNT162b2 vaccine doses, compared to an age- and sex-matched healthy control group. The first vaccine dose was given 1.3 years (median) after the last RTX infusion, the second dose one month after the first, and the third dose four weeks after treatment re-initiation. We analyzed SARS-CoV-2 S-directed antibody levels using enzyme-linked immunosorbent assay (ELISA), and the neutralization capacity of patient serum against SARS-CoV-2 S-pseudotyped lentivirus using luciferase reporter assay. In addition, we assessed switched memory (CD19+CD20+CD27+IgD-), unswitched memory (CD19+CD20+CD27+IgD+), naïve (CD19+CD20+CD27-IgD+), and double negative (DN, CD19+CD20+CD27-IgD-) B cell frequencies, as well as their SARS-CoV-2 S-specific (CoV+) and Decay Accelerating Factor-negative (DAF-) subpopulations, using flow cytometry. After two vaccine doses, S-binding antibody levels and neutralization capacity in SARS-CoV-2-naïve MS patients were comparable to vaccinated healthy controls, albeit with greater variation. Higher antibody response levels and CoV+-DN B cell frequencies after the second vaccine dose were predictive of a boost effect after the third dose, even after re-initiation of rituximab treatment. MS patients also exhibited lower frequencies of DAF- memory B cells, a suggested proxy for germinal centre activity, than control individuals. S-binding antibody levels in RTX-treated MS patients after two vaccine doses could help determine which individuals would need to move up their next vaccine booster dose or postpone their next RTX infusion. Our findings also offer first indications on the potential importance of antigenic stimulation of DN B cells and long-term impairment of germinal centre activity in rituximab-treated MS patients.

CXCR2 antagonism attenuates neuroinflammation after subarachnoid hemorrhage

ObjectivesOveractivation of neuroinflammation can worsen the prognosis of subarachnoid hemorrhage (SAH) patients. CXCR2 is a widely expressed G protein-coupled receptor that participates in the regulation of inflammation, indicating a potential role of CXCR2 in SAH. Materials and methodsHerein, we examined the expression pattern of CXCR2 in the ipsilateral brain tissue of SAH mice. Then, we evaluated the effects of CXCR2 antagonist on neuroinflammation and neurological function after SAH. ResultsWestern blotting and immunohistochemistry revealed that CXCR2 expression was upregulated following SAH. Our results demonstrated that treatment with SB225002 inhibited inflammatory cytokine (IL-1β, IL-6, TNF-α, MCP-1) production in the brain and cerebrospinal fluid (CSF) following SAH. Our further findings confirmed that treatment with SB225002 ameliorated astrocytosis and microgliosis after SAH. Interestingly, SB225002 significantly improved neurological impairment after SAH. ConclusionsAltogether, these results suggest that pharmacologically targeting CXCR2 may be an effective disease-modifying treatment for SAH.

Effect of Allergen-Specific Immunotherapy on Transcriptomic Changes in Canine Atopic Dermatitis.

Canine atopic dermatitis (cAD) is a genetic, chronic, and recurrent inflammatory and pruritic skin disorder. Allergen-specific immunotherapy (ASIT) is presently recognized as the only clinically effective disease-modifying treatment for allergies. The aim of our study was to analyze the changes in gene expression observed in the peripheral blood nuclear cells of cAD patients subjected to ASIT. Blood samples designated for transcriptomic analyses were collected from AD dogs twice, before and six months after ASIT, and also from healthy dogs. Statistical analysis revealed 521 differentially expressed transcripts, among which 241 transcripts represented genes with well-described functions. Based on the available literature, we chose nine differentially expressed genes (RARRES2, DPP10, SLPI, PLSCR4, MMP9, NTSR1, CBD103, DEFB122, and IL36G) which may be important in the context of the dysregulated immune response observed in cAD patients. The expressions of five out of the nine described genes (DPP10, PLSCR4, NTSR1, DEFB122, and IL36G) changed after the application of ASIT. The expressions of three of these genes returned to the level observed in the healthy control group. The genes listed above need further investigation to determine details of their role in the molecular mechanism of immune tolerance induction in response to allergen-specific immunotherapy.

Systematic druggable genome-wide Mendelian randomisation identifies therapeutic targets for Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is the leading cause of dementia. Currently, there are no effective disease-modifying treatments for AD. Mendelian randomisation (MR) has been widely used to repurpose licensed drugs and...