Preclinical Data Research Articles

Quantitative systems pharmacology model of α-synuclein pathology in Parkinson's disease-like mouse for investigation of passive immunotherapy mechanisms.

The main pathophysiological hallmark of Parkinson's disease (PD) is the accumulation of aggregated alpha-synuclein (αSyn). Microglial activation is an early event in PD and may play a key role in pathological αSyn aggregation and transmission, as well as in clearance of αSyn and immunotherapy efficacy. Our aim was to investigate how different proposed mechanisms of anti-αSyn immunotherapy may contribute to pathology reduction in various PD-like mouse models. Our mechanistic model of PD pathology in mouse includes αSyn production, aggregation, degradation and distribution in neurons, secretion into interstitial fluid, internalization, and subsequent clearance by neurons and microglia. It describes the influence of neuroinflammation on PD pathogenesis and dopaminergic neurodegeneration. Multiple data from mouse PD models were used for calibration and validation. Simulations of anti-αSyn passive immunotherapy adequately reproduce preclinical data and suggest that (1) immunotherapy is efficient in the reduction of aggregated αSyn in various models of PD-like pathology; (2) prevention of aSyn spread only does not reduce the pathology; (3) a decrease in microglial inflammatory activation and aSyn aggregation may be alternative therapy approaches in PD-like pathology.

The Therapeutic Potential of Glucagon-like Peptide 1 Receptor Agonists in Traumatic Brain Injury.

Traumatic brain injury (TBI), which is a global public health concern, can take various forms, from mild concussions to blast injuries, and each damage type has a particular mechanism of progression. However, TBI is a condition with complex pathophysiology and heterogenous clinical presentation, which makes it difficult to model for in vitro and in vivo studies and obtain relevant results that can easily be translated to the clinical setting. Accordingly, the pharmacological options for TBI management are still scarce. Since a wide spectrum of processes, such as glucose homeostasis, food intake, body temperature regulation, stress response, neuroprotection, and memory, were demonstrated to be modulated after delivering glucagon-like peptide 1 (GLP-1) or GLP-1 receptor agonists into the brain, we aimed to speculate on their potential role in TBI management by comprehensively overviewing the preclinical and clinical body of evidence. Based on promising preclinical data, GLP-1 receptor agonists hold the potential to extend beyond metabolic disorders and address unmet needs in neuroprotection and recovery after TBI, but also other types of central nervous system injuries such as the spinal cord injury or cerebral ischemia. This overview can lay the basis for tailoring new research hypotheses for future in vitro and in vivo models in TBI settings. However, large-scale clinical trials are crucial to confirm their safety and efficacy in these new therapeutic applications.

A Phase 1 Trial of Trebananib, an Angiopoietin 1 and 2 Neutralizing Peptibody, Combined with Pembrolizumab in Patients with Advanced Ovarian and Colorectal Cancer.

Ovarian cancers and microsatellite stable (MSS) colorectal cancers (CRC) are insensitive to anti-PD1 immunotherapy, and new immunotherapeutic approaches are needed. Preclinical data suggests a relationship between immunotherapy resistance and elevated angiopoietin 2 levels. We performed a phase 1 dose-escalation study of pembrolizumab and the angiopoietin 1/2 inhibitor trebananib (NCT03239145). This multicenter trial enrolled patients with metastatic ovarian cancer or MSS CRC. Trebananib was administered intravenously weekly for 12 weeks with 200 mg intravenous pembrolizumab every 3 weeks. The toxicity profile of this combination was manageable, and the protocol-defined highest dose level (trebananib 30 mg/kg weekly plus pembrolizumab 200 mg every 3 weeks) was declared the maximum tolerated dose. The objective response rate for all patients was 7.3% (90% confidence interval: 2.5-15.9%). Three patients with MSS CRC had durable responses for ≥3 years. One responding patient's CRC harbored a POLE mutation. The other two responding patients had left-sided CRCs with no baseline liver metastases, and genomic analysis revealed that they both had KRAS wild-type, ERBB2 amplified tumors. After development of acquired resistance, biopsy of one patient's KRAS wild-type, ERBB2 amplified tumor showed a substantial decline in tumor-associated T cells and an increase in immunosuppressive intratumoral macrophages. Future studies are needed to carefully assess whether clinicogenomic features, such as lack of liver metastases, ERBB2 amplification, and left-sided tumors, can predict increased sensitivity to PD1 immunotherapy combinations.

Immunomodulatory and anti-inflammatory properties of immunoglobulin G antibodies.

Antibodies provide an essential layer of protection from infection and reinfection with microbial pathogens. An impaired ability to produce antibodies results in immunodeficiency and necessitates the constant substitution with pooled serum antibodies from healthy donors. Among the five antibody isotypes in humans and mice, immunoglobulin G (IgG) antibodies are the most potent anti-microbial antibody isotype due to their long half-life, their ability to penetrate almost all tissues and due to their ability to trigger a wide variety of effector functions. Of note, individuals suffering from IgG deficiency frequently produce self-reactive antibodies, suggesting that a normal serum IgG level also may contribute to maintaining self-tolerance. Indeed, the substitution of immunodeficient patients with pooled serum IgG fractions from healthy donors, also referred to as intravenous immunoglobulin G (IVIg) therapy, not only protects the patient from infection but also diminishes autoantibody induced pathology, providing more direct evidence that IgG antibodies play an active role in maintaining tolerance during the steady state and during resolution of inflammation. The aim of this review is to discuss different conceptual models that may explain how serum IgG or IVIg can contribute to maintaining a balanced immune response. We will focus on pathways depending on the IgG fragment crystallizable (Fc) as pre-clinical data in various mouse model systems as well as human clinical data have demonstrated that the IgG Fc-domain recapitulates the ability of intact IVIg with respect to its ability to trigger resolution of inflammation. We will further discuss how the findings already have or are in the process of being translated to novel therapeutic approaches to substitute IVIg in treating autoimmune inflammation.

Clinical and Market Analysis of NanoBEO: A Public-Worth, Innovative Therapy for Behavioral and Psychological Symptoms of Dementia (BPSD)-Emerging Evidence and Its Implications for a Health Technology Assessment (HTA) and Decision-Making in National Health Systems.

According to scientific literature, some 99% of patients affected by Alzheimer's disease (AD) suffer from behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms (NPSs). In particular, agitation is one of the most difficult disorders to treat. States of agitation represent a very serious problem as they make these subjects dangerous for themselves and others and worsen as the disease advances. To date, there are no specific solutions for treating agitation. The only authorized drug is risperidone (as well as brexpiprazole, approved by the FDA on 11 May 2023), which can be used for no longer than 6-12 weeks because it increases the risk of death-owing to cardiocerebrovascular accidents-by 1.6-1.7 times. In order to address the latter noteworthy unmet medical need, NanoBEO was produced. The aim of the present work is to generate the health technology assessment (HTA) of this nanotechnological device. The latter consists of a controlled release system, based on solid lipid nanoparticles loaded with bergamot essential oil (BEO). The results of the present research assessed the current evidence in the field of non-pharmacological treatments for this condition, including relevant primary preclinical and clinical data studies supporting the use of this device and the production of the operative plan for its launch on the market. The findings offer recommendations for decision-making on its implementation in dementia. NanoBEO represents a public-worth innovation in this neglected area, marking a significant advancement in the history of dementia, moving from academic research to product development.

NX210c drug candidate peptide strengthens mouse and human blood-brain barriers

BackgroundAlterations of blood-brain barrier (BBB) and blood-spinal cord barrier have been documented in various animal models of neurodegenerative diseases and in patients. Correlations of these alterations with functional deficits suggest that repairing barriers integrity may represent a disease-modifying approach to prevent neuroinflammation and neurodegeneration induced by the extravasation of blood components into the parenchyma. Here, we screened the effect of a subcommissural organ-spondin-derived peptide (NX210c), known to promote functional recovery in several models of neurological disorders, on BBB integrity in vitro and in vivo.MethodsIn vitro, bEnd.3 endothelial cell (EC) monolayers and two different primary human BBB models containing EC, astrocytes and pericytes, in static and microfluidic conditions, were treated with NX210c (1-100 µM), or its vehicle, for 4 h and up to 5 days. Tight junction (TJ) protein levels, permeability to dextrans and transendothelial electrical resistance (TEER) were evaluated. In vivo, young and old mice (3- and 21-month-old, respectively) were treated daily intraperitoneally with NX210c at 10 mg/kg or its vehicle for 5 days and their brains collected at day 6 to measure TJ protein levels by immunohistochemistry.ResultsNX210c induced an increase in claudin-5 protein expression after 24-h and 72-h treatments in mouse EC. Occludin level was also increased after a 24-h treatment. Accordingly, NX210c decreased by half the permeability of EC to a 40-kDa FITC-dextran and increased TEER. In the human static BBB model, NX210c increased by ∼ 25% the TEER from 3 to 5 days. NX210c also increased TEER in the human 3D dynamic BBB model after 4 h, which was associated with a reduced permeability to a 4-kDa FITC-dextran. In line with in vitro results, after only 5 days of daily treatments in mice, NX210c restored aging-induced reduction of claudin-5 and occludin levels in the hippocampus, and also in the cortex for occludin.ConclusionsIn summary, we have gathered preclinical data showing the capacity of NX210c to strengthen BBB integrity. Through this property, NX210c holds great promises of being a disease-modifying treatment for several neurological disorders with high unmet medical needs.

Decorin, an exercise-induced secretory protein, is associated with improved prognosis in breast cancer patients but does not mediate anti-tumorigenic tissue crosstalk in mice

BackgroundRegular exercise can reduce incidence and progression of breast cancer, but the mechanisms for such effects are not fully understood. MethodsWe used a variety of rodent and human experimental model systems to determine whether exercise training can reduce tumor burden in breast cancer and to identify mechanism associated with any exercise training effects on tumor burden. ResultsWe show that voluntary wheel running slows tumor development in the mammary specific polyomavirus middle T antigen overexpression (MMTV-PyMT) mouse model of breast cancer but only when mice are not housed alone. We identify the proteoglycan decorin as a contraction-induced secretory factor that systemically increases in patients with breast cancer immediately following exercise. Moreover, high expression of decorin in tumors is associated with improved prognosis in patients, while treatment of breast cancer cells in vitro with decorin reduces cell proliferation. Notwithstanding, when we overexpressed decorin in murine muscle or injected recombinant decorin systemically into mouse models of breast cancer, elevated plasma decorin concentrations did not result in higher tumor decorin levels and tumor burden was not improved. ConclusionExercise training is anti-tumorigenic in a mouse model of luminal breast cancer, but the effect is abrogated by social isolation. The proteoglycan decorin is an exercise-induced secretory protein, and tumor decorin levels are positively associated with improved prognosis in patients. The hypothesis that elevated plasma decorin is a mechanism by which exercise training improves breast cancer progression in humans is not, however, supported by our pre-clinical data since elevated circulating decorin did not increase tumor decorin levels in these models.

Marine Bioactives in Cancer Prevention and Treatment

The twice high incidence risk of cancer in men was the reason for over a million new cases and deaths recorded globally in 2018. The two most frequent cancer-related fatalities are lung and breast cancer. Novel therapies have been made possible by developments in immunotherapy, biology, and pharmaceutical design. Novel cancer prevention and therapy elements are being made possible by technological advancements and studies on marine natural resources. The creation of innovative anticancer medications is utilizing marine-derived natural products (MNPs). Biologically active polyketides, high molecular weight organic sugars, terpenes, bioengineered alkaloids, and marine animal peptides are some examples of these MNPs. Anticancer drugs are also developed with the help of plants, animals, invertebrates, and microbes found on land. The National Cancer Institute is exploring the potential of nutrition and food in cancer prevention despite the absence of preclinical and clinical data. Marine organisms contain bioactive compounds that have potential anticancer effects. Polyphenols, polysaccharides, and alkaloids are some of the active components found in marine species. Polyphenols, found in edible seaweeds like Palmaria palmata, can lower cancer cell division and proliferation, while polysaccharides trigger the innate immune system, causing apoptosis in pancreatic islet cancer and human leukemia cells. Alkaloids, derived from marine sources, can inhibit cancer cell development. Peptides, found in various plant species, have shown cytotoxic effects on several human cell lines, including pancreatic, breast, lung, and bladder cancers. Marine drug approval faces challenges like the possibility of a resurgence of different metabolites due to environmental conditions and limited lead compound availability.

The association of azole antifungals with overall survival in patients with non-small cell lung cancer receiving immune checkpoint inhibitors.

Preclinical data suggest antifungal azole derivatives have antitumor efficacy that may modulate response to immune checkpoint inhibitors (ICIs). We aimed to evaluate the association of azole drugs with overall survival (OS) in a population of patients with non-small cell lung cancer (NSCLC) treated with ICI within the Veterans Health Administration (VHA). In this retrospective study, the VA Corporate Data Warehouse was queried for patients diagnosed with NSCLC and treated with ICI from 2010 to 2018. Concomitant oral azole use was defined as dispensation by a VA pharmacy within 90 days of the first ICI infusion. Patients who received azole after 30 days were excluded from the analysis to mitigate immortal time bias. OS was measured from the start of ICI. Cox regression and propensity score matching were used to adjust for confounders. We identified 3413 patients with NSCLC receiving ICI; 324 (9.5%) were exposed to concomitant azoles. As a group, azole use was not associated with OS (hazard ratio [HR] = 0.96; 95% CI, 0.84-1.09; P = .51). After stratification by azole type, clotrimazole had an association with better OS on univariable (HR = 0.75; 95% CI, 0.59-0.96; P = .024) and multivariable analysis (HR = 0.71; 95% CI, 0.56-0.91; P = .007). Propensity score matching of patients who received clotrimazole vs no azole yielded 101 patients per matched cohort. Clotrimazole was associated with improved OS, although this did not meet the threshold for statistical significance (HR = 0.74; 0.54-1.01; P = .058). This observational study demonstrated an association between clotrimazole and OS among patients with advanced NSCLC receiving ICI. These findings build upon preclinical evidence and support further investigation into the potential for clotrimazole as a repurposed FDA drug to improve cancer outcomes.

Lenacapavir: Playing the Long Game in the New Era of Antiretrovirals.

The mainstay of antiretroviral therapy (ART) has been combination oral therapy. While oral ART is highly effective, nonadherence remains a chief concern. Addressing this concern in recent years is the emergence of long-acting antiretrovirals for the treatment and prevention of HIV-1 infection. The most recently approved long-acting antiretroviral is the first-in-class capsid inhibitor lenacapavir (LEN) for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. Due to its biannual subcutaneous dosing scheme to inhibit the HIV-1 capsid, LEN exhibits unique pharmacokinetics and reinforces an evolving era of ART. In this review, we evaluate published and accepted research articles, conference proceedings, and clinical trial records to provide a comprehensive overview of LEN for treatment and preliminary data for the prevention of HIV-1 infection. These data include clinical trials outcomes, in vitro and in vivo resistance profiles, and preclinical data supporting downstream indications. We also discuss the unique clinical pharmacology of LEN with the goal of serving as a resource toward subsequent physiologically based, population-based, and other miscellaneous pharmacometric-focused analyses. Given the dynamic nature of the HIV treatment and prevention research fields, we also discuss ongoing studies related to LEN for treatment-naïve adults and for prevention. Lastly, we discuss important pharmacologic gaps in special populations, drug-drug interactions, and at the sites of action germane to HIV treatment and prevention. The information discussed in this review will provide knowledge and understanding of the unique pharmacologic properties of LEN to assist clinicians and researchers as they navigate the dynamic HIV research landscape.

Diabetes mellitus and female sexual response: what do animal models tell us?

One of the less explored effects of diabetes mellitus (DM) is female sexual dysfunction. Females of different species have been used as models. To analyze the information of animal models of DM and female sexual response (FSR). The literature of FSR in models of DM was reviewed. Paradigm- and diabetes-dependent changes have been found in various aspects of the FSR. Females in a type 1 DM (DM1) model show a decrease in the number of proestrus events, and ovariectomized females treated with sex hormones have been used. In these females, a reduction in lordosis has been reported; in proceptivity, the data are contradictory. These females present a decrease in sexual motivation that was restored after exogenous insulin. In the type 2 DM (DM2) model, females show regular estrous cycles, normal levels of lordosis behavior, and, depending on the paradigm, decreased proceptivity. These females display normal preference for sexually active males or their olfactory cues when having free physical contact; they lose this preference when tested in paradigms where physical interaction is precluded. Preclinical data showing the high deleterious effects of a DM1 model and the less drastic effects under a DM2 model are in accordance with clinical data revealing a much higher prevalence of sexual dysfunction in women with DM1 than DM2. The main strength is the analysis of the changes in various components of FSR in 2 models of DM. The main limitation is the difficulty in extrapolating the data on FSR from rats to women and that most studies focus on evaluating the impact of severe or chronic-moderate hyperglycemia/hyperinsulinemia on the sexual response, without considering other pathophysiologic alterations generated by DM. Females with severe hyperglycemia have a decrease in FSR, while those with moderate hyperglycemia show much less drastic effects.

Metformin Treatment Is Not Associated with Altered PD-L1 Expression in Diabetic Patients with Oral Squamous Cell Carcinoma.

Background: The anti-neoplastic activity of metformin is a subject of current debate. Preclinical data have suggested that metformin enhances PD-L1 anti-tumor effects in various cancer entities by decreasing insulin levels and inducing energetic stress. However, its impact on PD-L1 expression remains unclear in a clinical setting. Therefore, we aim to investigate the impact of metformin treatment in type 2 diabetes mellitus (DM) patients on PD-L1 expression in patients with oral squamous cell carcinoma (OSCC). Methods: We performed a retrospective analysis of patients with DM and OSCC treated at our tertiary referral center over a period of 12 years. The tumor proportion score (TPS), immune cell score (IC), and combined positive score (CPS) were used to quantify PD-L1 expression. PD-L1 expression of patients receiving metformin was compared to a control group without metformin prescription. Results: A total of 68 patients diagnosed with OSCC and DM were analyzed, with 24 receiving and 44 not receiving metformin therapy. No statistically significant differences were identified between the metformin and non-metformin groups for any of the scores (TPS: p = 0.818; IC: p = 0.748; CPS: p = 0.387). Conclusions: In contrast to previous studies, we could not find significant differences in PD-L1 expression between patients with and without metformin intake. Further research needs to shed light on the exact mechanism of metformin in different tumor entities. A comprehensive understanding of metformin's role in cancer therapy could provide valuable insights for potential use of metformin as an adjuvant treatment to immune checkpoint therapy.

Dry Eye Para-Inflammation Management: Preclinical and Clinical Evidence on a Novel 0.2% Hyaluronic Acid-Based Tear Substitute with 0.001% Hydrocortisone Sodium Phosphate.

Purpose: An innovative eyedrop formulation based on a combination of 0.2% hyaluronic acid and 0.001% hydrocortisone sodium phosphate (Idroflog®, Alfa Intes, Italy; HAC eyedrops) was granted a European Patent in 2016 and has been available on the market since 2019 in Europe and in other countries around the world. HAC eyedrops aim to synergize the moisturizing effects of hyaluronic acid with the mild anti-inflammatory properties of low-dose hydrocortisone, offering a more effective and safer alternative for treating dry eye disease (DED), targeting both tear film instability and dysfunctional para-inflammation. The activity of HAC eyedrops has been explored in different post-marketing clinical trials, in addition to preclinical studies. In this narrative review, we explored the available evidence on the use of HAC eyedrops for the management of para-inflammation in DED patients to provide a comprehensive overview of efficacy and safety data related to the use of this medical device in routine clinical practice. Methods: A literature search for preclinical and clinical data involving treatment with HAC eyedrops was conducted using PubMed/MEDLINE, considering only original research articles published in English, without time restrictions. Results: One preclinical and four clinical papers were retrieved. Preclinical evidence suggests that 0.001% hydrocortisone is able to control the expression of inflammatory markers, and this, together with the hydrating and lubricating properties of hyaluronic acid, leads to improvements in DED clinical signs, such as tear volume and the stability of the tear film. The results of clinical trials demonstrate that HAC eyedrops are able to improve the signs and symptoms of DED and that 0.001% low-dosage hydrocortisone can be helpful in preventing the progression to chronic stages of DED. Conclusions: HAC eyedrops represent a promising therapeutic strategy for the management of dysfunctional para-inflammation and offer a valuable addition to the armamentarium of treatments for DED.

Impact of a Pulse-Enriched Human Cuisine on Functional Attributes of the Gut Microbiome Using a Preclinical Model of Dietary-Induced Chronic Diseases.

Introducing grain legumes, i.e., pulses, into any food pattern effectively increases dietary fiber and other bioactive food components of public health concern; however, the impact depends on the amount consumed. Given the convergence of preclinical and clinical data indicating that intake of at least 300 g (1.5 cup) of cooked pulse per day has clinically observable benefit, the feasibility for a typical consumer was demonstrated by creation of a fourteen-day menu plan that met this criterion. This menu plan, named Bean Cuisine, was comprised of a combination of five cooked pulses: dry beans, chickpeas, cowpeas, dry peas, and lentils. As reported herein, the impact of each menu day of the fourteen-day plan on gut microbial composition and predicted function was evaluated in female C57BL/6J mice, a strain commonly used in studies of metabolic dysfunction-associated chronic diseases. We report that pulse-related effects were observed across a wide variety of food item combinations. In comparison to a pulse-free human cuisine, all pulse menu days enriched for a gut ecosystem were associated with changes in predicted metabolic pathways involving amino acids (lysine, tryptophan, cysteine), short-chain fatty acids (butyrate, acetate), and vitamins (B1, B6, B9, B12, K2) albeit via different combinations of microbiota, according to the PICRUSt2 estimates. The predicted metabolic functions correlating with the various pulses in the menus, indicate the value of a food pattern comprised of all pulse types consumed on a regular basis. This type of multi-pulse food pattern has the potential to enhance the taxonomic and functional diversity of the gut microbiome as a means of strengthening the resilience of the gut ecosystem to the challenges associated with the daily activities of living.

Examination of the antiallodynic effect of rosmarinic acid in neuropathic pain and possible mechanisms of action

This study aimed to explore the potential antiallodynic effects of rosmarinic acid, a natural antioxidant with a demonstrated safety profile across a broad dose range. Using a chronic constriction injury-induced neuropathic pain model, the impact of rosmarinic acid on allodynia was investigated. Furthermore, the involvement of adrenergic and opioidergic mechanisms in its activity was assessed. To evaluate rosmarinic acid’s efficacy, doses of 10, 20, and 40 mg/kg were administered and the electronic von Frey test was utilized along with an activity cage apparatus. % MPE values were calculated to gauge the extent of pain relief. Mechanistic insights were obtained by pretreating animals with the β-adrenergic receptor antagonist propranolol, the α1-adrenergic receptor antagonist prazosin, α2-adrenergic receptor antagonist yohimbine, and the opioid receptor antagonist naloxone. Rosmarinic acid demonstrated a statistically significant antiallodynic effect that was independent of locomotor activity. This effect was noteworthy as it resembled both the level and duration of relief provided by pregabalin. Additionally, the %MPE value of the group treated with 40 mg/kg rosmarinic acid showed a significant difference compared to the value of the pregabalin-treated group (P<0.001). Pre-administration of the antagonists revealed that the antiallodynic activity was shown to be mediated by the stimulation of opioid and adrenergic receptors, with a primary contribution from α2-adrenergic receptor stimulation. Our findings suggest that rosmarinic acid may hold promise as a potential therapeutic agent for neuropathic pain. By elucidating the involvement of adrenergic and opioidergic mechanisms, we have provided valuable preclinical data that could inform novel treatment approaches.

Recent advancements in targeting the immune system to treat hypertension

Hypertension is the key leading risk factor for death globally, affecting ∼1.3 billion adults, particularly in low- and middle-income countries. Most people living with hypertension have uncontrolled high blood pressure, increasing their likelihood of cardiovascular events. Significant issues preventing blood pressure control include lack of diagnosis, treatment, and response to existing therapy. For example, monotherapy and combination therapy are often unable to lower blood pressure to target levels. New therapies are urgently required to tackle this issue, particularly those that target the mechanisms behind hypertension instead of treating its symptoms. Acting via an increase in systemic and tissue-specific inflammation, the immune system is a critical contributor to blood pressure regulation and is considered an early mechanism leading to hypertension development. Here, we review the immune system's role in hypertension, evaluate clinical trials that target inflammation, and discuss knowledge gaps in pre-clinical and clinical data. We examine the effects of anti-inflammatory drugs colchicine and methotrexate on hypertension and evaluate the blockade of pro-inflammatory cytokines IL-1β and TNF-α on blood pressure in clinical trials. Lastly, we highlight how we can move forward to target specific components of the immune system to lower blood pressure. This includes targeting isolevuglandins, which accumulate in dendritic cells to promote T cell activation and cytokine production in salt-induced hypertension. We discuss the potential of the dietary fibre-derived metabolites short-chain fatty acids, which have anti-inflammatory and blood pressure-lowering effects via the gut microbiome. This would limit adverse events, leading to improved medication adherence and better blood pressure control.

Doxycycline Plus Bortezomib-Containing Regimens for the Treatment of Light-Chain Amyloidosis in the Frontline Setting: Experience from the Amyloidosis Program of Calgary.

Background: Pre-clinical and retrospective data suggest that doxycycline added to treatment regimens has benefit in AL amyloidosis. However, a recent multicenter, open-label, randomized controlled trial in AL amyloidosis patients treated with CyBorD did not demonstrate a progression-free survival (PFS) or cardiac PFS benefit with added doxycycline. Objective: The main objective of this study was to explore the role of doxycycline combined with bortezomib-containing regimens (BCRs) for newly diagnosed AL amyloidosis patients with cardiac involvement and to compare them with a cohort of concurrent patients treated with BCR only. Material and Methods: AL amyloidosis patients, newly diagnosed between January 2012 and March 2022, who were treated with BCR at the Amyloidosis Program of Calgary (APC) were evaluated. Results: Sixty-four concurrent patients were identified. Thirty-nine patients received doxycycline in addition to BCR (BCR-D) for a median of 8 months. The overall response rate was similar among the groups. No significant differences in VGPR/CR, dFLC at 1 month, time to first response, time to best response, or organ responses were noted between the BCR alone and BCR-D groups. Summary and Conclusions: Our retrospective study demonstrated that doxycycline combined with BCR failed to prolong OS, PFS, or cardiac responses compared with BCR alone in patients with cardiac AL amyloidosis.

Pulmonary Arterial Hypertension and TGF-β Superfamily Signaling: Focus on Sotatercept.

Pulmonary arterial hypertension (PAH) is a rare and progressive disease that continues to remain highly morbid despite multiple advances in medical therapies. There remains a persistent and desperate need to identify novel methods of treating and, ideally, reversing the pathologic vasculopathy that results in PAH development and progression. Sotatercept is a first-in-class fusion protein that is believed to primarily inhibit activin signaling resulting in decreased cell proliferation and differentiation, though the exact mechanism remains uncertain. Here, we review the currently available PAH therapies, data highlighting the importance of transforming growth factor-β (TGF-β) superfamily signaling in the development of PAH, and the published and on-going clinical trials evaluating sotatercept in the treatment of PAH. We will also discuss preclinical data supporting the potential use of the fusion protein KER-012 in the inhibition of aberrant TGF-β superfamily signaling to ameliorate the obstructive vasculopathy of PAH.

Beyond Pallidal or Subthalamic Deep Brain Stimulation to Treat Dystonia.

Deep brain stimulation of the subthalamic nucleus and globus pallidus internus is approved by the Food and Drug Administration for treating dystonia. Both targets have shown effectiveness in improving symptoms, but post-operative outcomes can vary significantly among patients. This variability has led researchers to explore alternative neuromodulation targets that might offer more consistent results. Emerging research has highlighted several promising new targets for DBS in dystonia. This review examines pre-clinical and clinical data on novel DBS targets for dystonia and explores non-invasive neuromodulation studies that shed light on the disease's underlying pathological circuitry.

Differential roles of eosinophils in cardiovascular disease.

Eosinophils are essential innate immune cells in allergic responses. Accumulating evidence indicates that eosinophils also participate in the pathogenesis of cardiovascular diseases (CVDs). In clinical studies, high blood eosinophil counts and eosinophil cationic protein levels have been associated with an increased risk of CVD, including myocardial infarction (MI), cardiac hypertrophy, atrial fibrillation, abdominal aortic aneurysm (AAA) and atherosclerosis. However, low blood eosinophil counts have also been reported to be a risk factor for MI, heart failure, aortic dissection, AAA, deep vein thrombosis, pulmonary embolism and ischaemic stroke. Although these conflicting clinical observations remain unexplained, CVD status, timing of eosinophil data collection, and tissue eosinophil phenotypic and functional heterogeneities might account for these discrepancies. Preclinical studies suggest that eosinophils have protective actions in MI, cardiac hypertrophy, heart failure and AAA. By contrast, cationic proteins and platelet-activating factor from eosinophils have been shown to promote vascular smooth muscle cell proliferation, vascular calcification, thrombomodulin inactivation and platelet activation and aggregation, thereby exacerbating atherosclerosis, atrial fibrillation, thrombosis and associated complications. Therefore, eosinophils seem to promote calcification and thrombosis in chronic CVD but are protective in acute cardiovascular settings. In this Review, we summarize the available clinical and preclinical data on the different roles of eosinophils in CVD.