Outcomes In Preclinical Models Research Articles

IL-1R signaling drives enteric glia-macrophage interactions in colorectal cancer

Enteric glia have been recently recognized as key components of the colonic tumor microenvironment indicating their potential role in colorectal cancer pathogenesis. Although enteric glia modulate immune responses in other intestinal diseases, their interaction with the colorectal cancer immune cell compartment remains unclear. Through a combination of single-cell and bulk RNA-sequencing, both in murine models and patients, here we find that enteric glia acquire an immunomodulatory phenotype by bi-directional communication with tumor-infiltrating monocytes. The latter direct a reactive enteric glial cell phenotypic and functional switch via glial IL-1R signaling. In turn, tumor glia promote monocyte differentiation towards pro-tumorigenic SPP1+ tumor-associated macrophages by IL-6 release. Enteric glia cell abundancy correlates with worse disease outcomes in preclinical models and colorectal cancer patients. Thereby, our study reveals a neuroimmune interaction between enteric glia and tumor-associated macrophages in the colorectal tumor microenvironment, providing insights into colorectal cancer pathogenesis.

Modulation of vagal activity may help reduce neurodevelopmental damage in the offspring of mothers with pre-eclampsia.

Maternal Immune Activation (MIA) has been linked to the pathogenesis of pre-eclampsia and adverse neurodevelopmental outcomes in the offspring, such as cognitive deficits, behavioral abnormalities, and mental disorders. Pre-eclampsia is associated with an activation of the immune system characterized by persistently elevated levels of proinflammatory cytokines, as well as a decrease in immunoregulatory factors. The Cholinergic Anti-inflammatory Pathway (CAP) may play a relevant role in regulating the maternal inflammatory response during pre-eclampsia and protecting the developing fetus from inflammation-induced damage. Dysregulation in the CAP has been associated with the clinical evolution of pre-eclampsia. Some studies suggest that therapeutic stimulation of this pathway may improve maternal and fetal outcomes in preclinical models of pre-eclampsia. Modulation of vagal activity influences the CAP, improving maternal hemodynamics, limiting the inflammatory response, and promoting the growth of new neurons, which enhances synaptic plasticity and improves fetal neurodevelopment. Therefore, we postulate that modulation of vagal activity may improve maternal and fetal outcomes in pre-eclampsia by targeting underlying immune dysregulation and promoting better fetal neurodevelopment. In this perspective, we explore the clinical and experimental evidence of electrical, pharmacological, physical, and biological stimulation mechanisms capable of inducing therapeutical CAP, which may be applied in pre-eclampsia to improve the mother's and offspring's quality of life.

Comedications with Immune Checkpoint Inhibitors: Involvement of the Microbiota, Impact on Efficacy and Practical Implications

Immune checkpoint inhibitors (ICIs) have been a major breakthrough in solid oncology over the past decade. The immune system and the gut microbiota are involved in their complex mechanisms of action. However, drug interactions have been suspected of disrupting the fine equilibrium necessary for optimal ICI efficacy. Thus, clinicians are facing a great deal of sometimes contradictory information on comedications with ICIs and must at times oppose conflicting objectives between oncological response and comorbidities or complications. We compiled in this review published data on the role of the microbiota in ICI efficacy and the impact of comedications. We found mostly concordant results on detrimental action of concurrent corticosteroids, antibiotics, and proton pump inhibitors. The timeframe seems to be an important variable each time to preserve an initial immune priming at ICIs initiation. Other molecules have been associated with improved or impaired ICIs outcomes in pre-clinical models with discordant conclusions in retrospective clinical studies. We gathered the results of the main studies concerning metformin, aspirin, and non-steroidal anti-inflammatory drugs, beta blockers, renin-angiotensin-aldosterone system inhibitors, opioids, and statins. In conclusion, one should always assess the necessity of concomitant treatment according to evidence-based recommendations and discuss the possibility of postponing ICI initiation or switching strategies to preserve the critical window.

Umbilical Cord Blood-Derived Cell Therapy for Perinatal Brain Injury: A Systematic Review & Meta-Analysis of Preclinical Studies.

Perinatal brain injury is a major contributor to long-term adverse neurodevelopment. There is mounting preclinical evidence for use of umbilical cord blood (UCB)-derived cell therapy as potential treatment. To systematically review and analyse effects of UCB-derived cell therapy on brain outcomes in preclinical models of perinatal brain injury. MEDLINE and Embase databases were searched for relevant studies. Brain injury outcomes were extracted for meta-analysis to calculate standard mean difference (SMD) with 95% confidence interval (CI), using an inverse variance, random effects model. Outcomes were separated based on grey matter (GM) and white matter (WM) regions where applicable. Risk of bias was assessed using SYRCLE, and GRADE was used to summarise certainty of evidence. Fifty-five eligible studies were included (7 large, 48 small animal models). UCB-derived cell therapy significantly improved outcomes across multiple domains, including decreased infarct size (SMD 0.53; 95% CI (0.32, 0.74), p < 0.00001), apoptosis (WM, SMD 1.59; 95%CI (0.86, 2.32), p < 0.0001), astrogliosis (GM, SMD 0.56; 95% CI (0.12, 1.01), p = 0.01), microglial activation (WM, SMD 1.03; 95% CI (0.40, 1.66), p = 0.001), neuroinflammation (TNF-α, SMD 0.84; 95%CI (0.44, 1.25), p < 0.0001); as well as improved neuron number (SMD 0.86; 95% CI (0.39, 1.33), p = 0.0003), oligodendrocyte number (GM, SMD 3.35; 95 %CI (1.00, 5.69), p = 0.005) and motor function (cylinder test, SMD 0.49; 95 %CI (0.23, 0.76), p = 0.0003). Risk of bias was determined as serious, and overall certainty of evidence was low. UCB-derived cell therapy is an efficacious treatment in pre-clinical models of perinatal brain injury, however findings are limited by low certainty of evidence.

Abstract 20: Gut Microbiota-derived Indole Metabolites Influence Outcomes After Neonatal-Hypoxic Ischemic Encephalopathy

Introduction: Neonatal Hypoxic Ischemic Encephalopathy (nHIE) is a leading cause of infant mortality and morbidity worldwide. Males are at greater risk than females, and survivors of nHIE suffer from major disability with limited therapeutic options. Growing clinical and pre-clinical evidence shows neurological injury adversely alters the microbial populations in the gut (dysbiosis) and depletes anti-inflammatory metabolites exclusively made by the gut microbiota. Replacing key microbially-derived beneficial metabolites improves cognitive outcomes in pre-clinical models of adult stroke. However, changes in the gut microbiota and its metabolites after nHIE have not been explored and may lay the foundation for future therapies. Hypothesis: nHIE leads to gut dysbiosis and reduces microbial-derived metabolites, which worsens neurological outcomes in males and females. Methods: A modified Rice Vannucci Model on PND9 C57BL/6 mice was used to model nHIE. Fecal, plasma, gut, and brain samples were collected acutely (24hrs) and chronically (7wks) after injury. Results: We found a significant decrease in 3-indolepropionic acid (p=0.0190, n=4-6), inoxyl-3-sulfate (p=0.0098, n=4-6) and indoxyl acetate (p=0.0096, n=4-6) in the plasma of male mice 24hrs after HIE compared to sham controls, with no significant changes in female plasma. There was a significant increase in indole metabolites in the ischemic hemisphere in both males and females 24hrs after HIE. 7wks after nHIE, there was a significant increase in anxiety-like behavior in males (decrease in % of time immobile during tail suspension=0.018, n=6) and decreased functional ability (nest building score p=0.0147, n=6) in males with HIE compared to sham controls. No significant changes were observed in females. 16S rRNA sequencing data showed dysbiotic microbiota composition after nHIE, consistent with the microbial-metabolite changes found by mass spectroscopy analysis. Conclusion: nHIE induced brain injury results in gut dysbiosis, with sex-specific alterations in circulating indole metabolites and behavioral deficits. This supports our hypothesis that a sex-specific reduction in bioavailability of microbial-metabolites worsens CNS damage after nHIE.

Abstract 94: Randomized, Double-blind, Placebo-controlled Phase 1 Study Of Vwf-binding Aptamer, Bb-031: Safety, Tolerability, Pharmacokinetic And Pharmacodynamic Activity In Healthy Volunteers

Introduction: Von Willebrand Factor (VWF) is a ubiquitous component of thrombi extracted by endovascular thrombectomy from patients with large vessel occlusion (LVO) stroke. BB-031 is a modified RNA aptamer that targets von Willebrand Factor (VWF) that lyses occlusive thrombi and improves outcomes in pre-clinical models of acute ischemic stroke (AIS). Hypothesis: BB-031 is safe, tolerable, and inhibits both VWF binding and activity in a dose-dependent manner. Methods: Healthy participants were randomized to receive BB-031 or placebo (6:2) by intravenous bolus injection at single ascending doses (SAD) of 0.1, 0.3, 1.0, 2.0 and 4.0 mg/kg (total n=40). Serial Clinical assessment, and blood sample collection for pharmacokinetic (PK) and pharmacodynamic (PD) analysis were performed. Non-compartmental PK analysis was conducted using Phoenix WinNonlin. PD evaluation included measurement of VWF inhibition and whole blood thrombosis (Platelet Function Analyzer [PFA-200]). Results: BB-031 was safe and well-tolerated for 28 days following single IV doses up to 4.0 mg/kg. There were no significant adverse events (SAEs), or treatment-emergent adverse events (TEAEs) leading to dose discontinuation. Minor events included bleeding at an IV site in 1 participant, and minor bleeding of an ulcer on the tongue in 1 participant. None of the minor TEAEs were dose-dependent. BB-031 demonstrated nonlinear, dose-dependent plasma PK across the dose range tested, with an apparent mean terminal half-life (t 1/2 ) of 18 min at 0.1 mg/kg to 67 min at 4.0 mg/kg. Dose-dependent changes in VWF binding were observed; &gt;95% maximal mean change from baseline was reached following a single IV dose of 4.0 mg/kg. Finally, PFA-200 results showed complete inhibition of clot formation (closing time ≥300 seconds) at all doses tested with a dose-dependent duration of inhibition and return to normal range. Conclusion: This first-in-human SAD study of BB-031 demonstrated safety following a single IV dose of 0.1 to 4 mg/kg, and dose-dependent patterns of VWF binding and platelet function changes. These results lay the foundation for future studies in patients suffering from thrombotic conditions including AIS.

Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease

Patients with multiple myeloma, an incurable malignancy of plasma cells, frequently develop osteolytic bone lesions that severely impact quality of life and clinical outcomes. Eliglustat, a U.S. Food and Drug Administration-approved glucosylceramide synthase inhibitor, reduced osteoclast-driven bone loss in preclinical in vivo models of myeloma. In combination with zoledronic acid, a bisphosphonate that treats myeloma bone disease, eliglustat provided further protection from bone loss. Autophagic degradation of TRAF3, a key step for osteoclast differentiation, was inhibited by eliglustat as evidenced by TRAF3 lysosomal and cytoplasmic accumulation. Eliglustat blocked autophagy by altering glycosphingolipid composition whilst restoration of missing glycosphingolipids rescued autophagy markers and TRAF3 degradation thus restoring osteoclastogenesis in bone marrow cells from myeloma patients. This work delineates both the mechanism by which glucosylceramide synthase inhibition prevents autophagic degradation of TRAF3 to reduce osteoclastogenesis as well as highlighting the clinical translational potential of eliglustat for the treatment of myeloma bone disease.

Effective and Safe Immune Checkpoint Blockade Induces Complete Responses in Murine PTCL Model of ALCL

Anaplastic large cell lymphoma (ALCL) is a rare T-cell non-Hodgkin lymphoma. In the majority of cases the disease is driven by a chromosomal translocation t(2;5)(p23;35) leading to the fusion of the anaplastic lymphoma kinase (ALK) gene with the nucleophosmin gene (NPM), constitutively activating ALK kinase. In the last decade immunotherapy turned out to be a real game-changer in cancer treatment, especially in the field of solid tumors. Regarding T-cell lymphomas (TCL), the significance of immune checkpoint inhibition is still highly debated. The outcomes in preclinical models as well as clinical trials are ranging from response to hyperprogression. Consequently, to provide a better understanding of the role and underlying mechanisms of targeting immune checkpoint axes, preclinical models of TCL are urgently needed to identify patients that benefit from immunotherapy as well as potential biomarkers. To examine disease biology and therapy effects of ALCL in vivo, we use a syngeneic retroviral bone marrow transplantation mouse model of ALK+ ALCL that closely resembles the disease in humans. In order to study the effect of blocking the PD-1/PD-L1-axis in ALCL in vivo, serial transplantations of lymphoma cells from a murine thymus were performed. We further investigated both spontaneous and immunotherapy-induced immune responses and characterized the interaction of innate and adaptive immune master players with flow cytometry, cytokine analysis, histology and transcriptome analysis. In our mouse model of ALK+ ALCL we confirmed the upregulation of PD-L1 on ALK+ lymphoma cells in vivo. Immune checkpoint inhibition of PD-L1 in vivo leads to high complete response rates, prolonged survival and significantly reduced lymphoma burden of treated animals. Flow cytometry analysis revealed that PD-L1 blockade reverses Treg-mediated immunosuppression and causes augmented circulation of CD8+ effector T-lymphocytes. Treatment with depletion antibodies of lymphocyte subpopulations unveils CD4+ T-cells and NK-cells but not CD8+ T-cells as master players of checkpoint-mediated immune response to ALK+ ALCL. Accordingly, we identified exhausted CD4+ T-cells in non-responders to checkpoint inhibition underlining the central role of CD4+ T-cells in ALCL immune surveillance and response. These results are contributing to a broader understanding of the immune surveillance and response in ALCL, with the outmost goal of better identifying patients that benefit from immunotherapy.

Dendrimer nanotherapy for severe COVID-19 attenuates inflammation and neurological injury markers and improves outcomes in a phase2a clinical trial.

Hyperinflammation triggered by SARS-CoV-2 is a major cause of disease severity, with activated macrophages implicated in this response. OP-101, a hydroxyl-polyamidoamine dendrimer-N-acetylcysteine conjugate that specifically targets activated macrophages, improves outcomes in preclinical models of systemic inflammation and neuroinflammation. In this multicenter, randomized, double-blind, placebo-controlled, adaptive phase 2a trial, we evaluated safety and preliminary efficacy of OP-101 in patients with severe COVID-19. Twenty-four patients classified as having severe COVID-19 with a baseline World Health Organization seven-point ordinal scale of ≥5 were randomized to receive a single intravenous dose of placebo (n = 7 patients) or OP-101 at 2 (n = 6), 4 (n = 6), or 8 mg/kg (n = 5 patients). All study participants received standard of care, including corticosteroids. OP-101 at 4 mg/kg was better than placebo at decreasing inflammatory markers; OP-101 at 4 and 8 mg/kg was better than placebo at reducing neurological injury markers, (neurofilament light chain and glial fibrillary acidic protein). Risk for the composite outcome of mechanical ventilation or death at 30 and 60 days after treatment was 71% (95% CI: 29%, 96%) for placebo and 18% (95% CI: 4%, 43%; P = 0.021) for the pooled OP-101 treatment arms. At 60 days, 3 of 7 patients given placebo and 14 of 17 OP-101-treated patients were surviving. No drug-related adverse events were reported. These data show that OP-101 was well tolerated and may have potential to treat systemic inflammation and neuronal injury, reducing morbidity and mortality in hospitalized patients with severe COVID-19.

Reduced microglia activation following metformin administration or microglia ablation is sufficient to prevent functional deficits in a mouse model of neonatal stroke

BackgroundNeonatal stroke is a devastating insult that can lead to life-long impairments. In response to hypoxic–ischaemic injury, there is loss of neurons and glia as well as a neuroinflammatory response mediated by resident immune cells, including microglia and astrocytes, which can exacerbate damage. Administration of the antidiabetic drug metformin has been shown to improve functional outcomes in preclinical models of brain injury and the cellular basis for metformin-mediated recovery is unknown. Given metformin’s demonstrated anti-inflammatory properties, we investigated its role in regulating the microglia activation and used a microglia ablation strategy to investigate the microglia-mediated outcomes in a mouse model of neonatal stroke.MethodsHypoxia-ischaemia (H-I) was performed on post-natal day 8. Metformin was administered for one week, starting one day after injury. Immunohistochemistry was used to examine the spatiotemporal response of microglia and astrocytes after hypoxia-ischaemia, with or without metformin treatment. To evaluate the effects of microglia depletion after hypoxia-ischaemia, we delivered Plexxikon 5622 for 1 or 2 weeks post-injury. The regional pattern of microglia and astrocyte depletion was assessed through immunohistochemistry. Motor behaviour was assessed with the righting reflex, hindlimb suspension, grip strength and cylinder tests.ResultsHerein, we revealed a spatiotemporally regulated response of microglia and astrocytes after hypoxia-ischaemia. Metformin treatment after hypoxia-ischaemia had no effect on microglia number and proliferation, but significantly reduced microglia activation in all regions examined, concomitant with improved behavioural outcomes in injured mice. Plexxikon 5622 treatment successfully ablated microglia, resulting in a > 90% depletion in microglia in the neonatal brain. Microglia rapidly repopulated upon treatment cessation of Plexxikon. Most interesting, microglia ablation was sufficient to reduce functional deficits after hypoxia-ischaemia, mimicking the effects of 1 week of metformin treatment post-injury.ConclusionThese results highlight the importance of regulating the neuroinflammatory response after neonatal stroke to promote recovery.

Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML.

We demonstrate that HDACis induce terminal differentiation of AML through epigenetic remodeling of pDCs, resulting in production of type I IFN that is important for the therapeutic effects of HDACis. The study demonstrates the important functional interplay between the immune system and leukemias in response to HDAC inhibition. This article is highlighted in the In This Issue feature, p. 1397.

Targeting the Angiopoietin/Tie Pathway: Prospects for Treatment of Retinal and Respiratory Disorders.

Anti-angiogenic approaches have significantly advanced the treatment of vascular-related pathologies. The ephemeral outcome and known side effects of the current vascular endothelial growth factor (VEGF)-based anti-angiogenic treatments have intensified research on other growth factors. The angiopoietin/Tie (Ang/Tie) family has an established role in vascular physiology and regulates angiogenesis, vascular permeability, and inflammatory responses. The Ang/Tie family consists of angiopoietins 1–4, their receptors, tie1 and 2 and the vascular endothelial-protein tyrosine phosphatase (VE-PTP). Modulation of Tie2 activation has provided a promising outcome in preclinical models and has led to clinical trials of Ang/Tie-targeting drug candidates for retinal disorders. Although less is known about the role of Ang/Tie in pulmonary disorders, several studies have revealed great potential of the Ang/Tie family members as drug targets for pulmonary vascular disorders as well. In this review, we summarize the functions of the Ang/Tie pathway in retinal and pulmonary vascular physiology and relevant disorders and highlight promising drug candidates targeting this pathway currently being or expected to be under clinical evaluation for retinal and pulmonary vascular disorders.

The More, the Better: High-Dose Omega-3 Fatty Acids Improve Behavioural and Molecular Outcomes in Preclinical Models in Mild Brain Injury.

Mild traumatic brain injury (mTBI) is a continuing healthcare concern worldwide contributing to significant cognitive and neurological impairment, consequently affecting activities of daily living. While mTBI recovery is becoming well studied, there are no interventions to reduce the known impairments of mTBI. Omega-3 fatty acids (N-3FA) are safe and beneficial for brain health; however, their potential effects in a pathophysiological environment such as that seen post-mTBI are unknown. Preclinical studies using rodent models are key to understanding molecular mechanisms underlying improvements post-injury. Studies to date have shown improved outcomes in rodent models following mTBI protocols, but these data have not been quantified using a systematic review and meta-analysis approach. Our systematic review assessed 291 studies identified from the literature. Of these studies, 18 studies met inclusion criteria. We conducted a meta-analysis examining the effect of high-dose n-3FA vs placebo on neurological, cognitive and molecular changes following mTBI. Quality of studies was rated as moderate to high quality, and while mostly compliant, some areas of risk of bias were identified. Results showed that preclinical doses of 10-370 mg/kg/day of n-3FA per day in rodents (equivalent to high clinical doses) resulted in improvements in neurological and cognitive performance (pooled effect sizes ranging between 1.52 and 3.55). Similarly, improvements in molecular and inflammatory markers were observed in treated rodents vs control (pooled effect sizes: 3.73-6.55). Overall, these findings highlight the potential for high-dose n-3FA for human clinical studies following mTBI.

Nanodiamonds and their potential applications in breast cancer therapy: a narrative review

Breast cancer remains the most commonly diagnosed cancer and the leading cause of cancer-related death among women worldwide. With the projected increase in breast cancer cases in recent years, optimising treatment becomes increasingly important. Current treatment modalities in breast cancer present major limitations, including chemoresistance, dose-limiting adverse effects and lack of selectivity in aggressive subtypes of breast cancers such as triple-negative breast cancer. Nanodiamonds have demonstrated promising outcomes in preclinical models from their unique surface characteristics allowing optimised delivery of various therapeutic agents, overcoming some of the significant hurdles in conventional treatment modalities. This review will present an update on preclinical findings of nanodiamond-based drug delivery systems for breast cancer therapy to date, challenges with the use of nanodiamonds along with considerations for future research.

Evaluation of nanoparticle drug-delivery systems used in preclinical studies.

Multifunctional nanoparticles have been identified as a promising drug-delivery system for sustainable drug release. The structural and size tunabilityand disease-targeting ability of nanoparticles have made them more suitable for multiple drug loading and delivery, thereby enhancing therapeutic results through synergistic effects. Nanoparticulate carriers with specific features such as target specificity and stimuli-responsiveness enable selectivedrug delivery with lower potential side effects. In this reviewwe have classified the recently published articles on polymeric and inorganic nanoparticle-mediated drug delivery into three different categories based on functionalityand discussed their efficiency fordrug deliveryand their therapeutic outcomes in preclinical models. Most of the drug-loaded nanodelivery systems discussed have demonstrated negligible or very low systemic toxicity throughout the experimental period in animal models compared withfree drug administration. In addition, somechallenges associated with thetranslation of nanoparticle-based drug carrier responses to clinical application are highlighted.

Systematic review of the impact of cannabinoids on neurobehavioural outcomes in preclinical models of traumatic and nontraumatic spinal cord injury

Systematic review of the impact of cannabinoids on neurobehavioural outcomes in preclinical models of traumatic and nontraumatic spinal cord injury

Revisiting promising preclinical intracerebral hemorrhage studies to highlight repurposable drugs for translation.

Intracerebral hemorrhage is a devastating global health burden with limited treatment options and is responsible for 49% of 6.5 million annual stroke-related deaths comparable to ischemic stroke. Despite the impact of intracerebral hemorrhage, there are currently no effective treatments and so weaknesses in the translational pipeline must be addressed. There have been many preclinical studies in intracerebral hemorrhage models with positive outcomes for potential therapies in vivo, but beyond advancing the understanding of intracerebral hemorrhage pathology, there has been no translation toward successful clinical application. Multidisciplinary preclinical research, use of multiple models, and validation in human tissue are essential for effective translation. Repurposing of therapeutics for intracerebral hemorrhage may be the most promising strategy to help relieve the global health burden of intracerebral hemorrhage. Here, we have reviewed the existing literature to highlight repurposable drugs with successful outcomes in preclinical models of intracerebral hemorrhage that have realistic potential for development into the clinic for intracerebral hemorrhage.

The Impact of Hypertension and Use of Calcium Channel Blockers on Tuberculosis Treatment Outcomes

Hypertension induces systemic inflammation, but its impact on the outcome of infectious diseases like tuberculosis (TB) is unknown. Calcium channel blockers (CCB) improve TB treatment outcomes in preclinical models, but their effect in patients with TB remain unclear. This retrospective cohort study, including all patients > 18 years receiving treatment for culture-confirmed, drug-sensitive TB from 2000 to 2016 at the National Taiwan University Hospital, assessed the association of hypertension and CCB use with all-cause and infection-related mortality during the first 9 months of TB treatment, as well as sputum smear microscopy and sputum culture positivity at 2 and 6 months. Of the 2894 patients, 1052 (36.4%) had hypertension. A multivariable analysis revealed that hypertension was associated with increased mortality due to all causes (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.23-1.99) and infections (HR, 1.87; 95% CI, 1.34-2.6), but there were no statistical differences in microbiological outcomes when stratified based on hypertensive group. Dihydropyridine-CCB (DHP-CCB) use was associated only with reduced all-cause mortality (HR, 0.67; 95% CI, .45-.98) by univariable Cox regression. There were no associations between DHP-CCB use and infection-related mortality (HR, 0.78; 95% CI, .46-1.34) or microbiological outcomes in univariable or multivariable regression analyses. Patients with hypertension have increased all-cause mortality and infection-related mortality during the 9 months following TB treatment initiation. DHP-CCB use may lower all-cause mortality in TB patients with hypertension. The presence of hypertension or the use of CCB did not result in a significant change in microbiological outcomes.

The Effect of PAOPA, a Novel Allosteric Modulator of Dopamine D2 Receptors, on Signaling Proteins Following Sub-Chronic Administration in Rats.

Allosteric modulators of G-protein coupled receptors regulate receptor activity by binding to sites other than the active site and have emerged as a new and highly desirable class of drugs. PAOPA (3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide), a peptidomimetic analog of L-prolyl-L-leucyl-glycinamide, is a potent dopamine D2 receptor allosteric modulator. PAOPA has shown therapeutic effects in pre-clinical models of schizophrenia and extrapyramidal dysfunction. In this study, we sought to examine the biomolecular underpinnings of PAOPA's therapeutic outcomes in pre-clinical models of schizophrenia. Following sub-chronic (daily for 7 days) administration of PAOPA, we assessed levels of dopamine D2 receptors, receptor kinases (GRK2 (G protein-coupled receptor kinase 2) and Arrestin- 3), and phosphorylated mitogen-activated protein kinase (MAPKs), namely, extracellular signal- regulated kinases (ERK1/2) in the hippocampus, medial pre-frontal cortex, nucleus accumbens, pre-frontal cortex, and dorsal striatum via protein quantification. Following 7 days of daily PAOPA treatment, we observed decreased GRK2 and increased dopamine D2 receptor expression in the dorsal striatum. These findings potentially underscore the therapeutic mechanism of action of PAOPA for the positive-like symptoms of schizophrenia in pre-clinical animal models. Additionally, we observed a decline in GRK2 in the hippocampus and an increase in phosphorylated ERK1 in the pre-frontal cortex, suggesting a role of PAOPA in treating cognitive and/or affective dysfunction in pre-clinical models. While further studies are required to elucidate the mechanism of action of PAOPA, this study discusses prior investigations and develops an early framework to describe the therapeutic mechanism of action of PAOPA.

Human cord blood-derived regulatory T-cell therapy modulates the central and peripheral immune response after traumatic brain injury.

Traumatic brain injury (TBI) causes a profound inflammatory response within the central nervous system and peripheral immune system, which contributes to secondary brain injury and further morbidity and mortality. Preclinical investigations have demonstrated that treatments that downregulate microglia activation and polarize them toward a reparative/anti‐inflammatory phenotype have improved outcomes in preclinical models. However, no therapy to date has translated into proven benefits in human patients. Regulatory T cells (Treg) have been shown to downregulate pathologic immune responses of the innate and adaptive immune system across a variety of pathologies. Furthermore, cellular therapy has been shown to augment host Treg responses in preclinical models; yet, studies investigating the use of Treg as a therapeutic for TBI are lacking. In a rodent TBI model, we demonstrate that human umbilical cord blood Treg modulate the central and peripheral immune response after injury in vitro and in vivo.