Examination of eQTL Polymorphisms Associated with Increased Risk of Progressive Complicated Sarcoidosis in European and African Descent Subjects.

Background: A limited pool of SNPs are linked to the development and severity of sarcoidosis, a systemic granulomatous inflammatory disease. By integrating genome-wide association studies (GWAS) data and expression quantitative trait loci (eQTL) single nuclear polymorphisms (SNPs), we aimed to identify novel sarcoidosis SNPs potentially influencing the development of complicated sarcoidosis.

Methods: A GWAS (Affymetrix 6.

Immune mechanisms of granuloma formation in sarcoidosis and tuberculosis.

Sarcoidosis is a complex immune-mediated disease characterized by clusters of immune cells called granulomas. Despite major steps in understanding the cause of this disease, many questions remain. In this Review, we perform a mechanistic interrogation of the immune activities that contribute to granuloma formation in sarcoidosis and compare these processes with its closest mimic, tuberculosis, highlighting shared and divergent immune activities.

A novel direct adenosine monophosphate kinase activator ameliorates disease progression in preclinical models of Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) mainly results from mutations in the PKD1 gene, which encodes polycystin 1. It is the most common inherited kidney disease and is characterized by a progressive bilateral increase in cyst number and size, often leading to kidney failure. The cellular energy sensor and regulator adenosine monophosphate stimulated protein kinase (AMPK) has been implicated as a promising new therapeutic target.

Evaluation of PXL065 - deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1).

Background & Aims: Pioglitazone (Pio) is efficacious in NASH, but its utility is limited by PPARγ-driven side effects. Pio is a mixture of two enantiomers (R, S). PXL065, deuterium-stabilized R-Pio, lacks PPARγ activity but retains non-genomic activity.

Immune mechanisms in fibrotic pulmonary sarcoidosis.

Sarcoidosis is an immune-mediated disorder. Its immunopathology has been steadily mapped out over the past few decades. Despite this, the underpinning mechanisms for progressive fibrotic sarcoidosis is an almost uncharted area.

Heterogeneity of Lung Function Phenotypes in Sarcoidosis: Role of Race and Sex Differences.

Historically, sarcoidosis was described as a restrictive lung disease, but several alternative phenotypes of pulmonary function have been observed. Pulmonary function phenotypes in sarcoidosis may represent different clinical and/or molecular phenotypes. To characterize the prevalence of different pulmonary function phenotypes in a large and diverse sarcoidosis cohort from a tertiary care referral center.

Beneficial Effects of the Direct AMP-Kinase Activator PXL770 in In Vitro and In Vivo Models of X-Linked Adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is a severe orphan disease caused by mutations in the peroxisomal transporter gene, leading to toxic accumulation of Very Long-Chain Fatty Acids (VLCFA - in particular C26:0) resulting in inflammation, mitochondrial dysfunction and demyelination. AMP-activated protein kinase (AMPK) is downregulated in ALD, and its activation is implicated as a therapeutic target. PXL770 is the first direct allosteric AMPK activator with established clinical efficacy and tolerability.

Therapeutic potential of deuterium-stabilized (R)-pioglitazone-PXL065-for X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) results from ABCD1 gene mutations which impair Very Long Chain Fatty Acids (VLCFA; C26:0 and C24:0) peroxisomal import and β-oxidation, leading to accumulation in plasma and tissues. Excess VLCFA drives impaired cellular functions (e.g.

Reduced lactic acidosis risk with Imeglimin: Comparison with Metformin.

The global prevalence of type 2 diabetes (T2D) is expected to exceed 642 million people by 2040. Metformin is a widely used biguanide T2D therapy, associated with rare but serious events of lactic acidosis, in particular with predisposing conditions (e.g.

Pharmacodynamic effects of direct AMP kinase activation in humans with insulin resistance and non-alcoholic fatty liver disease: A phase 1b study.

AMPK is an energy sensor modulating metabolism, inflammation, and a target for metabolic disorders. Metabolic dysfunction results in lower AMPK activity. PXL770 is a direct AMPK activator, inhibiting lipogenesis (DNL) and producing efficacy in preclinical models.

Rational prioritization strategy allows the design of macrolide derivatives that overcome antibiotic resistance.

Antibiotic resistance is a major threat to global health; this problem can be addressed by the development of new antibacterial agents to keep pace with the evolutionary adaptation of pathogens. Computational approaches are essential tools to this end since their application enables fast and early strategical decisions in the drug development process. We present a rational design approach, in which acylide antibiotics were screened based on computational predictions of solubility, membrane permeability, and binding affinity toward the ribosome.

Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study.

Background: AMP kinase (AMPK) is an energy sensor implicated in regulation of lipid metabolism, inflammation, and insulin sensitivity. We aimed to assess efficacy and safety of PXL770, a novel direct AMPK activator, in patients with non-alcoholic fatty liver disease (NAFLD).

Methods: STAMP-NAFLD, a randomised, double-blind, placebo-controlled phase 2a study, was done across 15 US clinical sites.

Direct AMPK Activation Corrects NASH in Rodents Through Metabolic Effects and Direct Action on Inflammation and Fibrogenesis.

No approved therapies are available for nonalcoholic steatohepatitis (NASH). Adenosine monophosphate-activated protein kinase (AMPK) is a central regulator of cell metabolism; its activation has been suggested as a therapeutic approach to NASH. Here we aimed to fully characterize the potential for direct AMPK activation in preclinical models and to determine mechanisms that could contribute to efficacy for this disease.

Transcriptomics of bronchoalveolar lavage cells identifies new molecular endotypes of sarcoidosis.

Background: Sarcoidosis is a multisystem granulomatous disease of unknown origin with a variable and often unpredictable course and pattern of organ involvement. In this study we sought to identify specific bronchoalveolar lavage (BAL) cell gene expression patterns indicative of distinct disease phenotypic traits.

Methods: RNA sequencing by Ion Torrent Proton was performed on BAL cells obtained from 215 well-characterised patients with pulmonary sarcoidosis enrolled in the multicentre Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study.

Imeglimin preserves islet β-cell mass in Type 2 diabetic ZDF rats.

Objectives: Type 2 diabetes (T2D) is driven by progressive dysfunction and loss of pancreatic β-cell mass. Imeglimin is a first-in-class novel drug candidate that improves glycaemia and glucose-stimulated insulin secretion in preclinical models and patients. Given evidence that imeglimin can attenuate β-cell dysfunction and protect β cells , we postulated that imeglimin could also exert longer term effects to prevent pancreatic β-cell death and preserve functional β-cell mass .

PLF+PS or ALIF+PS: which has a lower operative nonunion rate? Analysis of a cohort of 2,061 patients from a National Spine Registry.

Background Context: Although fusion rates in posterolateral lumbar fusions with pedicle screws (PLF+PS) and anterior lumbar interbody fusions with pedicle screws (ALIF+PS) have been reported, there has been no consensus on superiority with respect to clinical outcome and nonunion rates. Most studies determine nonunion rates based on radiographic studies; however, many of these nonunions are asymptomatic and may not require reoperations. Hence, a potentially more clinically useful measure is the reoperation rate for symptomatic nonunions, which we term the operative nonunion rate.

Imeglimin amplifies glucose-stimulated insulin release from diabetic islets via a distinct mechanism of action.

Pancreatic islet β-cell dysfunction is characterized by defective glucose-stimulated insulin secretion (GSIS) and is a predominant component of the pathophysiology of diabetes. Imeglimin, a novel first-in-class small molecule tetrahydrotriazine drug candidate, improves glycemia and GSIS in preclinical models and clinical trials in patients with Type 2 diabetes; however, the mechanism by which it restores β-cell function is unknown. Here, we show that imeglimin acutely and directly amplifies GSIS in islets isolated from rodents with Type 2 diabetes via a mode of action that is distinct from other known therapeutic approaches.

Mechanism of action of Imeglimin: A novel therapeutic agent for type 2 diabetes.

Imeglimin is an investigational first-in-class novel oral agent for the treatment of type 2 diabetes (T2D). Several pivotal phase III trials have been completed with evidence of statistically significant glucose lowering and a generally favourable safety and tolerability profile, including the lack of severe hypoglycaemia. Imeglimin's mechanism of action involves dual effects: (a) amplification of glucose-stimulated insulin secretion (GSIS) and preservation of β-cell mass; and (b) enhanced insulin action, including the potential for inhibition of hepatic glucose output and improvement in insulin signalling in both liver and skeletal muscle.

Operative Nonunion Rates in Posterolateral Lumbar Fusions: Analysis of a Cohort of 2591 Patients from a National Spine Registry.

Objective: Radiographic nonunion rates in the literature for posterolateral lumbar fusions with pedicle screws (PLFs) range from 8.1% to 43.3% but may not represent nonunion rates.

A data workflow to support plant breeding decisions from a terrestrial field-based high-throughput plant phenotyping system.

Field-based high-throughput plant phenotyping (FB-HTPP) has been a primary focus for crop improvement to meet the demands of a growing population in a changing environment. Over the years, breeders, geneticists, physiologists, and agronomists have been able to improve the understanding between complex dynamic traits and plant response to changing environmental conditions using FB-HTPP. However, the volume, velocity, and variety of data captured by FB-HTPP can be problematic, requiring large data stores, databases, and computationally intensive data processing pipelines.

Clinical and MRI phenotypes of sarcoidosis-associated myelopathy.

Objective: To determine the characteristic clinical and spinal MRI phenotypes of sarcoidosis-associated myelopathy (SAM), we analyzed a large cohort of patients with this disorder.

Methods: Patients diagnosed with SAM at a single center between 2000 and 2018 who met the established criteria for definite and probable neurosarcoidosis were included in a retrospective analysis to identify clinical profiles, CSF characteristics, and MRI lesion morphology.

Results: Of 62 included patients, 33 (53%) were male, and 30 (48%) were African American.

Association of Medication Adherence and Clinical Outcomes in Sarcoidosis.

Background: Sarcoidosis, one of the most common interstitial lung diseases, has significant health disparities. Approximately 50% of individuals affected with sarcoidosis will undergo spontaneous remission, but those who do not undergo remission often require long-term or lifelong treatment to prevent disease progression. We sought to assess the association between medication adherence and clinical outcomes in sarcoidosis.

Psychological burden associated with worse clinical outcomes in sarcoidosis.

Introduction: Sarcoidosis is a multisystem granulomatous inflammatory disorder. Sarcoidosis is associated with significant morbidity and rising healthcare utilisation. Patients with sarcoidosis report higher psychological symptoms than the general population.