👤 Jeffrey F Friedman

Despite the well-established benefits of statin therapy in reducing atherosclerotic cardiovascular disease (ASCVD) risk, many patients fail to achieve recommended low-density lipoprotein cholesterol (LDL-C) targets or experience statin intolerance, necessitating alternative approaches. This review examines advances in non-statin lipid-lowering therapies, focusing on proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (monoclonal antibodies and inclisiran), bempedoic acid, and other non-statin lipid medications. We evaluate their mechanisms of action, clinical efficacy, and safety profiles on the basis of landmark trials. A conceptual framework for personalized lipid management is proposed, addressing residual cardiovascular risk, statin intolerance, and complex patient profiles. Clinical decision pathways are presented for high-risk patients, statin-intolerant individuals, and those with adherence challenges. We explore emerging therapies targeting novel pathways, including lipoprotein(a), apolipoprotein C-III inhibitors, angiopoietin-like protein 3 (ANGPTL3) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, and gene-editing technologies. Implementation barriers, including cost considerations, insurance challenges, and global access disparities, are discussed alongside solutions. Show less

Intestinal remnant chylomicrons (CMs) are involved in cardiovascular residual risk and the atherogenic process. Microsomal triglyceride transfer protein (MTTP) catalyzes the assembly of lipids to apolipoprotein B48, generating CMs. Dysbiosis could alter this behavior. This study investigated the chemical composition of CMs and their associations with intestinal MTTP and gut fat depots in a diet-induced dysbiosis animal model. Male Wistar rats were fed either a standard diet (control, n=10) or a high-fat high-sucrose diet (HFSD, n=10) for 14 weeks. Measurements included serum glucose, lipid-lipoprotein profile, free fatty acids (FFAs), lipopolysaccharide (LPS) and the Compared to control, HFSD rats showed higher levels of LPS, triglycerides (TGs), non-high-density lipoprotein cholesterol (HDL-C) levels, TG/HDL-C ratio, FFAs, and the F/B ratio. HFSD CMs showed increased TG and phospholipids. TJ proteins levels were lower in the HFSD group, while histological scores showed no differences. CIF was increased in the HFSD group. No significant differences in apoB mRNA were found. MTTP expression was higher in the HFSD group, and directly correlated with CM-TG and inversely correlated with CIF. Our findings imply that gut TG content may constitute an important determinant of the secretion of TG-rich CMs, promoted by MTTP, with increased atherogenic potential. Show less

The 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP). To investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP. Utilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP. We found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub-haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up-regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down-regulating KANSL1. Single-nucleus RNA-seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up-regulates LRRC37A/LRRC37A2 in neuronal cells. The copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Show less

Microtubule-actin cross-linking factor 1 (MACF1) is a large protein of the spectraplakin family, which is essential for brain development. MACF1 interacts with microtubules through the growth arrest-specific 2 (Gas2)-related (GAR) domain. Heterozygous MACF1 missense variants affecting the zinc-binding residues in this domain result in a distinctive cortical and brain stem malformation. Evidence for other MACF1-associated disorders is still limited. Here, we present a cohort of 45 individuals with heterozygous or bi-allelic MACF1 variants to explore the phenotypic spectrum and assess possible pathogenic relevance. We observe that de novo heterozygous missense variants in the EF-hand domains also result in distinctive brain malformation and provide experimental evidence that variants in the EF-hand/GAR module increase microtubule binding, suggestive of a toxic gain of function. Notably, no phenotype-genotype correlation was possible for the remaining heterozygous variants in other domains. A clinical review of eight families with bi-allelic variants reveals a possible complex neurodevelopmental syndrome of the central and peripheral nervous systems. In these individuals, bi-allelic variants mostly affect the Plakin domain. Furthermore, RNA sequencing and chromatin immunoprecipitation (ChIP) analyses of human fetal brain tissue reveal five MACF1 isoforms with region-specific expression, differing in their exon 1 transcription start sites but splicing to a common exon 2. This differential expression explains the frontal-predominant lissencephaly in an individual with a homozygous stop-gain in exon 1 (MACF1-204: c.70C>T [p.Arg24∗]), as this isoform is preferentially expressed in the frontal cortex. We conclude that MACF1-related disorders are strictly linked to domain function and the level of transcript expression, explaining the observed wide clinical heterogeneity. Show less

While heterozygous Through collaborative efforts, we assembled a cohort of 10 affected individuals from 8 unrelated families with either biallelic or monoallelic non-GAR domain Clustering revealed two distinct phenotypic signatures, suggesting domain-specific effects. Variants outside the GAR domain associate with broader neurodevelopmental phenotypes and variable craniofacial and skeletal expressivity. Additionally, enrichment analysis (p < 0.001) using OMIM HPO sets supported these findings. In contrast to the GAR domain's strong correlation with lissencephaly and brainstem malformations, biallelic non-GAR domain These results expand the phenotypic spectrum of Show less

Multiplexed assays of variant effect (MAVEs) systematically measure variant function but have been limited to cancer cell lines rather than disease-relevant cell types. We developed saturation genome editing in human iPSCs (iPSC-SGE) to introduce variant libraries into a single allele of a target gene while programming the genetic background of the second allele, enabling variant assessment across differentiated cell types and genetic contexts at scale. We edited 1,137 variants into Show less

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (r Show less

Local metabolic demand within cells varies widely, and the extent to which individual mitochondria can be specialized to meet these functional needs is unclear. We examined the subcellular distribution of the mitochondrial contact site and cristae organizing system (MICOS) complex, a spatial and functional organizer of mitochondria, and discovered that it dynamically enriches at the tip of a minor population of mitochondria in the cell periphery. Based on their appearance, we term these mitochondria "METEORs". METEORs have a unique composition, and MICOS enrichment sites are depleted of mtDNA and matrix proteins and contain high levels of the Ca Show less

Despite a proposed causal role for LDL-C (low-density lipoprotein cholesterol) in aortic stenosis (AS), randomized controlled trials of lipid-lowering therapy failed to prevent severe AS. We aimed to assess the impact on AS and peak velocity across the aortic valve conferred by lifelong alterations in LDL-C levels mediated by protein-disrupting variants in 3 clinically significant genes for LDL (low-density lipoprotein) metabolism ( We used sequencing data and electronic health records from UK Biobank (UKB) and All of Us and magnetic resonance imaging data from UKB. We identified predicted protein-disrupting variants with the Loss Of Function Transcript Effect Estimator (LOFTEE) and AlphaMissense algorithms and evaluated their associations with LDL-C and peak velocity across the aortic valve (UK Biobank), as well as diagnosed AS and aortic valve replacement (UK Biobank and All of Us). We included 421 049 unrelated participants (5621 with AS) in UKB and 195 519 unrelated participants (1087 with AS) in All of Us. Carriers of protein-disrupting variants in Rare genetic variants that confer lifelong higher or lower LDL-C levels are associated with substantially increased and decreased risk of AS, respectively. Early and sustained lipid-lowering therapy may slow or prevent AS development. Show less

Interleukin-27 (IL-27) is known to play opposing roles in immunology. The present paper considers, specifically, the role IL-27 plays in cancer immunotherapy when combined with immune checkpoint inhibitor anti-PD-1. We first develop a mathematical model for this combination therapy, by a system of Partial Differential Equations, and show agreement with experimental results in mice injected with melanoma cells. We then proceed to simulate tumor volume with IL-27 injection at a variable dose F and anti-PD-1 at a variable dose g. We show that in some range of "small" values of g, as f increases tumor volume decreases as long as fShow less

The effects of disease-causing MYBPC3 or MYH7 genetic variants on atrial myopathy, atrial fibrillation (AF) clinical course, and catheter ablation efficacy remain unclear. The aim of this study was to characterize the atrial substrate of patients with MYBPC3- or MYH7-mediated hypertrophic cardiomyopathy (HCM) and its impact on catheter ablation outcomes. A retrospective single-center study of patients with HCM who underwent genetic testing and catheter ablation for AF was performed. Patients with MYBPC3- or MYH7-mediated HCM formed the gene-positive cohort; those without disease-causative genetic variants formed the control cohort. High-density electroanatomical mapping was performed using a 3-dimensional mapping system, followed by radiofrequency ablation. Twelve patients were included in the gene-positive cohort (mean age 55.6 ± 9.9 years, 83% men, 50% MYBPC3, 50% MYH7, mean ejection fraction 59.3% ± 13.7%, mean left atrial [LA] volume index 51.7 ± 13.1 mL/m Patients with MYBPC3- or MYH7-mediated HCM undergoing AF ablation have appreciably more low-amplitude LA signals, suggestive of fibrosis. However, catheter ablation remains an effective rhythm-control strategy. Show less

Local metabolic demand within cells varies widely and the extent to which individual mitochondria can be specialized to meet these functional needs is unclear. We examined the subcellular distribution of MICOS, a spatial and functional organizer of mitochondria, and discovered that it dynamically enriches at the tip of a minor population of mitochondria in the cell periphery that we term "METEORs". METEORs have a unique composition; MICOS enrichment sites are depleted of mtDNA and matrix proteins and contain high levels of the Ca Show less

To evaluate the correlation between several presumed candidate genes for obstructive sleep apnoea (OSA) and clinical OSA phenotypes and propose a predictive comprehensive model for diagnosis of OSA. This case-control study compared polysomnographic patterns, clinical data, morbidities, dental factors and genetic data for polymorphisms in The cohort consisted of 161 OSA cases and 81 controls. Mean age of cases was 53.5 ± 14.0 years, mostly males (57%) and mean body mass index (BMI) of 27.5 ± 4.3 kg/m No genetic variant tested showed a statistically significant association with OSA phenotype. Logistic regression analysis resulted in a predictive model for diagnosing OSA that, if validated by larger prospective studies, could be applied clinically to allow risk stratification for OSA. Show less

Melanocortin 3 receptors (MC3R) and melanocortin 4 receptors (MC4R) are vital in regulating a variety of functions across many species. For example, the dysregulation of these receptors results in obesity and dysfunction in sexual behaviors. Only a handful of studies have mapped the expression of MC3R and MC4R mRNA across the central nervous system, with the primary focus on mice and rats. Because Syrian hamsters are valuable models for functions regulated by melanocortin receptors, our current study maps the distribution of MC3R and MC4R mRNA in the Syrian hamster telencephalon, diencephalon, and midbrain using RNAscope. We found that the expression of MC3R mRNA was lowest in the telencephalon and greatest in the diencephalon, whereas the expression of MC4R mRNA was greatest in the midbrain. A comparison of these findings to previous studies found that MC3R and MC4R expression is similar in some brain regions across species and divergent in others. In addition, our study identifies novel brain regions for the expression of MC3Rs and MC4Rs, and identifies cells that co-express bothMC3 and MC4 receptors within certain brain regions. Show less

Artificial intelligence (AI) models applied to 12-lead ECG waveforms can predict atrial fibrillation (AF), a heritable and morbid arrhythmia. However, the factors forming the basis of risk predictions from AI models are usually not well understood. We hypothesized that there might be a genetic basis for an AI algorithm for predicting the 5-year risk of new-onset AF using 12-lead ECGs (ECG-AI)-based risk estimates. We applied a validated ECG-AI model for predicting incident AF to ECGs from 39 986 UK Biobank participants without AF. We then performed a genome-wide association study (GWAS) of the predicted AF risk and compared it with an AF GWAS and a GWAS of risk estimates from a clinical variable model. In the ECG-AI GWAS, we identified 3 signals ( Predicted AF risk from an ECG-AI model is influenced by genetic variation implicating sarcomeric, ion channel and body height pathways. ECG-AI models may identify individuals at risk for disease via specific biological pathways. Show less

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune skin disease which occurs independently and in conjunction with systemic lupus erythematosus. Drug development for CLE is severely lacking. Anandamide (AEA) is a primary endocannabinoid which exhibits immunomodulatory effects through mixed cannabinoid receptor agonism. We evaluated AEA as topical treatment for CLE and assessed benefits of nanoparticle encapsulation (AEA-NP) on cutaneous drug penetration, delivery and biological activity. Compared to untreated controls, AEA-NP decreased IL-6 and MCP-1 in UVB-stimulated keratinocytes (p < 0.05) in vitro. In BALB/c mice, AEA-NP displayed improved cutaneous penetration, extended release and persistence of AEA in the follicular unit extending to the base after 24 h. Utilizing the MRL-lpr lupus murine model, twice weekly treatment of lesions with topical AEA-NP for 10 weeks led to decreased clinical and histologic lesion scores compared to unencapsulated AEA and untreated controls (p < 0.05). Prophylactic application of AEA-NP to commonly involved areas on MRL-lpr mice similarly resulted in decreased clinical and histologic scores when compared to controls (p < 0.05), and reduced C3 and IBA-1 in lesional tissue (p < 0.05). The demonstrated clinical and immunomodulatory effects of treatment with AEA support its potential as therapy for CLE. This work also suggests that encapsulation of AEA improves penetration and treatment efficacy. Future studies will be conducted to assess full therapeutic potential. Show less

Chronic age-related imbalance is a common cause of falls and subsequent death in the elderly and can arise from dysfunction of the vestibular system, an elegant neuroanatomical group of pathways that mediates human perception of acceleration, gravity, and angular head motion. Studies indicate that 27-46% of the risk of age-related chronic imbalance is genetic; nevertheless, the underlying genes remain unknown. The cohort consisted of 50,339 cases and 366,900 controls in the Million Veteran Program. The phenotype comprised cases with two ICD diagnoses of vertigo or dizziness at least 6 months apart, excluding acute or recurrent vertiginous syndromes and other non-vestibular disorders. Genome-wide association studies were performed as individual logistic regressions on European, African American, and Hispanic ancestries followed by trans-ancestry meta-analysis. Downstream analysis included case-case-GWAS, fine mapping, probabilistic colocalization of significant variants and genes with eQTLs, and functional analysis of significant hits. Two significant loci were identified in Europeans, another in the Hispanic population, and two additional in trans-ancestry meta-analysis, including three novel loci. Fine mapping revealed credible sets of intronic single nucleotide polymorphisms (SNPs) in MLLT10 - a histone methyl transferase cofactor, BPTF - a subunit of a nucleosome remodeling complex implicated in neurodevelopment, and LINC01224 - a proto-oncogene receptor tyrosine kinase. Despite the difficulties of phenotyping the nature of chronic imbalance, we replicated two loci from previous vertigo GWAS studies and identified three novel loci. Findings suggest candidates for further study and ultimate treatment of this common elderly disorder. Show less

With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes. Show less

Contrasting with the predicted anorexigenic effect of increasing brain serotonin signaling, long-term use of selective serotonin reuptake inhibitor (SSRI) antidepressants correlates with body weight (BW) gain. This adverse outcome increases the risk of transitioning to obesity and interferes with treatment compliance. Here, we show that orally administered fluoxetine (Flx), a widely prescribed SSRI, increased BW by enhancing food intake in healthy mice at 2 different time points and through 2 distinct mechanisms. Within hours, Flx decreased the activity of a subset of brainstem serotonergic neurons by triggering autoinhibitory signaling through 5-hydroxytryptamine receptor 1a (Htr1a). Following a longer treatment period, Flx blunted 5-hydroxytryptamine receptor 2c (Htr2c) expression and signaling, decreased the phosphorylation of cAMP response element-binding protein (CREB) and STAT3, and dampened the production of pro-opiomelanocortin (POMC, the precursor of α-melanocyte stimulating hormone [α-MSH]) in hypothalamic neurons, thereby increasing food intake. Accordingly, exogenous stimulation of the melanocortin 4 receptor (Mc4r) by cotreating mice with Flx and lipocalin 2, an anorexigenic hormone signaling through this receptor, normalized feeding and BW. Flx and other SSRIs also inhibited CREB and STAT3 phosphorylation in a human neuronal cell line, suggesting that these noncanonical effects could also occur in individuals treated long term with SSRIs. By defining the molecular basis of long-term SSRI-associated weight gain, we propose a therapeutic strategy to counter this effect. Show less

Excess liver fat, called hepatic steatosis, is a leading risk factor for end-stage liver disease and cardiometabolic diseases but often remains undiagnosed in clinical practice because of the need for direct imaging assessments. We developed an abdominal MRI-based machine-learning algorithm to accurately estimate liver fat (correlation coefficients, 0.97-0.99) from a truth dataset of 4,511 middle-aged UK Biobank participants, enabling quantification in 32,192 additional individuals. 17% of participants had predicted liver fat levels indicative of steatosis, and liver fat could not have been reliably estimated based on clinical factors such as BMI. A genome-wide association study of common genetic variants and liver fat replicated three known associations and identified five newly associated variants in or near the Show less

While fibrosis stage predicts liver-associated mortality, cardiovascular disease (CVD) is still the major overall cause of mortality in patients with NASH. Novel NASH drugs should thus ideally reduce both liver fibrosis and CVD. Icosabutate is a semi-synthetic, liver-targeted eicosapentaenoic acid (EPA) derivative in clinical development for NASH. The primary aims of the current studies were to establish both the anti-fibrotic and anti-atherogenic efficacy of icosabutate in conjunction with changes in lipotoxic and atherogenic lipids in liver and plasma respectively. The effects of icosabutate on fibrosis progression and lipotoxicity were investigated in amylin liver NASH (AMLN) diet (high fat, cholesterol and fructose) fed ob/ob mice with biopsy-confirmed steatohepatitis and fibrosis and compared with the activity of obeticholic acid. APOE*3Leiden.CETP mice, a translational model for hyperlipidaemia and atherosclerosis, were used to evaluate the mechanisms underlying the lipid-lowering effect of icosabutate and its effect on atherosclerosis. In AMLN ob/ob mice, icosabutate significantly reduced hepatic fibrosis and myofibroblast content in association with downregulation of the arachidonic acid cascade and a reduction in both hepatic oxidised phospholipids and apoptosis. In APOE*3Leiden.CETP mice, icosabutate reduced plasma cholesterol and TAG levels via increased hepatic uptake, upregulated hepatic lipid metabolism and downregulated inflammation pathways, and effectively decreased atherosclerosis development. Icosabutate, a structurally engineered EPA derivative, effectively attenuates both hepatic fibrosis and atherogenesis and offers an attractive therapeutic approach to both liver- and CV-related morbidity and mortality in NASH patients. Show less

Radiotherapy is commonly used to treat a variety of solid human tumors, including localized prostate cancer. However, treatment failure often ensues due to tumor intrinsic or acquired radioresistance. Here we find that the MEK5/ERK5 signaling pathway is associated with resistance to genotoxic stress in aggressive prostate cancer cells. MEK5 knockdown by RNA interference sensitizes prostate cancer cells to ionizing radiation (IR) and etoposide treatment, as assessed by clonogenic survival and short-term proliferation assays. Mechanistically, MEK5 downregulation impairs phosphorylation of the catalytic subunit of DNA-PK at serine 2056 in response to IR or etoposide treatment. Although MEK5 knockdown does not influence the initial appearance of radiation- and etoposide-induced γH2AX and 53BP1 foci, it markedly delays their resolution, indicating a DNA repair defect. A cell-based assay shows that nonhomologous end joining (NHEJ) is compromised in cells with ablated MEK5 protein expression. Finally, MEK5 silencing combined with focal irradiation causes strong inhibition of tumor growth in mouse xenografts, compared with MEK5 depletion or radiation alone. These findings reveal a convergence between MEK5 signaling and DNA repair by NHEJ in conferring resistance to genotoxic stress in advanced prostate cancer and suggest targeting MEK5 as an effective therapeutic intervention in the management of this disease. Show less

Lipoprotein lipase (LPL) and endothelial lipase (EL) are involved in lipoprotein metabolism. In insulin-resistance, their behavior is altered. Peroxisome proliferator-activated receptors (PPAR) and apoproteins (apo)CII and CIII could be partly responsible for these alterations. To evaluate this response, we assessed Lpl and Lipg expression, protein levels, and enzyme activity in adipose tissue (AT) and heart in an obesity model. Besides, we assessed the role of PPAR and apoC. Male Wistar rats were fed with standard diet (Control, n = 14) or high-fat diet (HFD, n = 14) for 14 weeks. Glucose and lipoprotein profiles were measured. Histological studies were performed in heart and epididymal AT. Lpl and Lipg were assessed by reverse transcription polymerase chain reaction (RT-qPCR), protein levels by Western Blot, and activities by radiometric assays. Cardiac and AT PPAR expression were measured by Western Blot and hepatic Apoc2 and Apoc3 mRNA by RT-qPCR. In HFD, fat deposits were observed in hearts, whereas AT presented a higher adipocyte size. In heart and AT, no differences were found in Lipg mRNA between groups, while AT Lpl mRNA and LPL protein were decreased in HFD, without differences in heart. In both tissues, EL protein levels and activity were increased and inversely associated with decreased LPL activity, being partially responsible for the atherogenic lipoprotein profile in HFD. PPARγ expression in AT was decreased in HFD, without differences in cardiac PPARδ expression and hepatic apoC mRNA. The increase in EL activity could be an alternative pathway for fatty acid release from lipoproteins and uptake in tissues with decreased LPL activity. In AT, PPARγ could be involved in enzyme regulation. Show less

Pancreatic cancer is one of the most lethal human malignancies. A better understanding of the intracellular mechanism of migration and invasion is urgently needed to develop treatment that will suppress metastases and improve overall survival. Cyclic adenosine monophosphate (cyclic AMP) is a second messenger that has shown to regulate migration and invasion of pancreatic cancer cells. The rise of cyclic AMP suppressed migration and invasion of pancreatic ductal adenocarcinoma cells. Cyclic AMP is formed from cytosolic ATP by the enzyme adenylyl cyclase (AC). There are ten isoforms of ACs; nine are anchored in the plasma membrane and one is soluble. What remains unknown is the extent to which the expression of transmembrane AC isoforms is both modified in pancreatic cancer and mediates the inhibitory effect of forskolin on cell motility. Using real-time PCR analysis, ADCY3 was found to be highly expressed in pancreatic tumor tissues, resulting in a constitutive increase in cyclic AMP levels. On the other hand, ADCY2 was down-regulated. Migration, invasion, and filopodia formation in two different pancreatic adenocarcinoma cell lines, HPAC and PANC-1 deficient in AC1 or AC3, were studied. We found that AC3, upon stimulation with forskolin, enhanced cyclic AMP levels and inhibited cell migration and invasion. Unlikely to be due to a cytotoxic effect, the inhibitory effects of forskolin involved the quick formation of AC3/adenylyl cyclase-associated protein 1 (CAP1)/G-actin complex, which inhibited filopodia formation and cell motility. Using Western blotting analysis, forskolin, through AC3 activation, caused phosphorylation of CREB, but not ERK. The effect of CREB phosphorylation is likely to be associated with long-term signaling changes. © 2016 Wiley Periodicals, Inc. Show less

The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype. Show less

Low back pain (LBP) is responsible for more than 2.5 million visits to US emergency departments (EDs) annually. These patients are usually treated with nonsteroidal anti-inflammatory drugs, acetaminophen, opioids, or skeletal muscle relaxants, often in combination. To compare functional outcomes and pain at 1 week and 3 months after an ED visit for acute LBP among patients randomized to a 10-day course of (1) naproxen + placebo; (2) naproxen + cyclobenzaprine; or (3) naproxen + oxycodone/acetaminophen. This randomized, double-blind, 3-group study was conducted at one urban ED in the Bronx, New York City. Patients who presented with nontraumatic, nonradicular LBP of 2 weeks' duration or less were eligible for enrollment upon ED discharge if they had a score greater than 5 on the Roland-Morris Disability Questionnaire (RMDQ). The RMDQ is a 24-item questionnaire commonly used to measure LBP and related functional impairment on which 0 indicates no functional impairment and 24 indicates maximum impairment. Beginning in April 2012, a total of 2588 patients were approached for enrollment. Of the 323 deemed eligible for participation, 107 were randomized to receive placebo and 108 each to cyclobenzaprine and to oxycodone/acetaminophen. Follow-up was completed in December 2014. All participants were given 20 tablets of naproxen, 500 mg, to be taken twice a day. They were randomized to receive either 60 tablets of placebo; cyclobenzaprine, 5 mg; or oxycodone, 5 mg/acetaminophen, 325 mg. Participants were instructed to take 1 or 2 of these tablets every 8 hours, as needed for LBP. They also received a standardized 10-minute LBP educational session prior to discharge. The primary outcome was improvement in RMDQ between ED discharge and 1 week later. Demographic characteristics were comparable among the 3 groups. At baseline, median RMDQ score in the placebo group was 20 (interquartile range [IQR],17-21), in the cyclobenzaprine group 19 (IQR,17-21), and in the oxycodone/acetaminophen group 20 (IQR,17-22). At 1-week follow-up, the mean RMDQ improvement was 9.8 in the placebo group, 10.1 in the cyclobenzaprine group, and 11.1 in the oxycodone/acetaminophen group. Between-group difference in mean RMDQ improvement for cyclobenzaprine vs placebo was 0.3 (98.3% CI, -2.6 to 3.2; P = .77), for oxycodone/acetaminophen vs placebo, 1.3 (98.3% CI, -1.5 to 4.1; P = .28), and for oxycodone/acetaminophen vs cyclobenzaprine, 0.9 (98.3% CI, -2.1 to 3.9; P = .45). Among patients with acute, nontraumatic, nonradicular LBP presenting to the ED, adding cyclobenzaprine or oxycodone/acetaminophen to naproxen alone did not improve functional outcomes or pain at 1-week follow-up. These findings do not support use of these additional medications in this setting. clinicaltrials.gov Identifier: NCT01587274. Show less

A robust, bistable switch regulates the fluctuations between wakefulness and natural sleep as well as those between wakefulness and anesthetic-induced unresponsiveness. We previously provided experimental evidence for the existence of a behavioral barrier to transitions between these states of arousal, which we call neural inertia. Here we show that neural inertia is controlled by processes that contribute to sleep homeostasis and requires four genes involved in electrical excitability: Sh, sss, na and unc79. Although loss of function mutations in these genes can increase or decrease sensitivity to anesthesia induction, surprisingly, they all collapse neural inertia. These effects are genetically selective: neural inertia is not perturbed by loss-of-function mutations in all genes required for the sleep/wake cycle. These effects are also anatomically selective: sss acts in different neurons to influence arousal-promoting and arousal-suppressing processes underlying neural inertia. Supporting the idea that anesthesia and sleep share some, but not all, genetic and anatomical arousal-regulating pathways, we demonstrate that increasing homeostatic sleep drive widens the neural inertial barrier. We propose that processes selectively contributing to sleep homeostasis and neural inertia may be impaired in pathophysiological conditions such as coma and persistent vegetative states. Show less

Interindividual variation in response to anti-TNFalpha therapy may be explained by genetic variability in disease pathogenesis or mechanism of action. Recent genome-wide association studies (GWAS) in inflammatory bowel disease (IBD) have increased our understanding of the genetic susceptibility to IBD. The aim was to test associations of known IBD susceptibility loci and novel "pharmacogenetic" GWAS identified loci with primary nonresponse to anti-TNFalpha in pediatric IBD patients and develop a predictive model of primary nonresponse. Primary nonresponse was defined using the Harvey Bradshaw Index (HBI) for Crohn's disease (CD) and partial Mayo score for ulcerative colitis (UC). Genotyping was performed using the Illumina Infinium platform. Chi-square analysis tested associations of phenotype and genotype with primary nonresponse. Genetic associations were identified by testing known IBD susceptibility loci and by performing a GWAS for primary nonresponse. Stepwise multiple logistic regression was performed to build predictive models. Nonresponse occurred in 22 of 94 subjects. Six known susceptibility loci were associated with primary nonresponse (P < 0.05). Only the 21q22.2/BRWDI loci remained significant in the predictive model. The most predictive model included 3 novel "pharmacogenetic" GWAS loci, the previously identified BRWD1, pANCA, and a UC diagnosis (R(2) = 0.82 and area under the curve [AUC] = 0.98%). The relative risk of nonresponse increased 15-fold when number of risk factors increased from 0-2 to > or =3. The combination of phenotype and genotype is most predictive of primary nonresponse to anti-TNFalpha in pediatric IBD. Defining predictors of response to anti-TNFalpha may allow the identification of patients who will not benefit from this class of therapy. Show less