👤 Maryam Syed

The apolipoprotein E (APOE) gene ε4 allele leads to increased Alzheimer disease risk and neuroinflammation and is also believed to play a role in postoperative delirium. However, the safety and feasibility of modulating apoE protein signaling to reduce postoperative neuroinflammation and delirium in older adults are unclear. To assess the safety and feasibility of the apoE mimetic peptide CN-105 for reducing delirium incidence and severity and neuroinflammation after noncardiac or nonintracranial surgery in older adults. This triple-blind, escalating dose, phase 2 randomized clinical trial enrolled patients from April 17, 2019, to December 28, 2022, at a tertiary academic medical center. Included patients were 60 years or older and scheduled for a noncardiac or nonintracranial surgery. Exclusion criteria were incarceration, planned chemotherapy within 6 weeks after surgery, or inability to undergo lumbar punctures. Data analyses were based on a modified intention-to-treat approach and were performed from August 14, 2023, to August 22, 2025. Patients were randomly assigned 3:1 to the CN-105 group or placebo group. The CN-105 group received intravenous CN-105 doses of 0.1, 0.5, or 1 mg/kg starting within 1 hour before surgery and administered every 6 hours afterward until hospital discharge or 13 doses were received. Patients in the placebo group followed the same administration schedule. The primary outcome was safety-the incidence and number of postoperative adverse events (AEs). Secondary outcomes included feasibility (rate of drug doses administered within 90 minutes of schedule), postoperative delirium incidence and severity, and postoperative changes in cerebrospinal fluid (CSF) cytokine levels (interleukin [IL] 6, granulocyte-colony stimulating factor [G-CSF], monocyte chemoattractant protein-1 [MCP-1], and IL-8). Among 203 enrolled patients, 186 (mean [SD] age, 68.7 [5.2] years; 119 males [64.0%]) were randomized (137 to the CN-105 group, 49 to the placebo group) and underwent surgery. The rates of grade 2 or higher AEs among patients in the CN-105 and placebo groups were 76.6% and 87.8% (relative risk [RR], 0.87; 95% CI, 0.76-1.00; P = .10). The CN-105 vs placebo group had fewer grade 2 or higher AEs per patient (median [IQR], 1 [1-3] vs 2 [1-5]; P = .03). The percentage of CN-105 doses administered within the time window was 94.6% (860 of 909; 95% CI, 92.9%-96.0%) in the CN-105 group and 93.8% (346 of 369; 95% CI, 90.8%-96.0%) in the placebo group. Among patients in the CN-105 vs placebo group, the postoperative delirium incidence was 19.3% vs 26.5% (odds ratio [OR], 0.66; 95% CI, 0.31-1.42; P = .29); the median (IQR) postoperative delirium severity scores were 1 (1-2) vs 2 (1-2) (P = .19); and the median difference in preoperative to 24-hour postoperative CSF cytokine-level changes were as follows: -0.39 pg/mL (95% CI, -0.93 to 0.14 pg/mL, P = .12) for IL-6, -0.84 pg/mL (95% CI, -3.06 to 1.40 pg/mL; P = .18) for G-CSF,-23.32 pg/mL (95% CI, -94.36 to 44.93 pg/mL; P = .57) for IL-8, and -2.36 pg/mL (95% CI, -58.57 to 58.62 pg/mL; P = .50) for MCP-1. In this phase 2 randomized clinical trial of older surgical patients, CN-105 (vs placebo) administration was feasible and did not increase AEs. A phase 3 trial is warranted to further evaluate the efficacy of CN-105 for reducing postoperative AEs and to more precisely determine its effects on postoperative delirium incidence and severity. ClinicalTrials.gov Identifier: NCT03802396. Show less

Most brain organoids derived from human induced pluripotent stem cells (iPSCs) lack microglia and thus immune function. Microglia-like cells (MGCs) can be differentiated from iPSCs, while the characteristics of isogenic MGC-containing brain organoids in modeling neurodegeneration and cell-cell communications have not been well investigated. In this study, iPSC-derived MGCs are co-cultured with isogenic forebrain cortical organoids (iFCo), which are stimulated with extracellular vesicles (EVs) of brain organoids differentiated from Alzheimer's disease (AD) patient-derived iPSCs (APOE ε4/ε4 and presenilin 1). The AD EV-stimulated co-culture organoids are treated with EVs from healthy MGCs or co-culture. Differential responses of the co-cultured organoids and the MGCs to AD EVs are demonstrated. The co-cultured organoids mitigated pro-inflammatory gene expressions. EVs from healthy MGCs or co-culture reduced the expression of IL-12β, iNOS, TREM2, and CASS4, which are associated with neural inflammation and degeneration, as well as showed regulation on genes involved in microglial activation and carbon metabolism. AD EV cargo analysis by proteomics and microRNA-sequencing revealed APOE and APP proteins and microRNAs regulated pathways such as mitophagy. This study paves the way for understanding the role of microglia and brain organoids in modeling neural degeneration and the development of EV-based cell-free therapeutics for AD treatment. Show less

Current antiepileptic drugs are effective in suppressing motor seizures; however, they often do not address the underlying factors such as oxidative stress, inflammation, and neurotrophic imbalances that contribute to the development of epilepsy. Recently, flavonoids sourced from diet have attracted attention as neuromodulators that can target these root causes. This study evaluated the protective effects of sakuranetin-a flavonoid found in edible Prunus species-against pentylenetetrazole (PTZ)-induced seizures and neurochemical changes in mice. Swiss albino mice (n = 6/group) were treated with saline, PTZ (35 mg/kg, intraperitoneally), or PTZ combined with sakuranetin (10 or 20 mg/kg, orally) every other day for 28 days. The study assessed seizure activity, oxidative stress markers, inflammatory cytokines, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), and caspase-3 activity. Additionally, in silico docking and 100 ns molecular dynamics simulations were performed to investigate sakuranetin's interactions with BDNF, TrkB, and D₂-like receptors. The results showed that sakuranetin treatment significantly improved seizure parameters. The onset latency was extended with both doses. The duration of clonic-tonic seizures was reduced by half, and mortality rates dropped from 50% to 8%. PTZ-induced reductions in neurotransmitters (such as GABA, dopamine, norepinephrine, serotonin, and acetylcholine) were restored, antioxidant defenses (including superoxide dismutase, catalase, and glutathione) were enhanced, and both lipid peroxidation (measured by malondialdehyde) and nitrosative stress (nitric oxide) were significantly decreased. Pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) were reduced, BDNF and TrkB levels approached control levels, and caspase-3 activity was diminished. Docking studies and MM-GBSA analyses indicated that BDNF was the most favorable binding partner for sakuranetin (with a binding free energy of approximately - 57 kcal/mol), and the simulations affirmed the stability of the complex. These findings suggest that sakuranetin has substantial, multi-target anticonvulsant effects by restoring neurotransmitter balance, enhancing antioxidant capacity, suppressing neuroinflammation, and revitalizing BDNF/TrkB signaling. Given its dietary origin, sakuranetin warrants further investigation as a potential nutraceutical candidate for managing epilepsy. Show less

AD is a neurodegenerative disorder and is associated with the presence of amyloid-β plaques and neurofibrillary tangles leading to net loss of neurons, which demonstrates an urgent unmet need to develop new human health therapies based on the fundamental mechanisms of oxidative stress and neuroinflammation. This work is a computational assessment of the potential use of neolupenol, a triterpenoid produced in Pluchea lanceolata, as a pharmacologically active compound that exerted its beneficial effect through the modulation of the Keap1-Nrf2 axis, one of the central regulators of the antioxidant response. Using an integrated approach that combined network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we identified neolupenol as a high-affinity Keap1-binding molecule capable of activating the Nrf2-mediated neuroprotective pathway. Virtual screening of 25 phytochemicals from Pluchea lanceolata (retrieved from the PubChem database) with customized filters revealed neolupenol as the top candidate, showing strong binding affinity (- 8.22 kcal/mol; Ki = 1.45 µM) toward the Keap1 Kelch domain (PDB ID: 2FLU). The docked complex demonstrated hydrogen bonds with VAL463 (2.17 Å), THR560, and ILE559, along with hydrophobic interactions involving CYS513, ALA366, and VAL514, which collectively stabilized the ligand at the Neh2-binding interface. Network pharmacology yielded 30 of such common targets of AD-neolupenol (e.g., GSK3B, CASP3, TNF, and BACE1), enriched in pathways such as amyloid processing, tau phosphorylation, oxidative stress response, and lipid metabolism (FDR-adjusted p < 0.0001). Complex stability was verified by MD simulations (100 ns): RMSD of the backbone 2.34-3.84 = 2.34 Å, unchanged radius of gyration (17.8-18.0 Å), and stable inter-hydrogen bonding. Residues VAL561, PHE577, and SER602 were found to have an interaction occupancy of > 70%, providing a basis of dynamic stability. The triterpenoid cavity appeared in neolupenol contributing to pleasant PK, the ability to herald the blood-brain barrier, and suboptimal toxicity. These results position neolupenol as a potent, multi-target neuroprotective agent that disrupts Keap1-Nrf2 interaction, promoting Nrf2 nuclear translocation and antioxidant gene activation. Future work warrants in vivo validation of its efficacy in mitigating AD pathology and clinical translation. Show less

Prostate cancer (PCa) remains a significant global health challenge, with approximately 1.6 million new cases and 366,000 deaths annually. Despite high survival rates for localized prostate cancer, recurrence poses a substantial risk due to inherent biological factors and residual disease. Early detection and intervention are essential for enhancing patient outcomes and reducing mortality. However, traditional diagnostics such as PSA tests, digital rectal examinations, and biopsies often lack specificity resulting in overdiagnosis. There is a pressing need for novel biomarkers to enhance precision medicine approaches for PCa. This study employs a machine learning approach to identify DNA methylation and RNA expression biomarkers predictive of PCa recurrence using datasets from The Cancer Genome Atlas (TCGA). We analyzed 49,133 genes, identifying 684 differentially methylated genes (DMGs) and 691 differentially expressed genes (DEGs) between recurrence and non-recurrence groups. Ten genes (TNNI2, SPIN2, COL5A3, RNF169, CCND1, FGFR1, SLC17A2, FAMM71F2, RREB1, AOX1) were found to have significant correlations between methylation and expression, forming the basis for our predictive model. A support vector machine (SVM) model was developed using these ten genes, achieving an area under the curve (AUC) of 0.773, demonstrating robust predictive capability. Multivariate regression analysis confirmed the SVM score as an independent predictor of recurrence (HR = 0.45; 95% CI 0.28-0.69, P < 0.001). The analysis of recurrence-free survival suggested that patients with low-risk scores experienced significantly better outcomes compared to those with high-risk scores. Functional enrichment analyses of DMGs revealed significant involvement in biological processes such as transcription regulation, signal transduction, and immune response, highlighting the potential mechanistic pathways of these biomarkers. Validation using real-time PCR confirmed differential expression and methylation patterns of the identified genes in prostate cancer (PC3) and non-cancerous cell lines (PNT2). In conclusion, our study hihglights the DNA methylation biomarkers linked to PCa recurrence and introduces a promising SVM model for early prediction, potentially improving treatment outcomes. Further research is needed to explore the biological roles of these genes in PCa aiming to refine therapeutic approaches. Show less

Parkinson's disease (PD) arises from genetic and environmental factors. Human genetics has identified mutations in ~20 inherited familial genes linked to monogenic forms of PD. To investigate the effects of individual familial PD mutations, human pluripotent embryonic stem cells (hPSCs) carrying 12 distinct familial PD mutations were differentiated into midbrain lineage cells, including dopaminergic (mDA) neurons. Global gene expression and pre-mRNA splicing patterns were analyzed in midbrain cultures carrying pathogenic PD mutations in the Show less

Parkinson's disease (PD) is a neurodegenerative disorder caused by complex genetic and environmental factors. Genome-edited human pluripotent stem cells (hPSCs) offer a unique experimental platform to advance our understanding of PD etiology by enabling the generation of disease-relevant cell types carrying patient mutations along with isogenic control cells. To facilitate this approach, we generated a collection of 65 human stem cell lines genetically engineered to harbor high risk or causal variants in genes associated with PD ( Show less

Arsenic exposure is connected with lung toxicity and is related to lung fibrotic changes. Idiopathic pulmonary fibrosis (IPF) is characterized by extracellular matrix (ECM) deposition. Various genetic mechanisms and environmental factors induce or exacerbate pulmonary fibrosis. Collagen synthesis induced by sodium arsenite (NaAsO Show less

What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)? Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included. CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility. Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls. The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS). A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were N/A. The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken. This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH. This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine-a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests. Show less

Craniofacial osteosarcomas (CFOS) are uncommon malignant neoplasms of the head and neck with different clinical presentation, biological behavior and prognosis from conventional osteosarcomas of long bones. Very limited genetic data have been published on CFOS. In the current study, we performed comprehensive genomic studies in 15 cases of high-grade CFOS by SNP array and targeted next generation sequencing. Our study shows high-grade CFOS demonstrate highly complex and heterogenous genomic alterations and harbor frequently mutated tumor suppressor genes TP53, CDKN2A/B, and PTEN, similar to conventional osteosarcomas. Potentially actionable gene amplifications involving CCNE1, AKT2, MET, NTRK1, PDGFRA, KDR, KIT, MAP3K14, FGFR1, and AURKA were seen in 43% of cases. GNAS hotspot activating mutations were also identified in a subset of CFOS cases, with one case representing malignant transformation from fibrous dysplasia, suggesting a role for GNAS mutation in the development of CFOS. High-grade CFOS demonstrate highly complex and heterogenous genomic alterations, with amplification involving receptor tyrosine kinase genes, and frequent mutations involving tumor suppressor genes. Show less

Lymphoplasmacytic lymphoma (LPL) is an uncommon condition, accounting for only 2% of all non-Hodgkin's lymphoma cases. Individuals with LPL face the risk of vascular blockage when associated with type I cryoglobulinemia, leading to related symptoms. Until now, no instances of LPL with dry gangrene have been documented. However, we present a rare case involving LPL accompanied by dry gangrene in both the right upper extremity (RUE) and left lower extremity (LLE). The patient was effectively managed using a combination of chemotherapy, steroids, plasmapheresis, and salvage surgery. Show less

Monogenic obesity (MO) is a rare genetic disease characterized by severe early-onset obesity in affected individuals. Previous genetic studies revealed 8 definitive genes for monogenic non-syndromic obesity; many were discovered in consanguineous populations. Here, we examined MO in the Qatari population, whose population is largely consanguineous (54%) and characterized by extensive obesity (45%). Whole genome sequencing data of Qatar Biobank samples from 250 subjects with obesity and 250 subjects with normal weight, obtained in association with the Qatar Genome Programme, were searched for genetic variants in the genes known to be associated with MO (i.e., LEP, LEPR, POMC, PCSK1, MC3R, MC4R, MRAP2, and ADCY3). The impact of the variants identified was investigated utilizing in silico tools for prediction in combination with protein visualization by PyMOL. We identified potential MO variants in more than 5% of the cases in our cohort. We revealed 11 rare variants in 6 of the genes targeted, including two disease-causing variants in MC4R and MRAP2, all of which were heterozygous. Moreover, enrichment of a heterozygous ADCY3 variant (c.1658C>T; p.A553V) appeared to cause severe obesity in an autosomal dominant manner. These findings highlight the importance of implementing routine testing for genetic variants that predispose for MO in Qatar. Clearly, additional studies of this nature on populations not yet examined are required. At the same time, functional investigations, both in vitro and in vivo, are necessary in order to better understand the role of the variants identified in the pathogenesis of obesity. Show less

There is compelling evidence that head injury is a significant environmental risk factor for Alzheimer's disease (AD) and that a history of traumatic brain injury (TBI) accelerates the onset of AD. Amyloid-β plaques and tau aggregates have been observed in the post-mortem brains of TBI patients; however, the mechanisms leading to AD neuropathology in TBI are still unknown. In this study, we hypothesized that focal TBI induces changes in miRNA expression in and around affected areas, resulting in the altered expression of genes involved in neurodegeneration and AD pathology. For this purpose, we performed a miRNA array in extracts from rats subjected to experimental TBI, using the controlled cortical impact (CCI) model. In and around the contusion, we observed alterations of miRNAs associated with dementia/AD, compared to the contralateral side. Specifically, the expression of miR-9 was significantly upregulated, while miR-29b, miR-34a, miR-106b, miR-181a and miR-107 were downregulated. Via qPCR, we confirmed these results in an additional group of injured rats when compared to naïve animals. Interestingly, the changes in those miRNAs were concomitant with alterations in the gene expression of mRNAs involved in amyloid generation and tau pathology, such as β-APP cleaving enzyme (BACE1) and Glycogen synthase-3-β (GSK3β). In addition increased levels of neuroinflammatory markers (TNF-α), glial activation, neuronal loss, and tau phosphorylation were observed in pericontusional areas. Therefore, our results suggest that the secondary injury cascade in TBI affects miRNAs regulating the expression of genes involved in AD dementia. Show less

Bariatric surgery (BS) results in metabolic pathway recalibration. We have identified potential biomarkers in plasma of people achieving type 2 diabetes mellitus (T2DM) remission after BS. Longitudinal analysis was performed on plasma from 10 individuals following Roux-en-Y gastric bypass ( Show less

Glioblastoma (GBM) has poor median survival due to its resistance to chemoradiotherapy, which results in tumor recurrence. Recurrent GBMs currently lack effective treatments. DUSP6 is known to be pro-tumorigenic and is upregulated in GBM. We show that DUSP6 expression is significantly higher in recurrent GBM patient biopsies compared to expression levels in primary GBM biopsies. Importantly, although it has been reported to be a cytoplasmic protein, we found nuclear localization of DUSP6 in primary and recurrent patient samples and in parent and relapse populations of GBM cell lines generated from an in vitro radiation survival model. DUSP6 inhibition using BCI resulted in decreased proliferation and clonogenic survival of parent and relapse cells. Pharmacological or genetic inhibition of DUSP6 catalytic activity radiosensitized primary and, importantly, relapse GBM cells by inhibiting the recruitment of phosphorylated DNAPKcs (also known as PRKDC), subsequently downregulating the recruitment of phosphorylated histone H2AX (γH2AX) and 53BP1 (also known as TP53BP1). This resulted in decreased cell survival and prolonged growth arrest upon irradiation in vitro and significantly increased the progression-free survival in orthotopic mouse models of GBM. Our study highlights a non-canonical function of DUSP6, emphasizing the potential application of DUSP6 inhibitors in the treatment of recurrent GBM. Show less

Testosterone has historically been linked to sexual dysfunction; however, it has recently been shown to affect other physical and mental attributes. We attempted to determine whether changes in serum testosterone could play a role in chronic or degenerative diseases. We used two separate genetic instruments comprising of variants from Show less

Major Depressive Disorder (MDD) is a common psychiatric disorder for which available medications are often not effective. The high prevalence of MDD and modest response to existing therapies compels efforts to better understand and treat the disorder. Decreased hippocampal volume with increasing duration of depression suggests altered gene expression or even a decrease in neurogenesis. Tissue punches from the dentate gyrus were collected postmortem from 23 subjects with MDD and 23 psychiatrically-normal control subjects. Total RNA was isolated and whole transcriptome paired-end RNA-sequencing was performed using an Illumina NextSeq 500. For each sample, raw RNA-seq reads were aligned to the Ensembl GRCh38 human reference genome. Analysis revealed 30 genes differentially expressed in MDD compared to controls (FDR<0.05). Down-regulated genes included several with inflammatory function (ISG15, IFI44L, IFI6, NR4A1/Nur-77) and GABBR1 while up-regulated genes included several with cytokine function (CCL2/MCP-1), inhibitors of angiogenesis (ADM, ADAMTS9), and the KANSL1 gene, a histone acetyltransferase. Similar analyses of specific subsets of MDD subjects (suicide vs. non-suicide, single vs. multiple episodes) yielded similar, though not identical, results. Enrichment analysis identified an over-representation of inflammatory and neurogenesis-related (ERK/MAPK) signaling pathways significantly altered in the hippocampal dentate gyrus in MDD. Together, these data implicate neuro-inflammation as playing a crucial role in MDD. These findings support continued efforts to identify adjunctive approaches towards the treatment of MDD with drugs including anti-inflammatory and neuroprotective properties. Show less

Lower adipose-ChREBP and de novo lipogenesis (DNL) are associated with insulin resistance in humans. Here, we generated adipose-specific ChREBP knockout (AdChREBP KO) mice with negligible sucrose-induced DNL in adipose tissue (AT). Chow-fed AdChREBP KO mice are insulin resistant with impaired insulin action in the liver, muscle, and AT and increased AT inflammation. HFD-fed AdChREBP KO mice are also more insulin resistant than controls. Surprisingly, adipocytes lacking ChREBP display a cell-autonomous reduction in insulin-stimulated glucose transport that is mediated by impaired Glut4 translocation and exocytosis, not lower Glut4 levels. AdChREBP KO mice have lower levels of palmitic acid esters of hydroxy stearic acids (PAHSAs) in serum, and AT. 9-PAHSA supplementation completely rescues their insulin resistance and AT inflammation. 9-PAHSA also normalizes impaired glucose transport and Glut4 exocytosis in ChREBP KO adipocytes. Thus, loss of adipose-ChREBP is sufficient to cause insulin resistance, potentially by regulating AT glucose transport and flux through specific lipogenic pathways. Show less