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Macrophages can develop into pro-inflammatory M1-like macrophages and anti-inflammatory M2-like macrophages when stimulated by distinct internal environment. Dynamic changes of the two kinds of macrophages play key roles in atherosclerosis progression. The study aims to explore the role of ring finger protein 10 (RNF10) in regulating macrophage polarization during atherosclerosis. Mice with macrophage-specific depletion of RNF10 (RNF10 Show less

Familial chylomicronemia syndrome (FCS) is a rare, inherited lipid disorder characterized by severe hypertriglyceridemia and a risk of recurrent pancreatitis. Patients with biallelic pathogenic variants affecting lipoprotein lipase (LPL)-mediated triglyceride metabolism may remain refractory to conventional lipid-lowering therapies and strict dietary control, leading to recurrent critical illness and progressive multisystem complications. We report a female patient with genetically confirmed FCS and persistent triglyceride levels typically in the 4,000-5,000 mg/dL range despite adherence to diet and lipid-lowering therapy, without clear secondary contributors to severe hypertriglyceridemia. Her course included recurrent intensive care unit (ICU) admissions for hypertriglyceridemia-associated pancreatitis requiring insulin drips, with progression to chronic pancreatitis, pancreatic insufficiency requiring enzyme replacement, insulin-dependent diabetes with continuous glucose monitoring (CGM), chronic pain syndrome with opioid dependence concerns, and psychiatric comorbidity. During a hospitalization approximately 10 months prior to the most recent follow-up, the patient underwent placement of a right chest tunneled central venous catheter and initiated therapeutic plasmapheresis. She was concurrently followed by a triglyceride clinic and continued on olezarsen. At follow-up on February 25, 2025, she reported no hospitalizations since April 2024. A triglyceride value of 4,700 mg/dL was documented shortly before a scheduled plasmapheresis session. This case highlights the complexity of severe FCS when hypertriglyceridemia remains refractory to conventional management and illustrates a care pathway in which chronic outpatient plasmapheresis combined with emerging RNA-based therapy was associated with stabilization and avoidance of recurrent hospitalization. Sustained outpatient success required multidisciplinary coordination, addressing pancreatitis sequelae, glycemic management, chronic pain, psychiatric disease, and central-line monitoring. These observations are hypothesis-generating and highlight the potential role of coordinated outpatient plasmapheresis and emerging RNA-based therapies in the management of severe FCS. To our knowledge, reports describing long-term outpatient stabilization of severe FCS using combined chronic plasmapheresis and apolipoprotein C-III (APOC3)-targeted RNA therapy remain limited, and this case highlights a potential care pathway for patients with refractory disease. Show less

Accumulating evidence indicates that Alzheimer disease (AD) is caused by dysregulated microglial phagocytosis. The main risk factor for AD is age, and ageing reduces microglial phagocytosis of amyloid-β (Aβ) plaques, while increasing microglial phagocytosis of synapses and neurons. Most of the known genetic risk for AD can be linked to microglial phagocytosis, including ABCA1, ABI3, ACE, ADAM17, APOE, APP, BIN1, BLNK, CD2AP, CD33, CLU, CR1, CTSB, CTSH, EED, GRN, INPP5D, LILRB2, PICALM, PLCG2, PSEN1, PTK2B, SIGLEC11, SORL1, SPI1, TMEM106B and TREM2. Moreover, the only disease-modifying treatments for AD - anti-Aβ antibodies - work by increasing microglial phagocytosis of Aβ aggregates. Microglial phagocytosis of Aβ via TREM2, LRP1, CD33, TAM receptors and anti-Aβ antibodies appears to reduce AD pathology by pruning and compacting plaques, restricting subsequent tau pathology, whereas microglial phagocytosis of synapses and neurons seems detrimental in the later stages of AD, via complement, P2Y Show less

Lipoprotein(a) (Lp(a)) is a highly atherogenic lipoprotein and the target of investigational therapies. Using a Mendelian randomization study design, we aimed to clarify associations between genetically predicted Lp(a) levels and cerebrovascular disease outcomes and related phenotypes. We obtained genetic associations with Lp(a) levels ( Genetically predicted Lp(a) levels associated with significantly increased risk of all-cause ischemic stroke (odds ratio [OR], 1.04 [95% CI, 1.02-1.07], Elevated Lp(a) is primarily associated with ischemic stroke due to large artery atherosclerosis, while showing no link to cerebral small vessel disease. These findings support prioritization of patients with atherosclerotic cerebrovascular disease in Lp(a)-lowering stroke prevention trials. Show less

Apolipoprotein E (APOE) plays a tissue-specific role in diet-induced obesity: brain-expressed APOE promotes obesity, while hepatic APOE appears protective. Physiological plasma APOE levels facilitate clearance of atherogenic lipoproteins; however, supraphysiological levels induce hypertriglyceridemia and impair cholesterol clearance. APOE-induced hypertriglyceridemia has been linked to its carboxyl-terminal region (amino acids 260-270), particularly residues L261, W264, F265, L268, and V269. A bioengineered APOE4 variant, APOE4mut1, where these residues are substituted with alanine, promotes cholesterol clearance without inducing hypertriglyceridemia at any level of expression. This study examined APOE4mut1 effects on adipose tissue metabolism in vivo. Wild-type (C57BL/6) and APOE4 Show less

Primary renal small cell carcinoma (PRSCC) is a rare, poorly differentiated neuroendocrine carcinoma, and its clinicopathological features and the gene mutation spectrum associated with its pathogenesis remain to be elucidated. The present study aimed to characterize the genetic mutation spectrum associated with the pathogenesis of PRSCC, identify novel driver and predisposing genes for the disease, reveal its histopathological features associated with genetic mutations and systematically summarize the clinicopathologic characteristics and prognostic factors of PRSCC patients to provide a theoretical basis for molecularly targeted therapy and prognostic assessment of PRSCC. Whole-exome sequencing (WES) was performed on PRSCC samples to characterize the spectrum of genetic mutations and the results were validated using Sanger sequencing. Immunohistochemistry (IHC) was performed to reveal the histopathological features associated with these mutations. Furthermore, based on the published literature, a population-based study was conducted by searching PubMed and EMBASE databases to systematically summarize the clinicopathologic characteristics and prognostic factors of patients with PRSCC. WES identified 113 somatic single-nucleotide variants, 26 somatic insertions and deletions and mutations in 8 predisposing genes (DST, OR10H3, PTK2B, APOBR, ZNF606, CCN4, ADCK1, and MYH2) and 10 driver genes (KRTAP10-9, HYDIN, ZNF665, KRTAP10-2, GPAM, MUC12, KRT9, CCDC168, DUSP27 and MDC1). Sanger sequencing of germline DNA identified a germline A/G variant in the HYDIN sequence, first reported in PRSCC. Furthermore, IHC analysis indicated that PRSCC was positive for CD56, Syn, insulinoma associated protein 1, CgA and neuron specific enolase. In the population-based study, the majority of patients with PRSCC were elderly (57.92±15.75 years), with a pathological tumor (T) 3/4 stage (68.3%) and presented with lymph node involvement (51.7%) and distant metastasis (51.7%). T stage was an independent prognostic factor for overall survival in patients with PRSCC (P=0.004). Driver mutations in the HYDIN gene may be a key factor in the pathogenesis of PRSCC. HYDIN may serve as a prognostic marker and a target for immunotherapy in the management of PRSCC. However, due to the extreme rarity of PRSCC, the WES analysis in the present study was based solely on individual cases. To ensure the reliability and generalizability of genetic alterations detected by WES, additional PRSCC samples, along with cell and animal experiments, are warranted to confirm the role of these genetic variants (particularly HYDIN) in PRSCC pathogenesis. The functional role of HYDIN mutations in PRSCC pathogenesis requires further validation in future research. Show less

The β-secretase BACE1 (β-site amyloid precursor (APP) cleaving enzyme 1) is a major drug target for Alzheimer's disease (AD), as it catalyzes the first step in amyloid β (Aβ) generation, but has additional substrates and functions, in particular in the brain. Several advanced clinical trials with BACE1 inhibitors were stopped because of an adverse event, a mild cognitive worsening. The underlying mechanism is not yet known but may result from co-inhibition of the BACE1-homolog BACE2. While a cerebrospinal fluid (CSF) biomarker for measuring BACE2 activity is not yet established, VCAM-1 has been suggested as such a biomarker, but has not yet been tested upon prolonged dosing in vivo. Using CSF pharmacoproteomics and a subchronic dosing paradigm in non-human primates, we demonstrate that compound 89, a BACE inhibitor not yet tested in humans, and the clinically tested drug elenbecestat inhibit BACE1 in vivo, with little or no effect on BACE2, as seen with a reduction of substrates of BACE1, but not of the BACE2 substrate VCAM-1. As a control, verubecestat, which inhibits both BACE2 and BACE1, reduced CSF abundance of BACE1 substrates as well as of VCAM-1. This study demonstrates the suitability of VCAM-1 as a pharmacodynamic biomarker for measuring BACE2 target engagement in CSF. Show less

C1q/TNF-related proteins (CTRPs) belong to the adipokine family. Here, we aimed to assess the relation of CTRP4 levels in serum and perivascular adipose tissue (PVAT) with coronary artery disease (CAD), and investigate the effect of CTRP4 on atherosclerosis and the underlying mechanisms. CTRP4 levels were examined in serum and epicardial adipose tissue (a major PVAT) from patients with CAD. Atherosclerotic lesions were analysed in CTRP4 CTRP4 levels were lower in serum and epicardial adipose tissue of patients with CAD compared to non-CAD controls. CTRP4 knockout promoted atherosclerosis in ApoE Decreased CTRP4 levels in serum and epicardial adipose tissue are associated with CAD in patients. CTRP4 deficiency promotes the development of atherosclerosis in ApoE Show less

Genetic factors are key determinants in the pathophysiology of obesity, regulating energy homeostasis. Monogenic non-syndromic obesity accounts for 2-3% of obesity in both children and adults and is most often attributable to mutations in genes encoding components of the leptin-melanocortin pathway. Genetic testing is indicated in children with severe obesity before age 5, hyperphagia, a family history of obesity, and neurodevelopmental delay or organ dysfunction. Mutations associated with monogenic obesity follow autosomal recessive ( Show less

This study aims to evaluate the association between multiple lipid indices and coronary collateral circulation (CCC) in patients diagnosed with acute ST-segment elevation myocardial infarction (STEMI). This was a cross-sectional retrospective study involving 421 patients with STEMI who underwent coronary angiography between January 2022 and December 2024. Participants were categorized into a poor CCC group (Rentrop grade 0-1) and a good CCC group (Rentrop grade 2-3) according to Rentrop grading criteria. The following lipid parameters were evaluated as both continuous and categorical variables: total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a) [Lp(a)], apolipoprotein B (ApoB), apolipoprotein A-I (ApoA-I), non-HDL-C/HDL-C, ApoB/ApoA-I, atherogenic index of plasma (AIP), and lipoprotein composite index (LCI). The associations between these lipid indices and CCC status were assessed using multivariate logistic regression and receiver operating characteristic (ROC) curve analysis. Multivariate logistic regression analysis revealed that higher HDL-C quartiles were significantly associated with reduced odds of poor CCC (odds ratio [OR]: 0.544, 95% confidence interval [CI]: 0.351-0.771, P < 0.05), whereas elevated LDL-C (OR: 29.299, 95% CI: 3.562-240.976, P < 0.05), non-HDL-C (OR: 50.140, 95% CI: 5.408-464.834, P < 0.01), and non-HDL-C/HDL-C (OR: 4.510, 95% CI: 1.186-25.368, P < 0.05) quartiles were significantly associated with increased odds of poor CCC. Receiver operating characteristic (ROC) curve analysis demonstrated that LDL-C (cutoff: 3.265, AUC: 0.647, 95% CI: 0.573-0.721, P < 0.001), non-HDL-C (cutoff: 2.735, AUC: 0.752, 95% CI: 0.688-0.816, P < 0.001), and non-HDL-C/HDL-C (cutoff: 2.393, AUC: 0.686, 95% CI: 0.611-0.761, P < 0.001) exhibited favorable predictive performance for poor CCC. Stratification analysis showed that the highest prevalence of poor CCC was observed in patients with concurrently elevated levels of LDL-C, non-HDL-C, and non-HDL-C/HDL-C. Several lipid indices-including LDL-C, non-HDL-C, and the non-HDL-C/HDL-C ratio-are significantly associated with impaired CCC in patients with STEMI. Notably, non-HDL-C exhibits the strongest association with CCC dyscrasia and therefore warrants early clinical attention. Show less

Prior evidence indicate that differences in treatment settings between patients with colorectal cancer (CRC) from high-poverty areas (HPA, ≥ 20% residents living under poverty level) and low-poverty areas (LPA) might have contributed to disparities in their health outcomes. We sought to determine whether certain hospitals predominantly provided surgical care for patients with CRC from HPAs and examine associated patient outcomes. We identified patients undergoing surgery for nonmetastatic CRC diagnosed during 1/1/2009-12/31/2019 from SEER-Medicare. We defined poverty-area-serving (PAS) hospitals as hospitals with ≥ 50% patients from HPAs. We compared in-hospital adverse events, 30 day readmission, and long-term mortality between patients from HPAs and LPAs treated at PAS and non-PAS hospitals using logistic and Cox regression. Our cohort included 81,992 patients with CRC (median age = 78 years, 53.8% female, 15.9% in HPAs) treated by 991 hospitals. The 180 (18.2%) PAS hospitals treated 64.2% of patients from HPAs versus 2.6% from LPAs. Compared with patients from LPAs treated at non-PAS hospitals, patients from HPAs treated at PAS hospitals had more frequent in-hospital adverse events (OR[95%CI] = 1.17[1.07-1.29]), 30-day readmission (OR[95%CI] = 1.33[1.20-1.47]), worse all-cause (HR[95%CI] = 1.16[1.10-1.22]), and cancer-specific mortality (HR[95%CI] = 1.23[1.15-1.32]). A group of PAS hospitals treated a significant proportion of patients with CRC from HPAs and few from LPAs and was associated with worse short- and long-term patient outcomes. These findings highlight the presence and negative impact of healthcare segregation by area-level poverty and systemic inequities faced by individuals from HPAs. Multilevel resources are needed to address quality of care and other healthcare-associated needs for individuals from disadvantaged areas. Show less

The fat mass and obesity-associated (FTO) and melanocortin-4 receptor (MC4R) genes have been implicated in the pathophysiology of obesity. However, their regulatory behavior in human gastric tissue and association with postoperative weight loss following metabolic and bariatric surgery (MBS) remain unclear. In this prospective case-control study, gastric tissue from 50 patients with obesity undergoing laparoscopic sleeve gastrectomy and 48 non-obese controls was analyzed for FTO and MC4R mRNA expression using quantitative PCR. Adjusted Inverse propensity score weighting (IPSW-adjusted) and age-/sex-adjusted linear regression were applied. Receiver operating characteristic (ROC) curves were used to evaluate discriminatory thresholds. Correlation with 12-month percent total weight loss (%TWL) was assessed. FTO expression was significantly upregulated (mean fold-change: 4.68, p < 0.001) and MC4R downregulated (mean fold-change: - 0.91, p < 0.001) in patients with obesity. ROC analysis identified thresholds of > 1.515 for FTO (AUC = 1.00) and < 0.525 for MC4R (AUC = 1.00), both with high sensitivity and specificity. No significant correlation was observed between gene expression and %TWL at 12-month follow-up. Gastric expression of FTO and MC4R accurately discriminates between individuals with and without obesity but does not predict postoperative weight loss outcomes after sleeve gastrectomy. These findings indicate diagnostic potential, whereas prognostic value remains unsubstantial. Show less

Atherosclerosis, a key pathological basis of cardio-cerebrovascular diseases, is closely associated with aging and endothelial cell senescence. The role of microRNAs (miRNAs) in regulating endothelial cell senescence and atherosclerosis remains incompletely understood. In this study, we discovered that miR-375-3p expression was significantly elevated in the serum of both aged and atherosclerotic mice. Overexpression of miR-375-3p induced endothelial cell senescence, evidenced by increased senescence-associated β-galactosidase (SA-β-gal) staining, upregulation of p15, IL6, and IL8, and inhibited cell colony formation. In vivo inhibition of miR-375-3p in ApoE Show less

Tc17 cells (IL-17 The percentage of Tc17 cells, monocytes and IL-1β Higher populations of Tc17 cells, IL-1β The present results show that suppressing IL-1β expression by preventing CD80 [Figure: see text] The online version contains supplementary material available at 10.1186/s12964-026-02785-4. Show less

Breast cancer (BC) progression is intricately linked to the dysregulation of transfer RNA-derived fragments (tRFs). Through comprehensive analysis of The Cancer Genome Atlas (TCGA) data, it is demonstrated that 5'tRF-GlyGCC is overexpressed in BC tissues and negatively associated with patients' survival. Mechanistically, 5'tRF-GlyGCC binds to lactate dehydrogenase A (LDHA), enhancing its enzymatic activity and promoting glycolysis, which drives BC cell malignancy. This binding is mediated by the phosphorylation of LDHA at tyrosine 10, and facilitated by fibroblast growth factor receptor 1 (FGFR1), through the formation of a ternary complex that amplifies oncogenic signaling. Furthermore, 5'tRF-GlyGCC/LDHA axis induces macrophage infiltration and polarization toward an M2 phenotype, mediated by the chemokine CCL7, thereby reshaping the tumor microenvironment. Additionally, it is uncovered that the biogenesis of 5'tRF-GlyGCC is regulated by ALKBH3 and ANG, which also modulate LDHA activity. In vivo, targeting 5'tRF-GlyGCC/LDHA signaling significantly suppresses tumor growth and enhances the efficacy of immunotherapy. Collectively, these findings elucidate the pivotal role of 5'tRF-GlyGCC in BC progression, highlighting its potential as therapeutic target for BC treatment. Show less

KRAS We studied short-term changes in signaling and mechanisms of primary resistance to AZD4625 in twelve KRAS Sustained tumor regression in four (33%) PDXs was observed while the remaining eight models were intrinsically resistant to AZD4625. Organoid responses to AZD4625 were concordant with their derived PDXs. Acute AZD4625 exposure significantly decreased gene expression of the ERK1/2 negative regulator, DUSP6, in all models while protein MAPK and AKT/mTOR signals were downregulated more frequently in the AZD4625-sensitive than AZD4625-resistant cohorts. Analyzing PDX transcriptomes and proteomes identified mTOR signaling as a putative mechanism of primary resistance to AZD4625. Our findings confirm AZD4625 as a highly active KRAS Show less

This narrative review aims to synthesize and critically evaluate the complex molecular mechanisms by which amyloid-β (Aβ) accumulation disrupts hippocampal synaptic plasticity, the cellular cornerstone of learning and memory in Alzheimer's disease (AD). AD is characterized by progressive hippocampus-dependent cognitive decline, strongly linked to impaired synaptic plasticity, the cellular basis of learning and memory. This review deciphers how Aβ accumulation orchestrates synaptic sabotage in the hippocampus. We detail the core molecular machinery of hippocampal synaptic plasticity, emphasizing glutamate receptor trafficking (NMDAR/AMPAR), Ca Show less

In vitro maturation (IVM) is highly susceptible to influences of the culture environment, which can lead to increased intracellular reactive oxygen species (ROS) levels and thereby induce a stress response in oocytes, ultimately reducing the developmental potential of early embryos. Brain-derived neurotrophic factor (BDNF) is an ovarian endocrine factor that can enhance the function of follicular granulosa cells and promote oocyte maturation, but the specific pathways remain unclear. We supplemented IVM cultures of sheep oocytes with BDNF and examined aspects of oocyte nuclear and cytoplasmic maturation. The addition of 50 ng/mL BDNF promoted the expansion of cumulus cells and increased the rates of first polar body extrusion, cleavage, and blastocyst formation. Compared with untreated controls, BDNF-treated oocytes had improved Ca Show less

Neurodegenerative diseases, including Alzheimer's disease, are marked by cholinergic dysfunction, oxidative stress, and reduced neurotrophic support, which drives the quest for multifunctional therapeutic agents. This pilot study presents four novel monoterpene-aminoadamantane conjugates (MACs 1-4) designed to combine the antioxidant and neuromodulatory characteristics of monoterpenes with the neuroprotective properties of aminoadamantane derivatives. Their physicochemical characteristics, blood-brain barrier permeability, and binding affinity to human acetylcholinesterase (AChE) were evaluated using molecular docking and in silico descriptor analysis. In vivo, the neuroprotective efficacy of the MACs was investigated in a scopolamine-induced dementia model in rats, employing behavioral tests. Biochemical assays conducted in the hippocampus and prefrontal cortex assessed AChE activity, antioxidant enzyme performance, lipid peroxidation levels, total glutathione content, and BDNF concentrations. The findings indicate that MAC1, MAC3, and MAC4 demonstrate favorable calculated blood-brain barrier permeability, strong predicted affinity for AChE, and significant in vivo alleviation of scopolamine-induced memory deficits, in conjunction with improvement of key markers of oxidative stress and cholinergic function. These results show that the structural hybridization of myrtenal with aminoadamantane frameworks produces promising multifunctional ligands that are relevant for Alzheimer's-type neurodegeneration. Show less

Atherosclerotic cardiovascular disease, characterized by an imbalanced lipid metabolism and a dysregulated immune response, is a major cause of death worldwide. The AhR (aryl hydrocarbon receptor) is a ligand-activated transcription factor that is highly expressed in the liver and primarily known for its role in detoxification. However, recent studies suggest that the AhR also plays a key role in immune regulation, indicating that this receptor can influence the development of atherosclerosis. The number of circulating leukocytes was increased in Our study demonstrates a remarkable role for AhR in the pathogenesis of atherosclerosis, interfering with both lipid metabolism and inflammatory pathways. Although the underlying mechanisms remain unclear, these results demonstrate a novel and crucial role for AhR in atherosclerotic cardiovascular disease. Show less

Atherosclerosis (AS) is a chronic inflammatory disorder underlying most cardiovascular events sialic acid (SIA), a terminal metabolite of glycolipid catabolism, modulates vascular injury, but its role in endothelial dysfunction remains unclear. To investigate whether N-acetylneuraminic acid (Neu5Ac) accelerates AS development. ApoE Show less

AXIN1 (axis inhibition protein 1), as a rate-limiting component of canonical Wingless-type mouse mammary tumor virus integration site (Wnt)/β-catenin signaling pathway, may influence midbrain dopaminergic neurons. A recent genome-wide association study identified AXIN1 as a candidate gene for Parkinson's disease (PD). Our study aimed to investigate the potential relevance of AXIN1 single nucleotide polymorphisms (rs13337493 and rs9921222) in the risk, clinical characteristics, and pathology of PD. Data were collected from the Northern Han Chinese and Parkinson's Progression Markers Initiative (PPMI) cohorts. Associations between AXIN1 variants, PD-related biomarkers, and clinical manifestations were analyzed. Both loci were identified as risk factors in the Northern Han Chinese population, and the A allele of rs13337493 [odds ratio (OR) 1.320, 95% confidence interval (CI) 1.052, 1.653, P Our findings support a gatekeeper role for AXIN1; its polymorphisms contribute to increased PD susceptibility and accelerated motor progression, yet may also trigger a compensatory presynaptic response, as evidenced by elevated CSF DOPA levels, to counteract neurodegeneration. Future studies should include larger sample sizes, more diverse ethnic populations, and protein-level investigations. Show less

Omega-3 long-chain polyunsaturated fatty acids (n3-LCPUFAs) have strong triglyceride-lowering and anti-inflammatory properties, and high levels of these fatty acids have been associated with reduced risk of cardiovascular disease. The synthesis of n3-LCPUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and n6-LCPUFA, arachidonic acid, share a common pathway mediated by fatty acid desaturase genes, FADS1 and FADS2. LCPUFA synthesis is regulated by both modifiable and non-modifiable factors. Of particular interest is the role of genetic variants in the FADS gene cluster, which are associated with altered FADS1 and FADS2 expression, as well as LCPUFA levels. However, the specific functional variants and the precise molecular mechanisms by which these variants regulate FADS gene expression remain to be elucidated. Variation in the FADS gene cluster is thought to have arisen through natural selection and changing dietary patterns. Available evidence suggests these variants, either individually or as a haplotype, may alter FADS gene expression by modifying DNA methylation in regulatory regions, as well as microRNA and transcription factor binding sites. This review explores the current state of knowledge regarding the functional roles of these variants on LCPUFA synthesis and how these new insights will help support precision nutrition strategies aimed at improving an individual's n3-LCPUFA status and health. Identifying specific functional variants in or near the FADS gene cluster and elucidating the mechanisms by which these variants impact LCPUFA synthesis requires further investigation. However, hypothesis generating in vitro studies have revealed roles for epigenetics, non-coding RNAs, and modification of transcription factor binding sites. This knowledge will generate new insights that will help improve our understanding of the genetic basis underlying LCPUFA synthesis and how this may differ across populations. Show less

The heterogeneous nature of tumor-associated neutrophils (TANs) has been recognized, but how different cell states of TANs emerge, evolve, distribute, and impact cancer immunotherapy efficacy remain elusive. Using single-cell RNA sequencing, spatial transcriptomics, and genetic manipulations, we show that anti-PDL1 + CD40 agonist immunotherapy can induce interferon responses in TANs, allowing them to regain anti-tumor activities in squamous cell carcinomas (SCCs). In contrast, TANs residing at the tumor-stroma interface can preserve their immune-suppressive state. Importantly, we identify a group of SOX2 Show less

Persistent chylomicronemia is associated with severe hypertriglyceridemia (sHTG) and plasma triglycerides (TG) levels sustainably > 10 mmol/L (880 mg/dL) despite lipid lowering therapies. The main risk of persistent chylomicronemia is acute pancreatitis (AP). During the second and third trimester of pregnancy, TG levels significantly increase, which represents a serious risk of AP in women with preexisting chylomicronemia. New emerging therapies such as plozasiran, a GalNAc-conjugated small interfering RNA (siRNA) against ApoC3, are developed to manage persistent chylomicronemia, but no data are currently available on their safety and efficacy during pregnancy. We report herein the case of a woman with persistent chylomicronemia randomized in the PALISADE study to receive plozasiran 25 mg quarterly, who had an unplanned pregnancy during the clinical trial. The 34-year-old patient received one dose of plozasiran 8 weeks before conception and the experimental treatment was ceased afterwards. The pregnancy went well, TG levels did not rise above 10 mmol/L (880 mg/dL) during the whole pregnancy, even during the last two trimesters where TG levels usually increase two- to four-fold from baseline and she did not experience any AP episode. She delivered a healthy baby at 39 weeks. This case suggests that plozasiran might be safe for the mother and the fetus and could prevent incremental pregnancy-driven TG elevation and occurrence of AP in women with sHTG. This is consistent with the long duration of action and hepatic half-life of plozasiran in clinical studies where TG levels remained sustainably lower than baseline > 9 months after the last injection. Show less

Variants of uncertain significance represent the biggest challenge for genomics-based precision oncology. Activated fibroblast growth factor receptors (FGFRs) frequently drive tumorigenesis by different genetic aberrations. However, it remains unknown which of the many point mutations affecting FGFR1, FGFR2, FGFR3 or FGFR4 in cancer are druggable, that is, activating signaling while not mediating FGFR inhibitor resistance. Here we implemented a saturation mutational scanning platform to screen all 11,520 possible point mutations covering the kinase domains of FGFR1-4. Pooled positive selection screens identified 474 activating and 738 mutations mediating resistance to the FGFR inhibitors pemigatinib and futibatinib, together revealing 301 druggable FGFR mutations analogous to a strong PS3/BS3 evidence level. The screens also identified loss-of-function mutations and an association of gain-of-function mutations with hydrophobic changes. The functional screens identified 97% of acquired resistance mutations in clinical trials. Our comprehensive catalog of every druggable mutation in the FGFR kinase domains is readily available for clinical decision support. Show less

To determine whether genetic ancestry modulates Cross-sectional analysis of community-dwelling older adults from the Health and Aging Brain Study-Health Disparities (HABS-HD) cohort (N = 2733). Participants spanning the cognitive spectrum underwent cognitive assessment, neuroimaging, plasma biomarker collection, and genome-wide genotyping from 2018 to 2023. Cognitive performance (global cognition, memory, executive function, verbal ability), brain morphometry (cortical thickness, hippocampal volume), and plasma biomarkers (Aβ In the full cohort, Genetic ancestry modifies the effect of Show less

Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by progressive neuronal degeneration, predominantly caused by the accumulation of amyloid-beta (Aβ) and neuroinflammatory processes. Hypoxia, characterized by diminished oxygen levels, intensifies these mechanisms by stimulating hypoxia-inducible factor 1-alpha (HIF-1α), potentially enhancing BACE1 enzyme activity and resulting in increased Aβ synthesis and render neurons especially susceptible to hypoxia, exacerbating disease progression. Existing therapies are constrained by inadequate medication distribution across the blood-brain barrier and associated adverse effects. This study aims to identify potential therapeutic agents targeting HIF-1 We used Results identified several compounds with strong binding affinities and favorable ADMET profiles as potential inhibitors of HIF-1 Show less