The association of apolipoprotein AIV (APOA4) with depression or plasma levels of lipids and glucose has been inconsistently reported. However, interplays between APOA4 and depression on the levels ha Show more
The association of apolipoprotein AIV (APOA4) with depression or plasma levels of lipids and glucose has been inconsistently reported. However, interplays between APOA4 and depression on the levels have not been explored yet. The present study aimed to investigate plasma levels of APOA4, lipids, and glucose in adolescents with different genotypes of APOA4 rs5104 and with or without depression. Depressive symptoms were assessed in 631 adolescents by Beck Depression Inventory (BDI). A total score of 14 was defined as the cutoff point for depression. Plasma levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), glucose, and insulin were measured by routine methods, and APOA4 by enzyme-linked immunosorbent assays. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism analyses and verified by DNA sequencing. Female adolescents had higher prevalence of depression than male subjects only in G allele carriers (p = 0.015), but not in AA homozygotes. Risk factors of depression and predictors of depression severity were different between G allele carriers and AA homozygotes. Lower levels of glucose (p = 0.003) were observed in male G allele carriers than those in male AA homozygotes and increased TG levels (p = 0.008) in female G allele carriers when compared with those in female AA homozygotes. When both APOA4 rs5104 and depression were taken into account, subjects with depression had higher levels of plasma APOA4 than adolescents without depression only in female G allele carriers (p = 0.043), but no significant changes of plasma lipids and glucose. Depression augments plasma APOA4 levels without changes of plasma lipids and glucose in female adolescents carrying G allele of APOA4 rs5104. These results may provide a novel explanation for the inconsistent relationship between depression, APOA4, and plasma levels of lipids and glucose in the literature. Show less
NRBF2, a regulatory subunit of the ATG14-BECN1/Beclin 1-PIK3C3/VPS34 complex, positively regulates macroautophagy/autophagy. In this study, we report that NRBF2 is required for the clearance of apopto Show more
NRBF2, a regulatory subunit of the ATG14-BECN1/Beclin 1-PIK3C3/VPS34 complex, positively regulates macroautophagy/autophagy. In this study, we report that NRBF2 is required for the clearance of apoptotic cells and alleviation of inflammation during colitis in mice. NRBF2-deficient mice displayed much more severe colitis symptoms after the administration of ulcerative colitis inducer, dextran sulfate sodium salt (DSS), accompanied by prominent intestinal inflammation and apoptotic cell accumulation. Interestingly, we found that Show less
Patrick Sweeney, Can Chen, Indika Rajapakse+1 more · 2021 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Mutations in the melanocortin 4 receptor (MC4R) result in hyperphagia and obesity and are the most common cause of monogenic obesity in humans. Preclinical rodent studies have determined that the crit Show more
Mutations in the melanocortin 4 receptor (MC4R) result in hyperphagia and obesity and are the most common cause of monogenic obesity in humans. Preclinical rodent studies have determined that the critical role of the MC4R in controlling feeding can be mapped in part to its expression in the paraventricular nucleus of the hypothalamus (paraventricular nucleus [PVN]), where it regulates the activity of anorexic neural circuits. Despite the critical role of PVN MC4R neurons in regulating feeding, the in vivo neuronal activity of these cells remains largely unstudied, and the network activity of PVN MC4R neurons has not been determined. Here, we utilize in vivo single-cell endomicroscopic and mathematical approaches to determine the activity and network dynamics of PVN MC4R neurons in response to changes in energy state and pharmacological manipulation of central melanocortin receptors. We determine that PVN MC4R neurons exhibit both quantitative and qualitative changes in response to fasting and refeeding. Pharmacological stimulation of MC4R with the therapeutic MC4R agonist setmelanotide rapidly increases basal PVN MC4R activity, while stimulation of melanocortin 3 receptor (MC3R) inhibits PVN MC4R activity. Finally, we find that distinct PVN MC4R neuronal ensembles encode energy deficit and energy surfeit and that energy surfeit is associated with enhanced network connections within PVN MC4R neurons. These findings provide valuable insight into the neural dynamics underlying hunger and energy surfeit. Show less
G-quadruplex (G4) DNA is a type of quadruple helix structure formed by a continuous guanine-rich DNA sequence. Emerging evidence in recent years authenticated that G4 DNA structures exist both in cell Show more
G-quadruplex (G4) DNA is a type of quadruple helix structure formed by a continuous guanine-rich DNA sequence. Emerging evidence in recent years authenticated that G4 DNA structures exist both in cell-free and cellular systems, and function in different diseases, especially in various cancers, aging, neurological diseases, and have been considered novel promising targets for drug design. In this review, we summarize the detection method and the structure of G4, highlighting some non-canonical G4 DNA structures, such as G4 with a bulge, a vacancy, or a hairpin. Subsequently, the functions of G4 DNA in physiological processes are discussed, especially their regulation of DNA replication, transcription of disease-related genes (c-MYC, BCL-2, KRAS, c-KIT et al.), telomere maintenance, and epigenetic regulation. Typical G4 ligands that target promoters and telomeres for drug design are also reviewed, including ellipticine derivatives, quinoxaline analogs, telomestatin analogs, berberine derivatives, and CX-5461, which is currently in advanced phase I/II clinical trials for patients with hematologic cancer and BRCA1/2-deficient tumors. Furthermore, since the long-term stable existence of G4 DNA structures could result in genomic instability, we summarized the G4 unfolding mechanisms emerged recently by multiple G4-specific DNA helicases, such as Pif1, RecQ family helicases, FANCJ, and DHX36. This review aims to present a general overview of the field of G-quadruplex DNA that has progressed in recent years and provides potential strategies for drug design and disease treatment. Show less
Angiopoietin-like protein 4 (ANGPTL-4) had been reported to be associated with the risk of ischemic stroke, but its prognostic value remained unclear. The aim of this study was to investigate the asso Show more
Angiopoietin-like protein 4 (ANGPTL-4) had been reported to be associated with the risk of ischemic stroke, but its prognostic value remained unclear. The aim of this study was to investigate the association between plasma ANGPTL-4 concentrations and prognosis of ischemic stroke. Baseline plasma ANGPTL-4 concentrations were measured in 3379 acute ischemic stroke patients. The primary outcome was a combination of death or major disability (modified Rankin Scale score, ≥3) at 3 months after ischemic stroke. At 3 months after ischemic stroke, 850 (26.16%) participants experienced major disability or died (750 major disabilities and 100 deaths). After adjusting for important covariates, odds ratios for the highest tertile of plasma ANGPTL-4 concentrations were 1.59 (1.22-2.06) for primary outcome, 1.53 (1.18-1.97) for major disability, and 2.03 (1.03-4.00) for death when compared with the lowest tertile of plasma ANGPTL-4 concentrations. For 1-SD increase in log-ANGPTL-4 concentrations (0.44 ng/mL), the adjusted odds ratios were 1.24 (1.11-1.38), 1.14 (1.03-1.27), and 1.72 (1.32-2.23), respectively. Adding ANGPTL-4 to a model containing conventional risk factors improved risk prediction for composite outcome of death and major disability. Higher plasma ANGPTL-4 concentration was associated with poor prognosis in acute ischemic stroke patients, suggesting that ANGPTL-4 might be a prognostic marker for ischemic stroke. Show less
Trimethyltin chloride (TMT) is widely used as a constituent of fungicides and plastic stabilizers in the industrial and agricultural fields, and is generally acknowledged to have potent neurotoxicity, Show more
Trimethyltin chloride (TMT) is widely used as a constituent of fungicides and plastic stabilizers in the industrial and agricultural fields, and is generally acknowledged to have potent neurotoxicity, especially in the hippocampus; however, the mechanism of induction of neurotoxicity by TMT remains elusive. Herein, we exposed Neuro-2a cells to different concentrations of TMT (2, 4, and 8 μM) for 24 h. Proteomic analysis, coupled with bioinformatics analysis, revealed the important role of macroautophagy/autophagy-lysosome machinery in TMT-induced neurotoxicity. Further analysis indicated significant impairment of autophagic flux by TMT via suppressed lysosomal function, such as by inhibiting lysosomal proteolysis and changing the lysosomal pH, thereby contributing to defects in autophagic clearance and subsequently leading to nerve cell death. Mechanistically, molecular interaction networks of Ingenuity Pathway Analysis identified a downregulated molecule, KIF5A (kinesin family member 5A), as a key target in TMT-impaired autophagic flux. TMT decreased KIF5A protein expression, disrupted the interaction between KIF5A and lysosome, and impaired lysosomal axonal transport. Moreover, Show less
Breast cancer has surpassed lung cancer as the most commonly diagnosed cancer in women worldwide. Some therapeutic drugs and approaches could cause side effects and weaken the immune system. The combi Show more
Breast cancer has surpassed lung cancer as the most commonly diagnosed cancer in women worldwide. Some therapeutic drugs and approaches could cause side effects and weaken the immune system. The combination of conventional therapies and traditional Chinese medicine (TCM) significantly improves treatment efficacy in breast cancer. However, the chemical composition and underlying anti-tumor mechanisms of TCM still need to be investigated. The primary aim of this study is to provide unique insights to screen the natural components for breast cancer therapy using high-throughput transcriptome analysis. Differentially expressed genes were identified based on two conditions: single samples and groups were classified according to their pharmaceutical effect. Subsequently, the sample treated with Show less
Childhood obesity is one of the most common and costly nutritional problems with high heritability. The genetic mechanism of childhood obesity remains unclear. Here, we conducted a transcriptome-wide Show more
Childhood obesity is one of the most common and costly nutritional problems with high heritability. The genetic mechanism of childhood obesity remains unclear. Here, we conducted a transcriptome-wide association study (TWAS) to identify novel genes for childhood obesity. By integrating the GWAS summary of childhood body mass index (BMI), we conducted TWAS analyses with pre-computed gene expression weights in 39 obesity priority tissues. The GWAS summary statistics of childhood BMI were derived from the early growth genetics consortium with 35,668 children from 20 studies. We identified 15 candidate genes for childhood BMI after Bonferroni corrections. The most significant gene, ADCY3, was identified in 13 tissues, including adipose, brain, and blood. Interestingly, eight genes were only identified in the specific tissue, such as FAIM2 in the brain (P = 2.04 × 10 Our study identified multiple candidate genes for childhood BMI, providing novel clues for understanding the genetic mechanism of childhood obesity. Show less
Atypical antipsychotics such as risperidone cause drug-induced metabolic syndrome. However, the underlying mechanisms remain largely unknown. Here, we report a new mouse model that reliably reproduces Show more
Atypical antipsychotics such as risperidone cause drug-induced metabolic syndrome. However, the underlying mechanisms remain largely unknown. Here, we report a new mouse model that reliably reproduces risperidone-induced weight gain, adiposity, and glucose intolerance. We found that risperidone treatment acutely altered energy balance in C57BL/6 mice and that hyperphagia accounted for most of the weight gain. Transcriptomic analyses in the hypothalamus of risperidone-fed mice revealed that risperidone treatment reduced the expression of Mc4r. Furthermore, Mc4r in Sim1 neurons was necessary for risperidone-induced hyperphagia and weight gain. Moreover, we found that the same pathway underlies the obesogenic effect of olanzapine-another commonly prescribed antipsychotic drug. Remarkably, whole-cell patch-clamp recording demonstrated that risperidone acutely inhibited the activity of hypothalamic Mc4r neurons via the opening of a postsynaptic potassium conductance. Finally, we showed that treatment with setmelanotide, an MC4R-specific agonist, mitigated hyperphagia and obesity in both risperidone- and olanzapine-fed mice. Show less
Although the immune checkpoint role of programmed death ligand 1 (PD-L1) has been established and targeted in cancer immunotherapy, the tumor-intrinsic role of PD-L1 is less appreciated in tumor biolo Show more
Although the immune checkpoint role of programmed death ligand 1 (PD-L1) has been established and targeted in cancer immunotherapy, the tumor-intrinsic role of PD-L1 is less appreciated in tumor biology and therapeutics development, partly because of the incomplete mechanistic understanding. Here we demonstrate a potentially novel mechanism by which PD-L1 promotes the epithelial-mesenchymal transition (EMT) in triple-negative breast cancer (TNBC) cells by suppressing the destruction of the EMT transcription factor Snail. PD-L1 directly binds to and inhibits the tyrosine phosphatase PTP1B, thus preserving p38-MAPK activity that phosphorylates and inhibits glycogen synthase kinase 3β (GSK3β). Via this mechanism, PD-L1 prevents the GSK3β-mediated phosphorylation, ubiquitination, and degradation of Snail and consequently promotes the EMT and metastatic potential of TNBC. Significantly, PD-L1 antibodies that confine the tumor-intrinsic PD-L1/Snail pathway restricted TNBC progression in immunodeficient mice. More importantly, targeting both tumor-intrinsic and tumor-extrinsic functions of PD-L1 showed strong synergistic tumor suppression effect in an immunocompetent TNBC mouse model. Our findings support that PD-L1 intrinsically facilitates TNBC progression by promoting the EMT, and this potentially novel PD-L1 signaling pathway could be targeted for better clinical management of PD-L1-overexpressing TNBCs. Show less
Taxane-based reagents, such as Taxol, Taxotere, and Abraxane, are popular anti-cancer drugs that can differ in their clinical efficacy. This difference is generally attributed to their active pharmace Show more
Taxane-based reagents, such as Taxol, Taxotere, and Abraxane, are popular anti-cancer drugs that can differ in their clinical efficacy. This difference is generally attributed to their active pharmaceutical ingredients. Here, we report a serendipitous discovery that Taxol induces metabolic dysregulation and unfolded protein response. Surprisingly, these effects of Taxol are entirely dependent on its excipient, Cremophor EL (CrEL). We show that CrEL promotes aerobic glycolysis and in turn results in drastic upregulation of Show less
Label-free quantitative proteomics was applied to analyze differentially expressed proteins (DEPs) in the cerebrospinal fluid (CSF) of patients with encephalitis. The database was used to screen for p Show more
Label-free quantitative proteomics was applied to analyze differentially expressed proteins (DEPs) in the cerebrospinal fluid (CSF) of patients with encephalitis. The database was used to screen for possible biomarkers in encephalitis, followed by validation and preliminary investigation of the role of some DEPs in the pathogenesis of encephalitis using enzyme-linked immunosorbent assay (ELISA). We performed label-free quantitative proteomics on 16 cerebrospinal fluid samples (EM group, encephalitis with mental and behavioral disorders patients, A total of 941 proteins were found to be significantly differentially expressed, including 250 upregulated DEPs and 691 downregulated DEPs. GO analysis suggested that there were six enriched functions that intersect among the EM, NED, and N groups, including synapse organization, membrane, integral component of membrane, membrane part, G-protein-coupled receptor signaling pathway, and transmembrane signaling receptor activity. KEGG analysis revealed that there were three signaling pathways that intersect among the EM, NED, and N groups, including fructose and mannose metabolism, inositol phosphate metabolism, and Jak-STAT signaling pathway. Furthermore, four downregulated encephalitis-related neurological synapse proteins were identified after screening for differentially expressed proteins, including NRXN3, NFASC, LRRC4B, and NLGN2. The result of ELISA further verified that the expression of NLGN2 and LRRC4B was obviously higher in the NED group than in the N group. These findings demonstrated that NLGN2 and LRRC4B proteins were upregulated in the NED group and could be potential biomarkers for the diagnosis of encephalitis, but still needs a lot of multiomics studies to be used in clinical. Show less
We previously demonstrated that angiopoietin-like protein 8 (ANGPTL8) forms ANGPTL3/8 and ANGPTL4/8 complexes that increase with feeding to direct fatty acids (FA) toward adipose tissue through differ Show more
We previously demonstrated that angiopoietin-like protein 8 (ANGPTL8) forms ANGPTL3/8 and ANGPTL4/8 complexes that increase with feeding to direct fatty acids (FA) toward adipose tissue through differential modulation of lipoprotein lipase (LPL) activity. Each complex correlated inversely with high density lipoprotein cholesterol (HDL) in control subjects. We thus investigated ANGPTL3/8 and ANGPTL4/8 levels in type 2 diabetes patients, who can present with decreased HDL. While ANGPTL3/8 levels in type 2 diabetes patients were similar to those previously observed in normal controls, ANGPTL4/8 levels were roughly twice as high as those in control subjects. Concentrations of ANGPTL3/8 and ANGPTL4/8 in type 2 diabetes patients were inversely correlated with HDL, with the correlation being significant for ANGPTL4/8. We therefore measured the ability of the various ANGPTL proteins and complexes to inhibit endothelial lipase (EL), the enzyme which hydrolyzes phospholipids (PL) in HDL. While confirming ANGPTL3 as an EL inhibitor, we found that ANGPTL4 was a more potent EL inhibitor than ANGPTL3. Interestingly, we observed that while ANGPTL3/8 had increased EL-inhibitory activity compared to ANGPTL3 alone, ANGPTL4/8 exhibited decreased potency in inhibiting EL compared to ANGPTL4 alone. Together, these results show for the first time that ANGPTL4 is a more potent EL inhibitor than ANGPTL3 and suggest a possible reason for why ANGPTL4/8 levels are correlated inversely with HDL. Show less
Previous studies have shown that exogenous short-chain fatty acids (SCFAs) introduction attenuated the body fat deposition in conventional mice and pigs. However, limited studies have evaluated the ef Show more
Previous studies have shown that exogenous short-chain fatty acids (SCFAs) introduction attenuated the body fat deposition in conventional mice and pigs. However, limited studies have evaluated the effects of exogenously introduced SCFAs on the lipid and glucose metabolism independently of the gut microbiota. This study was to investigate the effects of exogenous introduction of SCFAs on the lipid and glucose metabolism in a germ-free (GF) pig model. Twelve hysterectomy-derived newborn pigs were reared in six sterile isolators. All pigs were hand-fed with sterile milk powder for 21 d, then the sterile feed was introduced to pigs for another 21 d. In the second 21-d period, six pigs were orally administrated with 25 mL/kg sterile saline per day and considered as the GF group, while the other six pigs were orally administrated with 25 mL/kg SCFAs mixture (acetic, propionic, and butyric acids, 45, 15, and 11 mmol/L, respectively) per day and regarded as FA group. Orally administrated with SCFAs tended to increase the adiponectin concentration in serum, enhance the CPT-1 activity in longissimus dorsi, and upregulate the ANGPTL4 mRNA expression level in colon (P < 0.10). Meanwhile, the mRNA abundances of ACC, FAS, and SREBP-1C in liver and CD36 in longissimus dorsi of the FA group were decreased (P < 0.05) compared with those in the GF group. Besides, the mRNA expression of PGC-1α in liver and LPL in longissimus dorsi tended to (P < 0.10) upregulate and downregulate respectively in the FA group. Moreover, oral administration of SCFAs tended to increase the protein level of GPR43 (P < 0.10) and decrease the protein level of ACC (P < 0.10) in liver. Also, oral administration of SCFAs upregulated the p-AMPK/AMPK ratio and the mRNA expressions of GLUT-2 and GYS2 in liver (P < 0.05). In addition, the metabolic pathway associated with the biosynthesis of unsaturated fatty acids was most significantly promoted (P < 0.05) by oral administration of SCFAs. Exogenous introduction of SCFAs might attenuate the fat deposition and to some extent improve the glucose control in the pig model, which occurred independently of the gut microbiota. Show less
The etiology of hypertriglyceridemia (HTG) and acute pancreatitis (AP) is complex. Herein, we dissected the underlying etiology in a patient with HTG and AP. The patient had a 20-year history of heavy Show more
The etiology of hypertriglyceridemia (HTG) and acute pancreatitis (AP) is complex. Herein, we dissected the underlying etiology in a patient with HTG and AP. The patient had a 20-year history of heavy alcohol consumption and an 8-year history of mild HTG. He was hospitalized for alcohol-triggered AP, with a plasma triglyceride (TG) level up to 21.4 mmol/L. A temporary rise in post-heparin LPL concentration (1.5-2.5 times of controls) was noted during the early days of AP whilst LPL activity was consistently low (50∼70% of controls). His TG level rapidly decreased to normal in response to treatment, and remained normal to borderline high during a ∼3-year follow-up period during which he had abstained completely from alcohol. Sequencing of the five primary HTG genes (i.e., Show less
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate glucose and energy homeostasis. Targeting both pathways with GIP receptor (GIPR) antagonist antibody (GI Show more
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate glucose and energy homeostasis. Targeting both pathways with GIP receptor (GIPR) antagonist antibody (GIPR-Ab) and GLP-1 receptor (GLP-1R) agonist, by generating GIPR-Ab/GLP-1 bispecific molecules, is an approach for treating obesity and its comorbidities. In mice and monkeys, these molecules reduce body weight (BW) and improve many metabolic parameters. BW loss is greater with GIPR-Ab/GLP-1 than with GIPR-Ab or a control antibody conjugate, suggesting synergistic effects. GIPR-Ab/GLP-1 also reduces the respiratory exchange ratio in DIO mice. Simultaneous receptor binding and rapid receptor internalization by GIPR-Ab/GLP-1 amplify endosomal cAMP production in recombinant cells expressing both receptors. This may explain the efficacy of the bispecific molecules. Overall, our GIPR-Ab/GLP-1 molecules promote BW loss, and they may be used for treating obesity. Show less
Metastatic renal cell carcinoma (mRCC) is the important factor for patient mortality, meanwhile gene mutation constantly changes cancer prognosis in tumor process. Exploring the driver mutation in mRC Show more
Metastatic renal cell carcinoma (mRCC) is the important factor for patient mortality, meanwhile gene mutation constantly changes cancer prognosis in tumor process. Exploring the driver mutation in mRCC process become more and more important. We obtained the 15 paired primary and metastatic mRCC samples and analyzed specific mutation genes in the metastatic foci (SMGs) by next generation sequencing. Moreover, we explored the Correlated networks, Pathway and Gene Ontology (GO) enrichment results, prediction analysis of AS sites and prognosis of survival. We identify EPCAM, TMEM127, EZH2, EXT1, CDKN2A, PRF1, AIP, CDK4, PRKARIA as SMGs and find that CDKN2A mutation sites affect the prognosis of mRCC by altering splicing elements. Based on the differential analysis for SMGs in KIRC, we found that EPCAM, PRF1 and EZH2 were differential expression in both primary tumors with metastasis compared to primary tumors without metastasis or metastatic tissues. By the AS prediction analysis, we suggest that CDKN2A mutation sites play an important role for RCC metastasis by affecting the p16/p14 expression. The SMGs could provide new molecular cues associated with tumor metastasis and have potential clinical implications for cancer prognosis and treatment. Definitive conclusions await further validation and follow up. Show less
Gene editing nucleases (GENs), represented by CRISPR/Cas9, have become major tools in biomedical research and offer potential cures for many human diseases. Gene editing therapy (GETx) studies in anim Show more
Gene editing nucleases (GENs), represented by CRISPR/Cas9, have become major tools in biomedical research and offer potential cures for many human diseases. Gene editing therapy (GETx) studies in animal models targeting genes such as proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein C3 (APOC3), angiopoietin Like 3 (ANGPTL3) and inducible degrader of the low-density lipoprotein receptor (IDOL) have demonstrated the benefits and advantages of GETx in managing atherosclerosis. Here we present our views on this brand new therapeutic option for cardiovascular diseases (CVD). Show less
Dyslipidemia is highly prevalent in youth with type 2 diabetes (T2D), yet the pathogenic components of dyslipidemia in youth with T2D are poorly understood. To evaluate the genetic determinants of lip Show more
Dyslipidemia is highly prevalent in youth with type 2 diabetes (T2D), yet the pathogenic components of dyslipidemia in youth with T2D are poorly understood. To evaluate the genetic determinants of lipid traits in youth with T2D through a genome-wide association study. We genotyped 206 928 variants and imputed 17 642 824 variants in 1076 youth (mean age 15.0 ± 2.48 years) with T2D from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) and SEARCH for Diabetes in Youth (SEARCH) studies as part of the Progress in Diabetes Genetics in Youth (ProDiGY) consortium. We performed association testing for triglyceride and low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (HDL-c) concentrations adjusted for the genetic relationship matrix within each substudy followed by meta-analyses for each trait. We identified a novel association between a deletion on chromosome 3 (3:67817380_AT/A_Deletion:RP11-81N13.1) and triglyceride levels at genome-wide level of significance ( Our genetic analyses of lipid traits in youth with T2D have identified 1 novel and 1 previously known locus. Additional studies are needed to further characterize the genetic architecture of dyslipidemia in youth with T2D. Show less
Thymus organogenesis and T cell development are coordinated by various soluble and cell-bound molecules. Heparan sulfate (HS) proteoglycans can interact with and immobilize many soluble mediators, cre Show more
Thymus organogenesis and T cell development are coordinated by various soluble and cell-bound molecules. Heparan sulfate (HS) proteoglycans can interact with and immobilize many soluble mediators, creating fields or gradients of secreted ligands. While the role of HS in the development of many organs has been studied extensively, little is known about its function in the thymus. Here, we examined the distribution of HS in the thymus and the effect of its absence on thymus organogenesis and T cell development. We found that HS was expressed most abundantly on the thymic fibroblasts and at lower levels on endothelial, epithelial, and hematopoietic cells. To study the function of HS in the thymus, we eliminated most of HS in this organ by genetically disrupting the glycosyltransferase Ext1 that is essential for its synthesis. The absence of HS greatly reduced the size of the thymus in fetal thymic organ cultures and in vivo, in mice, and decreased the production of T cells. However, no specific blocks in T cell development were observed. Wild-type thymic fibroblasts were able to physically bind the homeostatic chemokines CCL19, CCL21, and CXCL12 ex vivo. However, this binding was abolished upon HS degradation, disrupting the CCL19/CCL21 chemokine gradients and causing impaired migration of dendritic cells in thymic slices. Thus, our results show that HS plays an essential role in the development and growth of the thymus and in regulating interstitial cell migration. Show less
Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of mono- or symmetric dimethylarginine residues on histones and non-histone substrates and has been demonstrated to play important Show more
Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of mono- or symmetric dimethylarginine residues on histones and non-histone substrates and has been demonstrated to play important roles in many biological processes. In the present study, we observed that PRMT5 is abundantly expressed in spermatogonial stem cells (SSCs) and that Show less
Triple negative breast cancer (TNBC) is challenging to treat successfully because targeted therapies do not exist. Instead, systemic therapy is typically restricted to cytotoxic chemotherapy, which fa Show more
Triple negative breast cancer (TNBC) is challenging to treat successfully because targeted therapies do not exist. Instead, systemic therapy is typically restricted to cytotoxic chemotherapy, which fails more often in patients with elevated circulating cholesterol. Liver x receptors are ligand-dependent transcription factors that are homeostatic regulators of cholesterol, and are linked to regulation of broad-affinity xenobiotic transporter activity in non-tumor tissues. We show that LXR ligands confer chemotherapy resistance in TNBC cell lines and xenografts, and that LXRalpha is necessary and sufficient to mediate this resistance. Furthermore, in TNBC patients who had cancer recurrences, LXRalpha and ligands were independent markers of poor prognosis and correlated with P-glycoprotein expression. However, in patients who survived their disease, LXRalpha signaling and P-glycoprotein were decoupled. These data reveal a novel chemotherapy resistance mechanism in this poor prognosis subtype of breast cancer. We conclude that systemic chemotherapy failure in some TNBC patients is caused by co-opting the LXRalpha:P-glycoprotein axis, a pathway highly targetable by therapies that are already used for prevention and treatment of other diseases. Show less
Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack in-depth study. Here, through analysis of big databases and clin Show more
Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack in-depth study. Here, through analysis of big databases and clinical samples, we identified a carbamoyl phosphate synthetase 1 (CPS1)-deficient hepatocellular carcinoma (HCC) subtype, explored tumorigenesis mechanism of this HCC subtype, and aimed to investigate metabolic reprogramming as a target for HCC prevention. A pan-cancer study involving differentially expressed metabolic genes of 7,764 tumor samples in 16 cancer types provided by The Cancer Genome Atlas (TCGA) demonstrated that urea cycle (UC) was liver-specific and was down-regulated in HCC. A large-scale gene expression data analysis including 2,596 HCC cases in 7 HCC cohorts from Database of HCC Expression Atlas and 17,444 HCC cases from in-house hepatectomy cohort identified a specific CPS1-deficent HCC subtype with poor clinical prognosis. In vitro and in vivo validation confirmed the crucial role of CPS1 in HCC. Liquid chromatography-mass spectrometry assay and Seahorse analysis revealed that UC disorder (UCD) led to the deceleration of the tricarboxylic acid cycle, whereas excess ammonia caused by CPS1 deficiency activated fatty acid oxidation (FAO) through phosphorylated adenosine monophosphate-activated protein kinase. Mechanistically, FAO provided sufficient ATP for cell proliferation and enhanced chemoresistance of HCC cells by activating forkhead box protein M1. Subcutaneous xenograft tumor models and patient-derived organoids were employed to identify that blocking FAO by etomoxir may provide therapeutic benefit to HCC patients with CPS1 deficiency. In conclusion, our results prove a direct link between UCD and cancer stemness in HCC, define a CPS1-deficient HCC subtype through big-data mining, and provide insights for therapeutics for this type of HCC through targeting FAO. Show less
The pluripotency transcription factor SOX2 is essential for the maintenance of glioblastoma stem cells (GSC), which are thought to underlie tumor growth, treatment resistance, and recurrence. To under Show more
The pluripotency transcription factor SOX2 is essential for the maintenance of glioblastoma stem cells (GSC), which are thought to underlie tumor growth, treatment resistance, and recurrence. To understand how SOX2 is regulated in GSCs, we utilized a proteomic approach and identified the E3 ubiquitin ligase TRIM26 as a direct SOX2-interacting protein. Unexpectedly, we found TRIM26 depletion decreased SOX2 protein levels and increased SOX2 polyubiquitination in patient-derived GSCs, suggesting TRIM26 promotes SOX2 protein stability. Accordingly, TRIM26 knockdown disrupted the SOX2 gene network and inhibited both self-renewal capacity as well as in vivo tumorigenicity in multiple GSC lines. Mechanistically, we found TRIM26, via its C-terminal PRYSPRY domain, but independent of its RING domain, stabilizes SOX2 protein by directly inhibiting the interaction of SOX2 with WWP2, which we identify as a bona fide SOX2 E3 ligase in GSCs. Our work identifies E3 ligase competition as a critical mechanism of SOX2 regulation, with functional consequences for GSC identity and maintenance. Show less
There is an immunoreactive subtype of ovarian cancer with a favorable prognosis, but the majority of ovarian cancers have limited immune reactivity. The reason for this is poorly understood. This stud Show more
There is an immunoreactive subtype of ovarian cancer with a favorable prognosis, but the majority of ovarian cancers have limited immune reactivity. The reason for this is poorly understood. This study aimed to approach this question by identifying prognostically relevant genes whose prognostic mRNA expression levels correlated with a genomic event. Expression microarray and 5-year survival data on 170 ovarian tumors and aCGH data on 45 ovarian cancer cell lines were used to identify amplified/deleted genes associated with prognosis. Three immune-response genes were identified mapping to epigenetically modified chromosome 6p21.3. Genes were searched for roles in epigenetic modification, identifying KANSL1. Genome-wide association studies were searched to identify genetic variants in KANSL1 associated with altered immune profile. Sensitivity to HDAC inhibition in cell lines with KANSL1 amplification/rearrangement was studied. Expression of 196 genes was statistically significantly associated with survival, and expression levels correlated with copy number variations for 82 of them. Among these, 3 immune-response genes (HCP5, PSMB8, PSMB9) clustered together at epigenetically modified chromosome 6p21.3 and their expression was inversely correlated to epigenetic modification gene KANSL1. KANSL1 is amplified/rearranged in ovarian cancer, associated with lymphocyte profile, a biomarker for response to HDAC inhibition, and may drive expression of immune-response genes. This study identifies 82 genes with prognostic relevance and genomic alteration in ovarian cancer. Among these, immune-response genes have correlated expression which is associated with 5-year survival. KANSL1 may be a master gene altering immune-response gene expression at 6p21.3 and drive response to HDAC inhibitors. Future research should investigate KANSL1 and determine whether targeting it alters the immune profile of ovarian cancer and improves survival, HDAC inhibition, and/or immunotherapy response. Show less
BACKGROUNDTranscriptome sequencing (RNA-seq) improves diagnostic rates in individuals with suspected Mendelian conditions to varying degrees, primarily by directing the prioritization of candidate DNA Show more
BACKGROUNDTranscriptome sequencing (RNA-seq) improves diagnostic rates in individuals with suspected Mendelian conditions to varying degrees, primarily by directing the prioritization of candidate DNA variants identified on exome or genome sequencing (ES/GS). Here we implemented an RNA-seq-guided method to diagnose individuals across a wide range of ages and clinical phenotypes.METHODSOne hundred fifteen undiagnosed adult and pediatric patients with diverse phenotypes and 67 family members (182 total individuals) underwent RNA-seq from whole blood and skin fibroblasts at the Baylor College of Medicine (BCM) Undiagnosed Diseases Network clinical site from 2014 to 2020. We implemented a workflow to detect outliers in gene expression and splicing for cases that remained undiagnosed despite standard genomic and transcriptomic analysis.RESULTSThe transcriptome-directed approach resulted in a diagnostic rate of 12% across the entire cohort, or 17% after excluding cases solved on ES/GS alone. Newly diagnosed conditions included Koolen-de Vries syndrome (KANSL1), Renpenning syndrome (PQBP1), TBCK-associated encephalopathy, NSD2- and CLTC-related intellectual disability, and others, all with negative conventional genomic testing, including ES and chromosomal microarray (CMA). Skin fibroblasts exhibited higher and more consistent expression of clinically relevant genes than whole blood. In solved cases with RNA-seq from both tissues, the causative defect was missed in blood in half the cases but none from fibroblasts.CONCLUSIONSFor our cohort of undiagnosed individuals with suspected Mendelian conditions, transcriptome-directed genomic analysis facilitated diagnoses, primarily through the identification of variants missed on ES and CMA.TRIAL REGISTRATIONNot applicable.FUNDINGNIH Common Fund, BCM Intellectual and Developmental Disabilities Research Center, Eunice Kennedy Shriver National Institute of Child Health & Human Development. Show less
Ferroptosis is a mode of regulated cell death that depends on iron and plays pivotal roles in regulating various biological processes in human cancers. However, the role of ferroptosis in gastric canc Show more
Ferroptosis is a mode of regulated cell death that depends on iron and plays pivotal roles in regulating various biological processes in human cancers. However, the role of ferroptosis in gastric cancer (GC) remains unclear. In our study, a total of 2721 differentially expressed genes (DEGs) were filtered based on The Cancer Genome Atlas (TCGA) ( Show less