👤 Zexing Lin

Inflammatory breast cancer (IBC) is a rare and poorly characterized type of breast cancer with an aggressive clinical presentation. The biological mechanisms driving the IBC phenotype are relatively undefined-partially due to a lack of comprehensive, large-scale genomic studies and limited clinical cohorts. A retrospective analysis of 2457 patients with metastatic breast cancer who underwent targeted tumor-only DNA-sequencing was performed at Dana-Farber Cancer Institute. Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV) and tumor mutational burden (TMB) comparisons were made between clinically confirmed IBC cases within a dedicated IBC center versus non-IBC cases. Clinicopathologic differences between IBC and non-IBC cases were consistent with prior reports-including IBC being associated with younger age at diagnosis, higher grade, and enrichment with hormone receptor (HR)-negative and HER2-positive tumors. The most frequent somatic alterations in IBC involved Taken together, this study provides a comprehensive, clinically informed landscape of somatic alterations in a large cohort of patients with IBC. Our data support higher frequency of Show less

As one of the key metabolic enzymes in the glycolytic pathway, lactate dehydrogenase A (LDHA) might be linked to tumor proliferation by driving the Warburg effect. Circular RNAs (circRNAs) are widely implicated in tumor progression. Here, we report that circTATDN3, a circular RNA that interacts with LDHA, plays a critical role in proliferation and energy metabolism in CRC. We found that circTATDN3 expression was increased in CRC cells and tumor tissues and that high circTATDN3 expression was positively associated with poor postoperative prognosis in CRC patients. Additionally, circTATDN3 promoted the proliferation of CRC cells in vivo and vitro. Mechanistically, circTATDN3 was shown to function as an adaptor molecule that enhances the binding of LDHA to FGFR1, leading to increased LDHA phosphorylation and consequently promoting the Warburg effect. Moreover, circTATDN3 increased the expression of LDHA by sponging miR-511-5p, which synergistically promoted CRC progression and the Warburg effect. In conclusion, circTATDN3 may be a target for the treatment of CRC. Show less

Aberrant signaling via fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFR4 is a promising target for anticancer therapy. Herein, we designed and synthesized a series of bis-acrylamide covalent FGFR4 inhibitors and evaluated their inhibitory activity against FGFRs, FGFR4 mutants, and their antitumor activity. CXF-007, verified by mass spectrometry and crystal structures to form covalent bonds with Cys552 of FGFR4 and Cys488 of FGFR1, exhibited stronger selectivity and potent inhibitory activity for FGFR4 and FGFR4 cysteine mutants. Moreover, CXF-007 exhibited significant antitumor activity in hepatocellular carcinoma cell lines and breast cancer cell lines through sustained inhibition of the FGFR4 signaling pathway. In summary, our study highlights a novel covalent FGFR4 inhibitor, CXF-007, which has the potential to overcome drug-induced FGFR4 mutations and might provide a new strategy for future anticancer drug discovery. Show less

This study aimed to investigate the clinicopathological characteristics, diagnostic indicators, and critical factors for the differential diagnosis of rosette-forming glioneuronal tumor (RGNT). This retrospective study included six surgically treated RGNT cases. We analyzed and summarized their clinical manifestations, radiological features, histological morphology, immunophenotype, and molecular genetic changes, supplemented with a literature review. The patients comprised four males and two females with a mean age of 35 years. The tumors were located in the cerebellum (two cases); the fourth ventricle, quadrigeminal cistern, and third ventricle (one case each); and the fourth ventricle and brainstem (one case). Clinical manifestations included headaches in four cases, left eyelid ptosis in one case, and one asymptomatic case only identified during physical examination. Microscopically, the tumor cells were uniform in size and were marked by rosette-like or pseudorosette-like structures around the neuropil and blood vessels. Immunohistochemistry revealed biphasic patterns. The central neuropil components of the rosette-like structures around the neuropil and the pseudorosette structures of the perivascular regions expressed Syn, while the cells surrounding the rosettes expressed Olig2 and not GFAP. GFAP and S-100 were expressed in the glial components but not in the rosette or pseudorosette regions. The Ki-67 proliferation index was typically low. Molecular genetic analysis showed that the main molecular changes involved FGFR1 mutation accompanied by PIK3R1 mutation. None of the patients received chemoradiotherapy postoperatively. Follow-up durations varied between 4 and 23 months with no recorded recurrence or metastasis. RGNT is a comparatively rare mixed glioneuronal tumor that occurs in the midline structures. Its morphology shows certain overlaps with other low-grade neuroepithelial tumors. Identifying the rosettes around the neuropil is critical for morphological diagnosis, and the molecular identification of FGFR1 mutations accompanied by PIK3R1 mutations can facilitate diagnosis. Show less

Pancreatic ductal adenocarcinoma (PDAC) is often intrinsically-resistant to standard-of-care chemotherapies such as gemcitabine. Acquired gemcitabine resistance (GemR) can arise from treatment of initially-sensitive tumors, and chemotherapy can increase tumor aggressiveness. We investigated the molecular mechanisms of chemoresistance and chemotherapy-driven tumor aggressiveness, which are understood incompletely. Differential proteomic analysis was employed to investigate chemotherapy-driven chemoresistance drivers and responses of PDAC cells and patient-derived tumor xenografts (PDX) having different chemosensitivities. We also investigated the prognostic value of FGFR1 expression in the efficacy of selective pan-FGFR inhibitor (FGFRi)-gemcitabine combinations. Quantitative proteomic analysis of a highly-GemR cell line revealed fibroblast growth factor receptor 1 (FGFR1) as the highest-expressed receptor tyrosine kinase. FGFR1 knockdown or FGFRi co-treatment enhanced gemcitabine efficacy and decreased GemR marker expression, implicating FGFR1 in augmentation of GemR. FGFRi treatment reduced PDX tumor progression and prolonged survival significantly, even in highly-resistant tumors in which neither single-agent showed efficacy. Gemcitabine exacerbated aggressiveness of highly-GemR tumors, based upon proliferation and metastatic markers. Combining FGFRi with gemcitabine or gemcitabine+nab-paclitaxel reversed tumor aggressiveness and progression, and prolonged survival significantly. In multiple PDAC PDXs, FGFR1 expression correlated with intrinsic tumor gemcitabine sensitivity. FGFR1 drives chemoresistance and tumor aggressiveness, which FGFRi can reverse. Show less

Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) "primes" PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial-mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters. Animals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key "nodes" responsible for EMT induction. Multiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect. This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical-translational requirement for patient stratification. Show less

Acquired drug resistance poses a challenge for single-target FGFR inhibitors, leading to the development of dual- or multi-target FGFR inhibitors. Sulfatinib is a multi-target kinase inhibitor for treating neuroendocrine tumors, selectively targeting FGFR1/CSF-1R. To elucidate the molecular mechanisms behind its binding and kinase selectivity, we determined the crystal structures of sulfatinib with FGFR1/CSF-1R. The results reveal common structural features and distinct conformational adaptability of sulfatinib in response to FGFR1/CSF-1R binding. Further biochemical and structural analyses disclose sensitivity of sulfatinib to FGFR/CSF-1R gatekeeper mutations. The insensitivity of sulfatinib to FGFR gatekeeper mutations highlights the indispensable interactions with the hydrophobic pocket for FGFR selectivity, whereas the rotatory flexibility may enable sulfatinib to overcome CSF-1R Show less

Cytarabine is an important medicine for acute myeloid leukemia (AML) treatment, however, drug resistance hinders the treatment of AML. Although microRNA (miRNA or miR) alteration is one of the well-recognized mechanisms underlying drug resistance in AML, few studies have investigated the role and function of miRNAs in the development of cytarabine resistance. In the present study, total RNA was isolated from parental HL60 and cytarabine-resistant HL60 (R-HL60) cells. Subsequently, miRNAs and mRNAs were detected using small RNA sequencing and gene expression array, respectively. Differentially expressed mRNAs (DEMs) and differentially expressed genes (DEGs) with more than two-fold changes between HL60 and R-HL60 cells were screened out. Negatively associated miRNA-mRNA pairs were selected as candidate miRNA-mRNA target pairs according to the miRDB, Targetscan or miRTar databases. Functional enrichment analysis of DEGs included in the candidate miRNA-mRNA pairs was performed. The results indicated that 10 DEGs ( Show less

Survival of dormant, disseminated breast cancer cells contributes to tumor relapse and metastasis. Women with a body mass index greater than 35 have an increased risk of developing metastatic recurrence. Herein, we investigated the effect of diet-induced obesity (DIO) on primary tumor growth and metastatic progression using both metastatic and systemically dormant mouse models of breast cancer. This approach led to increased PT growth and pulmonary metastasis. We developed a novel protocol to induce obesity in Balb/c mice by combining dietary and hormonal interventions with a thermoneutral housing strategy. In contrast to standard housing conditions, ovariectomized Balb/c mice fed a high-fat diet under thermoneutral conditions became obese over a period of 10 weeks, resulting in a 250% gain in fat mass. Obese mice injected with the D2.OR model developed macroscopic pulmonary nodules compared with the dormant phenotype of these cells in mice fed a control diet. Analysis of the serum from obese Balb/c mice revealed increased levels of FGF2 as compared with lean mice. We demonstrate that serum from obese animals, exogenous FGF stimulation, or constitutive stimulation through autocrine and paracrine FGF2 is sufficient to break dormancy and drive pulmonary outgrowth. Blockade of FGFR signaling or specific depletion of FGFR1 prevented obesity-associated outgrowth of the D2.OR model. Overall, this study developed a novel DIO model that allowed for demonstration of FGF2:FGFR1 signaling as a key molecular mechanism connecting obesity to breakage of systemic tumor dormancy and metastatic progression. Show less

The human epidermal growth factor receptor 2 (HER2) negative luminal B1 subtype of breast cancer has been reported with a poorer outcome than luminal A in recent studies. This study aimed to investigate the molecular alterations and identify potential therapeutic targets by analyzing the genetic profiling from a cohort of luminal B1 breast cancer in Taiwan. We enrolled patients with luminal B1 breast cancer in our study. They were classified as patients who received curative surgery and adjuvant or neoadjuvant chemotherapy as the low-risk group, and who had advanced or metastatic disease or early relapse during the follow-up time as the high-risk group. Using targeted sequencing, we evaluated genomic alterations, interpreting variants with the ESMO Scale of clinical actionability of molecular targets (ESCAT). A total of 305 luminal B1 breast cancer patients underwent targeted sequencing analyses. The high-risk patients reported more actionable genes and called variants than the low-risk group (P < 0.05). PIK3CA (42%), FGFR1 (25%), and BRCA1/2 (10.5%) were the most prevalent ESCAT actionable alterations in luminal B1 breast cancer. There was no difference in the prevalence of actionable mutations between these two groups, except for ERBB2 oncogenic mutations, which were more prevalent among the high-risk than the low-risk group (P < 0.05). Alterations in PTEN, ERBB2, and BRCA1/2 were associated with disease relapse events in luminal B1 breast cancer. PIK3CA, FGFR1, and BRCA1/2 were the most prevalent actionable alterations among Taiwanese luminal B1 breast cancer. Moreover, PTEN and BRCA1/2 was significantly associated with disease relapse. Show less

Elevated fibroblast growth factor receptor (FGFR) activity correlates with pancreatic adenocarcinoma (PDAC) progression and poor prognosis. However, its potential as a therapeutic target remains largely unexplored. The mechanisms of action and therapeutic effects of selective pan-FGFR inhibitors (pan-FGFRi) were explored using in vitro and in vivo PDAC models ranging from gemcitabine-sensitive to highly gemcitabine-resistant (GemR). Gain-/loss-of-function investigations were employed to define the role of individual FGFRs in cell proliferation, migration, and treatment response and resistance. The pan-FGFRi NVP-BGJ398 significantly inhibited cell proliferation, migration, and invasion, and downregulated key cell survival- and invasiveness markers in multiple PDAC cell lines. Gemcitabine is a standard-of-care for PDAC, but development of resistance to gemcitabine (GemR) compromises its efficacy. Acquired GemR was modelled experimentally by developing highly GemR cells using escalating gemcitabine exposure in vitro and in vivo. FGFRi treatment inhibited GemR cell proliferation, migration, GemR marker expression, and tumour progression. FGFR2 or FGFR3 loss-of-function by shRNA knockdown failed to decrease cell growth, whereas FGFR1 knockdown was lethal. FGFR1 overexpression promoted cell migration more than proliferation, and reduced FGFRi-mediated inhibition of proliferation and migration. Single-agent FGFRi suppressed the viability and growth of multiple patient-derived xenografts inversely with respect to FGFR1 expression, underscoring the influence of FGFR1-dependent tumour responses to FGFRi. Importantly, secondary data analysis showed that PDAC tumours expressed FGFR1 at lower levels than in normal pancreas tissue. Single-agent FGFR inhibitors mediate selective, molecularly-targeted suppression of PDAC proliferation, and their effects are greatest in PDAC tumours expressing low-to-moderate levels of FGFR1. Show less

Androgen receptor (AR) pathway inhibition remains the cornerstone for prostate cancer therapies. However, castration-resistant prostate cancer (CRPC) tumors can resist AR signaling inhibitors through AR amplification and AR splice variants in AR-positive CRPC (ARPC), and conversion to AR-null phenotypes, such as double-negative prostate cancer (DNPC) and small cell or neuroendocrine prostate cancer (SCNPC). We have shown previously that DNPC can bypass AR-dependence through fibroblast growth factor receptor (FGFR) signaling. However, the role of the FGFR pathway in other CRPC phenotypes has not been elucidated. RNA-Seq analysis was conducted on patient metastases, LuCaP patient-derived xenograft (PDX) models, and CRPC cell lines. Cell lines (C4-2B, VCaP, and 22Rv1) and ex vivo LuCaP PDX tumor cells were treated with enzalutamide (ENZA) and FGFR inhibitors (FGFRi) alone or in combination and sensitivity was determined using cell viability assays. In vivo efficacy of FGFRi in ARPC, DNPC, and SCNPC were evaluated using PDX models. RNA-Seq analysis of FGFR signaling in metastatic specimens, LuCaP PDX models, and CRPC cell lines revealed significant FGF pathway activation in AR-low PC (ARLPC), DNPC, and SCNPC tumors. In vitro/ex vivo analysis of erdafitinib and CH5183284 demonstrated robust and moderate growth suppression of ARPC, respectively. In vivo studies using four ARPC PDX models showed that combination ENZA and CH5183284 significantly suppressed tumor growth. Additional in vivo studies using four ARPC PDX models revealed that erdafitinib monotherapy was as effective as ENZA in suppressing tumor growth, and there was limited combination benefit. Furthermore, two of three DNPC models and two of four SCNPC models responded to CH5183284 monotherapy, suggesting FGFRi responses were model dependent. RNA-Seq and gene set enrichment analysis of end-of-study ARPC tumors treated with FGFRi displayed decreased expression of E2F and MYC target genes and suppressed G2M checkpoint genes, whereas end-of-study SCNPC tumors had heterogeneous transcriptional responses. Although FGFRi treatments suppressed tumor growth across CRPC phenotypes, our analyses did not identify a single pathway or biomarker that would identify tumor response to FGFRi. This is very likely due to the array of FGFR1-4 expression and tumor phenotypes present in CRPC. Nevertheless, our data nominate the FGFR pathway as a clinically actionable target that promotes tumor growth in diverse phenotypes of treatment-refractory metastatic CRPC. Show less

Glioblastoma (GBM) is a malignant brain tumor that grows quickly, spreads widely, and is resistant to treatment. Fibroblast growth factor receptor (FGFR)1 is a receptor tyrosine kinase that regulates cellular processes, including proliferation, survival, migration, and differentiation. FGFR1 was predominantly expressed in GBM tissues, and FGFR1 expression was negatively correlated with overall survival. We rationally designed a novel small molecule CYY292, which exhibited a strong affinity for the FGFR1 protein in GBM cell lines Show less

Most organs are maintained lifelong by resident stem/progenitor cells. During development and regeneration, lineage-specific stem/progenitor cells can contribute to the growth or maintenance of different organs, whereas fully differentiated mature cells have less regenerative potential. However, it is unclear whether vascular endothelial cells (ECs) are also replenished by stem/progenitor cells with EC-repopulating potential residing in blood vessels. It has been reported recently that some EC populations possess higher clonal proliferative potential and vessel-forming capacity compared with mature ECs. Nevertheless, a marker to identify vascular clonal repopulating ECs (CRECs) in murine and human individuals is lacking, and, hence, the mechanism for the proliferative, self-renewal, and vessel-forming potential of CRECs is elusive. We analyzed colony-forming, self-renewal, and vessel-forming potential of ABCG2 (ATP binding cassette subfamily G member 2)-expressing ECs in human umbilical vessels. To study the contribution of In human and mouse vessels, ECs with higher These results are the first to establish that a single prospective marker identifies CRECs in mice and human individuals, which holds promise to provide new cell therapies for repair of damaged vessels in patients with endothelial dysfunction. Show less

Polycystic ovarian syndrome (PCOS) is the most common reproductive metabolic disorder in women of reproductive age. However, the underlying mechanism is unclear, because the main symptoms vary with age and the pathogenesis is complex and multifactorial. In order to explore the gene expression and regulation networks, and identify potential biomarkers for diagnosis and treatment of PCOS, we conducted whole RNA sequencing of protein-coding genes, lncRNAs, and miRNAs in peripheral blood with case-control design. RNA sequencing and weighted gene co-expression network analysis (WGCNA) were performed on four pairs of PCOS cases and control peripheral blood samples. The results showed that there were significant differences in the expression levels of 341 mRNAs, 252 lncRNAs and 47 miRNAs between PCOS patients and control groups. Bioinformatics analysis showed that these differentially expressed genes (DEGs) were mainly involved in the metabolic, immune, endocrine, and nervous systems, and also identified potential WGCNA module related with PCOS. The DEGs of PCOS as reported in other published literatures were used to verify our DEGs in this study. These results suggest that the ceRNA regulatory relationship between The online version contains supplementary material available at 10.1007/s43657-024-00183-9. Show less

In this study, we aimed to investigate the relationship between the intraocular levels of inflammatory factors and myopia-related retinal vascular and neuronal degeneration. One hundred and forty-seven patients with Implantable Collamer Lens (ICL) implantation were enrolled and all participants received comprehensive ophthalmic examination. About 100~150 ul of aqueous humor was collected immediately before ICL surgery. The levels of inflammatory factors including Aggrecan, April, BAFF, CCL5, CD163, Chi3l1, gp130, IL-6Rα, IL-8, IL-10, IL-11, IL-12, IL-19, IL-27, IL-28A, IL-34, IFN-β, IFN-γ, MMP-1, MMP-2, MMP-3 and PTX3 in the aqueous humor were measured using the Luminex Multiplexing system. Results showed that aqueous humor levels of pro-inflammatory factors Chi3l1, IL-6Rα, IL-8, IL-12, IL-27, inflammation-related cytokines April, BAFF and IL-34 progressively increased from the progression of myopic retinopathy. Conversely, the aqueous levels of IL-11 and Aggrecan gradually decreased from the progression of myopic retinopathy. Correlation analysis showed that the intraocular levels of Chi3l1, IL-6Rα, IL-8, IL-27 and BAFF were negatively correlated with retinal vascular density. The intraocular level of IL-6Rα was negatively correlated with retinal neuronal thickness. Protein-Protein Interaction (PPI) analysis revealed that Chi3l1 and Aggrecan were the upstream cytokines that affect IL-10 and IL-8 in the pathological myopic eyes. KEGG pathway analysis showed that cytokine-cytokine receptor interaction, JAK-STAT signaling pathway, rheumatoid arthritis, and chagas disease were influenced by these altered inflammatory factors (adjusted p-value<0.001). The production of inflammatory factors in the eyes of individuals with high myopia and pathological myopia was altered, and the elevated levels of intraocular pro-inflammatory factors such as Chi3l1, IL-6Rα, and IL-8 were closely associated with myopia-related retinal microvascular and neurodegeneration. Show less

Decidual regulatory T cells (Tregs) are essential for successful pregnancy outcome. A subset of Tregs, T cell immunoglobulin and mucin domain-containing protein 3-positive regulatory T cells (TregsTim-3+), plays a central role in the acceptance of the fetus during early stages of normal pregnancy. The molecular mechanism regulating the differentiation and function of TregsTim-3+ is unknown. Here, we investigated the role of the transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) on decidual TregTim-3+ differentiation. We demonstrated that Blimp-1 enhanced the coexpression of negative costimulatory molecules (Tim-3, T cell immunoreceptor with Ig and ITIM domains, and programmed cell death protein 1) on Tregs and improved their immunosuppressive functions, including increased IL-10 secretion, suppression of effector T cell proliferation, and promotion of macrophage polarization toward the M2 phenotype. Furthermore, we showed that IL-27 regulated the expression of Tim-3 and Blimp-1 through the STAT1 signaling pathway and that transfer of TregsBlimp-1+ into an abortion-prone mouse model effectively reduced embryo absorption rate. We postulated that abnormalities in the IL-27/Blimp-1 axis might be associated with recurrent pregnancy loss (RPL). These findings provided insights for developing more efficient immunotherapies for women with RPL. Show less

Inactivating mutations of Foxp3, the master regulator of regulatory T cell development and function, lead to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in mice and humans. IPEX is a fatal autoimmune disease, with allogeneic stem cell transplant being the only available therapy. In this study, we report that a single dose of adeno-associated virus (AAV)-IL-27 to young mice with naturally occurring Foxp3 mutation (Scurfy mice) substantially ameliorates clinical symptoms, including growth retardation and early fatality. Correspondingly, AAV-IL-27 gene therapy significantly prevented naive T cell activation, as manifested by downregulation of CD62L and upregulation of CD44, and immunopathology typical of IPEX. Because IL-27 is known to induce IL-10, a key effector molecule of regulatory T cells, we evaluated the contribution of IL-10 induction by crossing IL-10-null allele to Scurfy mice. Although IL-10 deficiency does not affect the survival of Scurfy mice, it largely abrogated the therapeutic effect of AAV-IL-27. Our study revealed a major role for IL-10 in AAV-IL-27 gene therapy and demonstrated that IPEX is amenable to gene therapy. Show less

Diabetic kidney disease (DKD) is one of the most common microvascular complications in patients with diabetes mellitus. In this condition, renal tubular epithelial mesenchymal transition (EMT) is an important factor accelerating the progression of DKD and a major cause of renal fibrosis and end-stage renal disease. However, the therapeutic effect is unsatisfactory because of the lack of effective drugs. Jia Wei Qingxin Lotus Seed Drink (QISD) is a traditional Chinese medicine compound formula that has shown to be effective in the clinical treatment of DKD. However, the potential of QISD in DKD-EMT treatment has yet to be fully explored. This study aimed to investigate the role of QISD in ameliorating DKD-EMT injury and its mechanism. The active ingredients of QISD were identified via ultra-performance liquid chromatography-mass spectrometry/mass spectrometry (UHPLC-MS/MS). A DKD mouse model was constructed by high-fat diet feeding and intraperitoneal injection of STZ (60 mg/kg), and QISD (14.46, 28.92, and 57.84 g/kg/day) was administered by gavage for 12 consecutive weeks. Dapagliflozin (1 mg/kg/d) was used as a positive control. Renal pathological damage was observed by HE, PAS, and Masson staining. The expression levels of EMT-related proteins and pathway proteins were detected via immunohistochemistry, RT-qPCR, and western blot. In in vitro experiments, EMT injury was induced in human kidney tubular epithelial cells (HK-2) by using lipopolysaccharide (LPS). A combination of CCK8 assay, wound healing assay, small-molecule inhibitor intervention, and overexpression lentiviral transfection was used to investigate the effects of QISD on cell migration ability, adhesion ability, fibrotic factor formation, and mesenchymal properties. Animal experiments showed that QISD improved blood glucose, body weight, symptoms of excessive drinking and eating, and renal pathological injury in mice, reduced extracellular matrix deposition, delayed renal EMT injury, and inhibited the activation of the histone demethylase JMJD1C. UHPLC-MS/MS and molecular docking indicated that baicalin, wogonoside, oroxylin A-7-O-β-D-glucuronide, and glulisine A found in QISD could bind to JMJD1C. The ameliorating effect of QISD on DKD-EMT injury might be related to JMJD1C. The improvement of DKD-EMT injury by QISD was accompanied by the reduction of SP1 and ZEB1 expression. The SP1 overexpression not only reversed the therapeutic effect of JIB-04, an inhibitor of JMJD1C, on DKD-EMT but also exacerbated the expression of ZEB1 and downstream EMT-related factors. Thus, QISD might affect the expression of the epithelial marker E-cadherin by inhibiting the JMJD1C/SP1/ZEB1 signaling pathway, consequently preventing the transformation of epithelial cells to mesenchymal cells and ameliorating DKD-EMT injury. This study was the first to demonstrate that QISD might ameliorate DKD-EMT injury by inhibiting the JMJD1C/SP1/ZEB1 signaling pathway. These findings provide strong pharmacologic evidence for the clinical use of QISD in the treatment of DKD. Show less

Autism spectrum disorder (ASD) is a partially heritable neurodevelopmental trait, and people with ASD may also have other co-occurring trait such as ADHD, anxiety disorders, depression, mental health issues, learning difficulty, physical health traits and communication challenges. The concomitant development of ASD and other neurological traits is assumed to result from a complex interplay between genetics and the environment. However, only a limited number of studies have performed multivariate genome-wide association studies (GWAS) for ASD. We conducted to-date the largest multivariate GWAS on ASD and 8 ASD co-occurring traits (ADHD, ADHD childhood, anxiety stress (ASDR), bipolar (BIP), disruptive behaviour (DBD), educational attainment (EA), major depression, and schizophrenia (SCZ)) using summary statistics from leading studies. Multivariate associations and central traits were further identified. Subsequently, colocalization and Mendelian randomization (MR) analysis were performed on the associations identified with the central traits containing ASD. To further validate our findings, pathway and quantified trait loci (QTL) resources as well as independent datasets consisting of 112 (45 probands) whole genome sequence data from the GEMMA project were utilized. Multivariate GWAS resulted in 637 significant associations (p < 5e-8), among which 322 are reported for the first time for any trait. 37 SNPs were identified to contain ASD and one or more traits in their central trait set, including variants mapped to known SFARI ASD genes MAPT, CADPS and NEGR1 as well as novel ASD genes KANSL1, NSF and NTM, associated with immune response, synaptic transmission, and neurite growth respectively. Mendelian randomization analyses found that genetic liability for ADHD childhood, ASRD and DBT has causal effects on the risk of ASD while genetic liability for ASD has causal effects on the risk of ADHD, ADHD childhood, BIP, WA, MDD and SCZ. Frequency differences of SNPs found in NTM and CADPS genes, respectively associated with neurite growth and neural/endocrine calcium regulation, were found between GEMMA ASD probands and controls. Pathway, QTL and cell type enrichment implicated microbiome, enteric inflammation, and central nervous system enrichments. Our study, combining multivariate GWAS with systematic decomposition, identified novel genetic associations related to ASD and ASD co-occurring driver traits. Statistical tests were applied to discern evidence for shared and interpretable liability between ASD and co-occurring traits. These findings expand upon the current understanding of the complex genetics regulating ASD and reveal insights of neuronal brain disruptions potentially driving development and manifestation. Show less

Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett's esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR. Furthermore, we constructed a protein-protein interaction network, unveiling potential associations among candidate proteins. Simultaneously, we acquired mRNA expression quantitative trait loci (eQTL) data from another GWAS encompassing four different tissues to identify additional drug targets. Meanwhile, we searched drug databases to evaluate these targets. Under Bonferroni correction (P < 4.8 × 10 Show less

Sulfur metabolites of methionine (Met) and vitamin E (VE) have antioxidant potential and can maintain liver health in chickens. This study explored the underlying mechanisms of Met sources, the ratio of total sulfur amino acids to lysine (TSAA: Lys), and VE levels on production performances, antioxidant potential, and hepatic oxidation in aged laying hens. Eight hundred and sixty-four, Hy-Line Brown laying hens (70-week age) were divided into 12 treatment groups, each having 6 repeats and 12 birds/each repeat. The dietary treatments consisted of DL-Met (DL-Met), DL-2-hydroxy-4-(methylthio)-butanoic acid (OH-Met), 3 ratios of TSAA: Lys (0.90, 0.95, and 1.00), and 2 levels of VE (20 and 40 g/ton). Albumen height and Haugh unit significantly increased at a lower level of VE (P < 0.05). Triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) in serum and superoxide dismutase (SOD) and catalase activities (CAT) in the liver significantly reduced at 0.95 TSAA: Lys ratio (P < 0.05). Fatty acid synthase (FAS), lipoprotein lipase (LPL), nuclear factor erythroid 2-related factor 2 (Nrf2), and carnitine palmitoyltransferase-1 alpha (CPT-1α) also upregulated at this TSAA: Lys ratio (P < 0.05). Compared with the DL-Met group, the OH-Met group had lower Dipeptidyl Peptidase 4 (DPP4) and higher TC, LDL, and VLDL concentrations (P < 0.05).The expression of FAS,CPT-1α), glutathione (GSH), glutathione disulfide (GSSG), glutathione synthetase (GSS), and Nrf2 were significantly higher in OH-Met compared with the DL-Met group (P < 0.05). OH-Met at 0.95 and DL-Met at 0.90 TSAA: Lys ratio showed higher CAT and lower aspartate aminotransferase (AST) activities. Moreover, OH-Met at 0.90 and DL-Met at 0.95 of the TSAA: Lys ratio had a significant reduction of malondialdehyde (MDA) (P < 0.05). Overall, these results suggest that OH-Met source with a lower level of VE positively influenced production performance and improved liver health in aged laying hens through improved lipid metabolism and hepatic antioxidant function. Show less

Composite lymphoma, defined as two or more distinct well-defined entities involving the same anatomic site, is rare. Here we report a 79-year-old woman with composite mantle cell lymphoma (MCL) and lymphoplasmacytic lymphoma (LPL) involving bone marrow at the time of initial diagnosis. The patient presented with splenomegaly and lymphadenopathy and laboratory studies showed an elevated serum IgM level and IgM kappa paraprotein. Bone marrow evaluation showed concurrent involvement by MCL and LPL, supported by immunophenotypic studies that revealed two distinct aberrant B-cell populations. Next-generation sequencing analysis identified concurrent MYD88 and CXCR4 mutations and fluorescence in-situ hybridization showed CCND1 translocation, supporting the diagnosis of concomitant MCL and LPL. In conclusion, composite lymphoma can present in the bone marrow. The use of ancillary studies was essential in reaching the diagnosis in this case, as the results excluded the possibility of MCL lymphoma with plasmacytic differentiation, as well as other CD5- and CD10-negative small B-cell lymphomas. Show less

As a transcription factor, Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1) binds to downstream target genes to participate in cell proliferation and cell differentiation. We found that the NR4A1 reached the highest expression at 60 h after the differentiation of goat intramuscular preadipocytes. Overexpression of goat NR4A1 increased the number of intracellular lipid droplets and up-regulated the expression of adipocyte-differentiation-related marker genes including Show less

Triglyceride (TG) /High density lipoprotein cholesterol (HDL-C) ratio (THR) represents a single surrogate predictor of hyperinsulinemia or insulin resistance that is associated with premature aging processes, risk of diabetes and increased mortality. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among subjects of European ancestry who had complete data from two exams collected about seven years apart from the Long Life Family Study (LLFS, n=1384), a study with familial clustering of exceptional longevity in the US and Denmark. Subjects with diabetes or using medications for dyslipidemia were excluded from this analysis. ΔTHR was derived using growth curve modeling, and adjusted for age, sex, field centers, and principal components (PCs). GWAS was conducted using a linear mixed model accounted for familial relatedness. Our linkage scan was built on haplotype-based IBD estimation with 0.5 cM average spacing. Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the our linkage-guided sequence analysis approach permitted our discovery of two novel gene variants Show less

Integrated analyses of plasma proteomics and genetic data in prospective studies can help assess the causal relevance of proteins, improve risk prediction, and discover novel protein drug targets for type 2 diabetes (T2D). We measured plasma levels of 2,923 proteins using Olink Explore among ∼2,000 randomly selected participants from China Kadoorie Biobank (CKB) without prior diabetes at baseline. Cox regression assessed associations of individual protein with incident T2D (n = 92 cases). Proteomic-based risk models were developed with discrimination, calibration, reclassification assessed using area under the curve (AUC), calibration plots, and net reclassification index (NRI), respectively. Two-sample Mendelian randomization (MR) analyses using cis-protein quantitative trait loci identified in a genome-wide association study of CKB and UK Biobank for specific proteins were conducted to assess their causal relevance for T2D, along with colocalization analyses to examine shared causal variants between proteins and T2D. Overall, 33 proteins were significantly associated (false discovery rate <0.05) with risk of incident T2D, including IGFBP1, GHR, and amylase. The addition of these 33 proteins to a conventional risk prediction model improved AUC from 0.77 (0.73-0.82) to 0.88 (0.85-0.91) and NRI by 38%, with predicted risks well calibrated with observed risks. MR analyses provided support for the causal relevance for T2D of ENTR1, LPL, and PON3, with replication of ENTR1 and LPL in Europeans using different genetic instruments. Moreover, colocalization analyses showed strong evidence (pH4 > 0.6) of shared genetic variants of LPL and PON3 with T2D. Proteomic analyses in Chinese adults identified novel associations of multiple proteins with T2D with strong genetic evidence supporting their causal relevance and potential as novel drug targets for prevention and treatment of T2D. Show less

The study aims to explore the relationship between lipoprotein lipase In total, 80 participants were involved in this study (54 patients with HLAP and 26 controls). All coding regions and intron-exon boundaries of the The rate of rare Detecting rare variants in Show less