Biomedical subjects

Li Ding

Publications and source records attributed to Li Ding.

At least 19 recordsLinked to original sources

PubMed2026

Proteogenomic analysis of pediatric and AYA high-grade glioma reveals age-dependent biology, female-male differences, and kinase targets.

High-grade gliomas (HGGs) in children and adolescents and young adults (AYA) exhibit distinct biology across the neurodevelopmental spectrum. To dissect tumor-intrinsic molecular characteristics independent of developmental variation, we perform comprehensive proteogenomic analyses of tumors from 112 HGG patients aged 0-40 years. Our multi-omics analysis identifies two AYA subgroups-adolescents (aged 15-26 years) and young adults (aged 26-40 years)-with distinct molecular profiles and survival outcomes. Tumor-normal comparisons and survival modeling highlight roles of oxidative phosphorylation and neuronal system biology in glioma progression. Causal network analysis and cell line studies provide a rationale for personalized therapies targeting candidate kinases, such as CDK8. Survival modeling, clustering, and immune-landscape analyses identify proteins, post-translational modifications, and immune signatures linked to outcomes and reveal clinically relevant differences between male and female patients.

adolescent and young adult glioma↗

PubMed2026

Spatial Mapping of the Precancer-to-Cancer Transition in Breast and Prostate.

UNLABELLED: Breast and prostate cancers are both hormone-driven adenocarcinomas that undergo analogous invasion programs. Using lightsheet microscopy on intact tumors, we identified transitional junctions between precancerous and invasive regions. We then developed a multimodal serial-section workflow integrating volumetric reconstruction with spatial transcriptomics. Analysis of 319 spatial assays from 51 cases revealed gene expression features and novel structural insights defining the shift from precancer to invasive disease. In breast cancer, loss of MGP and PLAT was associated with invasive transition and promoted tumorigenesis in functional assays. In prostate cancer, GDF15, ALDH1A3, ANPEP, and FASN were upregulated along invasive progression, and their knockdown in PC-3 cells suppressed proliferation and migration. Enrichment of tumor-associated macrophages (SPP1+ and MS4A6A+) along non-triple-negative breast cancer breast cancer transitions highlights immune involvement as a potential driver of invasiveness. SIGNIFICANCE: Our method of defining precise spatial locations of invasive transition allows for the direct interrogation of transition drivers, presenting new therapeutic targets for the two most prevalent cancers and providing a framework for studying spatially defined mechanisms of tumor progression. See related commentary by Jing and Li, p. 1720.

Humans↗

PubMed2026

Cefiderocol susceptibility rates in carbapenem-resistant Gram-negative bacteria in a comparative, multicenter surveillance study in China.

BACKGROUND: Cefiderocol is a siderophore cephalosporin with potent, broad spectrum of activity against carbapenem-resistant (CR) Gram-negative bacteria. The objective of this surveillance study was to assess cefiderocol susceptibility in molecularly characterized CR Gram-negative pathogens collected from hospitalized patients across China. METHODS: Susceptibility testing was performed by the broth microdilution method according to Clinical and Laboratory Standards Institute guidelines, using pre-prepared frozen 96-well microtiter Thermo Fisher plates. Susceptibilities to cefiderocol and most comparators were determined by Clinical and Laboratory Standards Institute breakpoints, to tigecycline by US Food and Drug Administration breakpoints, and to colistin by European Committee on Antimicrobial Susceptibility Testing criteria. Carbapenemases were identified by whole-genome sequencing and polymerase chain reaction. RESULTS: Of 149 CR Klebsiella pneumoniae, 95.3% were susceptible to cefiderocol (OXA-48-positive 100% [n = 15]; IMP-positive 100% [n = 9]; KPC-positive 95.4% [n = 108]; NDM-positive 88.2% [n = 17]) and against 103 NDM-positive CR Escherichia coli, cefiderocol susceptibility was 45.6%. Among comparator antibiotics, ceftazidime-avibactam was only active against K. pneumoniae carbapenemase-positive and OXA-48-positive K. pneumoniae isolates. Susceptibilities to tigecycline and colistin were between 22.2% and 97.1% and between 88.2% and 100% across CR Enterobacterales with different carbapenemases, respectively. High cefiderocol susceptibility rates were found for CR Pseudomonas aeruginosa (98.4%), CR Acinetobacter baumannii (99.6%), and Stenotrophomonas maltophilia (99.6%). Among comparator antibiotics, only colistin showed high activity against CR P. aeruginosa (99.2%) and CR A. baumannii (99.2%). CONCLUSIONS: Cefiderocol susceptibility rates were ≥88% against a collection of carbapenemase-positive CR Gram-negative isolates, except for lower susceptibility in NDM-positive CR E. coli isolates. Continuous monitoring of cefiderocol susceptibility is warranted.

Cefiderocol↗

PubMed2025

Genomic and Immune Landscape of Pancreatic Ductal Adenocarcinoma Associated with Germline Pathogenic Variants in ATM.

PURPOSE: Germline pathogenic variants (PV) in ATM increase the risk of pancreatic ductal adenocarcinoma (PDAC), but the underlying tumor biology of PDAC associated with germline PV in ATM has not been adequately explored. EXPERIMENTAL DESIGN: Whole-genome, whole-exome, and RNA sequencing were performed on PDAC tumors from 25 germline ATM PV carriers diagnosed at Mayo Clinic between 2007 and 2017. Somatic and copy-number alterations, mutational signatures, transcriptomic subtypes, and the immune landscape were evaluated. RESULTS: High-quality whole-exome and whole-genome sequencing were obtained from 21 and 15 tumors, respectively. Biallelic inactivation of ATM was observed in 87%, KRAS PV in 90%, CDKN2A homozygous loss in 60%, and TP53 alterations in <10% of these tumors. A predominant clock-like mutational signature was present in all samples. Whole-transcriptome analysis identified that the aberrantly differentiated endocrine exocrine subtype accounted for 18% of PDAC and was consistently associated with >5-year overall survival. In addition, a 28-gene expression-based signature associated with overall survival was identified and further validated in The Cancer Genome Atlas cohort. Immune landscape analysis through CODEX identified enriched CD4 T-helper cell/tumor interactions and reduced B7H3-high cell/tumor interactions in ATM PV carriers compared with noncarriers. CONCLUSIONS: The observed absence of TP53 PV and enrichment for CDKN2A alterations in ATM tumors, along with differences in the mutational signatures, transcriptomic subtypes and immune landscape, improve our understanding of the mechanistic pathways involved in PDAC development in germline ATM PV carriers and help identify potential targeted therapeutic strategies.

Humans↗

PubMed2025

Optimizing participant and community engagement in cancer genomic sequencing research.

PURPOSE: We describe strategies implemented across research centers of the Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network to optimize engagement of participants and communities in cancer genomics research. We also present consensus definitions of engagement and engagement optimization, informed by our shared experiences in the Network. METHODS: Key informant interviews and a document review identified engagement and optimization strategies across PE-CGS research centers. Findings were synthesized using qualitative content analysis. Consensus on definitions of engagement and optimization were developed through iterative review by PE-CGS members. RESULTS: PE-CGS research centers adopted tailored strategies based on community needs and scientific gaps. Engagement strategies included community-based efforts (eg, advisory boards and newsletters) and participant-focused approaches (eg, enhanced informed consent and decision support tools). Optimization strategies leveraged scientific methods (eg, randomized controlled trials and surveys) to evaluate engagement. Engagement was described as the sustained and meaningful interactions between researchers, participants, and communities. Optimization was described as the application of scientific methods to refine and improve engagement and research processes and outcomes. CONCLUSION: Engagement and optimization strategies have informed research planning, conduct, and dissemination across PE-CGS. These approaches and definitions provide a foundation for developing evidence-based practices to strengthen participant and community involvement in cancer genomics research.

Humans↗

PubMed2025

The histone modifier KAT2A presents a selective target in a subset of well-differentiated microsatellite-stable colorectal cancers.

Lysine acetyltransferase 2 A (KAT2A) plays a pivotal role in epigenetic gene regulation across various types of cancer. In colorectal cancer (CRC), increased KAT2A expression is associated with a more aggressive phenotype. Our study aims to elucidate the molecular underpinnings of KAT2A dependency in CRC and assess the consequences of KAT2A depletion. We conducted a comprehensive analysis by integrating CRISPR-Cas9 screening data with genomics, transcriptomics, and global acetylation patterns in CRC cell lines to pinpoint molecular markers indicative of KAT2A dependency. Additionally, we characterized the phenotypic effect of a CRISPR-interference-mediated KAT2A knockdown in CRC cell lines and patient-derived 3D spheroid cultures. Moreover, we assessed the effect of KAT2A depletion within a patient-derived xenograft mouse model in vivo. Our findings reveal that KAT2A dependency is closely associated with microsatellite stability, lower mutational burden, and increased molecular differentiation signatures in CRC, independent of the KAT2A expression levels. KAT2A-dependent CRC cells display higher gene expression levels and enriched H3K27ac marks at gene loci linked to enterocytic differentiation. Furthermore, loss of KAT2A leads to decreased cell growth and viability in vitro and in vivo, downregulation of proliferation- and stem cell-associated genes, and induction of differentiation markers. Altogether, our data show that a specific subset of CRCs with a more differentiated phenotype relies on KAT2A. For these CRC cases, KAT2A might represent a promising novel therapeutic target.

Humans↗

PubMed2006

Calcineurin-NFATc signaling pathway regulates AQP2 expression in response to calcium signals and osmotic stress.

The aquaporin (AQP)2 channel mediates the reabsorption of water in renal collecting ducts in response to arginine vasopressin (AVP) and hypertonicity. Here we show that AQP2 expression is induced not only by the tonicity-responsive enhancer binding protein (TonEBP)/nuclear factor of activated T cells (NFAT)5-mediated hypertonic stress response but also by the calcium-dependent calcineurin-NFATc pathway. The induction of AQP2 expression by the calcineurin-NFATc pathway can occur in the absence of TonEBP/NFAT5. Mutational and chromatin immunoprecipitation analyses revealed the existence of functional NFAT binding sites within the proximal AQP2 promoter responsible for regulation of AQP2 by NFATc proteins and TonEBP/NFAT5. Contrary to the notion that TonEBP/NFAT5 is the only Rel/NFAT family member regulated by tonicity, we found that hypertonicity promotes the nuclear translocation of NFATc proteins for the subsequent induction of AQP2 expression. Calcineurin activity was also found to be involved in the induction of TonEBP/NFAT5 expression by hypertonicity, thus further defining the signaling mechanisms that underlie the TonEBP/NFAT5 osmotic stress response pathway. The coordinate regulation of AQP2 expression by both osmotic stress and calcium signaling appears to provide a means to integrate diverse extracellular signals into optimal cellular responses.

Active Transport, Cell Nucleus↗

PubMed2006

Determination of palonosetron in human plasma by liquid chromatography-electrospray ionization-mass spectrometry.

A high performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS) method for the determination of palonosetron (PALO) in human plasma using naloxone as the internal standard (IS) was established. After adjustment to a weakly basic pH with saturated sodium bicarbonate, plasma samples were extracted with ethyl acetate and separated on a Hanbon Lichrospher 5-C18 column with a mobile phase of 40 mM ammonium acetate buffer solution containing 0.04% formic acid-methanol (46:54, v/v). PALO was determined with electrospray ionization-mass spectrometry (ESI-MS). HPLC-ESI-MS was performed in the selected-ion monitoring (SIM) mode using target ions at [M+H]+ m/z 297.2 for PALO and [M+H]+ m/z 328.2 for the IS. Calibration curve was linear over the range of 0.02124-10.62 ng/ml. The lower limit of quantification (LLOQ) was 0.02124 ng/ml. The intra- and inter-run variability values were all less than 10.4%. The method has been successfully applied to determine the plasma concentration of PALO in healthy Chinese volunteers.

Adult↗

PubMed2006

Determination of bencycloquidium bromide in rat plasma by liquid chromatography-electrospray ionization-mass spectrometry.

A liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) assay for the determination of bencycloquidium bromide (BCQB) in rat plasma was firstly developed and validated. After addition of 1-ethyl-bencycloquidium bromide as an internal standard (I.S.), the plasma samples were deproteinized with methanol and the supernatant was assayed by LC-ESI-MS. Chromatographic separation was achieved with a Hanbon Lichrospher 5-C18 column. The mobile phase consisted of methanol-40 mM ammonium acetate buffer-formic acid (75:25:0.25, v/v/v) and delivered at the flow rate of 1.0 ml/min. LC-ESI-MS was carried out on a single quadrupole mass spectrometer using electrospray ionization (ESI) and positive selected-ion monitoring (SIM). Target ions were monitored at [M](+)m/z 330.2 for BCQB and [M] (+)m/z 344.2 for I.S. Calibration curve was linear over the range of 3-1500 ng/ml. The lower limit of quantification (LLOQ) was 3.0 ng/ml. The intra- and inter-run relative standard deviations (R.S.D.%) of the assay were less than 7.1 and 12.3%, respectively. The accuracy determined at the concentrations of 3.0, 100.0, 500.0 and 1500 ng/ml for BCQB were within +/-15.0%. The established method has been applied successfully to study the pharmacokinetics of BCQB in rats after intranasal administration.

Animals↗

PubMed2006

The HOXB13:IL17BR expression index is a prognostic factor in early-stage breast cancer.

PURPOSE: We previously identified three genes, HOXB13, IL17BR and CHDH, and the HOXB13:IL17BR ratio index in particular, that strongly predicted clinical outcome in breast cancer patients receiving tamoxifen monotherapy. Confirmation in larger independent patient cohorts was needed to fully validate their clinical utility. PATIENTS AND METHODS: Expression of HOXB13, IL17BR, CHDH, estrogen receptor (ER) and progesterone receptor (PR) were quantified by real-time polymerase chain reaction in 852 formalin-fixed, paraffin-embedded primary breast cancers from 566 untreated and 286 tamoxifen-treated breast cancer patients. Gene expression and clinical variables were analyzed for association with relapse-free survival (RFS) by Cox proportional hazards regression models. RESULTS: ER and PR mRNA measurements were in close agreement with immunohistochemistry. In the entire cohort, expression of HOXB13 was associated with shorter RFS (P = .008), and expression of IL17BR and CHDH was associated with longer RFS (P < .0001 for IL17BR and P = .0002 for CHDH). In ER+ patients, the HOXB13:IL17BR index predicted clinical outcome independently of treatment, but more strongly in node-negative patients. In multivariate analysis of the ER+ node-negative subgroup including age, PR status, tumor size, S phase fraction, and tamoxifen treatment, the two-gene index remained a significant predictor of RFS (hazard ratio = 3.9; 95% CI, 1.5 to 10.3; P = .007). CONCLUSION: This tumor bank study demonstrated HOXB13:IL17BR index is a strong independent prognostic factor for ER+ node-negative patients irrespective of tamoxifen therapy.

Aged↗

PubMed2006

Determination of gambogic acid in human plasma by liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry.

A high-performance liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry (HPLC-APCI-MS) method was established for the determination of gambogic acid (GA) in human plasma using ursolic acid as the internal standard (I.S.). Plasma samples were extracted with ethyl acetate and separated on a Hanbon Lichrospher 5-C18 column with a mobile phase of acetonitrile-tetrahydrofuran-water (70:23:7, v/v). Gambogic acid was determined by using atmospheric pressure chemical ionization (APCI) in a single quadrupole mass spectrometer. HPLC-APCI-MS was performed in the selected ion monitoring (SIM) mode using target ions at [M-H](-)m/z 627.4 for gambogic acid and [M-H](-)m/z 455.4 for the I.S. Calibration curve was linear over the range of 3.108-4144 microg/L. The lower limit of quantification was 3.108 microg/L. The intra- and inter-run precisions were less than 12.3 and 14.1%, respectively. The method has been successfully applied to study the pharmacokinetics of gambogic acid in patients with malignant tumour.

Atmospheric Pressure↗

PubMed2006

Determination of azelnidipine in human plasma by liquid chromatography-electrospray ionization-mass spectrometry.

A liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) method for the determination of azelnidipine in human plasma was established. Nicardipine was used as the internal standard (IS). After adjustment to a basic pH with sodium hydroxide solution (0.1 M), plasma samples were extracted with cyclohexane-diethyl ether (1:1, v/v) and separated on a C(18) column with a mobile phase of 20 mM ammonium acetate solution-methanol-formic acid (25:75:0.5, v/v). The electrospray ionization was employed in a single quadrupole mass spectrometer for the determination. The method was linear over the concentration range of 0.05-40 ng/ml. The lower limit of quantification (LLOQ) was 0.05 ng/ml. The intra- and inter-run standard deviations were less than 9.5% and 11.0%, respectively. The method was successfully applied to study the pharmacokinetics of azelnidipine in healthy Chinese volunteers.

Administration, Oral↗

PubMed2006

Sensitive HPLC-APCI-MS method for the determination of cyclovirobuxine D in human plasma.

A sensitive high performance liquid chromatography-atmospheric pressure chemical ionisation-mass spectrometry (HPLC-APCI-MS) assay for determination of cyclovirobuxine D (CVB-D) in human plasma using mirtazapine as internal standard (I.S.) was established. After adjustment to a basic pH with sodium hydroxide, plasma was extracted by ethyl acetate and separated by high performance liquid chromatography (HPLC) on a reversed-phase C(18) column with a mobile phase of 30 mM ammonium acetate buffer solution containing 1% formic acid-methanol (48:52, v/v). CVB-D was determined with atmospheric pressure chemical ionisation-mass spectrometry (APCI-MS). HPLC-APCI-MS was performed in the selected-ion monitoring (SIM) mode using target ions at [M+H](+)m/z 403.4 for CVB-D and [M+H](+)m/z 266.2 for I.S. Calibration curves were linear over the range 10.11-4044 pg/ml. The lower limit of quantification was 10.11 pg/ml. The intra- and inter-run variability values were less than 9.5 and 12.4%, respectively. The mean plasma extraction recovery of CVB-D was in the range of 85.3-92.8%. The method was successfully applied to determine the plasma concentrations of CVB-D in Chinese volunteers.

Chromatography, High Pressure Liquid↗

PubMed2006

Determination of octopamine, synephrine and tyramine in Citrus herbs by ionic liquid improved 'green' chromatography.

Without adding any volatile organic solvents, aqueous solutions of room temperature ionic liquids (RTILs) were used as 'green' mobile phases to determine octopamine, synephrine and tyramine by liquid chromatography. The problems of the adrenergic amines separation, such as band tailing, low retention and low resolution were solved successfully by using RTIL. The effect of 1-ethyl-3-methylimidazolium tertafluoroborate ([EMIM][BF4]) was the best in the six investigated RTILs. The concentration of [EMIM][BF4], mobile phase pH and column temperature, which influenced the chromatographic behaviors of the analytes, were investigated in detail. The change of retention factors caused by pH shift was obviously suppressed by [EMIM][BF4]. The sensitivity, accuracy and repeatability of this method were found to be satisfactory. The contents of adrenergic amines in several Citrus herbs and extracts, such as Fructus aurantii immaturus, were simultaneously determined by this 'green' chromatographic method.

Adrenergic alpha-Agonists↗

PubMed2006

A sensitive LC-ESI-MS method for the determination of indapamide in human plasma: method and clinical applications.

A sensitive LC-ESI-MS method for the determination of indapamide in human plasma using glibenclamide as the internal standard (IS) was established. Following acidification with 1 M hydrochloric acid solution, plasma samples were extracted with ethyl acetate and separated on a C(18) column with a mobile phase of 10 mM ammonium acetate-methanol (22:78, v/v). Indapamide was determined using electrospray ionization in a single quadrupole mass spectrometer. LC-ESI-MS was performed in the selected ion monitoring (SIM) mode using target ions at m/z 364.3 for indapamide and m/z 492.4 for the IS. Calibration curves were linear over the ranges of 0.1-100 ng/ml for indapamide. The lower limit of quantification was 0.1 ng/ml. The intra- and inter-assay precisions were less than 9.5% and 10.6%, respectively. The mean plasma extraction recovery of indapamide was 90.5-93.9%. The method has been successfully applied to study the pharmacokinetics of indapamide in healthy male Chinese volunteers.

Administration, Oral↗

PubMed2006

Congenital progressive hydronephrosis (cph) is caused by an S256L mutation in aquaporin-2 that affects its phosphorylation and apical membrane accumulation.

Congenital progressive hydronephrosis (cph) is a spontaneous recessive mutation that causes severe hydronephrosis and obstructive nephropathy in affected mice. The mutation has been mapped to the distal end of mouse chromosome 15, but the mutated gene has not been found. Here, we describe the identification of a single base pair change in aquaporin-2 (Aqp2) in cph mutants through genetic linkage mapping. The C-T change led to the substitution of a Ser (S256) by a Leu in the cytoplasmic tail of the Aqp2 protein, preventing its phosphorylation at S256 and the subsequent accumulation of Aqp2 on the apical membrane of the collecting duct principal cells. The interference with normal trafficking of Aqp2 by this mutation resulted in a severe urine concentration defect. cph homozygotes demonstrated polydipsia and produced a copious amount of hypotonic urine. The urine concentration defect could not be corrected by [deamino-Cys1,D-Arg8]-vasopressin (DDAVP, a vasopressin analog), characteristic of nephrogenic diabetes insipidus. The nephrogenic diabetes insipidus symptoms and the absence of developmental defects in the pyeloureteral peristaltic machinery in the mutants before the onset of hydronephrosis suggest that the congenital obstructive nephropathy is most likely a result of the polyuria. This study has revealed the genetic basis for the classical cph mutation and has provided direct genetic evidence that S256 in Aqp2 is indispensable for the apical accumulation, but not the general glycosylation or membrane association, of Aqp2.

Amino Acid Sequence↗

PubMed2006

A novel bacterium associated with lymphadenitis in a patient with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a rare inherited disease of the phagocyte NADPH oxidase system causing defective production of toxic oxygen metabolites, impaired bacterial and fungal killing, and recurrent life-threatening infections. We identified a novel gram-negative rod in excised lymph nodes from a patient with CGD. Gram-negative rods grew on charcoal-yeast extract, but conventional tests could not identify it. The best 50 matches of the 16S rRNA (using BLAST) were all members of the family Acetobacteraceae, with the closest match being Gluconobacter sacchari. Patient serum showed specific band recognition in whole lysate immunoblot. We used mouse models of CGD to determine whether this organism was a genuine CGD pathogen. Intraperitoneal injection of gp91(phox -/-) (X-linked) and p47 (phox -/-) (autosomal recessive) mice with this bacterium led to larger burdens of organism recovered from knockout compared with wild-type mice. Knockout mouse lymph nodes had histopathology that was similar to that seen in our patient. We recovered organisms with 16S rRNA sequence identical to the patient's original isolate from the infected mice. We identified a novel gram-negative rod from a patient with CGD. To confirm its pathogenicity, we demonstrated specific immune reaction by high titer antibody, showed that it was able to cause similar disease when introduced into CGD, but not wild-type mice, and we recovered the same organism from pathologic lesions in these mice. Therefore, we have fulfilled Koch's postulates for a new pathogen. This is the first reported case of invasive human disease caused by any of the Acetobacteraceae. Polyphasic taxonomic analysis shows this organism to be a new genus and species for which we propose the name Granulobacter bethesdensis.

Adult↗

PubMed2006

CCNs, fibulin-1C and S100A4 expression in leiomyoma and myometrium: inverse association with TGF-beta and regulation by TGF-beta in leiomyoma and myometrial smooth muscle cells.

Connective tissue growth factor (CTGF; CCN2) is considered to serve as downstream midiator of TGF-beta action in tissue fibrosis. We tested this hypothesis in paired leiomyoma and myometrium by evaluating the expression of TGF-beta1/TGF-beta3 and CCN2, the other members of the CCN family, CCN3 and CCN4, as well as fibulin-1C and S100A4, calcium-binding proteins that interact with CCNs. The regulatory function of TGF-beta1 on the expression of these genes was further evaluated using leiomyoma (L) and myometrial (M) smooth muscle cells (SMC). Real-time PCR, Western blotting and immunohistochemistry revealed that leiomyomas and myometrium express CCNs, fibulin-1C and S100A4, whose levels of expression with the exception of fibulin-1C were lower in leiomyomas and inversely correlated with the expression of TGF-beta1 and TGF-beta3 (P<0.05). The expression of these genes was menstrual cycle-independent and GnRHa therapy increased the expression of CCN2 in leiomyomas, while inhibiting CCN3, CCN4 and S100A4 in myometrium (P<0.05). TGF-beta (2.5 ng/ml) in a time- and cell-dependent manner, and through MAPK and Smad pathways, differentially regulated the expression of these genes in LSMC and MSMC. We concluded that CCNs, fibulin-1C and S100A4 are expressed in leiomyomas/myometrium with relative expression levels inversely correlating with TGF-betas and influenced by GnRHa and TGF-beta regulatory actions. The results suggest that unlike other fibrotic disorders, CCN2 (CTGF), at least at tissue level, may not serve as a downstream mediator of TGF-beta action in leiomyomas.

Blotting, Western↗