A prediction model based on digital breast pathology image information.

BACKGROUND: The workload of breast cancer pathological diagnosis is very heavy. The purpose of this study is to establish a nomogram model based on pathological images to predict the benign and malignant nature of breast diseases and to validate its predictive performance. METHODS: In retrospect, a total of 2,723 H&E-stained pathological images were collected from 1,474 patients at Qingdao Central Hospital between 2019 and 2022. The dataset consisted of 509 benign tumor images (adenosis and fibroadenoma) and 2,214 malignant tumor images (infiltrating ductal carcinoma). The images were divided into a training set (1,907) and a validation set (816). Python3.7 was used to extract the values of the R channel, G channel, B channel, and one-dimensional information entropy from all images. Multivariable logistic regression was used to select variables and establish the breast tissue pathological image prediction model. RESULTS: The R channel value, B channel value, and one-dimensional information entropy of the images were identified as independent predictive factors for the classification of benign and malignant pathological images (P < 0.05). The area under the curve (AUC) of the nomogram model in the training set was 0.889 (95% CI: 0.869, 0.909), and the AUC in the validation set was 0.838 (95% CI: 0.7980.877). The calibration curve results showed that the calibration curve of this nomogram model was close to the ideal curve. The decision curve results indicated that the predictive model curve had a high value for auxiliary diagnosis. CONCLUSION: The nomogram model for the prediction of benign and malignant breast diseases based on pathological images demonstrates good predictive performance. This model can assist in the diagnosis of breast tissue pathological images.

Cardiovascular profile of contemporary treatments of renal cell carcinoma: A single-center prospective study.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). Emerging data suggest that these agents can result in clinically significant cardiotoxicity, compromising the care. METHODS: We conducted a prospective longitudinal study to evaluate the incidence of de novo cardiac dysfunction as assessed by echocardiography and blood biomarkers in mRCC patients receiving TKI with or without ICI followed at baseline, 3-month and 6-month. We recruited consecutive newly diagnosed mRCC patients treated at our institution between 2015 and 2018 as well as patients with localized RCC not treated with systemic therapies and healthy control (HC) subjects for comparison. RESULTS: Twenty-eight patients were enrolled in the mRCC group (a mean age of 65.2 ± 7.5 years), 29 patients in the localized RCC group (63.6 ± 8.9 years), and 20 volunteers in the HC group (52.9 ± 9.6 years). At baseline, patients from all three groups had normal cardiac function as measured by left ventricular ejection fraction (LVEF), although patients with mRCC or localized RCC had significantly lower mean LVEF compared to HC (61.9%, 62.4%, and 68.1% respectively). Otherwise, there were no statistically significant changes in echocardiographic parameters or incidence of clinical heart failure from baseline to 6-months in patients with mRCC. Cardiac blood biomarkers including troponin I, brain natriuretic peptide, and galectin-3 remained stable over time. CONCLUSION: Our findings suggest that contemporary treatment strategies of mRCC at this single institution are well tolerated without clinically meaningful overt declines in cardiac function over time. Further studies are warranted to include a larger number of patients to better assess the overall cardiovascular safety associated with contemporary treatments of mRCC.

Ginsenoside Rg2 Ameliorates Brain Injury After Intracerebral Hemorrhage in a Rat Model of Preeclampsia.

The incidence of maternal hemorrhagic stroke is elevated in women with preeclampsia during pregnancy. Panax ginseng is a traditional medicinal herb with numerous applications, and ginsenosides are the key bioactive compounds in Panax ginseng. This study aims to evaluate the effects of ginsenoside Rg2 on pregnancy outcomes and brain injury after intracerebral hemorrhage (ICH) in a rat model of preeclampsia. Preeclampsia was induced in rats by N(ω)-nitro-L-arginine methyl ester. Then, an ICH model was prepared by intrastriatal injection of bacterial collagenase. Ginsenoside Rg2 markedly elevated the survival ratio of fetuses. The placental and body weights were increased in the ginsenoside Rg2 group. Compared with the preeclampsia group, the Garcia test score of ginsenoside Rg2-treated rats was significantly increased. Ginsenoside Rg2 treatment ameliorated the ICH-induced augmentation of Evans blue extravasation, inhibited the ICH-induced elevation of brain water content, and reduced the interleukin-1ß and tumor necrosis factor-α levels in the hemorrhagic hemisphere after ICH in preeclampsia model rats. Furthermore, ginsenoside Rg2 treatment not only inhibited augmentation of TLR-4, MyD88, p-IκBα, and p-NF-κB expression but also abated the reduction of occludin and claudin-5 expression in the hemorrhagic hemisphere. The findings indicated that ginsenoside Rg2 improved pregnancy outcomes in a rat model of preeclampsia without decreasing the blood pressure and urine protein level. The findings also demonstrated that ginsenoside Rg2 ameliorated ICH-induced neurological disorder and blood-brain barrier dysfunction in an animal model of preeclampsia by regulating the TLR4/NF-κB signaling pathway.

Surfactant-Free Synthesis of Three-Dimensional Metallic Nanonetworks via Nanobubble-Assisted Self-Assembly.

Three-dimensional metallic nanonetworks (3D-MNWs) demonstrate unique performances across a wide range of fields, and their facile and green synthetic method is of high significance. Herein, we report a self-generated-nanobubble scaffolding strategy for the fabrication of 3D-MNWs, which employs aqua ammonia (AA) as a nanobubble reservoir and avoids the use of any surfactants or polymeric capping agents. Benefiting from the interaction between ammonia and metallic nanoparticles, finely interlocked nanonetworks (Au, Pt, Ag, and Cu) with curved geometry and abundant pores are obtained by precisely controlling the anisotropic kinetic growth using a strong reducing agent and a high concentration of AA. As a demonstration, the methanol oxidation reaction (MOR) is tested to assess the electrocatalytic performance of the Pt 3D-MNWs. The peak current of Pt 3D-MNWs reaches 152 mA/mgPt, which is 2.5 times higher than that of commercial Pt black. This unique nanobubble-assisted strategy has great potential in the basic synthetic prototype for polyporous nanomaterials.

Atrial Fibrillation in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation.

PURPOSE: To examine the incidence and risk factors for de novo atrial fibrillation (AF) after allogeneic hematopoietic cell transplantation (HCT) and to describe the impact of AF on HCT-related outcomes. METHODS: A retrospective cohort study design was used to examine AF and associated outcomes in 487 patients who underwent allogeneic HCT from 2014 to 2016 and to characterize patient- and HCT-related risk factors. A nested case-control study design was used to describe the association between pre-HCT echocardiographic measures and future AF events. RESULTS: The median age at HCT was 52.4 years (18.1-78.6); the median time to AF was 117.5 days (4.0-1,405.0). The 5-year cumulative incidence of AF was 10.6%. Older (≥ 50 years) age (hazard ratio [HR], 2.76; 95% CI, 1.37 to 5.58), HLA-unrelated donor (HR, 2.20; 95% CI, 1.18 to 4.12), dyslipidemia (HR, 2.40; 95% CI, 1.23 to 4.68), and pre-HCT prolonged QTc interval (HR, 2.55; 95% CI, 1.38 to 4.72) were independent risk factors for AF. Despite having comparable left ventricular systolic function, patients who developed AF were significantly more likely to have lower left atrial ejection fraction, left atrial reservoir function, and elevated tricuspid regurgitant jet velocity prior to HCT, compared with patients who did not. The incidence rate of stroke after AF was 143 per 1,000 person-years. In adjusted analyses, AF was associated with a 12.8-fold (HR, 12.76; 95% CI, 8.76 to 18.57) risk of all-cause mortality and 15.8-fold (HR, 15.78; 95% CI, 8.70 to 28.62) risk of nonrelapse mortality. CONCLUSION: The burden of AF after allogeneic HCT population is substantial, and the development of AF is associated with poor survival. We identified important associations between patient demographics, pre-HCT cardiac parameters, HCT-related exposures, and risk of AF, setting the stage for targeted prevention strategies during and after HCT.

Endocarditis following Consumption of Cereal Associated with Salmonella enterica Subtype Mbandaka Outbreak.

A 69-year-old immunocompromised man developed mitral valve endocarditis due to Salmonella enterica serotype Mbandaka, contracted from the cereal outbreak. The patient had a history of HLA-matched related hematopoietic stem cell transplant with persistent graft-versus-host disease (GVHD). This case report discusses prior international outbreaks that occurred due to Salmonella enterica subtype Mbandaka, the risks of developing endovascular infections from salmonellosis, and persistent infections that may develop more frequently with S. enterica serotype Mbandaka. The patient received a six-week course of intravenous antibiotics and remains on oral suppressive antibiotics, with his length of therapy to be determined based on his GVHD treatment.

Exosomes from MiR-30d-5p-ADSCs Reverse Acute Ischemic Stroke-Induced, Autophagy-Mediated Brain Injury by Promoting M2 Microglial/Macrophage Polarization.

BACKGROUND/AIMS: Recent studies have indicated that exosomes secreted from adipose-derived stem cells (ADSCs) have important effects in the treatment of ischemic injury. However, the treatment mechanism is unclear. This study aimed to investigate whether ADSC-derived exosomes enriched with microRNA (miR)-30d-5p have a protective effect on acute ischemic stroke (AIS). METHODS: In the current study, inflammatory factors and miR-30d-5p expression were assessed in 70 subjects with AIS and 35 healthy controls. Exosomes were characterized by transmission electron microscopy and further examined using nanoparticle tracking analyses. A rat model of AIS and an in vitro model of oxygen- and glucose-deprived (OGD) primary microglia were established to study the protective mechanism of exosomes from miR-30d-5p-overexpressing ADSCs in ischemia-induced nerve injury. RESULTS: The results showed that following AIS, the expression of inflammatory cytokines increased, while the anti-inflammatory cytokines IL-4, IL-10, and miR-30d-5p decreased both in patients and in animal models. Moreover, in vitro studies demonstrated that suppression of autophagy significantly reduced the OGD-induced inflammatory response. In addition, exosome treatment was more effective in suppressing the inflammatory response by reversing OGD-induced and autophagy-mediated microglial polarization to M1. Furthermore, in vivo studies showed that exosomes derived from ADSCs significantly decreased the cerebral injury area of infarction by suppressing autophagy and promoting M2 microglia/macrophage polarization. CONCLUSIONS: Our results suggest that miR-30d-5p-enhanced ADSC-derived exosomes prevent cerebral injury by inhibiting autophagy-mediated microglial polarization to M1.

Downregulation of circ_008018 protects against cerebral ischemia-reperfusion injury by targeting miR-99a.

Circular RNAs (circRNAs) are highly expressed in eukaryotic cells and regulate physiological and pathophysiological processes. However, the role of circRNAs in cerebral ischemia-reperfusion (I/R) injury remains largely unknown. In this study, we found that circ_008018 level was higher in the cortical tissue of mice with middle cerebral artery occlusion as compared to those in the sham group 24 h after reperfusion. Knockdown of circ_008018 attenuated cerebral I/R-induced brain tissue damage and neurological deficits in mice by inducing microRNA miR-99a overexpression. The decreased phosphorylation of Akt and glycogen synthase kinase 3ß caused by I/R was partly reversed by circ_008018 silencing or miR-99a overexpression. Taken together, these results provide new insight into the mechanisms of apoptosis resulting from cerebral I/R injury and suggest that targeted inhibition of circ_008018 can protect against subsequent neurological damage.

[Research on engine remaining useful life prediction based on oil spectrum analysis and particle filtering].

The spectrometric oil analysis(SOA) is an important technique for machine state monitoring, fault diagnosis and prognosis, and SOA based remaining useful life(RUL) prediction has an advantage of finding out the optimal maintenance strategy for machine system. Because the complexity of machine system, its health state degradation process can't be simply characterized by linear model, while particle filtering(PF) possesses obvious advantages over traditional Kalman filtering for dealing nonlinear and non-Gaussian system, the PF approach was applied to state forecasting by SOA, and the RUL prediction technique based on SOA and PF algorithm is proposed. In the prediction model, according to the estimating result of system's posterior probability, its prior probability distribution is realized, and the multi-step ahead prediction model based on PF algorithm is established. Finally, the practical SOA data of some engine was analyzed and forecasted by the above method, and the forecasting result was compared with that of traditional Kalman filtering method. The result fully shows the superiority and effectivity of the

Luteinizing-hormone-releasing-hormone-containing biodegradable polymer micelles for enhanced intracellular drug delivery.

A biodegradable triblock copolymer, poly(ethylene oxide)-block-poly(allyl glycidyl ether)-block-poly(dl-lactide) (mPEG-b-PAGE-b-PLA), with allyl groups on its middle block was designed and synthesized through anionic polymerization of allyl glycidyl ether (AGE) with PEG monomethyl ether sodium salt as the macroinitiator and subsequent ring-opening polymerization of dl-lactide. Luteinizing hormone-releasing hormone (LHRH) was conjugated to the PAGE block through a linkage of -SCH2CH2C([double bond, length as m-dash]O)NH- between the allyl and LHRH residues. The LHRH content in the conjugate was ca. 25 wt%. Owing to the amphiphilic nature of the conjugate, it was self-assembled into micelles of 15-40 nm in diameter and with the LHRH moieties in the hydrophilic corona of the micelles. Cellular uptake experiments were carried out using flow cytometry and confocal laser scanning microscopy (CLSM) with HeLa cells as LHRH-receptor overexpressing cells and HepG-2 cells as normal cells. HeLa cells displayed more cellular uptake of the LHRH-micelles than the normal cells. In vivo biodistribution of the LHRH-containing micelles and LHRH-free micelles was studied using a CRI Maestro™ imaging system. Preferred accumulation in tumor sites of LHRH-containing micelles was observed at 24 hours post injection. Therefore, LHRH-conjugated amphiphilic copolymers might be used as a potential drug delivery system for the treatment of LHRH receptor overexpressing carcinoma.

Induction of pluripotent stem cells transplantation therapy for ischemic stroke.

Stroke can cause permanent neurological damage, complications, and even death. However, there is no treatment exists to restore its lost function. Human embryonic stems transplantation therapy was a novel and potential therapeutic approach for stroke. However, as we have seen, the ethical controversy pertains to embryonic stem cell research. Human induced pluripotent stem cells (iPSCs) are the latest generation of stem cells that may be a solution to the controversy of using embryonic cells. In our study, we generated iPSCs from adult human fibroblasts by introduction of four defined transcription factors (Oct4, Sox2, Nanog, and Lin-28). And then, we investigated the efficacy of iPSCs transplantation therapy for stroke on the animal models of middle cerebral artery occlusion. Surprisingly, we found that transplanted iPSCs migrated to injured brain areas, and differentiated into neuron-like cells successfully. After 4-16 days iPSCs grafting, sensorimotor function of rats has been improved significantly. In one word, we may prove that iPSCs therapy in stroke to be an effective form of treatment.

Inhibitory effect of small interfering RNA targeting insulin-like growth factor-I receptor in ovarian cancer OVCAR3 cells.

AIM: Insulin-like growth factor-I receptor (IGF-IR) is widely overexpressed in a variety of human cancers including ovarian cancer. It plays an important role in cancer cell proliferation and tumor growth. In this study, small interfering RNA (siRNA) was used to silence IGF-IR gene expression in the human ovarian cancer cell line OVCAR3 and then its effects on proliferation, apoptosis, angiogenesis, and the growth of tumor cells in vitro and in nude mice were evaluated. METHODS: Three siRNA sequences for the IGF-IR gene were cloned into expression plasmids and transfected into OVCAR3 cells. The downregulation of IGF-IR expression at both mRNA and protein levels were detected by real-time polymerase chain reaction and western blot analysis. Cell proliferation inhibition rates were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Nude mice (n = 6 per group) were subcutaneously xenografted with 2 × 10(6) OVCAR3 cancer cells. Tumor growth, cellular proliferation (Ki-67 immunohistochemistry), apoptosis, and angiogenesis (CD31 immunohistochemistry) were compared for mice administered either IGF-IR-specific or negative control siRNA over 5 weeks. RESULTS: The mRNA and protein expression of IGF-IR was significantly decreased at 48 hours after transfection, leading to a potent suppression of tumor cell proliferation in vitro. The IGF-IR-specific siRNA dramatically suppressed tumor growth and cellular proliferation, as well as promoted tumor cellular apoptosis and inhibited angiogenesis in an OVCAR3 s.c. xenograft model. CONCLUSIONS: The siRNA targeting of IGF-IR can effectively inhibit the growth of ovarian cancer cells and may be used as a potent therapy.

Growth inhibition of human ovarian cancer cells by blocking STAT3 activation with small interfering RNA.

OBJECTIVE: Signal transducer and activator of transcription 3 (STAT3) are constitutively activated in a variety of cancers and it is a common feature of ovarian cancer. Thus, STAT3 represents a promising molecular target for tumor therapy. We applied a DNA vector-based STAT3-specific RNA interference approach which specifically blocks over-activated STAT3, to treat human ovarian cancer cells, and evaluated the cellular proliferation ability and investigated the molecular mechanisms in vitro. STUDY DESIGN: A DNA vector-based RNA interference approach was used to knockdown STAT3 expression in human ovarian cancer cells in vitro. RESULTS: The STAT3 siRNA down-regulated the expression of cyclin D1, survivin, and VEGF in ovarian cancer cells both at transcription and translation levels. Inhibition of STAT3 and its related genes was accompanied by growth suppression and induction of apoptosis in cancer cells in vitro. CONCLUSIONS: These data indicate that STAT3 signaling is a promising molecular target for ovarian cancer therapy.

Local expression of insulin-like growth factor-I, insulin-like growth factor-I receptor, and estrogen receptor alpha in ovarian cancer.

BACKGROUND: Epidemiological evidence supports a role for the insulin-like growth factors (IGFs) and their receptor, IGF-IR, in the induction and progression of various cancers. Estrogen receptor alpha (ERalpha), which plays a role in the etiology of ovarian cancer, both regulates and is influenced by the IGF family. PATIENTS AND METHODS: We present a case control study conducted in the Northeast region of China between 2007 and 2008. Fresh specimens were collected from ovarian cancer patients and matched controls who underwent surgery for benign diseases. IGF-I, IGF-IR, and ERalphaexpression was analyzed using quantitative real-time polymerase chain reaction. RESULTS: Expression of IGF-I and IGF-IR was increased in ovarian cancer compared to benign tumors. The association was dose-dependent and was more evident in premenopausal women than in postmenopausal women. Both IGF-I and IGF-IR expression were found to be higher in tumors with poor prognosis. Patients with either suboptimal debulking or with residual tumor after surgery had slightly higher IGF-IR expression. Intratumoral IGF-I expression was positively correlated with the expression of IGF-IR, but not with ERalpha. CONCLUSION: The increased intratumoral IGF-I and IGF-IR expression suggests an involvement of the IGF-I/IGF-IR axis in the biological behavior of ovarian cancers in this population and could define a potential therapeutic target.

Decreased serum levels of carboxylesterase-2 in patients with ovarian cancer.

AIMS AND BACKGROUND: Carboxylesterase-2 has been identified as the key enzyme in the metabolic activation ofirinotecan, a topoisomerase I inhibitor commonly used in the treatment of many solid tumors. Previous studies have shown that carboxylesterase-2 is down-regulated in colorectal cancer following progression of the disease. However, very limited information is available on carboxylesterase-2 expression in ovarian cancer. The aim of the present study was to detect the serum level and the tissue expression of carboxylesterase-2 in human ovarian cancer patients at different stages of the disease. METHODS: Carboxylesterase-2 levels in the serum of ovarian cancer patients were investigated by western blot and ELISA and in the tumor mass of ovarian cancer patients by western blot. RESULTS: Both the serum carboxylesterase-2 level and the expression of carboxylesterase-2 in tumor tissues were significantly different among patients at different stages of the disease (n = 40). No positive correlation was found between the serum carboxylesterase-2 level and the cancer antigen 125 level (n = 40). Serum carboxylesterase-2 is more sensitive than cancer antigen 125 in detecting the early stage patient with ovarian cancer. CONCLUSIONS: Our results indicate that serum carboxylesterase-2 level might be a potential marker in the diagnosis of the early stage ovarian cancer.

IFATS collection: Human adipose tissue-derived stem cells induce angiogenesis and nerve sprouting following myocardial infarction, in conjunction with potent preservation of cardiac function.

The administration of therapeutic cell types, such as stem and progenitor cells, has gained much interest for the limitation or repair of tissue damage caused by a variety of insults. However, it is still uncertain whether the morphological and functional benefits are mediated predominantly via cell differentiation or paracrine mechanisms. Here, we assessed the extent and mechanisms of adipose-derived stromal/stem cells (ASC)-dependent tissue repair in the context of acute myocardial infarction. Human ASCs in saline or saline alone was injected into the peri-infarct region in athymic rats following left anterior descending (LAD) coronary artery ligation. Cardiac function and structure were evaluated by serial echocardiography and histology. ASC-treated rats consistently exhibited better cardiac function, by all measures, than control rats 1 month following LAD occlusion. Left ventricular (LV) ejection fraction and fractional shortening were improved in the ASC group, whereas LV remodeling and dilation were limited in the ASC group compared with the saline control group. Anterior wall thinning was also attenuated by ASC treatment, and post-mortem histological analysis demonstrated reduced fibrosis in ASC-treated hearts, as well as increased peri-infarct density of both arterioles and nerve sprouts. Human ASCs were persistent at 1 month in the peri-infarct region, but they were not observed to exhibit significant cardiomyocyte differentiation. Human ASCs preserve heart function and augment local angiogenesis and cardiac nerve sprouting following myocardial infarction predominantly by the provision of beneficial trophic factors.

Prognostic factors of patients with ovarian yolk sac tumors: a study in Chinese patients.

BACKGROUND: The aim of this study was to investigate the prognostic factors of ovarian yolk sac tumors (YST) and the survival rates in Chinese patients. PATIENTS AND METHODS: We retrospectively reviewed 76 patients with ovarian YST from the Department of Obstetrics and Gynecology, Liaoning Cancer Hospital & Institute, China, between 1984 and 2007. RESULTS: Five-year overall survival rates in stages I, II, III, and IV were 91.8, 88.9, 39.5, and 25.0%, respectively. Age, histologic type, preoperative serum alpha-fetoprotein level, fertility-sparing surgery, tumor size and lymphadenectomy did not affect the prognosis of YST in our study. Multivariate analysis confirmed cisplatin-based chemotherapy (hazard ratio (HR) = 4.945), chemotherapy courses > 3 (HR = 2.954), residual tumor < or = 2 cm (HR = 0.224) and ascites volume < or = 100 ml (HR = 0.389) as independent predictors for overall survival. CONCLUSIONS: Our study demonstrated that the 5-year overall survival rate of YST was 53.9% for the Liaoning Cancer Hospital & Institute, China. Cisplatin-based chemotherapy, chemotherapy courses, residual tumor size and ascites volume were independent prognosis factors.

Isolation of human mesenchymal stem cells from third-trimester amniotic fluid.

OBJECTIVE: To determine whether mesenchymal stem cells (MSCs) can be isolated in third-trimester amniotic fluid (AF) and their differentiation induced. METHOD: Sufficient numbers of MSCs were isolated from the AF of 15 healthy women undergoing cesarean delivery in the third trimester to be cultured and induced to differentiate into osteocytes. RESULTS: Reverse-transcriptase polymerase chain reaction showed the MSCs to express the pluripotency marker gene OCT4, and flow cytometry showed these cells to be positive for CD29, CD73, CD90, and CD105 and negative for CD31, CD45, and CD61. The MSCs were also determined to be nontumorigenic. CONCLUSION: Multipotent MSCs can be obtained from AF in the third trimester, which may be less dangerous than the second trimester to women and their fetuses.

Raised serum levels of matrix metalloproteinase-9 in women with polycystic ovary syndrome and its association with insulin-like growth factor binding protein-1.

BACKGROUND: It has been suggested in recent studies that matrix metalloproteinases (MMPs) may be implicated in the pathogenesis of polycystic ovary syndrome (PCOS) through regulating ovarian tissue remodeling. In addition to degrading the extracellular matrix, MMPs exhibit the ability to cleave insulin-like growth factor binding protein-1 (IGFBP-1), the major regulator of insulin-like growth factor-I (IGF-I) in serum. The present study aimed to investigate the possible role of MMPs in the pathophysiology of PCOS. METHODS: Serum levels of MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), IGF-I and IGFBP-1 were measured in 42 patients with PCOS and 30 healthy women with regular menstruation, matched for age and body mass index. Correlation between IGFBP-1 and other parameters in the PCOS group was analyzed by Pearson's linear correlations. RESULTS: Serum MMP-9 concentrations and MMP-9/TIMP-1 ratios were significantly higher in PCOS women than in controls. Serum levels of IGFBP-1 were markedly lower in the PCOS group. There was a negative correlation between serum IGFBP-1 and MMP-9 in women with PCOS. CONCLUSION: Our results raise the possibility that MMPs may be implicated in the pathophysiology of PCOS either by regulating ovarian tissue remodeling or indirectly by facilitating IGF-I bioavailability through proteolysis of IGFBP-1.

A central role for hepatocyte growth factor in adipose tissue angiogenesis.

Hepatocyte growth factor (HGF) is a potent mitogenic and angiogenic factor produced in human adipose tissue. In this study, we use 3T3-F442A preadipocytes to study the contribution of HGF to angiogenesis in an in vivo fat pad development model. As observed for human adipocytes, HGF is synthesized and secreted by 3T3-F442A preadipocytes and mature adipocytes. HGF knockdown with small-interfering RNA reduced HGF mRNA expression 82.3 +/- 4.2% and protein secretion 82.9 +/- 1.4% from 3T3-F442A preadipocytes. Silencing of HGF resulted in a 70.5 +/- 19.0% reduction in endothelial progenitor cell migration to 3T3-F442A-conditioned medium in vitro. 3T3-F442A preadipocytes injected under the skin of mice form a fat pad containing mature, lipid-filled adipocytes and a functional vasculature. At 72 h postinjection, expression of the endothelial cell genes TIE-1 and platelet endothelial cell adhesion molecule (PECAM)-1 was decreased 94.4 +/- 2.2 and 91.5 +/- 2.5%, respectively, in 3T3-F442A fat pads with HGF silencing. Knockdown of HGF had no effect on differentiation of 3T3-F442A preadipocytes to mature adipocytes in vitro or in vivo. In developing fat pads under the skin of HGF overexpressing transgenic mice, TIE-1 and PECAM-1 mRNA was increased 16.5- and 21.4-fold, respectively, at 72 h postinjection. The increase in gene expression correlated with immunohistochemical evidence of endothelial cell migration in the developing fat pad. These data suggest that HGF has a central role in regulating angiogenesis in adipose tissue.