An observational radiative constraint on hydrologic cycle intensification.

Intensification of the hydrologic cycle is a key dimension of climate change, with substantial impacts on human and natural systems. A basic measure of hydrologic cycle intensification is the increase in global-mean precipitation per unit surface warming, which varies by a factor of three in current-generation climate models (about 1-3 per cent per kelvin). Part of the uncertainty may originate from atmosphere-radiation interactions. As the climate warms, increases in shortwave absorption from atmospheric moistening will suppress the precipitation increase. This occurs through a reduction of the latent heating increase required to maintain a balanced atmospheric energy budget. Using an ensemble of climate models, here we show that such models tend to underestimate the sensitivity of solar absorption to variations in atmospheric water vapour, leading to an underestimation in the shortwave absorption increase and an overestimation in the precipitation increase. This sensitivity also varies considerably among models due to differences in radiative transfer parameterizations, explaining a substantial portion of model spread in the precipitation response. Consequently, attaining accurate shortwave absorption responses through improvements to the radiative transfer schemes could reduce the spread in the predicted global precipitation increase per degree warming for the end of the twenty-first century by about 35 per cent, and reduce the estimated ensemble-mean increase in this quantity by almost 40 per cent.

Biochemical Pathways and Modeling.

The precise etiology of the biochemical changes and the resulting constellation of symptoms seen in polycystic ovary syndrome (PCOS) has remained a mystery. Despite advances in our knowledge, the pathogenesis and alterations in the biochemical pathways underlying this disease are still not fully understood. PCOS is a multifactorial syndrome where a combination of genetics, lifestyle, and hormone abnormalities all play an intertwining role. This article will provide an in-depth look at the multitude of biochemical pathways that are dysregulated in PCOS and their relation to alterations in female physiology.

Age-dependent insulin resistance in male mice with null deletion of the carcinoembryonic antigen-related cell adhesion molecule 2 gene.

AIMS/HYPOTHESIS: Cc2 -/- mice lacking the gene encoding the carcinoembryonic-antigen-related cell adhesion molecule 2 (Cc2 [also known as Ceacam2]) exhibit hyperphagia that leads to obesity and insulin resistance. This starts at 2 months of age in female mice. Male mutants maintain normal body weight and insulin sensitivity until the last age previously examined (7-8 months), owing to increased sympathetic tone to white adipose tissue and energy expenditure. The current study investigates whether insulin resistance develops in mutant male mice at a later age and whether this is accompanied by changes in insulin homeostasis. METHODS: Insulin response was assessed by insulin and glucose tolerance tests. Energy balance was analysed by indirect calorimetry. RESULTS: Male Cc2 -/- mice developed overt metabolic abnormalities at about 9 months of age. These include elevated global fat mass, hyperinsulinaemia and insulin resistance (as determined by glucose and insulin intolerance, fed hyperglycaemia and decreased insulin signalling pathways). Pair-feeding experiments showed that insulin resistance resulted from hyperphagia. Indirect calorimetry demonstrated that older mutant male mice had compromised energy expenditure. Despite increased insulin secretion caused by Cc2 deletion, chronic hyperinsulinaemia did not develop in mutant male mice until about 9 months of age, at which point insulin clearance began to decline substantially. This was probably mediated by a marked decrease in hepatic CEACAM1 expression. CONCLUSIONS/INTERPRETATION: The data demonstrate that at about 9 months of age, Cc2 -/- male mice develop a reduction in energy expenditure and energy imbalance which, combined with a progressive decrease in CEACAM1-dependent hepatic insulin clearance, causes chronic hyperinsulinaemia and sustained age-dependent insulin resistance. This represents a novel mechanistic underpinning of age-related impairment of hepatic insulin clearance.

Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2).

Carcinoembryonic antigen-related cell adhesion molecule 2 (CEACAM2) regulates food intake as demonstrated by hyperphagia in mice with the Ceacam2 null mutation (Cc2(-/-)). This study investigated whether CEACAM2 also regulates insulin secretion. Ceacam2 deletion caused an increase in ß-cell secretory function, as assessed by hyperglycemic clamp analysis, without affecting insulin response. Although CEACAM2 is expressed in pancreatic islets predominantly in non-ß-cells, basal plasma levels of insulin, glucagon and somatostatin, islet areas, and glucose-induced insulin secretion in pooled Cc2(-/-) islets were all normal. Consistent with immunofluorescence analysis showing CEACAM2 expression in distal intestinal villi, Cc2(-/-) mice exhibited a higher release of oral glucose-mediated GLP-1, an incretin that potentiates insulin secretion in response to glucose. Compared with wild type, Cc2(-/-) mice also showed a higher insulin excursion during the oral glucose tolerance test. Pretreating with exendin(9-39), a GLP-1 receptor antagonist, suppressed the effect of Ceacam2 deletion on glucose-induced insulin secretion. Moreover, GLP-1 release into the medium of GLUTag enteroendocrine cells was increased with siRNA-mediated Ceacam2 down-regulation in parallel to an increase in Ca(2+) entry through L-type voltage-dependent Ca(2+) channels. Thus, CEACAM2 regulates insulin secretion, at least in part, by a GLP-1-mediated mechanism, independent of confounding metabolic factors.

CEACAM2 negatively regulates hemi (ITAM-bearing) GPVI and CLEC-2 pathways and thrombus growth in vitro and in vivo.

Carcinoembryonic antigen-related cell adhesion molecule-2 (CEACAM2) is a cell-surface glycoprotein expressed on blood, epithelial, and vascular cells. CEACAM2 possesses adhesive and signaling properties mediated by immunoreceptor tyrosine-based inhibitory motifs. In this study, we demonstrate that CEACAM2 is expressed on the surface and in intracellular pools of platelets. Functional studies of platelets from Ceacam2(-/-)-deficient mice (Cc2(-/-)) revealed that CEACAM2 serves to negatively regulate collagen glycoprotein VI (platelet) (GPVI)-FcRγ-chain and the C-type lectinlike receptor 2 (CLEC-2) signaling. Cc2(-/-) platelets displayed enhanced GPVI and CLEC-2-selective ligands, collagen-related peptide (CRP), collagen, and rhodocytin (Rhod)-mediated platelet aggregation. They also exhibited increased adhesion on type I collagen, and hyperresponsive CRP and CLEC-2-induced α and dense granule release compared with wild-type platelets. Furthermore, using intravital microscopy to ferric chloride (FeCl3)-injured mesenteric arterioles and laser-induced injury of cremaster muscle arterioles, we herein show that thrombi formed in Cc2(-/-) mice were larger and more stable than wild-type controls in vivo. Thus, CEACAM2 is a novel platelet immunoreceptor that acts as a negative regulator of platelet GPVI-collagen interactions and of ITAM receptor CLEC-2 pathways.

Evidence of increased centrally enhanced bladder compliance with ageing in a mouse model.

OBJECTIVE: To test the hypothesis that ageing is associated with increasing neurogenic enhancement of bladder filling compliance. MATERIALS AND METHODS: Female B6 mice (aged 2, 12, 22 and 26 months) underwent cystometry while alive and immediately after death. Bladder compliance was calculated from pressure-time data. Pressure data were transformed using Fast Fourier Transform to obtain power spectra of bladder pressure variations attributable to contractile activity during filling in both alive and dead mice. A cut-off frequency (CF) was determined for each mouse, above which any power content would be primarily neurogenic. Compliance and power spectra results were compared among age groups, and correlations sought. RESULTS: A reversible loss of bladder compliance and non-voiding contractile (NVC) activity followed abolition of voiding reflexes in female colony mice in all age groups. Bladder filling compliance increased with age in urethane-anaesthetised and post-mortem conditions, and more so in the former. Power below the CF did not significantly vary with age. Neurogenic power increased with age, and significantly correlated with compliance. CONCLUSIONS: An increase in neurogenic power during filling accompanies increased centrally mediated compliance enhancement with age. A bladder control model in which brain processes related to micturition may compensate for age-associated changes; thereby preserving voiding function is suggested. Urinary dysfunction could be viewed as the result of homeostatic failure rather than strictly end-organ pathology.

Genetic alterations affecting cholesterol metabolism and human fertility.

Single nucleotide polymorphisms (SNPs) represent genetic variations among individuals in a population. In medicine, these small variations in the DNA sequence may significantly impact an individual's response to certain drugs or influence the risk of developing certain diseases. In the field of reproductive medicine, a significant amount of research has been devoted to identifying polymorphisms which may impact steroidogenesis and fertility. This review discusses current understanding of the effects of genetic variations in cholesterol metabolic pathways on human fertility that bridge novel linkages between cholesterol metabolism and reproductive health. For example, the role of the low-density lipoprotein receptor (LDLR) in cellular metabolism and human reproduction has been well studied, whereas there is now an emerging body of research on the role of the high-density lipoprotein (HDL) receptor scavenger receptor class B type I (SR-BI) in human lipid metabolism and female reproduction. Identifying and understanding how polymorphisms in the SCARB1 gene or other genes related to lipid metabolism impact human physiology is essential and will play a major role in the development of personalized medicine for improved diagnosis and treatment of infertility.

Simvastatin induces degradation of the extracellular matrix in human leiomyomata: novel in vitro, in vivo, and patient level evidence of matrix metalloproteinase involvement.

OBJECTIVES: To assess the effect of simvastatin on uterine leiomyoma growth and extracellular matrix (ECM) deposition. DESIGN: Laboratory analysis of human leiomyoma cell culture, xenograft in a mouse model, and patient tissue from a clinical trial. SETTING: Academic research center. PATIENT(S): Tissue culture from human leiomyoma tissue and surgical leiomyoma tissue sections from a placebo-controlled randomized clinical trial. INTERVENTION(S): Simvastatin treatment. MAIN OUTCOME MEASURE(S): Serum concentrations, xenograft volumes, and protein expression. RESULTS: Mice xenografted with 3-dimensional human leiomyoma cultures were divided as follows: 7 untreated controls; 12 treated with activated simvastatin at 10 mg/kg body weight; and 15 at 20 mg/kg body weight. Simvastatin was detected in the serum of mice injected at the highest dose. Xenograft volumes were significantly smaller (mean 53% smaller at the highest concentration). There was dissolution of compact ECM, decreased ECM formation, and lower collagen protein expression in xenografts. Membrane type 1 matrix metalloproteinase was increased in vitro and in vivo. Matrix metalloproteinase 2 and low-density lipoprotein receptor-related protein 1 were increased in vitro. CONCLUSIONS: Simvastatin exhibited antitumoral activity with ECM degradation and decreased leiomyoma tumor volume in vivo. Activation of the matrix metalloproteinase 2, membrane type 1 matrix metalloproteinase, and low-density lipoprotein receptor-related protein 1 pathway may explain these findings.

Characteristics of prehospital ST-segment elevation myocardial infarctions.

INTRODUCTION: Despite attention directed at treatment times of ST-segment elevation myocardial infarctions (STEMIs), little is known about the types of STEMIs presenting to the emergency department (ED). OBJECTIVE: The purpose of this study was to determine the relative frequencies and characteristics of emergency medical services (EMS) STEMIs compared with those in patients who present to the ED by walk-in. This information may be applied in EMS training, system planning, and public education. METHODS: This was a query of a prospectively gathered database of all STEMIs in patients presenting to Summa Akron City Hospital ED in 2009 and 2010. We collected demographic information, chief complaint, mode and time of arrival, and STEMI pattern (anterior, lateral, inferior, or posterior). We excluded transfers and in-hospital STEMIs. We calculated means, percentages, significance, and 95% confidence intervals (CIs) ± 10%. RESULTS: We analyzed data from 308 patients. Most patients (241/308, 78%, CI 73%-83%) arrived by EMS, were male (203/308, 66%, CI 60%-71%), and were white (286/308, 93%, CI 89%-96%). Patients arriving by EMS were older (average 63 years, range 35-95) than walk-in patients (average 57 years, range 24-92). Two percent (5/241, 2%, CI 1%-5%) of EMS STEMI patients were under 40 years of age, compared with 10% (7/67, 10%, CI 4%-20%) of walk-in patients (p = 0.0017). The most common chief complaint was chest pain (278/308, 90%, CI 86%-93%). Inferior STEMIs were most common (167/308, 54%, CI 49%-60%), followed by anterior (127/308, 41%, CI 48%-60%), lateral (8/308, 3%, CI 1%-5%), and posterior (6/308, 2%, CI 1%-4%). A day-of-the-week analysis showed that no specific day was most common for STEMI presentation. Forty percent (122/308, 40%, CI 34%-45%) of patients presented during open catheterization laboratory hours (Monday through Friday, 0730-1700 hours). There was no significant statistical difference between EMS and walk-in patients with regard to STEMI pattern or patient demographics. CONCLUSIONS: In this study, 95% (294/308) of all STEMIs were inferior or anterior infarctions, and these types of presentations should be stressed in EMS education. Most STEMI patients at this institution arrived by ambulance and during off-hours. Younger patients were more likely to walk in. We need further study, but we may have identified a target population for future interventions. Key words: emergency medical services; allied health personnel; electrocardiography; myocardial infarction; heart catheterization; STEMI.

Curcumin inhibits human leiomyoma xenograft tumor growth and induces dissolution of the extracellular matrix.

OBJECTIVE: To determine whether a curcumin-supplemented diet would prevent and/or treat uterine leiomyoma growth in our mouse xenograft model. DESIGN: Animal study. SETTING: Laboratory study. PATIENT(S): N/A. INTERVENTION(S): Curcumin-supplemented diet. MAIN OUTCOME MEASURE(S): Dietary intake, blood concentrations, tumor size, extracellular matrix protein concentrations, apoptosis markers. RESULT(S): We found that curcumin was well tolerated as a dietary supplement, free curcumin and its metabolites were detected in the serum, and exposure resulted in approximately 60% less leiomyoma xenograft growth as well as dissolution of the peripheral extracellular matrix architecture of the xenografts. The production of matrix proteins, including collagens, decreased, whereas the number of apoptotic cells in the xenografts increased. Additionally, when xenografts were placed in a uterine intramural location, we found a significantly increased apoptotic response to curcumin in the diet. CONCLUSION(S): Mice on a diet supplemented with curcumin could achieve serum concentrations sufficient to regulate human leiomyoma xenograft growth, and curcumin could play both preventive and curative roles in the treatment of uterine leiomyoma as an oral nutritional supplement.

Detrusor expulsive strength is preserved, but responsiveness to bladder filling and urinary sensitivity is diminished in the aging mouse.

The prevalence of urinary symptoms increases with age and is a significant source of distress, morbidity, and expense in the elderly. Recent evidence suggests that symptoms in the aged may result from sensory dysfunction, rather than abnormalities of detrusor performance. Therefore, we employed a pressure/flow multichannel urethane-anesthetized mouse cystometry model to test the hypothesis that in vivo detrusor performance does not degrade with aging. Secondarily, we sought to evaluate sensory responsiveness to volume using pressure-volume data generated during bladder filling. Cystometric data from 2-, 12-, 22-, and 26-mo-old female C57BL6 mice were compared. All 2- and 12-mo-old mice, 66% of 22-mo-old mice, and 50% of 26-mo-old mice responded to continuous bladder filling with periodic reflex voiding. Abdominal wall contraction with voiding had a minimal contribution to expulsive pressure, whereas compliance pressure was a significant contributor. Maximum bladder pressure, estimated detrusor pressure, detrusor impulse (pressure-time integral), as well as indices of detrusor power and work, did not decrease with aging. Bladder precontraction pressures decreased, compliance increased, and nonvoiding contraction counts did not change with increasing age. Intervoid intervals, per-void volumes, and voiding flow rates increased with age. Calculations approximating wall stress during filling suggested loss of bladder volume sensitivity with increasing age. We conclude that aging is associated with an impaired ability to respond to the challenge of continuous bladder filling with cyclic voiding, yet among responsive animals, voiding detrusor contraction strength does not degrade with aging in this murine model. Furthermore, indirect measures suggest that bladder volume sensitivity is diminished. Thus, changes in homeostatic reserve and peripheral and/or central sensory mechanisms may be important contributors to aging-associated changes in bladder function.

Evidence of central modulation of bladder compliance during filling phase.

AIMS: Bladder compliance is one expression of the pressure and volume relationship as the bladder fills. In addition to passive elements, autonomous micromotional detrusor activity contributes to this relationship. In the mouse cystometric model, compliance pressure contributes to voiding expulsive pressure. During attempts to isolate the detrusor contractile component of this filling pressurization, we found that compliance reversibly diminishes under conditions which remove central control from the micturition cycle. METHODS: Ten mature female mice underwent constant infusion pressure/flow cystometry under urethane anesthesia, and five awake mature female mice underwent constant infusion pressure cystometry. Following baseline cystometry, all mice were anesthetized with isoflurane to abolish the micturition reflex, and cystometry conducted with manual emptying of the bladders. Animals were then allowed to recover from isoflurane to re-establish the micturition reflex, and cystometry again conducted. The urethane group was also studied immediately post-mortem. Repeated measures comparisons of cystometric parameters were made across conditions. RESULTS: Compliance reversibly decreased in all mice with the abolishment of micturition responses by isoflurane anesthesia. A similar decrease was observed immediately post-mortem in the urethaned mice. Bladder filling and voiding were not different between the intact micturition segments of the testing. CONCLUSIONS: Enhanced compliance in mice with intact micturition responses suggests that autonomous micromotional activity is suppressed by central processes during normal filling. Since afferent activity during filling is also determined by the relationship between bladder pressure and volume, a feed-forward afferent signal conditioning mechanism may exist, creating novel therapeutic targets for urinary dysfunctions.

Carcinoembryonic antigen-related cell adhesion molecule 2 controls energy balance and peripheral insulin action in mice.

BACKGROUND & AIMS: The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a transmembrane glycoprotein with pleotropic functions, including clearance of hepatic insulin. We investigated the functions of the related protein CEACAM2, which has tissue-specific distribution (kidney, uterus, and crypt epithelia of intestinal tissues), in genetically modified mice. METHODS: Ceacam2-null mice (Cc2-/-) were generated from a 129/SvxC57BL/6J background. Female mice were assessed by hyperinsulinemic-euglycemic clamp analysis and indirect calorimetry and body fat composition was measured. Cc2-/- mice and controls were fed as pairs, given insulin tolerance tests, and phenotypically characterized. RESULTS: Female, but not male Cc2-/- mice exhibited obesity that resulted from hyperphagia and reduced energy expenditure. Pair feeding experiments showed that hyperphagia led to peripheral insulin resistance. Insulin action was normal in liver but compromised in skeletal muscle of female Cc2-/- mice; the mice had incomplete fatty acid oxidation and impaired glucose uptake and disposal. The mechanism of hyperphagia in Cc2-/- mice is not clear, but appears to result partly from increased hyperinsulinemia-induced hypothalamic fatty acid synthase levels and activity. Hyperinsulinemia was caused by increased insulin secretion. CONCLUSIONS: In mice, CEACAM2 is expressed by the hypothalamus. Cc2-/- mice develop obesity from hyperphagia and reduced energy expenditure, indicating its role in regulating energy balance and insulin sensitivity.

Three-dimensional human leiomyoma xenografts induce angiogenesis by inducing hypoxia inducible factor-1 alpha.

OBJECTIVE: To characterize the method by which angiogenesis occurred in three-dimensional (3D) leiomyoma xenografts, and to assess the impact of hypoxia on two-dimensional (2D) and 3D myometrial and leiomyoma cells and leiomyoma xenografts in vivo. DESIGN: Laboratory study. SETTING: Academic research. PATIENT(S): Cell cultures from patient-matched myometrial and leiomyoma tissues. INTERVENTION(S): In vivo 3D leiomyoma xenografts from ovariectomized mice treated with gonadal hormones; myometrial and leiomyoma cells in 2D and 3D growth formats exposed to 1% oxygen. MAIN OUTCOME MEASURE(S): Protein expression. RESULT(S): Blood vessels in the xenograft estradiol group are identified with anti-mouse/anti-rat CD31/PECAM-1 antibody. Hormone-stimulated 3D leiomyoma xenografts stain positively for adrenomedullin (ADM). Myometrial cells exposed to 1% oxygen demonstrated an increase in hypoxia-inducible factor (HIF)-1α at 6 hours and a marked increase at 24 hours. Under normoxic conditions, leiomyoma cells at 6 hours show increased expression of HIF-1α, which is further increased at 24 hours. Leiomyoma cells under hypoxia demonstrated a 1.14-fold decrease in HIF-1α expression at 6 hours and no change at 24 hours. Hypoxic myometrium decreased the proangiogenic protein ADM expression at 6 hours and showed a >1.5-fold increase at 24 hours. Normoxic leiomyoma decrease ADM at 24 hours and showed a >1.5-fold increase at 24 hours of hypoxia. CONCLUSION(S): Hypoxia-induced HIF-1α expression facilitates angiogenesis in 3D xenografts in vivo by increasing the expression of the proangiogenic protein ADM. Angiogenesis contributes to the viability and extended survival of these xenografts. Furthermore, 2D myometrial and leiomyoma cells increase HIF-1α and ADM expression in vitro under hypoxic conditions.

Carcinoembryonic antigen-related cell adhesion molecule 1: a key regulatory protein involved in leiomyoma growth.

OBJECTIVE: To assess and characterize the role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in the development of uterine leiomyoma. DESIGN: Laboratory study. SETTING: Academic research center. PATIENT(S): Not applicable. INTERVENTION(S): Laboratory investigation. In vitro assessment of human leiomyoma and myometrial tissue specimens as well as immortalized leiomyoma and myometrial cell lines. MAIN OUTCOME MEASURE(S): Western blotting and immunohistochemical analyses were performed to assess differences in CEACAM1 content between leiomyoma and myometrial samples. Small interfering RNA silencing experiments and transient transfection experiments were performed to characterize the regulatory role of CEACAM1 on downstream signaling cascades. RESULT(S): Analysis of RNA sequencing data revealed decreased CEACAM1 expression in human uterine leiomyoma specimens compared with that in myometrial samples. This translated to a significant down-regulation in CEACAM1 protein content in human leiomyoma compared with patient-matched myometrial tissue samples (0.236 ± 0.05-fold). A similar decrease in CEACAM1 protein content was observed in matched immortalized leiomyoma cell (ILC) and immortalized myometrial cell lines (0.21 ± 0.07). Immunohistochemical analysis revealed decreased staining intensity in leiomyoma surgical specimens compared with the matched myometrium of placebo patients. Lower CEACAM1 levels in leiomyoma were associated with increased activation of both the mitogen-activated protein kinase (MAPK) and the phosphoinositide 3-kinase/protein kinase B pathways compared with that in myometrial cells. This is significant because activation of these pathways plays an important role in leiomyoma growth. Treatment of myometrial cells with CEACAM1 small interfering RNA resulted in a significant down-regulation of CEACAM1 at the protein level (0.272 ± 0.06-fold) and was associated with increased activation of the MAPK (1.62 ± 0.21-fold) and phosphoinositide 3-kinase/protein kinase B (1.79 ± 0.35-fold) pathways, as well as increased collagen production (2.1 ± 0.49-fold). Rescue of CEACAM1 expression in leiomyoma cells by transient transfection restored regulatory control and resulted in lower activation of the MAPK pathway (0.58 ± 0.37-fold). CONCLUSION(S): CEACAM1 is an important protein involved in regulating many signal transduction pathways. Decreased CEACAM1 expression in leiomyoma allows permissive uncontrolled overactivation and up-regulation of downstream pathways that may contribute to leiomyoma growth.

Insulin acutely decreases hepatic fatty acid synthase activity.

Insulin is viewed as a positive regulator of fatty acid synthesis by increasing fatty acid synthase (FAS) mRNA transcription. We uncover a new mechanism by which insulin acutely reduces hepatic FAS activity by inducing phosphorylation of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and its interaction with FAS. Ceacam1 null mice (Cc1(-/-)) show loss of insulin's ability to acutely decrease hepatic FAS activity. Moreover, adenoviral delivery of wild-type, but not the phosphorylation-defective Ceacam1 mutant, restores the acute effect of insulin on FAS activity in Cc1(-/-) primary hepatocytes. Failure of insulin to acutely reduce hepatic FAS activity in hyperinsulinemic mice, including L-SACC1 transgenics with liver inactivation of CEACAM1, and Ob/Ob obese mice, suggests that the acute effect of insulin on FAS activity depends on the prior insulinemic state. We propose that this mechanism acts to reduce hepatic lipogenesis incurred by insulin pulses during refeeding.

Cross-talk between Janus kinase-signal transducer and activator of transcription pathway and transforming growth factor beta pathways and increased collagen1A1 production in uterine leiomyoma cells.

OBJECTIVE: To characterize the potential interaction between interleukin-6 (IL6), Janus kinase (JAK)-signal transducer and activator of transcription (STAT)-3 (JAK/STAT3) pathway, and Transforming growth factor beta (TGFß)-3 , and to determine whether such cross-talk was a contributing factor in the dysregulation of type I collagen production in leiomyomas. DESIGN: Laboratory study. SETTING: University research laboratory. PATIENTS: None. INTERVENTIONS: Exposure of leiomyoma and myometrial cell lines to IL6 and STAT3 activators/inhibitors. Western immunoblot analysis and immunohistochemistry. MAIN OUTCOME MEASURES: Expression of STAT3, pSTAT3, SOCS3, COL1A1, and TGFb3. RESULTS: We observed that IL6 increased pSTAT3 as well as collagen1A1 in uterine leiomyoma cells. Direct activation of the JAK/STAT3 pathway increased collagen1A1 production in leiomyoma cells, whereas inhibition of the pathway significantly decreased collagen1A1 production. We further observed that modulation of the JAK/STAT3 pathway also increased the expression of TGFß3 protein. Leiomyoma cells exposed to TGFß3 demonstrated a significant decrease in pSTAT3 protein. Myometrial cells demonstrated a less sensitive response to STAT3 modulation and collagen production. CONCLUSION: Cross-talk between the TGFß pathway and JAK/STAT3 pathway contributes to the fibrotic nature of uterine leiomyomas.

Characterization of the role of Activator Protein 1 signaling pathway on extracellular matrix deposition in uterine leiomyoma.

OBJECTIVE: To characterize the role Activator Protein 1 (AP 1) family members play in mediating extracellular matrix deposition in uterine leiomyoma. DESIGN: Laboratory study. SETTING: University research laboratory. INTERVENTION(S): Exposure of leiomyoma and myometrial cell lines to either an AP 1 inhibitor alone, AP 1 inhibitor plus transforming growth factor (TGF)ß3, or TGFß3 alone. MAIN OUTCOME MEASURE(S): Western immunoblot analysis was performed to assess for changes in AP 1 family member protein expression. RESULT(S): In patient-matched myometrial and leiomyoma cell lines, the only AP 1 member found to be elevated significantly in leiomyoma compared with myometrium was FOSB (3.47 ± 0.12-fold), whereas others were decreased significantly: FRA1 (0.67 ± 0.02-fold), FRA2 (0.45 ± 0.01-fold), c FOS (0.37 ± 0.01-fold), Phos c FOS (0.19 ± 0.02-fold), Phos c JUN (0.75 ± 0.02-fold), JUNB (0.81 ± 0.04-fold), and JUND (0.65 ± 0.03-fold). c JUN (0.93 ± 0.03-fold) concentration was reduced but at nonsignificant levels. Following stimulation with TGF ß 3, fibronectin (2.16 ± 0.14-fold) and versican (4.71 ± 0.15-fold) protein concentrations were increased at 24 hours. Collagen 1A demonstrated a time-dependent significant increased concentration beginning at 6 hours (1.32 ± 0.01-fold) and increased to (6.49 ± 0.02-fold) at 24 hours. Following treatment with AP 1 inhibitor (SR11302), there were significant reductions in Collagen 1A concentration at 4 hours (0.59 ± 0.03-fold) and 6 hours (0.42 ± 0.05-fold). Activator Protein 1 inhibition did not reduce significantly versican concentration until 6 hours of treatment (0.84 ± 0.04-fold). SR11302 also decreased significantly fibronectin concentration (0.68 ± 0.05-fold) at 8 hours of treatment. CONCLUSION(S): Activator Protein 1 signaling is well described in fibrotic diseases, and, herein, we demonstrated that signaling via AP 1 family members promotes extracellular matrix deposition in leiomyoma.

Removal of 132-pound ovarian mucinous cystadenoma: A case report.

Ovarian masses larger than 100 pounds are rarely encountered in developed countries given advancements in early diagnosis and treatment. Their successful resections pose unique surgical and anesthetic challenges. An otherwise healthy 38-year-old para 1 woman developed a 50 × 60 cm pelvic mass. An exploratory laparotomy, left salpingo-oophorectomy and anterior abdominal wall reconstruction were performed. A total of 60 L of cystic fluid were drained. Close monitoring of hemodynamics and massive volume resuscitation required intensive care. Inpatient physical rehabilitation reinstated independent mobility. Final pathology revealed benign ovarian mucinous cystadenoma. A multidisciplinary approach in the preoperative, intraoperative and postoperative stages of management optimizes patient outcomes.