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Biomedical subjects

James M Roberts

Publications and source records attributed to James M Roberts.

At least 19 recordsLinked to original sources
PubMed2007

Kinase-independent function of cyclin E.

E-type cyclins are thought to drive cell-cycle progression by activating cyclin-dependent kinases, primarily CDK2. We previously found that cyclin E-null cells failed to incorporate MCM helicase into DNA prereplication complex during G(0) --> S phase progression. We now report that a kinase-deficient cyclin E mutant can partially restore MCM loading and S phase entry in cyclin E-null cells. We found that cyclin E is loaded onto chromatin during G(0) --> S progression. In the absence of cyclin E, CDT1 is normally loaded onto chromatin, whereas MCM is not, indicating that cyclin E acts between CDT1 and MCM loading. We observed a physical association of cyclin E with CDT1 and with MCMs. We propose that cyclin E facilitates MCM loading in a kinase-independent fashion, through physical interaction with CDT1 and MCM. Our work indicates that-in addition to their function as CDK activators-E cyclins play kinase-independent functions in cell-cycle progression.

Animals↗
PubMed2007

Agonistic angiotensin II type 1 receptor autoantibodies in postpartum women with a history of preeclampsia.

Activating angiotensin II type 1 autoantibodies (AT1-AAs) develop in women with preeclampsia and may contribute to the disorder. Insulin resistance and serum concentrations of the antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt-1) are also increased in women with preeclampsia compared with normal pregnancy. sFlt-1 and insulin resistance decrease substantially after delivery; however, significant group differences persist postpartum. Women who have had preeclampsia are at increased cardiovascular risk later in life. We measured AT1-AAs in groups of women with previous preeclampsia (n=29) and previous normal pregnancies (n=35) 18+/-9 months after the first completed pregnancy. These women had had sFlt-1, insulin resistance homeostasis model assessment score, and related cardiovascular risk factors measured. Activating antibodies were detected by the chronotropic response of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists (losartan and prazosin). AT1-AAs were detected in 17.2% of women with previous preeclampsia versus 2.9% of women with previous uncomplicated pregnancies (P<0.05). In contrast, there was no difference in the prevalence of autoantibodies against the alpha1-adrenoceptor (10% of previous preeclamptic versus 14% of previous normal pregnant). Women with activating autoantibodies had significantly increased sFlt-1, reduced free vascular endothelial growth factor, and higher insulin resistance homeostasis model assessment values compared with autoantibody-negative women. These data suggest that, as with sFlt-1 and insulin resistance, the AT1-AA does not regress completely after delivery and, secondarily, that correlations exist among these variables. The impact of AT1-AA after preeclampsia, especially in the context of cardiovascular risk, remains to be determined.

Adult↗
PubMed2007

Emerging concepts in preeclampsia investigation.

Preeclampsia is a disorder that uniquely affects pregnancy and profoundly alters the short- and long-term health of the mother and fetus. The pathophysiologic processes that underlie preeclampsia can be thought of in two stages: stage 1, reduced placental perfusion, and stage 2, the maternal clinical syndrome. Multiple pathophysiologic processes influence stage one, affecting trophoblast invasion and placental function. These processes in some women result in stage two, with subsequent maternal inflammatory, metabolic, and thrombotic responses, converging to alter vascular and endothelial health. An increasingly comprehensive understanding of these factors is emerging, which we will introduce in this chapter and which will be detailed in the chapters that follow. The translation of this understanding into clinical trials and ultimately into effective preventive and therapeutic measures remains the ultimate goal of preeclampsia research.

Female↗
PubMed2006

p27(Kip1) and cyclin E expression and breast cancer survival after treatment with adjuvant chemotherapy.

BACKGROUND: Abnormal expression of the cell cycle regulatory proteins p27(Kip1) (p27) and cyclin E may be associated with breast cancer survival and relapse. We studied these markers in a clinical trial setting with patients with breast cancer treated by a uniform drug regimen so that treatment was not associated with variability in outcome. METHODS: We used tissue microarrays to evaluate the expression of p27 and cyclin E proteins by immunohistochemistry in tumor tissue from 2123 (68%) of 3122 patients with moderate-risk primary breast cancer who were enrolled in Southwest Oncology Group-Intergroup Trial S9313, in which patients were assigned to receive doxorubicin and cyclophosphamide administered concurrently (n = 1595) or sequentially (n = 1527). Disease-free and overall survival were equivalent in the two arms. Expression of the proteins was rated on a scale of 1-7, and the median value was used as the cut point. Log-rank tests and Cox regression analyses were used to assess associations with survival. Overall survival was defined as time to death from all causes; disease-free survival was defined as time to recurrence or death. All P values were from two-sided statistical tests. RESULTS: Lower p27 expression was associated with worse overall survival (unadjusted hazard ratio [HR] = 1.50, 95% confidence interval [CI] = 1.21 to 1.86) and disease-free survival (unadjusted HR = 1.31, 95% CI = 1.10 to 1.57) than higher p27 expression. Among hormone receptor-positive patients, lower p27 expression was associated with worse overall survival (HR = 1.42, 95% CI = 1.05 to 1.94) and worse disease-free survival (HR = 1.27, 95% CI = 0.99 to 1.63) than higher p27 expression after adjustment for treatment, menopausal status, tumor size, and number of positive lymph nodes. Among these patients, 5-year overall survival associated with higher p27 expression (0.91, 95% CI = 0.89 to 0.93) was similar to that associated with lower p27 expression (0.85, 95% CI = 0.82 to 0.87). No association between p27 expression and survival was found in hormone receptor-negative patients. Cyclin E expression was not statistically significantly associated with overall survival (HR = 1.12, 95% CI = 0.91 to 1.38) or disease-free survival (HR = 1.09, 95% CI = 0.92 to 1.29). CONCLUSIONS: Low p27 expression appears to be associated with poor prognosis, especially among patients with steroid receptor-positive tumors.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Coupling cell cycle exit, neuronal differentiation and migration in cortical neurogenesis.

The generation of new neurons in the cerebral cortex requires that progenitor cells leave the cell cycle and activate specific programs of differentiation and migration. Genetic studies have identified some of the molecules controlling these cellular events, but how the different aspects of neurogenesis are integrated into a coherent developmental program remains unclear. One possible mechanism implicates multifunctional proteins that regulate, both cell cycle exit and cell differentiation.(1) A prime example is the cyclin-dependent kinase inhibitor p27(Kip1), which has recently been shown to function beyond cell cycle regulation and promote both neuronal differentiation and migration of newborn cortical neurons, through distinct and separable mechanisms. p27(Kip1) is therefore part of a machinery that couples the multiple events of neurogenesis in the cerebral cortex.

Animals↗
PubMed2006

Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer.

Decreased expression of the CDK inhibitor p27kip1 in human tumors directly correlates with increased resistance to chemotherapies, increased rates of metastasis, and an overall increased rate of patient mortality. It is thought that decreased p27 expression in tumors is caused by increased proteasomal turnover, in particular activation of the pathway governed by the SCFskp2 E3 ubiquitin protein ligase. We have directly tested the importance of the SCFskp-mediated degradation of p27 in tumorigenesis by analyzing the tumor susceptibility of mice that express a form of p27 that cannot be ubiquitinated and degraded by this pathway (p27T187A). In mouse models of both lung and colon cancer down-regulation of p27 promotes tumorigenesis. However, we found that preventing p27 degradation by the SCFskp2 pathway had no impact on tumor incidence or overall survival in either tumor model. Our study unveiled a previously unrecognized role for the control of p27 mRNA abundance in the development of non-small cell lung cancers. In the colon cancer model, the frequency of intestinal adenomas was similarly unaffected by the p27T187A mutation, but, unexpectedly, we found that it inhibited progression of intestinal adenomas to carcinomas. These studies may guide the choice of clinical settings in which pharmacologic inhibitors of the Skp2 pathway might be of therapeutic value.

Animals↗
PubMed2006

Cyclin I protects podocytes from apoptosis.

The limited regenerative capacity of the glomerular podocyte following injury underlies the development of glomerulosclerosis and progressive renal failure in a diverse range of kidney diseases. We discovered that, in the kidney, cyclin I is uniquely expressed in the glomerular podocyte, and have constructed cyclin I knock-out mice to explore the biological function of cyclin I in these cells. Cyclin I knock-out (-/-) podocytes showed an increased susceptibility to apoptosis both in vitro and in vivo. Following induction of experimental glomerulonephritis, podocyte apoptosis was increased 4-fold in the cyclin I -/- mice, which was associated with dramatically decreased renal function. Our previous data showed that the Cdk inhibitor p21(Cip1/Waf1) protects podocytes from certain apoptotic stimuli. In cultured cyclin I -/- podocytes, the level of p21(Cip1/Waf1) was lower at base line, had a shorter half-life, and declined more rapidly in response to apoptotic stimuli than in wild-type cells. Enforced expression of p21(Cip1/Waf1) reversed the susceptibility of cyclin I -/- podocytes to apoptosis. Cyclin I protects podocytes from apoptosis, and we provide preliminary data to suggest that this is mediated by stabilization of p21(Cip1/Waf1).

Animals↗
PubMed2006

Association between infant birth weight and maternal cardiovascular risk factors in the health, aging, and body composition study.

PURPOSE: Mothers who deliver a low-birth-weight (LBW) infant may themselves be at excess risk for cardiovascular disease. We investigated whether older women who bore LBW infants had higher blood pressure, lipid, glucose, insulin, interleukin 6 (IL-6), and C-reactive protein concentrations, and pulse wave velocity compared to women with normal-weight births. METHODS: Participants were 446 women with a mean age of 80 years and 47% black. Women reported birth weight and complications for each pregnancy. Analysis was limited to first births not complicated by hypertension or preeclampsia. RESULTS: Women who had delivered a first-birth infant weighing less than 2500 g had a lower body mass index (BMI) compared with women with a normal-weight (>or=2500 g) infant (26.7 versus 28.4 kg/m2; p=0.02), but they had a larger abdominal circumference for BMI (97.9 versus 95.5 cm; p=0.05). They also were marginally more likely to be administered antihypertensive medication (p=0.06). After adjustment for BMI, race, and age, women with a history of a small infant had elevations in systolic blood pressure (p=0.05) and greater IL-6 levels (p=0.02) and were more insulin resistant (p=0.05) compared with women with a normal-weight infant. CONCLUSIONS: These findings suggest that a history of LBW delivery identifies women with elevated cardiovascular risk factors.

Black or African American↗
PubMed2006

Angiotensin II decreases system A amino acid transporter activity in human placental villous fragments through AT1 receptor activation.

Reduced transport of amino acids from mother to fetus can lead to fetal intrauterine growth restriction (IUGR). The activities of several amino acid transport systems, including system A, are decreased in placental syncytiotrophoblast of IUGR pregnancies. Na(+)-K(+)-ATPase activity provides an essential driving force for Na(+)-coupled system A transport, is decreased in the placenta of IUGR pregnancies, and is decreased by angiotensin II in several tissues. Several reports have shown activation of the fetoplacental renin-angiotensin system (RAS) in IUGR. We investigated the effect of angiotensin II on placental system A transport and Na(+)-K(+)-ATPase activity in placental villi. Placental system A activity in single primary villous fragments was measured as the Na(+)-dependent uptake of alpha-(methylamino)isobutyric acid, and Na(+)/K(+) ATPase activity was measured as ouabain-sensitive uptake of (86)rubidium. Angiotensin II decreased system A activity in a concentration-dependent fashion (10-500 nmol/l). Angiotensin II type 1 receptor (AT1-R) antagonists losartan and AT1-R anti-peptide blocked the angiotensin II effect, but the angiotensin II type 2 receptor antagonist PD-123319 was without effect. System A activity was not altered by preincubation with AT1-R-independent vasoconstrictors, and antioxidants did not prevent the decrease in activity mediated by angiotensin II. Angiotensin II decreased Na(+)-K(+)-ATPase activity by an AT1-R dependent mechanism, and inhibition of Na(+)-K(+)-ATPase activity decreased system A activity in a dose-response fashion. These data suggest that angiotensin II, via AT1-R signaling, decreases system A activity by suppressing Na(+)-K(+)-ATPase in human placental villi, consistent with possible adverse effects of enhanced placental RAS on fetal growth.

Amino Acid Transport System A↗
PubMed2006

Periconceptional multivitamin use reduces the risk of preeclampsia.

The objective was to assess the independent effect of regular periconceptional multivitamin use on the risk of preeclampsia. Pregnant women (n=1,835) enrolled in the Pregnancy Exposures and Preeclampsia Prevention Study (Pittsburgh, Pennsylvania, 1997-2001) at less than 16 weeks' gestation were asked whether they regularly used multivitamins or prenatal vitamins in the past 6 months. Women were classified as users or nonusers. The unadjusted prevalence of preeclampsia was 4.4% in nonusers and 3.8% in users. After adjustment for race/ethnicity, marital status, parity, prepregnancy physical activity, and income in a multiple logistic regression model, regular use of multivitamins was associated with a 45% reduction in preeclampsia risk compared with nonuse (odds ratio (OR)=0.55, 95% confidence interval (CI): 0.32, 0.95). Prepregnancy overweight modified this effect. After confounder adjustment, lean multivitamin users had a 71% reduction in preeclampsia risk compared with lean nonusers (OR=0.29, 95% CI: 0.12, 0.65). In contrast, there was no relation between multivitamin use and preeclampsia among overweight women (OR=1.08, 95% CI: 0.52, 2.25). A sensitivity analysis for unmeasured confounding by fruit and vegetable intake supported these conclusions. If confirmed by others, these results suggest that regular use of a multivitamin supplement in the periconceptional period may help to prevent preeclampsia, particularly among lean women.

Adolescent↗
PubMed2006

p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex.

The generation of neurons by progenitor cells involves the tight coordination of multiple cellular activities, including cell cycle exit, initiation of neuronal differentiation, and cell migration. The mechanisms that integrate these different events into a coherent developmental program are not well understood. Here we show that the cyclin-dependent kinase inhibitor p27(Kip1) plays an important role in neurogenesis in the mouse cerebral cortex by promoting the differentiation and radial migration of cortical projection neurons. Importantly, these two functions of p27(Kip1) involve distinct activities, which are independent of its role in cell cycle regulation. p27(Kip1) promotes neuronal differentiation by stabilizing Neurogenin2 protein, an activity carried by the N-terminal half of the protein. p27(Kip1) promotes neuronal migration by blocking RhoA signaling, an activity that resides in its C-terminal half. Thus, p27(Kip1) plays a key role in cortical development, acting as a modular protein that independently regulates and couples multiple cellular pathways contributing to neurogenesis.

Animals↗
PubMed2006

A new description of cellular quiescence.

Cellular quiescence, defined as reversible growth/proliferation arrest, is thought to represent a homogenous state induced by diverse anti-mitogenic signals. We used transcriptional profiling to characterize human diploid fibroblasts that exited the cell cycle after exposure to three independent signals--mitogen withdrawal, contact inhibition, and loss of adhesion. We show here that each signal caused regulation of a unique set of genes known to be important for cessation of growth and division. Therefore, contrary to expectation, cells enter different quiescent states that are determined by the initiating signal. However, underlying this diversity we discovered a set of genes whose specific expression in non-dividing cells was signal-independent, and therefore representative of quiescence per se, rather than the signal that induced it. This fibroblast "quiescence program" contained genes that enforced the non-dividing state, and ensured the reversibility of the cell cycle arrest. We further demonstrate that one mechanism by which the reversibility of quiescence is insured is the suppression of terminal differentiation. Expression of the quiescence program was not simply a downstream consequence of exit from the cell cycle, because key parts, including those involved in suppressing differentiation, were not recapitulated during the cell cycle arrest caused by direct inhibition of cyclin-dependent kinases. These studies form a basis for understanding the normal biology of cellular quiescence.

Cell Adhesion↗
PubMed2006

A pathway in quiescent cells that controls p27Kip1 stability, subcellular localization, and tumor suppression.

We have created two knock-in mouse models to study the mechanisms that regulate p27 in normal cells and cause misregulation of p27 in tumors: p27(S10A), in which Ser10 is mutated to Ala; and p27(CK-), in which point mutations abrogate the ability of p27 to bind cyclins and CDKs. These two mutant alleles identify steps in a pathway that controls the proteasomal degradation of p27 uniquely in quiescent cells: Dephosphorylation of p27 on Ser10 inhibits p27 nuclear export and promotes its assembly into cyclin-CDK complexes, which is, in turn, necessary for p27 turnover. We further show that Ras-dependent lung tumorigenesis is associated with increased phosphorylation on Ser10 and cytoplasmic mislocalization of p27. Indeed, we find that p27(S10A) is refractory to Ras-induced cytoplasmic translocation and that p27(S10A) mice are tumor resistant. Thus, phosphorylation of p27 on Ser10 is an important event in the regulation of the tumor suppressor function of p27.

Amino Acid Substitution↗
PubMed2006

Uric acid concentrations in early pregnancy among preeclamptic women with gestational hyperuricemia at delivery.

OBJECTIVE: We investigated changes in serum uric acid across pregnancy in women with gestational hyperuricemia at delivery, with and without preeclampsia, compared with normal pregnant and women with preeclampsia without gestational hyperuricemia. STUDY DESIGN: This was a nested case-control study of 116 controls, 27 women with preeclampsia with predelivery hyperuricemia, 37 women with preeclampsia without predelivery hyperuricemia, and 35 women with gestational hypertension with hyperuricemia at delivery but without proteinuria. Serum uric acid and creatinine was measured across pregnancy. RESULTS: Women with predelivery hyperuricemia, with and without preeclampsia, had increased uric acid concentrations across pregnancy compared with controls, after 25 weeks' gestation compared with women with preeclampsia without predelivery hyperuricemia. Adjusting for differences in glomerular filtration by serum creatinine accounted for part but not all of the increase in serum uric acid among women with preeclampsia and predelivery hyperuricemia. CONCLUSIONS: Among women with hyperuricemia at delivery, elevations in uric acid occur early. Multiple mechanisms may contribute to increased uric acid including changes in renal function.

Adult↗
PubMed2006

The NICHD-MFMU antibiotic treatment of preterm PROM study: impact of initial amniotic fluid volume on pregnancy outcome.

OBJECTIVE: The purpose of this study was to evaluate the associations between measured amniotic fluid volume and outcome after preterm premature rupture of membranes (PROM). STUDY DESIGN: This was a secondary analysis of 290 women, with singleton pregnancies, who participated in a trial of antibiotic therapy for preterm PROM at 24(0) to 32(0) weeks. Each underwent assessment of the 4 quadrant amniotic fluid index (AFI) and a maximum vertical fluid pocket (MVP) before randomization. The impact of low AFI (< 5.0 cm) and low MVP (< 2.0 cm) on latency, amnionitis, neonatal morbidity, and composite morbidity (any of death, RDS, early sepsis, stage 2-3 necrotizing enterocolitis, and/or grade 3-4 intraventricular hemorrhage) was assessed. Logistic regression controlled for confounding factors including gestational age at randomization, GBS carriage, and antibiotic study group. RESULTS: Low AFI and low MVP were identified in 67.2% and 46.9% of women, respectively. Delivery occurred by 48 hours, 1 and 2 weeks in 32.4%, 63.5% and 81.7% of pregnancies, respectively. Both low AFI and low MVP were associated with shorter latency (P < .001), and with a higher rate of delivery at 48 hours, 1, and 2 weeks (P = .02 for each). However, neither test offered significant additional predictive value over the risk in the total population. Low AFI and low MVP were not associated with increased amnionitis. After controlling for other factors, both low MVP and low AFI were associated with shorter latency (P < or = .002), increased composite morbidity (P = .03), and increased RDS (P < or = .01), but not with increased neonatal sepsis (P = .85) or pneumonia (P = .53). Alternatively, after controlling for fluid volume, gestational age, and GBS carriage, the antibiotic study group had longer latency, and suffered less common primary outcomes and neonatal sepsis. CONCLUSION: Oligohydramnios should not be a consideration in determining which women will be candidates for expectant management or antibiotic treatment when it is identified at initial assessment of preterm PROM remote from term.

Amniotic Fluid↗
PubMed2006

Seasonal variation in gestational blood pressure.

OBJECTIVE: To assess seasonal variability in antenatal blood pressure (BP). METHODS: We studied 1919 pregnant women who contributed 21,119 antenatal BP measurements. RESULTS: BP peaked in winter and reached a nadir in summer. After confounder adjustment, systolic BP was 1.0 to 1.7 mm Hg higher January to May, 0.6 mm Hg higher in September and October, and 0.8 mm Hg higher in November and December compared with August. After stratifying by overweight status, BP showed strong seasonal variability among lean women, whereas there were no seasonal trends among overweight women. CONCLUSION: Environmental factors may regulate gestational BP and may be relevant to seasonality of hypertensive disorders of pregnancy.

Adolescent↗