bluuebunny/crossref_metadata_2025_split huggingface dataset:
c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches
Authors: Hallaert Delfine Y. H. , Jaspers Annelieke , van Noesel Carel J. , van Oers Marinus H. J. , Kater Arnon P. , Eldering Eric 
Published: September 2008

Abstract
In lymph node (LN) proliferation centers in chronic lymphocytic leukemia (CLL), the environment protects from apoptotic and cytotoxic triggers. Here, we aimed to define the molecular basis for the increased drug resistance and searched for novel strategies to circumvent it. The situation in CLL LN could be mimicked by prolonged in vitro CD40 stimulation, which resulted in up-regulation of antiapoptotic Bcl-xL, A1/Bfl-1, and Mcl-1 proteins, and afforded resistance to various classes of drugs (fludarabine, bortezomib, roscovitine). CD40 stimulation also caused ERK-dependent reduction of Bim-EL protein, but ERK inhibition did not prevent drug resistance. Drugs combined with sublethal doses of the BH3-mimetic ABT-737 displayed partial and variable effects per individual CD40-stimulated CLL. The antiapoptotic profile of CD40-triggered CLL resembled BCR-Abl–dependent changes seen in chronic myeloid leukemia (CML), which prompted application of c-Abl inhibitors imatinib or dasatinib. Both compounds, but especially dasatinib, prevented the entire antiapoptotic CD40 program in CLL cells, and restored drug sensitivity. These effects also occurred in CLL samples with dysfunctional p53. Importantly, ex vivo CLL LN samples also displayed strong ERK activation together with high Bcl-xL and Mcl-1 but low Bim levels. These data indicate that CLL cells in chemoresistant niches may be sensitive to therapeutic strategies that include c-Abl inhibitors.
The Glut1 and Glut4 glucose transporters are differentially expressed during perinatal and postnatal erythropoiesis
Authors: Montel-Hagen Amélie , Blanc Lionel , Boyer-Clavel Myriam , Jacquet Chantal , Vidal Michel , Sitbon Marc , Taylor Naomi 
Published: September 2008

AbstractGlucose is a major source of energy for living organisms, and its transport in vertebrates is a universally conserved property. Of all cell lineages, human erythrocytes express the highest level of the Glut1 glucose transporter with more than 200 000 molecules per cell. However, we recently reported that erythrocyte Glut1 expression is a specific trait of vitamin C–deficient mammalian species, comprising only higher primates, guinea pigs, and fruit bats. Here, we show that in all other tested mammalian species, Glut1 was transiently expressed in erythrocytes during the neonatal period. Glut1 was up-regulated during the erythroblast stage of erythroid differentiation and was present on the vast majority of murine red blood cells (RBCs) at birth. Notably though, Glut1 was not induced in adult mice undergoing anemia-induced erythropoiesis, and under these conditions, the up-regulation of a distinct transporter, Glut4, was responsible for an increased glucose transport. Sp3 and Sp1 transcriptions factors have been proposed to regulate Glut1 transcription, and we find that the concomitant repression of Glut1 and induction of Glut4 was associated with a significantly augmented Sp3/Sp1 ratio. Glucose transporter expression patterns in mice and human erythrocytes are therefore distinct. In mice, there is a postnatal switch from Glut1 to Glut4, with Glut4 further up-regulated under anemic conditions.
Requirement of vasculogenesis and blood circulation in late stages of liver growth in zebrafish
Authors: Korzh Svetlana , Pan Xiufang , Garcia-Lecea Marta , Winata Cecilia Lanny , Pan Xiaotao , Wohland Thorsten , Korzh Vladimir , Gong Zhiyuan 
Published: September 2008

Abstract
Background
Early events in vertebrate liver development have been the major focus in previous studies, however, late events of liver organogenesis remain poorly understood. Liver vasculogenesis in vertebrates occurs through the interaction of endoderm-derived liver epithelium and mesoderm-derived endothelial cells (ECs). In zebrafish, although it has been found that ECs are not required for liver budding, how and when the spatio-temporal pattern of liver growth is coordinated with ECs remains to be elucidated.

Results
To study the process of liver development and vasculogenesis in vivo, a two-color transgenic zebrafish line Tg(lfabf:dsRed; elaA:EGFP) was generated and named LiPan for liver-specific expression of DsRed RFP and exocrine pancreas-specific expression of GFP. Using the LiPan line, we first followed the dynamic development of liver from live embryos to adult and showed the formation of three distinct yet connected liver lobes during development. The LiPan line was then crossed with Tg(fli1:EGFP)y1 and vascular development in the liver was traced in vivo. Liver vasculogenesis started at 55–58 hpf when ECs first surrounded hepatocytes from the liver bud surface and then invaded the liver to form sinusoids and later the vascular network. Using a novel non-invasive and label-free fluorescence correction spectroscopy, we detected blood circulation in the liver starting at ~72 hpf. To analyze the roles of ECs and blood circulation in liver development, both cloche mutants (lacking ECs) and Tnnt2 morphants (no blood circulation) were employed. We found that until 70 hpf liver growth and morphogenesis depended on ECs and nascent sinusoids. After 72 hpf, a functional sinusoidal network was essential for continued liver growth. An absence of blood circulation in Tnnt2 morphants caused defects in liver vasculature and small liver.

Conclusion
There are two phases of liver development in zebrafish, budding and growth. In the growth phase, there are three distinct stages: avascular growth between 50–55 hpf, where ECs are not required; endothelium-dependent growth, where ECs or sinusoids are required for liver growth between 55–72 hpf before blood circulation in liver sinusoids; and circulation-dependent growth, where the circulation is essential to maintain vascular network and to support continued liver growth after 72 hpf.
Somatic mutation analysis of MYH11in breast and prostate cancer
Authors: Alhopuro Pia , Karhu Auli , Winqvist Robert , Waltering Kati , Visakorpi Tapio , Aaltonen Lauri A 
Published: September 2008

Abstract

Background

MYH11 (also known as SMMHC) encodes the smooth-muscle myosin heavy chain, which has a key role in smooth muscle contraction. Inversion at the MYH11 locus is one of the most frequent chromosomal aberrations found in acute myeloid leukemia. We have previously shown that MYH11 mutations occur in human colorectal cancer, and may also be associated with Peutz-Jeghers syndrome. The mutations found in human intestinal neoplasia result in unregulated proteins with constitutive motor activity, similar to the mutant myh11 underlying the zebrafish meltdown phenotype characterized by disrupted intestinal architecture. Recently, MYH1 and MYH9 have been identified as candidate breast cancer genes in a systematic analysis of the breast cancer genome.

Methods
The aim of this study was to investigate the role of somatic MYH11 mutations in two common tumor types; breast and prostate cancers. A total of 155 breast cancer and 71 prostate cancer samples were analyzed for those regions in MYH11 (altogether 8 exons out of 42 coding exons) that harboured mutations in colorectal cancer in our previous study.

Results
In breast cancer samples only germline alterations were observed. One prostate cancer sample harbored a frameshift mutation c.5798delC, which we have previously shown to result in a protein with unregulated motor activity.

Conclusion
Little evidence for a role of somatic MYH11 mutations in the formation of breast or prostate cancers was obtained in this study.
The cancer secretome: a reservoir of biomarkers
Authors: Xue Hua , Lu Bingjian , Lai Maode 
Published: September 2008

Abstract
Biomarkers are pivotal for cancer detection, diagnosis, prognosis and therapeutic monitoring. However, currently available cancer biomarkers have the disadvantage of lacking specificity and/or sensitivity. Developing effective cancer biomarkers becomes a pressing and permanent need. The cancer secretome, the totality of proteins released by cancer cells or tissues, provides useful tools for the discovery of novel biomarkers. The focus of this article is to review the recent advances in cancer secretome analysis. We aim to elaborate the approaches currently employed for cancer secretome studies, as well as its applications in the identification of biomarkers and the clarification of carcinogenesis mechanisms. Challenges encountered in this newly emerging field, including sample preparation, in vivo secretome analysis and biomarker validation, are also discussed. Further improvements on strategies and technologies will continue to drive forward cancer secretome research and enable development of a wealth of clinically valuable cancer biomarkers.
Severe Mandibuloacral Dysplasia-Associated Lipodystrophy and Progeria in a Young Girl with a Novel Homozygous Arg527Cys LMNA Mutation
Authors: Agarwal Anil K. , Kazachkova Irina , Ten Svetlana , Garg Abhimanyu 
Published: September 2008

Context: Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome due to mutations in genes encoding nuclear lamina proteins, lamins A/C (LMNA) or prelamin A processing enzyme, and zinc metalloproteinase (ZMPSTE24).Objective: The aim of the study was to investigate the underlying genetic and molecular basis of the phenotype of a 7-yr-old girl with MAD belonging to a consanguineous pedigree and with severe progeroid features and lipodystrophy.Design and Patient: The patient developed mandibular hypoplasia during infancy and joint stiffness, skin thinning, and mottled hyperpigmentation at 15 months. Progressive clavicular hypoplasia, acroosteolysis, and severe loss of hair from the temporal and occipital areas were noticed at 3 yr. At 5 yr, cranial sutures were still open and lipodystrophy of the limbs was prominent. GH therapy from the ages of 3–7 yr did not improve the short stature. Severe joint contractures resulted in abnormal posture and decreased mobility. We studied her skin fibroblasts for nuclear morphology and immunoblotting and determined the in vitro effects of various pharmacological interventions on fibroblasts.Results: LMNA gene sequencing revealed a homozygous missense mutation, c.1579C&gt;T, p.Arg527Cys. Immunoblotting of skin fibroblast lysate with lamin A/C antibody revealed no prelamin A accumulation. Immunofluorescence staining of the nuclei for lamin A/C in fibroblasts revealed marked nuclear morphological abnormalities. This abnormal phenotype could not be rescued with inhibitors of farnesyl transferase, geranylgeranyl transferase, or histone deacetylase.Conclusion: Severe progeroid features in MAD could result from LMNA mutation, which does not lead to accumulation of prenylated lamin A or prelamin A.
Selective Use of Bilateral Inferior Petrosal Sinus Sampling in Patients with Adrenocorticotropin-Dependent Cushing’s Syndrome Prior to Transsphenoidal Surgery
Authors: Jehle Sigrid , Walsh Jane E. , Freda Pamela U. , Post Kalmon D. 
Published: September 2008

Context: Few data are available on the selective use of bilateral inferior petrosal sinus sampling (BIPSS) in the presurgical evaluation of patients with ACTH-dependent Cushing’s syndrome, so we investigated whether its use only in patients without a clear adenoma on magnetic resonance imaging and/or inconsistent biochemical testing affected remission and long-term outcome after surgery in patients with Cushing’s disease (CD).
Setting: This was a retrospective review of patients treated for CD by one pituitary neurosurgeon at tertiary medical centers in New York City.
Patients: A total of 193 consecutive adult patients who underwent initial transsphenoidal surgery (TS) for presumed CD between 1987 and 2005 were included.
Main Outcome Measures: We examined preoperative pituitary imaging and biochemical data, results of BIPSS and surgical pathology, and outcome based on biochemical tests after initial TS and long term after subsequent therapies.
Results: Remission rate after the first TS was 80.8% overall, 79.1% in the BIPSS group (n = 105), and 83.0% in the No-BIPSS group (n = 88). Recurrences occurred in 13.5% after the first TS at a mean of 4.8 ± 3.5 yr (range, 0.7–12.4 yr) with no difference between BIPSS and No-BIPSS groups. Long-term remission was achieved after surgeries and radiotherapy in 85% (86.7% of BIPSS group, 83.0% of No-BIPSS group). CD was ultimately confirmed in all but one patient in each group.
Conclusions: Selective use of BIPSS in the preoperative evaluation of patients with presumed CD did not lead to misdiagnosis in the No-BIPSS group or adversely affect remission rates or long-term outcome.
Novel Inactivating Mutations of the Calcium-Sensing Receptor: The Calcimimetic NPS R-568 Improves Signal Transduction of Mutant Receptors
Authors: Rus Ramona , Haag Christine , Bumke-Vogt Christiane , Bähr Volker , Mayr Bernhard , Möhlig Matthias , Schulze Egbert , Frank-Raue Karin , Raue Friedhelm , Schöfl Christof 
Published: September 2008

Context and Objective: Inactivating mutations in the calcium-sensing receptor (CaSR) gene cause neonatal severe hyperparathyroidism and familial hypocalciuric hypercalcemia (FHH). The aims of the present study were the functional characterization of novel mutations of the CaSR found in FHH patients, the comparison of in vitro receptor function with clinical parameters, and the effect of the allosteric calcimimetic NPS R-568 on the signaling of mutant receptors.Methods: Wild-type and mutant CaSRs (W530G, C568Y, W718X, M734R, L849P, Q926R, and D1005N) were expressed in human embryonic kidney 293 cells. Receptor signaling was studied by measuring intracellular free calcium in response to different concentrations of extracellular calcium ([Ca2+]o).Results: Four CaSR mutations (C568Y, W718X, M734R, and L849P) demonstrated a complete lack of a [Ca2+]o-induced cytosolic Ca2+ response up to 30 mm [Ca2+]o, whereas the CaSR mutants W530G, Q926R, and D1005N retained some sensitivity to [Ca2+]o. There was no significant relation between the in vitro calcium sensitivity, serum calcium, and intact PTH levels in the patients. Patients with C-terminal CaSR mutations had a calcium to creatine ratio above the established diagnostic threshold of 0.01 for FHH. The calcimimetic NPS R-568 enhanced the responsiveness to [Ca2+]o in CaSR mutants of the extracellular domain (W530G and C568Y) as well as the intracellular C-terminal domain (Q926R and D1005N).Conclusion: Therefore, calcimimetics might offer medical treatment for symptomatic FHH patients, and more important, for patients with neonatal severe hyperparathyroidism that harbor calcimimetic-sensitive CaSR mutants.
Breast Safety and Efficacy of Genistein Aglycone for Postmenopausal Bone Loss: A Follow-Up Study
Authors: Marini Herbert , Bitto Alessandra , Altavilla Domenica , Burnett Bruce P. , Polito Francesca , Di Stefano Vincenzo , Minutoli Letteria , Atteritano Marco , Levy Robert M. , D'Anna Rosario , Frisina Nicola , Mazzaferro Susanna , Cancellieri Francesco , Cannata Maria Letizia , Corrado Francesco , Frisina Alessia , Adamo Vincenzo , Lubrano Carla , Sansotta Carlo , Marini Rolando , Adamo Elena Bianca , Squadrito Francesco 
Published: September 2008

Context: Genistein aglycone improves bone metabolism in women. However, questions about the long-term safety of genistein on breast as well as its continued efficacy still remain.
Objective: We assessed the continued safety profile of genistein aglycone on breast and endometrium and its effects on bone after 3 yr of therapy.
Design: The parent study was a randomized, double-blind, placebo-controlled trial involving 389 osteopenic, postmenopausal women for 24-months. Subsequently, a subcohort (138 patients) continued therapy for an additional year.
Patients and Interventions: Participants received 54 mg of genistein aglycone daily (n = 71) or placebo (n = 67). Both treatment arms received calcium and vitamin D3 in therapeutic doses.
Main Outcomes: Mammographic density was assessed at baseline, 24 and 36 months by visual classification scale and digitized quantification. BRCA1 and BRCA2, sister chromatid exchange, and endometrial thickness were also evaluated. Lumbar spine and femoral neck bone mineral density were also assessed. Secondary outcomes were biochemical levels of bone markers.
Results: After 36 months, genistein did not significantly change mammographic breast density or endometrial thickness, BRCA1 and BRCA2 expression was preserved, whereas sister chromatid exchange was reduced compared with placebo. Bone mineral density increases were greater with genistein for both femoral neck and lumbar spine compared to placebo. Genistein also significantly reduced pyridinoline, as well as serum carboxy-terminal cross-linking telopeptide and soluble receptor activator of NF-κB ligand while increasing bone-specific alkaline phosphatase, IGF-I, and osteoprotegerin levels. There were no differences in discomfort or adverse events between groups.
Conclusions: After 3 yr of treatment, genistein exhibited a promising safety profile with positive effects on bone formation in a cohort of osteopenic, postmenopausal women.
Insulin-Like Growth Factor Binding Protein 1 as a Novel Specific Marker of Hepatic Insulin Sensitivity
Authors: Kotronen Anna , Lewitt Moira , Hall Kerstin , Brismar Kerstin , Yki-Järvinen Hannele 
Published: September 2008

Background and Aims: The liver is the main source and insulin the main regulator of IGF binding protein 1 (IGFBP-1) in humans. Here we examined how serum IGFBP-1 concentrations are related to directly measured hepatic insulin sensitivity and liver fat content in humans.
Methods: We measured fasting serum (fS) IGFBP-1 concentrations and liver fat content by proton magnetic resonance spectroscopy in 113 nondiabetic subjects. In addition, hepatic insulin sensitivity was measured using the euglycemic hyperinsulinemic clamp (insulin 0.3 mU/kg·min) technique in combination with the infusion of [3-(3)H]glucose in 78 subjects.
Results: fS-IGFBP-1 concentrations were inversely related to liver fat content (r = −0.38, P &lt; 0.0001). Of circulating parameters, fS-IGFBP-1 was better correlated to hepatic insulin sensitivity (r = 0.48, P &lt; 0.0001) than fS-insulin (r = −0.42, P = 0.0001), fS-C-peptide (r = −0.41, P = 0.0002), fS-triglyceride (r = −0.33, P = 0.003), or fS-high-density lipoprotein cholesterol (r = 0.30, P = 0.007). In multiple linear regression analyses, body mass index (P &lt; 0.0001) and fS-IGFBP-1 (P = 0.008), but neither age nor gender, were independently associated with hepatic insulin sensitivity (P &lt; 0.0001 for ANOVA). Neither fS-insulin nor fS-C-peptide were independent determinants of hepatic insulin sensitivity after adjusting for age, gender, and body mass index.
Conclusions: fS-IGFBP-1 is inversely correlated with liver fat and is an obesity-independent and liver-specific circulating marker of hepatic insulin sensitivity.
Selecting a Portfolio of Suppliers Under Demand and Supply Risks
Authors: Federgruen Awi , Yang Nan 
Published: September 2008

We analyze a planning model for a firm or public organization that needs to cover uncertain demand for a given item by procuring supplies from multiple sources. Each source faces a random yield factor with a general probability distribution. The model considers a single demand season. All supplies need to be ordered before the start of the season. The planning problem amounts to selecting which of the given set of suppliers to retain, and how much to order from each, so as to minimize total procurement costs while ensuring that the uncertain demand is met with a given probability. The total procurement costs consist of variable costs that are proportional to the total quantity delivered by the suppliers, and a fixed cost for each participating supplier, incurred irrespective of his supply level. Each potential supplier is characterized by a given fixed cost and a given distribution of his random yield factor. The yield factors at different suppliers are assumed to be independent of the season's demand, which is described by a general probability distribution. Determining the optimal set of suppliers, the aggregate order and its allocation among the suppliers, on the basis of the exact shortfall probability, is prohibitively difficult. We have therefore developed two approximations for the shortfall probability. Although both approximations are shown to be highly accurate, the first, based on a large-deviations technique (LDT), has the advantage of resulting in a rigorous upper bound for the required total order and associated costs. The second approximation is based on a central limit theorem (CLT) and is shown to be asymptotically accurate, whereas the order quantities determined by this method are asymptotically optimal as the number of suppliers grows. Most importantly, this CLT-based approximation permits many important qualitative insights.
A Randomized Quasi-Monte Carlo Simulation Method for Markov Chains
Authors: L'Ecuyer Pierre , Lécot Christian , Tuffin Bruno 
Published: September 2008

We introduce and study a randomized quasi-Monte Carlo method for the simulation of Markov chains up to a random (and possibly unbounded) stopping time. The method simulates n copies of the chain in parallel, using a (d+1)-dimensional, highly uniform point set of cardinality n, randomized independently at each step, where d is the number of uniform random numbers required at each transition of the Markov chain. The general idea is to obtain a better approximation of the state distribution, at each step of the chain, than with standard Monte Carlo. The technique can be used in particular to obtain a low-variance unbiased estimator of the expected total cost when state-dependent costs are paid at each step. It is generally more effective when the state space has a natural order related to the cost function.We provide numerical illustrations where the variance reduction with respect to standard Monte Carlo is substantial. The variance can be reduced by factors of several thousands in some cases. We prove bounds on the convergence rate of the worst-case error and of the variance for special situations where the state space of the chain is a subset of the real numbers. In line with what is typically observed in randomized quasi-Monte Carlo contexts, our empirical results indicate much better convergence than what these bounds guarantee.