bluuebunny/crossref_metadata_2025_split huggingface dataset:
SHP-2 phosphatase is required for hematopoietic cell transformation by Bcr-Abl
Authors: Chen Jing , Yu Wen-Mei , Daino Hanako , Broxmeyer Hal E. , Druker Brian J. , Qu Cheng-Kui 
Published: September 2006

AbstractSHP-2 phosphatase forms a stable protein complex with and is heavily tyrosine-phosphorylated by the oncogenic tyrosine kinase Bcr-Abl. However, the role of SHP-2 in Bcr-Abl–mediated leukemogenesis is unclear. In the present report, we provide evidence that SHP-2 is required for hematopoietic cell transformation by Bcr-Abl. In vitro biological effects of Bcr-Abl transduction were diminished in SHP-2Δ/Δ hematopoietic cells, and the leukemic potential of Bcr-Abl–transduced SHP-2Δ/Δ cells in recipient animals was compromised. Further analyses showed that Bcr-Abl protein (p210) was degraded, and its oncogenic signaling was greatly decreased in SHP-2Δ/Δ cells. Treatment with proteasome inhibitors or reintroduction of SHP-2 restored p210 level in Bcr-Abl–transduced SHP-2Δ/Δ cells. Subsequent investigation revealed that SHP-2 interacted with heat shock protein 90, an important chaperone protein protecting p210 from proteasome-mediated degradation. The role of SHP-2 in the stability of p210 is independent of its catalytic activity. Blockade of SHP-2 expression in p210-expressing cells by antisense or small-interfering RNA approaches decreased p210 level, causing cell death. Inhibition of SHP-2 enzymatic activity by overexpression of catalytically inactive SHP-2 mutant did not destabilize p210 but enhanced serum starvation-induced apoptosis, suggesting that SHP-2 also plays an important role in downstream signaling of p210 kinase. These studies identified a novel function of SHP-2 and suggest that SHP-2 might be a useful target for controlling Bcr-Abl–positive leukemias.
Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia
Authors: Byrd John C. , Lin Thomas S. , Dalton James T. , Wu Di , Phelps Mitch A. , Fischer Beth , Moran Mollie , Blum Kristie A. , Rovin Brad , Brooker-McEldowney Michelle , Broering Sarah , Schaaf Larry J. , Johnson Amy J. , Lucas David M. , Heerema Nyla A. , Lozanski Gerard , Young Donn C. , Suarez Jose-Ramon , Colevas A. Dimitrios , Grever Michael R. 
Published: September 2006

AbstractDespite promising preclinical studies with the cyclin-dependent kinase inhibitor flavopiridol in chronic lymphocytic leukemia (CLL) and other diseases, previous clinical trials with this agent have been disappointing. The discovery of differential protein binding of flavopiridol in human and bovine serum contributed to an effective pharmacokinetic-derived schedule of administration of this agent. On the basis of pharmacokinetic modeling using our in vitro results and data from a previous trial, we initiated a phase 1 study using a 30-minute loading dose followed by 4 hours of infusion administered weekly for 4 of 6 weeks in patients with refractory CLL. A group of 42 patients were enrolled on 3 cohorts (cohort 1, 30 mg/m2 loading dose followed by 30 mg/m2 4-hour infusion; cohort 2, 40 mg/m2 loading dose followed by 40 mg/m2 4-hour infusion; and cohort 3, cohort 1 dose for treatments 1 to 4, then a 30 mg/m2 loading dose followed by a 50 mg/m2 4-hour infusion). The dose-limiting toxicity using this novel schedule was hyperacute tumor lysis syndrome. Aggressive prophylaxis and exclusion of patients with leukocyte counts greater than 200 × 109/L have made this drug safe to administer at the cohort 3 dose. Of the 42 patients treated, 19 (45%) achieved a partial response with a median response duration that exceeds 12 months. Responses were noted in patients with genetically high-risk disease, including 5 (42%) of 12 patients with del(17p13.1) and 13 (72%) of 18 patients with del(11q22.3). Flavopiridol administered using this novel schedule has significant clinical activity in refractory CLL. Patients with bulky disease and high-risk genetic features have achieved durable responses, thereby justifying further study of flavopiridol in CLL and other diseases.
Paucity of CD4+CCR5+ T cells is a typical feature of natural SIV hosts
Authors: Pandrea Ivona , Apetrei Cristian , Gordon Shari , Barbercheck Joseph , Dufour Jason , Bohm Rudolf , Sumpter Beth , Roques Pierre , Marx Preston A. , Hirsch Vanessa M. , Kaur Amitinder , Lackner Andrew A. , Veazey Ronald S. , Silvestri Guido 
Published: September 2006

AbstractIn contrast to lentiviral infections of humans and macaques, simian immunodeficiency virus (SIV) infection of natural hosts is nonpathogenic despite high levels of viral replication. However, the mechanisms underlying this absence of disease are unknown. Here we report that natural hosts for SIV infection express remarkably low levels of CCR5 on CD4+ T cells isolated from blood, lymph nodes, and mucosal tissues. Given that this immunologic feature is found in 5 different species of natural SIV hosts (sooty mangabeys, African green monkeys, mandrills, sun-tailed monkeys, and chimpanzees) but is absent in 5 nonnatural/recent hosts (humans, rhesus, pigtail, cynomolgus macaques, and baboons), it may represent a key feature of the coevolution between the virus and its natural hosts that led to a nonpathogenic infection. Beneficial effects of low CCR5 expression on CD4+ T cells may include the reduction of target cells for viral replication and a decreased homing of activated CD4+ T cells to inflamed tissue.
In vitro–expanded donor alloantigen–specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance
Authors: Golshayan Dela , Jiang Shuiping , Tsang Julia , Garin Marina I. , Mottet Christian , Lechler Robert I. 
Published: September 2006

AbstractCD4+CD25+ regulatory T (Treg) cells play a critical role in the induction and maintenance of peripheral immune tolerance. In experimental transplantation models in which tolerance was induced, donor-specific Treg cells could be identified that were capable of transferring the tolerant state to naive animals. Furthermore, these cells appeared to have indirect allospecificity for donor antigens. Here we show that in vivo alloresponses can be regulated by donor alloantigen-specific Treg cells selected and expanded in vitro. Using autologous dendritic cells pulsed with an allopeptide from H2-Kb, we generated and expanded T-cell lines from purified Treg cells of CBA mice (H2k). Compared with fresh Treg cells, the cell lines maintained their characteristic phenotype, suppressive function, and homing capacities in vivo. When cotransferred with naive CD4+CD25− effector T cells after thymectomy and T-cell depletion in CBA mice that received CBK (H2k+Kb) skin grafts, the expanded Treg cells preferentially accumulated in the graft-draining lymph nodes and within the graft while preventing CBK but not third-party B10.A (H2k+Dd) skin graft rejection. In wild-type CBA, these donor-specific Treg cells significantly delayed CBK skin graft rejection without any other immunosuppression. Taken together, these data suggest that in vitro–generated tailored Treg cells could be considered a therapeutic tool to promote donor-specific transplant tolerance.
Characterization of a progenitor cell population in childhood T-cell acute lymphoblastic leukemia
Authors: Cox Charlotte V. , Martin Hannah M. , Kearns Pamela R. , Virgo Paul , Evely Roger S. , Blair Allison 
Published: September 2006

Abstract
A significant proportion of children with T-cell acute lymphoblastic leukemia (T-ALL) continue to fail therapy. Consequently, characterization of the cells that proliferate to maintain the disease should provide valuable information on the most relevant therapeutic targets. We have used in vitro suspension culture (SC) and nonobese diabetic–severe combined immune deficient (NOD/SCID) mouse assays to phenotypically characterize and purify T-ALL progenitor cells. Cells from 13 pediatric cases were maintained in vitro for at least 4 weeks and expanded in 8 cases. To characterize the progenitors, cells were sorted for expression of CD34 and CD4 or CD7 and the subfractions were evaluated in vitro and in vivo. The majority of cells capable of long-term proliferation in vitro were derived from the CD34+/CD4− and CD34+/CD7− subfractions. Moreover, the CD34+/CD4− or CD7− cells were the only subfractions capable of NOD/SCID engraftment. These T-ALL cells successfully repopulated secondary and tertiary recipients with equivalent levels of engraftment, demonstrating self-renewal ability. The immunophenotype and genotype of the original leukemia cells were preserved with serial passage in the NOD/SCID mice. These data demonstrate the long-term repopulating ability of the CD34+/CD4− and CD34+/CD7− subfractions in T-ALL and suggest that a cell with a more primitive phenotype was the target for leukemic transformation in these cases.
Construction of doxycyline-dependent mini-HIV-1 variants for the development of a virotherapy against leukemias
Authors: Jeeninga Rienk E , Jan Barbara , van den Berg Henk , Berkhout Ben 
Published: September 2006

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk type of blood-cell cancer. We describe the improvement of a candidate therapeutic virus for virotherapy of leukemic cells. Virotherapy is based on the exclusive replication of a virus in leukemic cells, leading to the selective removal of these malignant cells. To improve the safety of such a virus, we constructed an HIV-1 variant that replicates exclusively in the presence of the nontoxic effector doxycycline (dox). This was achieved by replacement of the viral TAR-Tat system for transcriptional activation by the Escherichia coli-derived Tet system for inducible gene expression. This HIV-rtTA virus replicates in a strictly dox-dependent manner. In this virus, additional deletions and/or inactivating mutations were introduced in the genes for accessory proteins. These proteins are essential for virus replication in untransformed cells, but dispensable in leukemic T cells. These minimized HIV-rtTA variants contain up to 7 deletions/inactivating mutations (TAR, Tat, vif, vpR, vpU, nef and U3) and replicate efficiently in the leukemic SupT1 T cell line, but do not replicate in normal peripheral blood mononuclear cells. These virus variants are also able to efficiently remove leukemic cells from a mixed culture with untransformed cells. The therapeutic viruses use CD4 and CXCR4 for cell entry and could potentially be used against CXCR4 expressing malignancies such as T-lymphoblastic leukemia/lymphoma, NK leukemia and some myeloid leukemias.
Comparative gene expression by WC1+ γδ and CD4+ αβ T lymphocytes, which respond to Anaplasma marginale, demonstrates higher expression of chemokines and other myeloid cell-associated genes by WC1+ γδ T cells
Authors: Lahmers Kevin K , Hedges Jodi F , Jutila Mark A , Deng Mingqi , Abrahamsen Mitchell S , Brown Wendy C 
Published: September 2006

Abstract
The functions of γδ T cells are enigmatic, and these cells are often considered as evolutionary remnants of well-characterized αβ T cells. However, their conservation throughout evolution suggests that γδ T cells are biologically unique. In ruminants, γδ T cells expressing the workshop cluster 1 (WC1) scavenger receptor comprise a large proportion of circulating lymphocytes, suggesting these cells are biologically relevant and functionally different from αβ T cells. In fact, bovine WC1+ γδ T cells can act as APC for αβ T cells, indicating they may express genes encoding proteins associated with innate immunity. The present study was designed to compare immune function gene expression profiles of clonal populations of WC1+ γδ and CD4+ αβ T cells derived from the same animal, which respond to major surface protein 2 (MSP2) of the intraerythrocytic rickettsial pathogen of cattle, Anaplasma marginale. Gene expression profiles of activated T cell clones were compared using a microarray format, and differential gene expression was confirmed by real-time RT-PCR and protein analyses. We demonstrate that although MSP2-specific αβ and γδ T cell clones express many of the same genes, γδ T cell clones express high levels of genes associated with myeloid cells, including chemokines CCL2, CXCL1, CXCL2, CXCL6, and surface receptors CD68, CD11b, macrophage scavenger receptor 1, macrophage mannose receptor, and galectin-3. It is important that many of these genes were also expressed at higher levels in polyclonal WC1+ γδ T cells when compared with CD4+ αβ T cells selected from peripheral blood.
CYP11B2 −344T/C Gene Polymorphism and Blood Pressure in Patients with Acromegaly
Authors: Mulatero Paolo , Veglio Franco , Maffei Pietro , Bondanelli Marta , Bovio Silvia , Daffara Fulvia , Leotta Giannina , Angeli Alberto , Calvo Chiara , Martini Chiara , degli Uberti Ettore C. , Terzolo Massimo 
Published: September 2006

Abstract
Context: The pathogenesis of increased blood pressure (BP) in acromegaly is unclear, and the role of IGF-I levels and the renin-angiotensin-aldosterone system (RAAS) in this disease remains controversial.
Objective and Design: The aim of this study was to investigate the role of gene polymorphisms of the RAAS and involved in sodium handling on BP in acromegaly.
Setting and Patients: We conducted a multicentric retrospective study that included 100 consecutive patients with acromegaly referred during the period 2000–2003.
Intervention: All patients were genotyped for ACE I/D, AGT M235T, CYP11B2 −344T/C, B2R −58T/C, and α-adducin G460W polymorphisms.
Main Outcome Measure: We assessed the prevalence of hypertension and BP according to the genotype.
Results: Patients with the CYP11B2 −344CC genotype displayed a significant increase in the risk of hypertension compared with patients with CT/TT genotypes (odds ratio = 4.0; 95% confidence interval = 1.4–11.6; P = 0.01). Consistently, a significant proportion of patients with the CYP11B2 −344CC genotypes were under antihypertensive treatment (73.1%) compared with patients with the TT/TC genotypes (38.2%; P = 0.003). Patients with the −344CC genotype displayed a significant increase in systolic BP (10.2 ± 4.3 mm Hg; P = 0.02) but not a significant increase in diastolic BP (2.6 ± 2.6 mm Hg; P = 0.32) compared with patients with the CT/TT genotype.
Conclusions: We have shown an association of the −344T/C CYP11B2 gene polymorphism with BP in patients affected by acromegaly. These findings suggest that the RAAS is implicated in the pathogenesis of hypertension in acromegaly.
Sleep-Related Breathing Disorders in Prepubertal Children with Prader-Willi Syndrome and Effects of Growth Hormone Treatment
Authors: Festen D. A. M. , de Weerd A. W. , van den Bossche R. A. S. , Joosten K. , Hoeve H. , Hokken-Koelega A. C. S. 
Published: September 2006

Abstract
Context: Recently, several cases of sudden death in GH-treated and non-GH-treated, mainly young Prader-Willi syndrome (PWS), patients were reported. GH treatment in PWS results in a remarkable growth response and an improvement of body composition and muscle strength. Data concerning effects on respiratory parameters, are however, limited.
Objective: The objective of the study was to evaluate effects of GH on respiratory parameters in prepubertal PWS children.
Design: Polysomnography was performed before GH in 53 children and repeated after 6 months of GH treatment in 35 of them.
Patients: Fifty-three prepubertal PWS children (30 boys), with median (interquartile range) age of 5.4 (2.1–7.2) yr and body mass index of +1.0 sd score (−0.1–1.7).
Intervention: Intervention included treatment with GH 1 mg/m2·d.
Results: Apnea hypopnea index (AHI) was 5.1 per hour (2.8–8.7) (normal 0–1 per hour). Of these, 2.8 per hour (1.5–5.4) were central apneas and the rest mainly hypopneas. Duration of apneas was 15.0 sec (13.0–28.0). AHI did not correlate with age and body mass index, but central apneas decreased with age (r = −0.34, P = 0.01). During 6 months of GH treatment, AHI did not significantly change from 4.8 (2.6–7.9) at baseline to 4.0 (2.7–6.2; P = 0.36). One patient died unexpectedly during a mild upper respiratory tract infection, although he had a nearly normal polysomnography.
Conclusions: PWS children have a high AHI, mainly due to central apneas. Six months of GH treatment does not aggravate the sleep-related breathing disorders in young PWS children. Our study also shows that monitoring during upper respiratory tract infection in PWS children should be considered.
Insulinomas May Present with Normoglycemia after Prolonged Fasting but Glucose-Stimulated Hypoglycemia
Authors: Kar Partha , Price Paul , Sawers Stewart , Bhattacharya Satya , Reznek Rodney H. , Grossman Ashley B. 
Published: September 2006

Abstract
Background: Insulinomas are rare but are the most common cause of hyperinsulinemic hypoglycemia in the adult population. Diagnosis of this pathology relies on clinical features along with laboratory tests and imaging investigations to aid in localization. One of the most robust standard tests used for establishing a biochemical diagnosis is the prolonged (72 h) fast. Currently, it is recommended that a prolonged supervised fast be performed, at least for 48 h if not for 72 h, and many would take the absence of hypoglycemia after a 72-h fast as evidence excluding the diagnosis.
Methods: We employed prolonged fasts and standard glucose tolerance tests, plus imaging studies and surgical pathology, in two patients with suspected insulinomas.
Results: The prolonged 72-h fast was normal in both the patients, whereas in both cases a prolonged oral glucose tolerance test clearly demonstrated the induction of severe hyperinsulinemia followed by significant hypoglycemia. Surgical removal confirmed the presence of insulinomas in each case.
Conclusions: Although the sensitivity of the 72-h fast is high and still plays an important role in the diagnosis of an insulinoma, we suggest that a “normal” test result should be interpreted in the light of clinical symptoms.
Induction of Surfactant Protein A Expression by Cortisol Facilitates Prostaglandin Synthesis in Human Chorionic Trophoblasts
Authors: Sun Kang , Brockman Diane , Campos Begona , Pitzer Brad , Myatt Leslie 
Published: September 2006

AbstractContext: Surfactant protein A (SP-A) may be an important link between the maturation of fetal organs and the initiation of parturition. However, the local expression of SP-A and the effect of SP-A on prostaglandin synthesis in human fetal membranes have not been resolved.Objective: Our objective was to examine SP-A expression and the effect of SP-A on prostaglandin synthesis in human fetal membranes.Design: SP-A expression was examined with immunohistochemistry and PCR. The effect of SP-A on prostaglandin synthesis was investigated in cultured human chorionic trophoblasts.Patients: Patients were normal-term pregnant women undergoing elective cesarean sections.Results: Both SP-A protein and mRNA were present in amnion epithelial cells, fibroblasts, and chorionic trophoblasts. Cortisol (10−7 and 10−6m, 24 h) induced SP-A expression in cultured chorionic trophoblasts, which could be blocked by the glucocorticoid receptor antagonist RU486. Treatment of chorionic trophoblasts with SP-A (10–100 μg/ml, 24 h) caused a dose-dependent increase of prostaglandin E2 release and an induction of cyclooxygenase type 2 but not cytosolic phospholipase A2 and microsomal prostaglandin E synthase expression.Conclusions: SP-A can be synthesized locally in human fetal membranes, which can be induced by glucocorticoids. SP-A appeared to induce prostaglandin E2 synthesis in chorionic trophoblasts via induction of cyclooxygenase type 2 expression.
Synthesis and Application of Fluorous-tagged Oligonucleotides
Authors: Mishra Roli , Mishra Satyendra , Misra Krishna 
Published: September 2006

Abstract
Nucleoside phosphoramidites bearing a adsorbent tert-butylphenyl-1H,1H,2H,2H-heptafluorodecyloxysilyl (BPFOS) group were used to synthesize fluorous-tagged oligonucleotides, viz. 5-mer, 10-mer, 13-mer, 17-mer, and 19-mer, which were subjected to liquid-phase extraction. The labeled oligomers were found to be highly hydrophobic in nature, become precipitated in water, therefore allowing easy purification from the failure sequences. The silyl fluorous group was deprotected by TBAF treatment and oligomers were easily purified by CH3CN/FC-72 liquid–liquid extraction. Fluorous-tagged oligonucleotides have high selectivity for the removal of failure sequences, high recoveries (typically 70–100%).
Urine free cortisol analysis by automated immunoassay and high-performance liquid chromatography for the investigation of Cushing's syndrome
Authors: Ching Simon Y L , Lim Ee Mun , Beilby John , Bhagat Chotoo , Rossi Enrico , Walsh John P , Pullan Peter 
Published: September 2006

Background: We compared a widely used immunoassay method for urine free corticoids with a high-performance liquid chromatography (HPLC) method for the investigation of Cushing's syndrome. Methods: Urine free corticoid analysis using an Immulite:2000 automated immunoassay analyser and urine free cortisol analysis by a specific HPLC method on 39 patients with an elevated baseline immunoassay 24 h urine free corticoid result who were referred from 2000 to 2004. Results: Reference ranges for urine free corticoids by immunoassay and for urine free cortisol by HPLC were <900 and <170 nmol/day, respectively. Of the 39 patients with an elevated immunoassay urine free corticoid result, Cushing's syndrome was surgically proven in 22 patients, giving a positive predictive value of 56%. Cushing's syndrome was excluded in 12 of the remaining 17 patients by applying the specific HPLC method and at least one of the following: a clinical evaluation which was not suggestive or adequate suppression of plasma cortisol following dexamethasone. Urine free cortisol analysis by HPLC gave a positive predictive value of 81% for Cushing's syndrome. Conclusions: Although immunoassay has a low specificity for urine cortisol, it is a widely available test which serves as a valid initial investigation of Cushing's syndrome.
Reflective testing - what do our service users think?
Authors: Darby Denise , Kelly Anne-Marie 
Published: September 2006

Background: Reflective testing incorporates the clinical judgement, knowledge and experience of an individual biochemist to request additional tests appropriate to the clinical scenario. Despite being vigorously debated within the biochemistry profession, little is known about how the clinicians directly involved in patient care feel about it. We have conducted a survey to elicit our service users' opinion of reflective testing. Methods: Ten clinical scenarios, each involving the possible addition of a specific test, were circulated to 520 hospital doctors and 152 general practitioners. The four response options were to add further tests, phone and discuss the case, add a comment to the original results or do nothing. Results: A total of 216 (32%) responses were received. Overall, the majority were in favour of 'adding on' free triiodothyronine (86%), γ-glutamyltransferase (78%), lipid profile (59%), thyroid peroxidase antibodies (63%), pituitary hormones (58%), troponin (55%) and serum electrophoresis (68%) in the given scenarios. However, only 30% would like a pregnancy test added and only 45% a prostate-specific antigen added without prior consultation. The response differed according to grade and specialty. Conclusions: Reflective testing is generally welcomed by our service users, provided the nature and implications of the specific test is considered in addition to the full clinical scenario.