bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of Drug Sensitization to TRA-8, an Agonistic Death Receptor 5 Antibody, Involve Modulation of the Intrinsic Apoptotic Pathway in Human Breast Cancer Cells
Authors: Amm Hope M. , Zhou Tong , Steg Adam D. , Kuo Huichien , Li Yufeng , Buchsbaum Donald J. 
Published: February 2011

Abstract
TRA-8, a monoclonal antibody to death receptor 5 induces apoptosis in various cancer cells; however, the degree of sensitivity varies from highly sensitive to resistant. We have previously shown that resistance to TRA-8 can be reversed by using chemotherapeutic agents, but the mechanism underlying this sensitization was not fully understood. Here, we examined the combination of TRA-8 with doxorubicin or bortezomib in breast cancer cells. In TRA-8–resistant BT-474 and T47D cells, both chemotherapy agents synergistically sensitized cells to TRA-8 cytotoxicity with enhanced activation of apoptosis shown by cleavage of caspases and PARP, reduced Bid, increased proapoptotic Bcl-2 proteins, and increased mitochondrial membrane depolarization. Doxorubicin or bortezomib combined with TRA-8 also reduced Bcl-XL and X-linked inhibitors of apoptosis (XIAP) in treated cells. Furthermore, targeting these proteins with pharmacologic modulators, AT-101, BH3I-2′ and AT-406, produced sensitization to TRA-8. TRA-8 combined with AT-101 or BH3I-2′, inhibitors of antiapoptotic Bcl-2 proteins, produced synergistic cytotoxicity against ZR-75-1, BT-474, and T47D cells. The IAP-targeting compound, AT-406, was synergistic with TRA-8 in BT-474 cells, and to a lesser extent T47D cells. Activation of the intrinsic apoptotic pathway was a common mechanism associated with sensitization of TRA-8–resistant breast cancer cell lines. Collectively, these studies show that the Bcl-2 and IAP families of proteins are involved in TRA-8 and chemotherapy resistance via their modulation of the intrinsic apoptotic pathway. Targeting these proteins with novel agents sensitized TRA-8–resistant breast cancer cells, suggesting this approach may represent a potent therapeutic strategy in the treatment of breast cancer. Mol Cancer Res; 9(4); 403–17. ©2011 AACR.
Upregulation of ABCG2 by Romidepsin via the Aryl Hydrocarbon Receptor Pathway
Authors: To Kenneth K.W. , Robey Robert , Zhan Zhirong , Bangiolo Lois , Bates Susan E. 
Published: February 2011

Abstract
Histone deacetylase inhibitors (HDACI) are promising anticancer agents and their use in combination with conventional anticancer drugs is currently under investigation. We previously reported cell line–specific upregulation of ABCG2, a multidrug resistance transporter shown to control oral bioavailability and CNS penetration, by the HDACI romidepsin, although the precise mechanism in a particular cell line remains to be determined. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by numerous environmental contaminants and has been shown to be a client protein of heat shock protein 90 (Hsp90). A xenobiotic response element was defined in the ABCG2 promoter and was shown to mediate AhR signaling. Activated AhR was found to be associated with the ABCG2 promoter only in cell line models that respond to romidepsin with ABCG2 upregulation. Our data suggest that romidepsin acetylated Hsp70 and inhibited the chaperone function of Hsp90, thereby allowing the dissociation of AhR from Hsp90. The dissociation of AhR from Hsp90 may be a prerequisite for the differential upregulation of ABCG2 by romidepsin. Increasing our understanding of the mechanism(s) governing differential upregulation of ABCG2 in response to romidepsin could provide an insight into strategies needed to tackle resistance to HDACIs in cancer therapeutics. Mol Cancer Res; 9(4); 516–27. ©2011 AACR.
Activation of Interferon-Stimulated Genes by γ-Ray Irradiation Independently of the Ataxia Telangiectasia Mutated–p53 Pathway
Authors: Sugihara Takashi , Murano Hayato , Nakamura Masako , Ichinohe Kazuaki , Tanaka Kimio 
Published: February 2011

Abstract
The ataxia telangiectasia mutated (ATM)-p53 pathway is a well-known main signal transduction pathway for cellular responses, which is activated by γ-ray irradiation. Microarray analysis showed changes in the expressions of IFN-stimulated genes (ISG) in γ-ray–irradiated Balb/cA/Atm-deficient mouse embryonic fibroblasts (MEF) (ATM-KO), indicating that another pathway for cellular responses besides the ATM-p53 pathway was activated by γ-ray irradiation. The basal expression levels of Irf7 and Stat1 in ATM-KO and p53-deficient MEFs (p53-KO) were higher than those in Atm–wild-type MEFs (ATM-WT) and p53-wild-type MEFs (p53-WT), respectively. Irradiation stimulated the expressions of Irf7 and Stat1 in ATM-KO, p53-KO, ATM-WT, and p53-WT, indicating that upregulation of Irf7 and Stat1 expressions by irradiation did not depend on the ATM-p53 pathway. When conditioned medium (CM) obtained from irradiated ATM-WT or ATM-KO was added to nonirradiated MEFs, the expressions of Irf7 and Stat1 increased. We predicted that gene activation in nonirradiated MEFs was caused by IFN-α/β. Unexpectedly, significant amount of IFN-α/β could not be detected in the CM from irradiated ATM-WT or ATM-KO. Meanwhile, increased expression of Ccl5 (RANTES) protein was detected in the CM from irradiated MEFs. These results indicate that ISGs were activated by γ-ray irradiation independently of the ATM-p53 pathway and gene activation was caused by radiation-induced soluble factors. Mol Cancer Res; 9(4); 476–84. ©2011 AACR.
The Adverse Impact of Diabetes Mellitus on Left Ventricular Remodeling and Function in Patients With Severe Aortic Stenosis
Authors: Lindman Brian R. , Arnold Suzanne V. , Madrazo José A. , Zajarias Alan , Johnson Stephanie N. , Pérez Julio E. , Mann Douglas L. 
Published: February 2011

Background—
The diabetic heart exhibits increased left ventricular (LV) mass and reduced ventricular function. However, this relationship has not been studied in patients with aortic stenosis (AS), a disease process that causes LV hypertrophy and dysfunction through a distinct mechanism of pressure overload. The aim of this study was to determine how diabetes mellitus (DM) affects LV remodeling and function in patients with severe AS.

Methods and Results—

Echocardiography was performed on 114 patients with severe AS (mean aortic valve area [AVA], 0.6 cm
2
) and included measures of LV remodeling and function. Multivariable linear regression models investigated the independent effect of DM on these aspects of LV structure and function. Compared to patients without diabetes (n=60), those with diabetes (n=54) had increased LV mass and LV end-systolic and end-diastolic dimensions, and decreased LV ejection fraction (EF) and longitudinal systolic strain (all
P
<0.01). In multivariable analyses adjusting for age, sex, systolic blood pressure, AVA, body surface area, and coronary disease, DM was an independent predictor of increased LV mass (β=26 g,
P
=0.01), LV end-systolic dimension (β=0.5 cm,
P
=0.008), and LV end-diastolic dimension (β=0.3 cm,
P
=0.025). After also adjusting for LV mass, DM was associated with reduced longitudinal systolic strain (β=1.9%,
P
=0.023) and a trend toward reduced EF (β=−5%,
P
=0.09). Among patients with diabetes, insulin use (as a marker of disease severity) was associated with larger LV end-systolic dimension and worse LV function. LV mass was a strong predictor of reduced EF and systolic strain (both
P
<0.001).

Conclusions—
DM has an additive adverse effect on hypertrophic remodeling (increased LV mass and larger cavity dimensions) and is associated with reduced systolic function in patients with AS beyond known factors of pressure overload.
Pulmonary Vascular Resistance as Assessed by Bicycle Stress Echocardiography in Patients With Atrial Septal Defect Type Secundum
Authors: Van De Bruaene Alexander , La Gerche Andre , Prior David L. , Voigt Jens-Uwe , Delcroix Marion , Budts Werner 
Published: February 2011

Background—
Volume overload of the pulmonary circulation in patients with atrial septal defect (ASD)-type secundum causes pulmonary vascular disease over a long period of time. This study aimed at (1) evaluating pulmonary vascular resistance (PVR) and (2) investigating the relation between PVR and exercise capacity in patients with open and closed ASD.

Methods and Results—

Forty-six patients with ASD-type secundum (18 open, 28 closed) and 20 age-matched controls were enrolled. All underwent standard and symptom-limited bicycle stress echocardiography and cardiopulmonary exercise testing. PVR was calculated as the slope of a pulmonary artery systolic pressure (PAP)-flow plot or as the ratio of PAP to cardiac output (total PVR). The slope of PAP-flow was higher in patients with open (5.1±2.2 versus 3.0±0.8 mm Hg/L per min;
P
=0.002) and closed ASD (4.0±1.7 versus 3.0±0.8 mm Hg/L per min) compared with controls. In patients with an open ASD, total PVR did not change from rest to peak exercise. In patients with a closed ASD and controls, total PVR decreased from rest to peak exercise. However, in patients with an ASD closed later in life (≥34 years, median age at repair), the slope of PAP-flow was higher (5.1±1.4 versus 3.0±0.8 mm Hg/L per min;
P
<0.0001), but total PVR did not change from rest to peak exercise. Peak oxygen consumption correlated inversely with the slope of the PAP-flow plots in patients with open (
P
=0.013) and closed ASD (
P
=0.005).

Conclusions—
In patients with an open ASD, the slope of PAP-flow was higher and total PVR did not change from rest to peak exercise. In patients with an ASD closed later in life, the slope of PAP-flow was higher and total PVR did not change from rest to peak exercise, indicating altered pulmonary hemodynamics in these patients.
Unique progenitors in mouse lymph node develop into CD127+ NK cells: thymus-dependent and thymus-independent pathways
Authors: Luther Claudia , Warner Kathrin , Takei Fumio 
Published: February 2011

AbstractA subset of natural killer (NK) cells in normal mouse lymph node (LN) expresses CD127 (IL-7 receptor-α chain) and is thought to derive from the thymus. However, CD127+ NK cells are found in the LN of athymic mice. Therefore, the origin of CD127+ NK cells in the LN is unclear. Here, we have identified unique NK-cell progenitors (NKPs) in the LN that express the pan-NK cell marker CD49b and CD127 but lack CD122 and lineage markers. The LN NKPs develop in vitro into CD127+ NK cells that display natural cytotoxicity and cytokine production capacity. They also become CD127+ NK cells in lymphopenic mice that received a transplant. LN NKPs can be divided into stem cell antigen-1 (Sca-1)hi and Sca-1lo subsets. The latter comprise ∼ 60% of LN NKPs in normal mouse and < 10% of athymic mouse LN NKPs. Whereas both Sca-1hi and Sca-1lo NKPs develop into CD127+ NK cells in vitro, only those derived from Sca-1lo LN NKPs have rearranged TCRγ genes. Thus, CD127+ NK cells in the LN seem to be generated, at least in part, from both thymus-dependent Sca-1lo and thymus-independent Sca-1hi LN NKPs.
The EMT regulator Zeb2/Sip1 is essential for murine embryonic hematopoietic stem/progenitor cell differentiation and mobilization
Authors: Goossens Steven , Janzen Viktor , Bartunkova Sonia , Yokomizo Tomomasa , Drogat Benjamin , Crisan Mihaela , Haigh Katharina , Seuntjens Eve , Umans Lieve , Riedt Tamara , Bogaert Pieter , Haenebalcke Lieven , Berx Geert , Dzierzak Elaine , Huylebroeck Danny , Haigh Jody J. 
Published: February 2011

Abstract
Zeb2 (Sip1/Zfhx1b) is a member of the zinc-finger E-box–binding (ZEB) family of transcriptional repressors previously demonstrated to regulate epithelial-to-mesenchymal transition (EMT) processes during embryogenesis and tumor progression. We found high Zeb2 mRNA expression levels in HSCs and hematopoietic progenitor cells (HPCs), and examined Zeb2 function in hematopoiesis through a conditional deletion approach using the Tie2-Cre and Vav-iCre recombination mouse lines. Detailed cellular analysis demonstrated that Zeb2 is dispensable for hematopoietic cluster and HSC formation in the aorta-gonadomesonephros region of the embryo, but is essential for normal HSC/HPC differentiation. In addition, Zeb2-deficient HSCs/HPCs fail to properly colonize the fetal liver and/or bone marrow and show enhanced adhesive properties associated with increased β1 integrin and Cxcr4 expression. Moreover, deletion of Zeb2 resulted in embryonic (Tie2-Cre) and perinatal (Vav-icre) lethality due to severe cephalic hemorrhaging and decreased levels of angiopoietin-1 and, subsequently, improper pericyte coverage of the cephalic vasculature. These results reveal essential roles for Zeb2 in embryonic hematopoiesis and are suggestive of a role for Zeb2 in hematopoietic-related pathologies in the adult.
The E3 ubiquitin ligase RAD18 regulates ubiquitylation and chromatin loading of FANCD2 and FANCI
Authors: Williams Stacy A. , Longerich Simonne , Sung Patrick , Vaziri Cyrus , Kupfer Gary M. 
Published: February 2011

Abstract
Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, congenital abnormalities, and an increased risk for cancer and leukemia. Components of the FA-BRCA pathway are thought to function in the repair of DNA interstrand cross-links. Central to this pathway is the monoubiquitylation and chromatin localization of 2 FA proteins, FA complementation group D2 (FANCD2) and FANCI. In the present study, we show that RAD18 binds FANCD2 and is required for efficient monoubiquitylation and chromatin localization of both FANCD2 and FANCI. Human RAD18-knockout cells display increased sensitivity to mitomycin C and a delay in FANCD2 foci formation compared with their wild-type counterparts. In addition, RAD18-knockout cells display a unique lack of FANCD2 and FANCI localization to chromatin in exponentially growing cells. FANCD2 ubiquitylation is normal in cells containing a ubiquitylation-resistant form of proliferating cell nuclear antigen, and chromatin loading of FA core complex proteins appears normal in RAD18-knockout cells. Mutation of the RING domain of RAD18 ablates the interaction with and chromatin loading of FANCD2. These data suggest a key role for the E3 ligase activity of RAD18 in the recruitment of FANCD2 and FANCI to chromatin and the events leading to their ubiquitylation during S phase.
Doxorubicin, vinblastine, and gemcitabine (CALGB 50203) for stage I/II nonbulky Hodgkin lymphoma: pretreatment prognostic factors and interim PET
Authors: Straus David J. , Johnson Jeffrey L. , LaCasce Ann S. , Bartlett Nancy L. , Kostakoglu Lale , Hsi Eric D. , Schöder Heiko , Hall Nathan C. , Jung Sin-Ho , Canellos George P. , Schwartz Lawrence H. , Takvorian Ronald W. , Juweid Malik E. , Cheson Bruce D. ,   for Cancer and Leukemia Group B
Published: February 2011

AbstractTo reduce doxorubicin, bleomycin, vinblastine and dacarbazine toxicity, the Cancer and Leukemia Group B conducted a phase 2 trial of doxorubicin, vinblastine, and gemcitabine for newly diagnosed, nonbulky stages I and II Hodgkin lymphoma. Ninety-nine assessable patients received 6 cycles of doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and gemcitabine 800 mg/m2 (1000 mg/m2 in first 6) on days 1 and 15 every 28 days. Computed tomography (CT) and positron emission tomography (PET) were performed before and after 2 and 6 cycles. Complete remission (CR)/CR unconfirmed was achieved in 72 of 99 patients (72.7%) and partial remission in 24 of 99 patients (24.2%). The CR rate was 81% when using PET criteria. Two patients have died of Hodgkin lymphoma progression. Median follow-up for nonprogressing patients is 3.3 years. The progression-free survival (PFS) at 3 years was 77% (95% confidence interval, 68%-84%). The relapse rate was less than 10% for patients with favorable prognostic factors. The 2-year PFS for cycle 2 PET-negative and -positive patients was 88% and 54%, respectively (P = .0009), compared with 89% and 27% for cycle 6 PET-negative and -positive patients (P = .0001). Although the CR rate and PFS were lower than anticipated, patients with favorable prognostic features had a low rate of relapse. Cycle 2 PET and cycle 6 PET were predictive of PFS. This clinical trial is registered at www.clinicaltrials.gov as #NCT00086801.
Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice
Authors: Finberg Karin E. , Whittlesey Rebecca L. , Andrews Nancy C. 
Published: February 2011

Abstract
The hereditary hemochromatosis protein HFE promotes the expression of hepcidin, a circulating hormone produced by the liver that inhibits dietary iron absorption and macrophage iron release. HFE mutations are associated with impaired hepatic bone morphogenetic protein (BMP)/SMAD signaling for hepcidin production. TMPRSS6, a transmembrane serine protease mutated in iron-refractory iron deficiency anemia, inhibits hepcidin expression by dampening BMP/SMAD signaling. In the present study, we used genetic approaches in mice to examine the relationship between Hfe and Tmprss6 in the regulation of systemic iron homeostasis. Heterozygous loss of Tmprss6 in Hfe−/− mice reduced systemic iron overload, whereas homozygous loss caused systemic iron deficiency and elevated hepatic expression of hepcidin and other Bmp/Smad target genes. In contrast, neither genetic loss of Hfe nor hepatic Hfe overexpression modulated the hepcidin elevation and systemic iron deficiency of Tmprss6−/− mice. These results indicate that genetic loss of Tmprss6 increases Bmp/Smad signaling in an Hfe-independent manner that can restore Bmp/Smad signaling in Hfe−/− mice. Furthermore, these results suggest that natural genetic variation in the human ortholog TMPRSS6 might modify the clinical penetrance of HFE-associated hereditary hemochromatosis, raising the possibility that pharmacologic inhibition of TMPRSS6 could attenuate iron loading in this disorder.
Causal relationship between hyperfibrinogenemia, thrombosis, and resistance to thrombolysis in mice
Authors: Machlus Kellie R. , Cardenas Jessica C. , Church Frank C. , Wolberg Alisa S. 
Published: February 2011

AbstractEpidemiologic studies have correlated elevated plasma fibrinogen (hyperfibrinogenemia) with risk of cardiovascular disease and arterial and venous thrombosis. However, it is unknown whether hyperfibrinogenemia is merely a biomarker of the proinflammatory disease state or is a causative mechanism in the etiology. We raised plasma fibrinogen levels in mice via intravenous infusion and induced thrombosis by ferric chloride application to the carotid artery (high shear) or saphenous vein (lower shear); hyperfibrinogenemia significantly shortened the time to occlusion in both models. Using immunohistochemistry, turbidity, confocal microscopy, and elastometry of clots produced in cell and tissue factor-initiated models of thrombosis, we show that hyperfibrinogenemia increased thrombus fibrin content, promoted faster fibrin formation, and increased fibrin network density, strength, and stability. Hyperfibrinogenemia also increased thrombus resistance to tenecteplase-induced thrombolysis in vivo. These data indicate that hyperfibrinogenemia directly promotes thrombosis and thrombolysis resistance and does so via enhanced fibrin formation and stability. These findings strongly suggest a causative role for hyperfibrinogenemia in acute thrombosis and have significant implications for thrombolytic therapy. Plasma fibrinogen levels may be used to identify patients at risk for thrombosis and inform thrombolytic administration for treating acute thrombosis/thromboembolism.
Essential role for Ptpn11 in survival of hematopoietic stem and progenitor cells
Authors: Chan Gordon , Cheung Laurene S. , Yang Wentian , Milyavsky Michael , Sanders Ashley D. , Gu Shengqing , Hong Wan Xing , Liu Aurora X. , Wang Xiaonan , Barbara Mary , Sharma Tarun , Gavin Joehleen , Kutok Jeffery L. , Iscove Norman N. , Shannon Kevin M. , Dick John E. , Neel Benjamin G. , Braun Benjamin S. 
Published: February 2011

AbstractSrc homology 2 domain-containing phosphatase 2 (Shp2), encoded by Ptpn11, is a member of the nonreceptor protein-tyrosine phosphatase family, and functions in cell survival, proliferation, migration, and differentiation in many tissues. Here we report that loss of Ptpn11 in murine hematopoietic cells leads to bone marrow aplasia and lethality. Mutant mice show rapid loss of hematopoietic stem cells (HSCs) and immature progenitors of all hematopoietic lineages in a gene dosage-dependent and cell-autonomous manner. Ptpn11-deficient HSCs and progenitors undergo apoptosis concomitant with increased Noxa expression. Mutant HSCs/progenitors also show defective Erk and Akt activation in response to stem cell factor and diminished thrombopoietin-evoked Erk activation. Activated Kras alleviates the Ptpn11 requirement for colony formation by progenitors and cytokine/growth factor responsiveness of HSCs, indicating that Ras is functionally downstream of Shp2 in these cells. Thus, Shp2 plays a critical role in controlling the survival and maintenance of HSCs and immature progenitors in vivo.
Transmission of Beauveria bassiana from male to female Aedes aegypti mosquitoes
Authors: García-Munguía Alberto M , Garza-Hernández Javier A , Rebollar-Tellez Eduardo A , Rodríguez-Pérez Mario A , Reyes-Villanueva Filiberto 
Published: February 2011

Abstract

Background
Resistance to chemical insecticides plus high morbidity rates have lead to rising interest in fungi as candidates for biocontrol agents of mosquito vectors. In most studies fungal infections have been induced by exposure of mosquitoes to various surfaces treated with conidia. In the present study eight Mexican strains of Beauveria bassiana were assessed against Aedes aegypti by direct exposure of females to 6 × 108 conidia ml -1 on a filter paper, afterwards, the transmission of the least and most virulent isolates was evaluated by mating behavior from virgin, fungus-contaminated male to females, to examine this ethological pattern as a new approach to deliver conidia against the dengue vector.

Methods
In an exposure chamber with a filter paper impregnated with 6 × 108 conidia ml -1 of the least and most virulent strains of B. bassiana, 6-8 day old males of A. aegypti were exposed for 48 hours, and then transferred individually (each one was a replicate) to another chamber and confined with twenty healthy females of the same age. Clean males were used in controls. Survival, infection by true mating (insemination) or by mating attempts (no insemination) and fecundity were daily registered until the death of last female. Data analysis was conducted with proc glm for unbalanced experiments and means were separated with the Ryan test with SAS.

Results
All strains were highly virulent with LT50 ranging from 2.70 (± 0.29) to 5.33 (± 0.53) days. However the most (Bb-CBG2) and least virulent (Bb-CBG4) isolates were also transmitted by mating behavior; both killed 78-90% of females in 15 days after being confined with males that had previously been exposed for 48 hours to fungi. Of these mortality rates, 23 and 38% respectively, were infections acquired by copulations where insemination occurred. The LT50 for sexually-infected females were 7.92 (± 0.46) and 8.82 (± 0.45) days for both strains, while the one in control was 13.92 (± 0.58). Likewise, fecundity decreased by 95% and 60% for both Bb-CBG2 and Bb-CBG4 isolates in comparison with control. The role of mating attempts in this delivery procedure of B. bassiana is discussed.

Conclusions
This is the first report about transmission of B. bassiana by mating behavior from virgin, fungus-contaminated males to females in A. aegypti. Fungal infections acquired by this route (autodissemination) infringed high mortality rates (90%) in mated or approached females. However, prior to releasing virgin, fungus-contaminated males to spread B. basasiana among females of A. aegypti, this novel alternative needs further investigations.