Miracle-dz/UniFAR-FTUs huggingface dataset:
AKT Antagonist AZD5363 Influences Estrogen Receptor Function in Endocrine-Resistant Breast Cancer and Synergizes with Fulvestrant (ICI182780) In Vivo

PI3K/AKT/mTOR signaling plays an important role in breast cancer. Its interaction with estrogen receptor (ER) signaling becomes more complex and interdependent with acquired endocrine resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility; however, a negative feedback loop exists downstream of PI3K/AKT/mTOR. Direct blockade of AKT together with endocrine therapy may improve breast cancer treatment. AZD5363, a novel pan-AKT kinase catalytic inhibitor, was examined in a panel of ER+ breast cancer cell lines (MCF7, HCC1428, T47D, ZR75.1) adapted to long-term estrogen deprivation (LTED) or tamoxifen (TamR). AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50 < 500 nmol/L) except HCC1428 and HCC1428-LTED. T47D-LTED and ZR75-LTED were the most sensitive of the lines (GI50 ∼100 nmol/L). AZD5363 resensitized TamR cells to tamoxifen and acted synergistically with fulvestrant. AZD5363 decreased p-AKT/mTOR targets leading to a reduction in ERα-mediated transcription in a context-specific manner and concomitant decrease in recruitment of ER and CREB-binding protein (CBP) to estrogen response elements located on the TFF1, PGR, and GREB1 promoters. Furthermore, AZD5363 reduced expression of cell-cycle–regulatory proteins. Global gene expression highlighted ERBB2-ERBB3, ERK5, and IGFI signaling pathways driven by MYC as potential feedback-loops. Combined treatment with AZD5363 and fulvestrant showed synergy in an ER+ patient-derived xenograft and delayed tumor progression after cessation of therapy. These data support the combination of AZD5363 with fulvestrant as a potential therapy for breast cancer that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response, supporting the need for clinical evaluation. Mol Cancer Ther; 14(9); 2035–48. ©2015 AACR.
Analysis of risk factors for over‐anticoagulation in patients receiving long‐term warfarin

A cohort of patients with an INR >7.0 were identified prospectively and compared with a group of patients with stable anticoagulant control. During the study 15 100 INR measurements were recorded and 31 (0.2%) were >7.0. Odds ratios of patient characteristics were calculated as an estimate of relative risk for the development of a high INR. The highest risk factor was a target INR of 3.5 (OR 7.3, 95% CI 2.6–20.2). The second highest risk factor was antibiotic therapy in the 4 weeks preceding the high INR (OR 6.2, 95% CI 1.4–27.7). Bleeding was reported more frequently in the high INR group (OR 5.4, 95% CI 2.1–13.9). Five major bleeds occurred in this group compared to none in the stable group. This analysis identifies risk factors for over‐anticoagulation and hence when to intensify monitoring and when to consider pre‐emptive warfarin dose reductions.
Laminin Isoforms and Epithelial Development

ABSTRACT: Several different approaches suggest that basement‐membrane assembly is important for epithelial development. Basement membranes contain isoforms of collagen IV, proteoglycans, and noncollagenous glycoproteins such as the laminins and nidogens. The expression and role of laminins for epithelial morphogenesis is reviewed. Laminins are large heterotrimeric proteins composed of α, β, and γ chains. Many major epithelial laminins and their receptors have been identified recently, and, the extracellular protein‐protein interactions that drive basement‐membrane assembly are beginning to be understood. Three laminin α‐chains are typically made by epithelial, α1, α3, and α5. Three major epithelial heterotrimers can at present be distinguished‐laminin‐1 (α1β1γ1), laminin‐5 (α3β3γ2), and laminin‐10 (α5β1γ1)‐but other heterotrimers may exist in epithelia. Laminins containing either α1 or α3 chains are largely limited to epithelia, whereas the α5 is also found in endothelial and muscle basement membranes, particularly in the adult. Some epithelial cell types express several laminin α‐chains, so it is relevant to test how the different laminins affect epithelial cells. Laminins interact with integrin type of receptors on the cell surface, but binding to other proteins has also recently been demonstrated. Two important recent discoveries are the identification of dystroglycan as a major laminin receptor in muscle and epithelia, and nidogen as a high‐affinity laminin‐binding protein important for basement‐membrane assembly. Antibody perturbation experiments suggest these protein‐protein interactions are important for epithelial morphogenesis.
Prospective Comparison of One-Piece and Three-Piece Tecnis Aspheric Intraocular Lenses: 1-year Stability and its Effect on Visual Function

Abstract Purpose: To compare the stability and visual function of one-piece hydrophobic intraocular lens (IOL) (ZCB00, Abbot Medical Optics) and a three-piece hydrophobic IOL (ZA9003, Abbot Medical Optics) after cataract surgery. Materials and methods: Eighteen eyes of 18 patients with the one-piece IOL and 20 eyes of 20 patients with the three-piece IOL who underwent cataract surgery were evaluated prospectively on best corrected distance visual acuity, postoperative refractive error, IOL decentration and tilt, anterior chamber depth (ACD), spherical aberration and contrast sensitivity. Measurements were performed 1 week and 1, 3, 6 and 12 months postoperatively. The postoperative outcomes were compared between the two groups. Results: In the one-piece group, a hyperopic refractive error (p < 0.002) and deeper ACDs during 1-year post-operatively were observed compared with the three-piece group. There were no significant differences in BCVA, IOL tilt, spherical aberration or contrast sensitivity. Conclusions: The stability of the one-piece IOL was greater than that of the three-piece IOL. The postoperative ACD and refractive error demonstrated that an anteriorly offset haptic in the one-piece IOL allowed incremental fixation to the posterior capsule.
Synthesis of platelet-activating factor and its receptor expression in Kupffer cells in rat carbon tetrachloride-induced cirrhosis.

AIM To determine the platelet-activating factor (PAF) synthesis and its receptor expression in Kupffer cells in rat carbon tetrachloride-induced cirrhosis. METHODS Kupffer cells, isolated from the livers of control and CCl4-induced cirrhotic rats, were placed in serum-free medium overnight. PAF saturation binding, ET-1 saturation and competition binding were assayed. ET-1 induced PAF synthesis, mRNA expression of PAF, preproendothelin-1, endothelin A (ETA) and endothelin B (ETB) receptors were also determined. RESULTS A two-fold increase of PAF synthesis (1.42 +/- 0.14 vs 0.66 +/- 0.04 pg/microg DNA) and a 1.48-fold increase of membrane-bound PAF (1.02 +/- 0.06 vs 0.69 +/- 0.07 pg/microg DNA) were observed in activated Kupffer cells of cirrhotic rats. The application of ET-1 to Kupffer cells induced PAF synthesis in a concentration-dependent manner in both cirrhotic and normal rats via ETB receptor, but PAF synthesis in the activated Kupffer cells was more effective than that in the normal Kupffer cells. In activated Kupffer cells, PAF receptor expression and PAF binding capacity were markedly enhanced. Activated Kupffer cells raised the [125 I]-ET-1 binding capacity, but changed neither the affinity of the receptors, nor the expression of ETA receptor. CONCLUSION Kupffer cells in the course of CCl4-induced cirrhosis are the main source of increased PAF. ET-1 is involved endogenously in stimulating the PAF synthesis in activated Kupffer cells via ETB receptor by paracrine. ETA receptor did not appear in activated Kupffer cells, which may exacerbate the hepatic and extrahepatic complications of cirrhosis.
Ras-dependent Activation of c-Jun N-terminal Kinase/Stress-activated Protein Kinase in Response to Interleukin-3 Stimulation in Hematopoietic BaF3 Cells*

Activation of the c-Jun N-terminal kinase (JNK)/stress-activated protein kinase pathway in response to stimulation of the interleukin (IL)-3 or granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor was examined in mouse hematopoietic BaF3-derived cell lines (BaF3-N6 and -V2 cells). Significant increase in the activity of JNK1 was observed within 30 min following IL-3 or GM-CSF stimulation at physiological concentrations. Dominant-negative Ras(S17N), which is conditionally expressed in the presence of isopropyl-1-thio-β-D-galactoside in BaF3-N6 cells, prevented the IL-3 stimulation of JNK1, whereas anisomycin-induced JNK1 activation was unaffected. Furthermore, a deletion mutant of the common β subunit for IL-3 and GM-CSF receptors that consists of only the membrane-proximal region, including box 1 and box 2 motifs, was incapable of facilitating JNK1 activity as well as Ras activation. These results provide evidence that Ras is required for IL-3-stimulated JNK1 activation. We also examined if constitutively active Ras(G12V) alone could stimulate JNK1 activity by using the inducible expression system. Isopropyl-1-thio-β-D-galactoside induction of Ras(G12V) in the BaF3-V2 cell line caused no significant increase in JNK1 activity, which could be activated by IL-3 or anisomycin. On the contrary, the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway was fully activated following Ras(G12V) induction. Together with these results, it seems likely that the Ras protein is indispensable for the IL-3 stimulation of JNK1 although Ras activation by itself is insufficient for JNK1 activation.
Exaggerated insulin secretion in Pima Indians and African‐Americans but higher insulin resistance in Pima Indians compared to African‐Americans and Caucasians

Aims African‐Americans have a higher prevalence of Type 2 diabetes than Caucasians, but a lower prevalence than Pima Indians. Studies suggest that both African‐Americans and Pima Indians are more insulin resistant and have higher acute insulin secretory responses to glucose than Caucasians; however, a direct comparison between these three populations is lacking.
Survey of pediatric resident experiences with resuscitation training and attendance at actual cardiopulmonary arrests

Objective: The literature suggests pediatric residents are inadequately prepared to perform resuscitation maneuvers when a child suffers a cardiopulmonary arrest (CPA). Our objective was to characterize the resuscitation training and CPA resuscitation experience of residents, including hands on experience with discharging a defibrillator. Design: Cross-sectional survey. Setting: Tertiary care, academic pediatric residency program. Subjects: Pediatric residents. Measurements and Main Results: Seventy-six of 80 (95%) pediatric residents responded. The median (interquartile range) number of CPAs attended increased significantly by level of training, with some attending as many as 20 CPAs during residency (postgraduate year [PGY]1: 2.0 [1.0–3.0] vs. PGY2: 5.0 [3.0–8.0] vs. PGY3: 10.0 [5.0–12.0], p < 0.001). Nine of 25 (36%) senior residents had led a resuscitation. The proportion of third-year residents who had attended at least 1 CPA in the following locations was: general ward 20 of 25 (80%), Emergency Department 18 of 25 (72%), Neonatal intensive care unit 24 of 25 (96%), pediatric intensive care unit 23 of 25 (92%), and secondary training hospital 19 of 25 (76%). Twelve of 76 (16%) residents had discharged a defibrillator on an actual patient; however, 25 of 76 (33%) had never discharged a defibrillator, either on a patient or during training exercises. Although most residents had received required training in American Heart Association Basic Life Support and Pediatric Advance Life Support (i.e., BLS and PALS), 6 of 76 (8%) residents had never taken basic life support and 4 of 48 (8%) of upper level residents had never taken pediatric advanced life support. Multivariate analysis revealed that level of training, pediatric advanced life support training, and attendance at a mock code in the past year were not independently associated with having discharged a defibrillator (i.e., patient, mannequin, etc.), whereas attendance at an institutional Code Team training course was. Conclusions: Almost every pediatric resident was involved in attempting to resuscitate a child suffering a CPA, yet many were inadequately trained to respond. Formal mechanisms are needed to guarantee adequate resuscitation training for pediatric residents, especially regarding participation in basic life support and hands on defibrillator training.
Increased incidence of multidrug-resistant tuberculosis in diabetic patients on the Bellevue Chest Service, 1987 to 1997.

STUDY OBJECTIVES To investigate the characteristics of tuberculosis infection in diabetic patients at Bellevue Hospital. DESIGN We conducted a case-control study retrospectively reviewing the records of patients at Bellevue Hospital Center from 1987 to 1997 with a discharge diagnosis of tuberculosis and diabetes mellitus. SETTING Bellevue Hospital Center is a 1,200-bed, inner-city municipal hospital located in the Lower East Side of New York City. PATIENTS Fifty-three identified patients had verified tuberculosis infection and diabetes; of these, 50 charts were available for review. One hundred five control cases were selected from nondiabetic patients with a discharge diagnosis of tuberculosis during the same time period. MEASUREMENTS AND RESULTS Thirty-six percent (18 cases) of the patients with diabetes and tuberculosis had multidrug-resistant tuberculosis (MDR-TB) compared to only 10% (10 cases) in the control group (p < 0.01) Controlling for homelessness, HIV status, and directly observed therapy, the relative risk of MDR-TB was calculated to be 8.6 (confidence interval, 3.1 to 23.6) in the diabetic group compared to the control group. CONCLUSIONS There was a significant association between diabetes and MDR-TB. Diabetes continues to be a risk factor for tuberculosis and was associated with MDR-TB in our patients.
Political Connections, Local Corruption, and Firm's Bank Pool Structures: Empirical Evidence from Vietnam

This paper investigates the effects of political connections and local corruption on the structures of firms’ bank pools. Using a manually collected data set of 389 listed Vietnamese companies in 2013, it finds that politically connected firms tend to establish their main bank relationships with connected banks. It also finds that connected firms reduce their numbers of banks and their diversity of bank ownership types in their bank pools when they achieve main bank relationships with connected banks; such firms maintain these bank pool structures when corruption is prevalent in their home provinces. Results demonstrate that local corruption is associated positively with number of banks and diversification of bank ownership types.
Transcranial Doppler Sonography in the Early Stage of Critical Enteroviral Infection

Objective.There is a high fatality rate in enteroviral infection with central nervous system involvement. Our aim was to investigate the change in intracranial blood flow to disclose the characteristic findings in the early stage of critical enteroviral infection.Methods. We examined 27 patients in critical condition with enteroviral infection in our pediatric intensive care unit. We performed transcranial Doppler sonography within 12 hours of admission to the unit. The data were compared with those of a group of 11 patients with nonenteroviral encephalitis. Results. The peak systolic, end‐diastolic, and mean velocities of the critical enteroviral infection group were significantly higher than those of the control group (P < .05). Gosling pulsatility index and Pourcelot resistive index values for the right and left middle cerebral arteries (pulsatility index, [mean ± SD], 0.68 ± 0.22 and 0.77 ± 0.19, respectively; resistive index, 0.48 ± 0.01 and 0.52 ± 0.01) in patients with critical enteroviral infection were significantly lower than those of patients with nonenteroviral encephalitis (pulsatility index, 1.10 ± 0.30 and 0.98 ± 0.22; resistive index, 0.62 ± 0.01 and 0.60 ± 0.01; P < .05)Conclusions. Low pulsatility index and resistive index values for cerebral blood flow were observed in the early stage of critical enteroviral infection. This characteristic finding of cerebral blood flow might be associated with the increased sympathetic discharge induced by a brain stem–involved systemic inflammatory response and dysfunction of autoregulation caused by the infection or other disorders of autoregulation that might cause severe or fatal complications.
Cyclophosphamide boluses induce micronuclei expression in buccal mucosa cells of patients with systemic lupus erythematosus independent of cytochrome P450 2D6 status.

OBJECTIVE To assess the effect of cyclophosphamide (CYC) and the influence of CYP2D6 polymorphism on micronuclei expression in patients with systemic lupus erythematosus (SLE). METHODS Micronuclei (MN) assays were performed in oral mucosa sweeps of 49 patients with SLE, receiving and not receiving CYC therapy, and 43 healthy controls. In patients receiving CYC the MN assay was repeated 14 days after CYC administration. SLE patients underwent determination of the CYP2D6 allele expressed in peripheral blood by polymerase chain reaction amplification. These results were compared with CYP2D6 distribution in a healthy population from the same geographic area. The results were analyzed by Mann-Whitney U and chi-square tests. RESULTS Twenty-four patients with SLE received CYC boluses. The mean age of SLE patients was 32 +/- 10 years; mean disease duration was 7 +/- 6 years. Basal expression of MN was similar in the groups investigated and increased significantly in those exposed to CYC (CYC group 44%, no CYC group 5%, healthy controls 9%; p = 0.001). We found no association between the CYP2D6 allele expressed and MN induction. Poor metabolizers were overrepresented in SLE subjects as compared with 139 healthy controls (p < 0.05). CONCLUSION Genotoxicity, as assessed by the MN assay, is increased in patients with SLE after CYC boluses. The CYP2D6 allele expressed in SLE patients does not have a role in CYC induced chromosomal injury.
Fluid uptake from the renal medulla into the ascending vasa recta in anaesthetized rats.

1. We have investigated fluid movements between superficial ascending vasa recta (AVR) and the interstitium of exposed papillae of the renal medullae in 15‐day‐old Sprague‐Dawley rats anaesthetized with Hypnorm and Hypnovel. 2. Using a development of the red cell micro‐occlusion technique, fluid filtration and reabsorption rates per unit area of vessel wall (Jv/A) were determined in 54 single perfused AVR at known microvascular pressures (Pc). The relation between Jv/A and Pc was non‐linear suggesting hydraulic permeabilities (Lp) of 50‐100 x 10(‐7) cm s‐1 cmH2O‐1 when Pc was between 0‐10 cmH2O and 150‐200 x 10(‐7) cm s‐1 cmH2O‐1 when Pc was 10‐15 cmH2O. 3. Rates of fluid reabsorption into the AVR estimated by a densitometric technique in a further fourteen vessels were consistent with Lp values of 50‐100 x 10(‐7) cm s‐1 cmH2O‐1 when Pc was ‐2 to 0 cmH2O. 4. The effective oncotic pressures of perfusates containing bovine serum albumin (BSA) were consistent with minimum values for the reflection coefficients of the walls of the AVR to BSA of between 0.59 and 0.72. 5. The concentration of native serum albumin in the papillary interstitial fluid was 9.1 +/‐ 0.6 mg ml‐1 (mean +/‐ S.E.M., n = 16, from 9 rats), which is approximately 25% of the plasma level. 6. After their microinjection into the medullary interstitium, Patent Blue V and Evans Blue‐albumin cleared within 1 min. There was no evidence of preferential movement of either dye towards the base of the exposed renal medulla. 7. Because Lp of the AVR is high, mean pressures of only approximately 3 cmH2O are necessary to account for the total clearance of fluid from the medullary interstitium into the AVR. From published data and from our own observations, it appears that differences in hydrostatic and oncotic pressure across the walls of the AVR are more than sufficient to provide this driving force. The possibility of the clearance of protein from the interstitium into the AVR is discussed.
Beneficial effects of dietary restriction in type 2 diabetic rats: the role of adipokines on inflammation and insulin resistance

Inflammation plays an important role in diabetes mellitus and its complications. In this context, the negative cross-talk between adipose tissue and skeletal muscle leads to disturbances in muscle cell insulin signalling and induces insulin resistance. Because several studies have shown that energy restriction brings some benefits to diabetes, the aim of the present study was to evaluate the effects of dietary restriction on systemic and skeletal muscle inflammatory biomarkers, such C-reactive protein, adipokines and cytokines, and in insulin resistance in Goto-Kakizaki rats. This is an animal model of spontaneous non-obese type 2 diabetes with strongly insulin resistance and without dyslipidaemia. Animals were maintained during 2 months of dietary restriction (50 %) and were killed at 6 months of age. Some biochemical determinations were done using ELISA and Western blot. Data from the present study demonstrate that in Goto-Kakizaki rats the dietary restriction improved insulin resistance, NEFA levels and adipokine profile and ameliorated inflammatory cytokines in skeletal muscle. These results indicate that dietary restriction in type 2 diabetes enhances adipose tissue metabolism leading to an improved skeletal muscle insulin sensitivity.
Analysis of the structure of HIV‐1 protease complexed with a hexapeptide inhibitor. Part II: Molecular dynamic studies of the active site region

Six models of the catalytic site of HIV‐1 protease complexed with a reduced peptide inhibitor, MVT‐101, were investigated. These studies focused on the details of protonation of the active site, its total net charge and hydrogen bonding pattern, which was consistent with both the observed coplanar configuration of the acidic groups of the catalytic aspartates (Asp‐25 and Asp‐125) and the observed binding mode of the inhibitor. Molecular dynamic simulations using AMBER 4.0 indicated that the active site should be neutral. The planarity of the aspartate dyad may be due to the formation of two hydrogen bonds: one between the inner Oδ1oxygen atoms of the two catalytic aspartates and another between the Oδ2atom of Asp‐125 and the nitrogen atom of the reduced peptide bond of the bound inhibitor. This would require two additional protonations, either of both aspartates, or of one Asp and the amido nitrogen atom of Nle‐204. Our results favor the Asp‐inhibitor protonation but the other one is not excluded. Implications of these findings for the mechanism of enzymatic catalysis are discussed. Dynamic properties of the hydrogen bond network in the active site and an analysis of the interaction energy between the inhibitor and the protease are presented. © 1997 Wiley‐Liss, Inc.
Japan’s ODA in Globally Integrated CLMV Economies: Aid Effectiveness and Political Economy

The CLMV (Cambodia, Laos, Myanmar and Vietnam) countries have globally integrated in recent years achieving high growth and increasing living standard that are attributable to expanded trade and FDI and especially ODA. To complement other studies on CLMV growth and development causality from an empirical perspective, the paper develops a new economic integration model of endogenous growth to study specifically the impact of Japan’s ODA on trade and growth in the CLMV countries. The model is then applied to each of the four CLMV countries to investigate the impact of Japan’s ODA, openness, and FDI on its growth and trade. The purpose is to provide useful input to support evidence-based policy analysis of ODA, development, trade, and FDI in these countries to meet United Nations 2015 sustainable development goals. The approach and findings are particularly relevant to new emerging donors in Asia such as China and Thailand and especially Korea where outgoing foreign aid has greatly increased since 1987 reaching USD1,915.25m in 2015.