bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Reduced Zone on Time-Dependent Analysis of Tunnels
Authors: Fattah Mohammed Y. , Shlash Kais T. , Salim Nahla M.
Published: June 2011

The problem of the proposed “Baghdad metro line” which consists of two routes of 32 km long and 36 stations is analyzed. The tunnel is circular in cross-section with a 5.9 m outer diameter. The finite element analyses were carried out using elastic-plastic and modified Cam clay models for the soil. The excavation has been used together with transient effects through a fully coupled Biot formulation. All these models and the excavation technique together with Biot consolidation are implemented into finite-element computer program named “Modf-CRISP” developed for the purpose of these analyses. The results indicate that there is an inward movement at the crown and this movement is restricted to four and half tunnel diameters. A limited movement can be noticed at spring line which reaches 0.05% of tunnel diameter, while there is a heave at the region below the invert, which reaches its maximum value of about 0.14% of the diameter and is also restricted to a region extending to 1.5 diameters. The effect of using reduced zone on excess pore water pressure and surface settlement (vertical and horizontal) was also considered and it was found that the excess pore water pressure increases while the settlement trough becomes deeper and narrower using reduced .
Efficacy of Brazilian Propolis against Herpes Simplex Virus Type 1 Infection in Mice and Their Modes of Antiherpetic Efficacies
Authors: Shimizu Tomomi , Takeshita Youhei , Takamori Yasushi , Kai Hisahiro , Sawamura Rie , Yoshida Hiroki , Watanabe Wataru , Tsutsumi Atsuko , Park Yong Kun , Yasukawa Ken , Matsuno Koji , Shiraki Kimiyasu , Kurokawa Masahiko
Published: June 2011

Ethanol extracts (AF‐06, 07, and 08, 10 mg/kg) of Brazilian propolis were administered orally to cutaneously herpes simplex virus type 1 (HSV‐1)‐infected mice three times daily on days 0 to 6 after infection to evaluate their efficacies against HSV‐1 infection and significantly limited development of herpetic skin lesions. AF‐07 and 08 significantly reduced virus titers in brain and/or skin on day 4 without toxicity, but AF‐08 had no anti‐HSV‐1 activity in vitro. AF‐06 and 08 significantly enhanced delayed‐type hypersensitivity (DTH) to inactivated HSV‐1 antigen in infected mice. Oral AF‐08‐administration significantly augmented interferon (IFN)‐γ production by HSV‐1 antigen from splenocytes of HSV‐1‐infected mice, while direct exposure of splenocytes of infected mice to AF‐06 significantly elevated IFN‐γ production in vitro. Thus, AF‐08 might have components that are active in vivo even after oral administration and those of AF‐06 might be active only in vitro. Because DTH is a major host defense for intradermal HSV‐1 infection, augmentation of DTH response by AF‐06 or 08, directly or indirectly, respectively, may contribute to their efficacies against HSV‐1 infection. In addition, AF‐06 and 07 possibly contain anti‐HSV‐1 components contributing to their efficacies. Such biological activities of Brazilian propolis may be useful to analyze its pharmacological actions.
Quality of Life and Related Dimensions in Cancer Patients Treated with Mistletoe Extract(Iscador): A Meta-Analysis
Authors: Büssing Arndt , Raak Christa , Ostermann Thomas
Published: June 2011

Objectives. The aim of this meta-analysis was to determine the effectiveness of the fermented plant extractIscador, produced from the white-berry European mistletoe, in the treatment of patients with cancer with respect to quality-of-life- (QoL-) associated measures.Methods. We searched databases such as PubMed/Medline, Excerpta Medica Database (EMBASE), CAMbase, and other for controlled clinical studies on parameters associated with QoL. Outcome data were extracted and converted into standardized mean differences and their standard errors.Results. Thirteen prospective and controlled studies which met the inclusion/exclusion criteria reported positive effects in favor of theIscadorapplication. A random-effect meta-analysis estimated the overall treatment effect at standardized mean difference=0.56(CI: 0.41 to 0.71,P<.0001). However, the methodological quality of the studies was poor.Conclusions. The analyzed studies give some evidence thatIscadortreatment might have beneficial short-time effects on QoL-associated dimensions and psychosomatic self-regulation.
Akt-Dependent Glucose Metabolism Promotes Mcl-1 Synthesis to Maintain Cell Survival and Resistance to Bcl-2 Inhibition
Authors: Coloff Jonathan L. , Macintyre Andrew N. , Nichols Amanda G. , Liu Tingyu , Gallo Catherine A. , Plas David R. , Rathmell Jeffrey C.
Published: June 2011

Most cancer cells utilize aerobic glycolysis, and activation of the phosphoinositide 3-kinase/Akt/mTOR pathway can promote this metabolic program to render cells glucose dependent. Although manipulation of glucose metabolism may provide a means to specifically eliminate cancer cells, mechanistic links between cell metabolism and apoptosis remain poorly understood. Here, we examined the role and metabolic regulation of the antiapoptotic Bcl-2 family protein Mcl-1 in cell death upon inhibition of Akt-induced aerobic glycolysis. In the presence of adequate glucose, activated Akt prevented the loss of Mcl-1 expression and protected cells from growth factor deprivation-induced apoptosis. Mcl-1 associated with and inhibited the proapoptotic Bcl-2 family protein Bim, contributing to cell survival. However, suppression of glucose metabolism led to induction of Bim, decreased expression of Mcl-1, and apoptosis. The proapoptotic Bcl-2/Bcl-xL/Bcl-w inhibitor, ABT-737, shows clinical promise, but Mcl-1 upregulation can promote resistance. Importantly, inhibition of glucose metabolism or mTORC1 overcame Mcl-1–mediated resistance in diffuse large B cell leukemic cells. Together these data show that Mcl-1 protein synthesis is tightly controlled by metabolism and that manipulation of glucose metabolism may provide a mechanism to suppress Mcl-1 expression and sensitize cancer cells to apoptosis. Cancer Res; 71(15); 5204–13. ©2011 AACR.
Inhibition of miR-193a Expression by Max and RXRα Activates K-Ras and PLAU to Mediate Distinct Aspects of Cellular Transformation
Authors: Iliopoulos Dimitrios , Rotem Asaf , Struhl Kevin
Published: June 2011

MicroRNA profiling in isogenic models of cellular transformation involving either breast epithelial cells or fibroblasts reveals that expression of miR-193a is lower in transformed cells than in nontransformed cells. The transcription factors Max and RXRα bind directly to the miR-193a promoter and inhibit miR-193a expression during transformation. miR-193a inhibits cellular transformation by directly targeting the 3′ untranslated regions of PLAU and K-Ras. Interestingly, miR-193a controls anchorage-independent growth in soft agar through K-Ras, whereas it affects invasive growth through PLAU. miR-193a overexpression inhibits the tumorigenicity of developmentally diverse but not all cancer cell types, and it inhibits tumor growth in colon- and breast-derived xenografts. Finally, expression of miR-193a is inversely correlated with PLAU and K-Ras in human colon adenocarcinomas. Thus, a pathway in which Max and RXRα inhibit miR-193a expression, thereby activating the PLAU and K-Ras oncogenes is important for distinct aspects of cellular transformation, as well as tumor growth and colon (and perhaps other types of) cancer. Cancer Res; 71(15); 5144–53. ©2011 AACR.
New Strategies in Metastatic Melanoma: Oncogene-Defined Taxonomy Leads to Therapeutic Advances
Authors: Flaherty Keith T. , Fisher David E.
Published: June 2011

The discovery of BRAF and KIT mutations provided the first basis for a molecular classification of cutaneous melanoma on therapeutic grounds. As BRAF-targeted therapy quickly moves toward regulatory approval and incorporation as standard therapy for patients with metastatic disease, proof of concept has also been established for targeting mutated KIT in melanoma. NRAS mutations have long been known to be present in a subset of melanomas and represent an elusive subgroup for targeted therapies. Matching patient subgroups defined by genetic aberrations in the phosphoinositide 3-kinase and p16/cyclin dependent kinase 4 (CDK4) pathways with appropriate targeted therapies has not yet been realized. And, an increasing understanding of lineage-specific transcriptional regulators, most notably MITF, and how they may play a role in melanoma pathophysiology, has provided another axis to approach with therapies. The foundation has been established for individual oncogene targeting, and current investigations seek to understand the intersection of these susceptibilities and other described potential targets and pathways. The melanoma field stands poised to take the lead among cancer subtypes in advancing combination therapy strategies that simultaneously target multiple biologic underpinnings of the disease. Clin Cancer Res; 17(15); 4922–8. ©2011 AACR.
Inhibition of Src Family Kinases and Receptor Tyrosine Kinases by Dasatinib: Possible Combinations in Solid Tumors
Authors: Montero Juan Carlos , Seoane Samuel , Ocaña Alberto , Pandiella Atanasio
Published: June 2011

Dasatinib is a small molecule tyrosine kinase inhibitor that targets a wide variety of tyrosine kinases implicated in the pathophysiology of several neoplasias. Among the most sensitive dasatinib targets are ABL, the SRC family kinases (SRC, LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK), and the receptor tyrosine kinases c-KIT, platelet-derived growth factor receptor (PDGFR) α and β, discoidin domain receptor 1 (DDR1), c-FMS, and ephrin receptors. Dasatinib inhibits cell duplication, migration, and invasion, and it triggers apoptosis of tumoral cells. As a consequence, dasatinib reduces tumoral mass and decreases the metastatic dissemination of tumoral cells. Dasatinib also acts on the tumoral microenvironment, which is particularly important in the bone, where dasatinib inhibits osteoclastic activity and favors osteogenesis, exerting a bone-protecting effect. Several preclinical studies have shown that dasatinib potentiates the antitumoral action of various drugs used in the oncology clinic, paving the way for the initiation of clinical trials of dasatinib in combination with standard-of-care treatments for the therapy of various neoplasias. Trials using combinations of dasatinib with ErbB/HER receptor antagonists are being explored in breast, head and neck, and colorectal cancers. In hormone receptor–positive breast cancer, trials using combinations of dasatinib with antihormonal therapies are ongoing. Dasatinib combinations with chemotherapeutic agents are also under development in prostate cancer (dasatinib plus docetaxel), melanoma (dasatinib plus dacarbazine), and colorectal cancer (dasatinib plus oxaliplatin plus capecitabine). Here, we review the preclinical evidence that supports the use of dasatinib in combination for the treatment of solid tumors and describe various clinical trials developed following a preclinical rationale. Clin Cancer Res; 17(17); 5546–52. ©2011 AACR.
The a3 Isoform Vacuolar Type H+-ATPase Promotes Distant Metastasis in the Mouse B16 Melanoma Cells
Authors: Nishisho Toshihiko , Hata Kenji , Nakanishi Masako , Morita Yoshihiro , Sun-Wada Ge-Hong , Wada Yoh , Yasui Natsuo , Yoneda Toshiyuki
Published: June 2011

Accumulating evidence indicates that the acidic microenvironments critically influence malignant behaviors of cancer including invasiveness, metastasis, and chemoresistance. Because the vacuolar-type H+-ATPase (V-ATPase) has been shown to cause extracellular acidification by pumping protons, we studied the role of V-ATPase in distant metastasis. Real-time PCR analysis revealed that the high-metastatic B16-F10 melanoma cells strongly expressed the a3 isoform V-ATPase compared to the low-metastatic B16 parental cells. Consistent with this, B16-F10 cells created acidic environments in lung metastases by acridine orange staining and strong a3 V-ATPase expression in bone metastases by immunohistochemistry. Immunocytochemical analysis showed B16-F10 cells expressed a3 V-ATPase not only in cytoplasm but also plasma membrane, whereas B16 parental cells exhibited its expression only in cytoplasm. Of note, knockdown of a3 V-ATPase suppressed invasiveness and migration with reduced MMP-2 and MMP-9 expression in B16-F10 cells and significantly decreased lung and bone metastases, despite that tumor growth was not altered. Importantly, administration of a specific V-ATPase a3 inhibitor FR167356 reduced bone metastasis of B16-F10 cells. These results suggest that a3 V-ATPase promotes distant metastasis of B16-F10 cells by creating acidic environments via proton secretion. Our results also suggest that inhibition of the development of cancer-associated acidic environments by suppressing a3 V-ATPase could be a novel therapeutic approach for the treatment of cancer metastasis. Mol Cancer Res; 9(7); 845–55. ©2011 AACR.
Fetal Urinoma in Females without Obstructive Uropathy
Authors: Zaccara A. , Brizzi C. , Mobili L. , Nahom A. , Carnevale E. , Marciano A. , Giorlandino C. , De Gennaro M.
Published: June 2011

Objective: Prenatal diagnosis of urinomas has long been established with underlying obstructive uropathy generally responsible for urinary extravasation. Because urinoma formation represents a pop-off mechanism in cases of posterior urethral valves, the number of affected males greatly exceeds the number of females. Fetal urinoma has rarely been reported without obstruction and in females it has only been described as a consequence of a complicated amniocentesis. Methods: Three cases of fetal urinoma in female fetuses without any dilatation of the urinary tract are described. Since the fetus remained healthy, they were all conservatively managed. Results: Two urinomas resolved after birth and 1 exhibited significant regression. In the second case, a compressed kidney was visualized with fetal MRI. Renal function was impaired in cases 1 and 3 and absent in case 2 (the kidney was no longer visualized). Conclusions: Fetal urinomas can occur even in the absence of urinary tract obstruction and in a low-pressure system as is found in female fetuses. Fetal MRI may help both visualize the ipsilateral kidney and differentiate the mass from other conditions. In a healthy fetus, fetal urinomas can be conservatively managed, but renal function after birth is often absent or impaired. Whether or not in utero aspiration may be beneficial for the preservation of renal function remains unclear.
Prenatal Detection of Congenital Heart Defects: A Survey on Clinical Practice in Spain
Authors: Galindo Alberto , Herraiz Ignacio , Escribano David , Lora David , Melchor Juan Carlos , de la Cruz Javier
Published: June 2011

Introduction: Second-trimester fetal screening for congenital heart defects (CHD) included in routine obstetric care provides relevant information for decision making. The aim of this study was to describe the clinical practice of prenatal detection of CHD in terms of the process and results. Methods: The characteristics and results of ultrasound screening for major CHD were documented using data provided by hospitals for a national survey in Spain over the period of 2004–2006. Sixty-seven percent of eligible centers (56/83), covering 36% of total births nationwide, responded to the survey; 33 of these returned complete data regarding the screening results. Results: The number of major CHD occurring in the centers which provided data with results of screening was 1,060. The overall prenatal detection rate of major CHD was 65.7% (95% CI 57.8–74.7), but the detection rate in the routine second-trimester scan was 52.6% (95% CI 45.6–60.8). In 61% of these cases the parents chose to terminate the pregnancy. Two independent predictors of increased detection by center were identified: first, the uniformity and systematic character of the examination of the heart showing at least the 4-chamber view and outflow tracts (prevalence ratio 1.3, 95% CI 1.0–1.8) and second, the local availability of specialists in fetal echocardiography (prevalence ratio 1.4, 95% CI 1.1–1.9). Conclusions: The detection of major CHD in the first half of pregnancy has an important impact on parental decision making. The prenatal screening program for CHD should be globally strengthened in terms of qualifications and methodological approaches. To improve its performance locally, close collaboration with fetal heart specialists should be promoted.
Early Detection of Preeclampsia Using Inhibin A and Other Second-Trimester Serum Markers
Authors: Ree Park Hea , Hahn Won Bo , Chang Sung Woon , Jung Sang Hee , Kang Jin Hee , Cha Dong Hyun , Kang Myung Seo , Huh Ji Young
Published: June 2011

Objective: The purpose of this study was to determine whether second-trimester maternal serum markers including inhibin A are useful for the detection of preeclampsia. Methods: Between January 2005 and March 2009, we analyzed the data of 4,764 subjects who underwent second-trimester multiple-marker screening for Down syndrome. Serum samples were assayed at 15+0 to 20+6 weeks for maternal serum alpha-fetoprotein (MSAFP), human chorionic gonadotrophin (hCG), unconjugated estriol (uE3) and inhibin A. We reviewed all medical records retrospectively, and assessed the relationships of several markers with preeclampsia using logistic regression analysis. Results: The study sample included 41 patients who developed preeclampsia and a control group consisting of the other 4,723 healthy subjects treated between January 2005 and March 2009. There were no significant differences in gestational ages at blood sampling, maternal weights, gravidity and parity between the two groups. However, the mean ages, Apgar scores, gestational age at delivery and neonatal weights were significantly different between the study group and the control group. The levels of markers in the study group were significantly increased compared to the control group, 1.76 ± 2.68 for inhibin A, 1.18 ± 0.69 for MSAFP, and 1.62 ± 1.18 for hCG, but uE3 did not differ significantly between the two groups. The AUC of inhibin A was 0.715, but the AUC of a three-marker combination model (0.800) was even better. A mid-trimester inhibin A concentration of 1.5 MoM or greater had a sensitivity of 60% and a false-positive rate of 16% for the prediction of preeclampsia. Inhibin A was the best predictor of preeclampsia. Three other markers were reliable predictive markers of preeclampsia. Conclusions: Inhibin A and other second-trimester serum markers may be useful for early detection of preeclampsia. Inhibin A was in fact the most important predictable marker among the markers we surveyed. The results of this study support those of previous studies, and provide quantified data elucidating the occurrence of preeclampsia.
Quality Control for Intravascular Intrauterine Transfusion Using Cumulative Sum (CUSUM) Analysis for the Monitoring of Individual Performance
Authors: Lindenburg Irene T.M. , Wolterbeek Ron , Oepkes Dick , Klumper Frans J.C.M. , Vandenbussche Frank P.H.A. , van Kamp Inge L.
Published: June 2011

Introduction: Intravascular intrauterine transfusion (IUT) is an effective and relatively safe method for the treatment of fetal anemia. Although implemented in centers all over the world in the 1980s, the length and strength of the learning curve for this procedure has never been studied. Cumulative sum (CUSUM) analysis has been increasingly used as a graphical and statistical tool for quality control and learning curve assessment in clinical medicine. We aimed to test the feasibility of CUSUM analysis for quality control in fetal therapy by using this method to monitor individual performance of IUT in the learning phase and over the long term. Methods: IUTs performed in the Dutch referral center for fetal therapy from 1987 to 2009 were retrospectively classified as successful or failed. Failed was defined as no net transfusion or the occurrence of life-threatening procedure-related complications. The CUSUM statistical method was used to estimate individual learning curves and to monitor long-term performance. Four operators who each performed at least 200 procedures were included. Results: Individual CUSUM graphs were easily assessed. Both operators pioneering IUT in the late 1980s had long learning phases. The 2 operators learning IUT in later years in an experienced team performed acceptably from the start and reached a level of competence after 34 and 49 procedures. Discussion: CUSUM analysis is a feasible method for quality control in fetal therapy. In an experienced setting, individual competence may be reached after 30 to 50 IUTs. Our data suggest that operators need at least 10 procedures per year to keep a level of competence.
Large Umbilical Artery Aneurysm with a Live Healthy Baby Delivered at 31 Weeks
Authors: Olog Adriana , Thomas Joseph T. , Petersen Scott , Cattanach Stephen , Lourie Rohan , Gardener Glenn
Published: June 2011

Umbilical artery aneurysm is a rare structural anomaly. We report a case of a large cord mass monitored closely with MCA PSV aiding the decision for delivery in an appropriately grown fetus.
Delayed Childbearing: Effects on Fertility and the Outcome of Pregnancy
Authors: Balasch Juan , Gratacós Eduard
Published: June 2011

In modern societies, the proportion of women who delay childbearing beyond the age of 35 years has greatly increased in recent decades. They are falsely reassured by popular beliefs that advances in new reproductive technologies can compensate for the age-related decline in fertility. Yet age remains the single most important determinant of male and female fertility, either natural or treated. The consequences of advancing maternal age are not only relevant for the risk of natural and assisted conception, but also for the outcome of pregnancy. Although the absolute rate of poor pregnancy outcomes may be low from an individual standpoint, the impact of delaying childbearing from a public health perspective cannot be overestimated and should be in the agenda of public health policies for the years to come. This review summarizes available evidence regarding the impact of delaying childbearing on fertility and pregnancy outcomes.
Clinical Estimation of Fetal Weight: Is Accuracy Acquired with Professional Experience?
Authors: Levin Ishai , Gamzu Ronni , Buchman Vladimir , Skornick Rapaport Avital , Pauzner David , Lessing Joseph B. , Almog Benny
Published: June 2011

Objective: This study was conducted in order to determine whether experience and type of obstetrical profession improves the accuracy in the clinical estimation of fetal weight among obstetricians and midwives in the delivery room. Methods: Four groups of professionals in the delivery room clinically estimated the fetal weight in 236 parturients in active labor. Obstetric parameters such as gravidity, parity, gestational age, body mass index, amniotomy, station and cervical dilatation were recorded. Fetal weight estimations were compared with the actual birth weight after delivery. Results: The mean error rate of fetal weight estimation by attending obstetricians, residents, experienced and junior midwives was 7.9 ± 8.8, 8.0 ± 8.4, 7.8 ± 6.3 and 8.5 ± 6.8%, respectively. Error rates of the 4 groups of examiners were similar, although it was increased in all subgroups when estimating birth weights <2,500 and >4,000 g. Major discrepancies of fetal weight estimation (>10% of the actual fetal birth weight) occurred in 27.2, 28.9, 31.9 and 34.7% by attending obstetricians, residents, experienced and junior midwives, respectively. Conclusions: We found no additional value for experience and type of obstetrical training in the accuracy of clinical fetal weight estimation.
Maternal Serum Adiponectin at 11–13 Weeks of Gestation in Pregnancies Delivering Small for Gestation Neonates
Authors: Nanda Surabhi , Akolekar Ranjit , Sodre Danielle , Vaikousi Eirini , Nicolaides Kypros H.
Published: June 2011

Objective: To investigate whether maternal serum levels of adiponectin in the first trimester are altered in pregnancies that subsequently deliver small for gestational age (SGA) neonates. Methods: Maternal serum adiponectin and pregnancy-associated plasma protein A (PAPP-A) were measured at 11–13 weeks’ gestation in 50 singleton normotensive pregnancies that delivered SGA neonates and 300 non-SGA controls. The median adiponectin and PAPP-A levels in the SGA and non-SGA groups, expressed as multiple of the unaffected median (MoM), were compared. Results: The distribution of serum adiponectin was made gaussian by square root (sqrt) transformation. Regression analysis in the non-SGA group demonstrated that for sqrt adiponectin a significant independent contribution was provided by maternal age, weight, smoking status, African and South-Asian racial origin. Each value in the SGA and non-SGA group was then converted into a multiple of the non-SGA median (MoM) after adjustment for maternal characteristics. In the SGA group, compared to the non-SGA controls, median maternal serum PAPP-A was decreased (0.79, interquartile range [IQR] 0.54–1.06 MoM vs. 1.00, IQR 0.71–1.39 MoM) but adiponectin MoM was not significantly different (0.89, IQR 0.65–1.31 MoM vs. 1.02, IQR 0.70–1.29 MoM). Conclusion: Maternal serum adiponectin is not a useful biochemical marker for early prediction of SGA.
Prenatal Findings in Congenital Leukemia: A Case Report
Authors: Sato Yukiyasu , Izumi Yukiko , Minegishi Katsura , Komada Munekazu , Yamada Shigehito , Kakui Kazuyo , Tatsumi Keiji , Mikami Yoshiki , Fujiwara Hiroshi , Konishi Ikuo
Published: June 2011

We here describe a case of congenital leukemia that ended in intrauterine fetal demise at 30 weeks of gestation. Acute enlargement of the fetal trunk, elevated pulsatility index of the umbilical artery with concomitant decline of pulsatility index of the middle cerebral artery, pleural effusion, and polyhydramnios preceded the fetal death. Diagnosis of congenital myeloid leukemia was suggested by microscopic examination of the placental tissue, revealing immature myeloid precursors filling the lumina of fetal vessels in the umbilical cord and chorionic villi. Extensive vascular involvement of the placenta by leukemic cells was considered to be a primary cause of the fetal death.
Treating Primary Liver Cancer with Hepatic Arterial Infusion of Floxuridine and Dexamethasone: Does the Addition of Systemic Bevacizumab Improve Results
Authors: Kemeny Nancy E. , Schwartz Lawrence , Gönen Mithat , Yopp Adam , Gultekin David , D’Angelica Michael I. , Fong Yuman , Haviland Dana , Gewirtz Alexandra N. , Allen Peter , Jarnagin William R.
Published: June 2011

Objectives: This study investigated the efficacy and safety of adding systemic (IV) bevacizumab (Bev) to hepatic arterial infusion (HAI) with floxuridine (FUDR)/dexamethasone (Dex) in unresectable primary liver cancer. Methods: Patients with unresectable intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC) were treated with HAI FUDR/Dex plus IV Bev. Results were compared to a recent study of HAI without Bev in a similar patient population. Results: Twenty-two patients (18 ICC, 4 HCC) were treated with HAI FUDR/Dex plus Bev; 7 (31.8%) had partial response and 15 (68.2%) had stable disease. Median survival was 31.1 months (CI 14.14–33.59), progression-free survival (PFS) 8.45 months (CI 5.53–11.05), and hepatic PFS 11.3 months (CI 7.93–15.69). In the previous trial with HAI alone (no Bev), the response was 50%; median survival, PFS, and hepatic PFS were 29.5, 7.3, and 10.1 months. In the present trial, bilirubin elevation (>2 mg/dl) was seen in 24% of patients and biliary stents were placed in 13.6%, versus 5.8 and 0%, respectively, in the HAI trial without Bev. Due to increased biliary toxicity, the trial was prematurely terminated. Conclusion: Adding Bev to HAI FUDR/Dex appeared to increase biliary toxicity without clear improvement in outcome (median PFS 8.45 vs. 7.3 months, and median survival 31.1 vs. 29.5 months, for HAI + Bev vs. HAI alone groups, respectively).
End-of-Life Hospital Costs in Cancer Patients: Do Advance Directives or Routes of Hospital Admission Make a Difference?
Authors: Tan Tow S. , Jatoi Aminah
Published: June 2011

Objective: End-of-life cancer care is costly. The current study explored whether advance directives or route of hospital admission reduced cancer patients’ terminal hospitalization costs. Methods: This single-institution study focused on solid tumor patients who died on an inpatient oncology service in 2008 and 2009. Patients’ total costs were compared based on advance directives and route of hospitalization. Results: Among 120 patients, all except 4 had an incurable malignancy. Forty-six (38%) had an advance directive. Sixteen (13%) were admitted after an oncology clinic visit and 6 (5%) from hospice; others were admitted via other routes, most commonly from the emergency department. The median total cost for hospitalization (range) per patient was USD 12,962 (1,244–138,877). Patients with advance directives had no statistically significant difference in cost (p = 0.30), even after adjusting for age and time in the hospital. Those admitted after an oncology clinic or from hospice also had no difference in cost compared to those admitted via another route. Use of cardiopulmonary resuscitation, intensive care unit monitoring and intubation were similar between all compared groups. Conclusion: Advance directives and route of admission do not appear to impact the cost of terminal hospitalization for cancer patients.
Carcinosarcoma of the Ovary: Analysis of 13 Cases and Review of the Literature
Authors: Loizzi Vera , Cormio Gennaro , Camporeale Anna , Falagario Maddalena , De Mitri Paola , Scardigno Doriana , Putignano Giuseppe , Selvaggi Luigi E.
Published: June 2011

Objectives: The aim of this study was to evaluate our experience with patients affected by ovarian carcinosarcoma. Patients and Methods: During a 16-year period, data on 13 patients with ovarian carcinosarcoma were collected. They were obtained from hospital charts and follow-up visits. Survival curves were estimated by the Kaplan-Meier method and compared using the log-rank test. All tests were two-tailed with p values <0.05 considered significant. Results: Our study was conducted on 13 patients with ovarian carcinosarcoma referred to our unit, during an observation time of about 16 years (March 1994 to October 2010). An improved survival was observed in patients treated with optimal cytoreductive surgery with residual tumors <2 cm (30 vs. 5 months; p = 0.042). All patients underwent adjuvant chemotherapy based on the combination of cisplatin, epirubicin and ifosfamide (PEI) and taxol and carboplatin (TAX-CBDCA) regimen. Overall survival of the patient population was 17 months. Conclusions: Similarly to data published in the literature, we observed that malignant mixed mullerian ovarian tumors are very aggressive and are usually diagnosed at an advanced age and at an advanced stage of disease. Therefore, due to the rarity of the tumor we would like to add our series to those already published in the literature, although our treatment recommendations are actually based upon retrospective studies with a small patient population.
Outpatient versus Inpatient Observation after Percutaneous Native Kidney Biopsy: A Cost Minimization Study
Authors: Maripuri Saugar , Penson David F. , Ikizler T. Alp , Cavanaugh Kerri L.
Published: June 2011

Background/Aims: Percutaneous kidney biopsy (PKB) is the primary diagnostic tool for kidney disease. Outpatient ‘day surgery’ (ODS) following PKB in low-risk patients has previously been described as a safe alternative to inpatient observation (IO). This study aims to determine if ODS is less costly compared to IO while accounting for all institutional costs (IC) associated with post-PKB complications, including death. Methods: A cost minimization study was performed using decision analysis methodology which models relative costs in relation to outcome probabilities yielding an optimum decision. The potential outcomes included major complications (bleeding requiring blood transfusion or advanced intervention), minor complications (bleeding or pain requiring additional observation), and death. Probabilities were obtained from the published literature and a base case was selected. IC were obtained for all complications from institutional activity-based cost estimates. The base case assumed a complication rate of 10% with major bleeding occurring in 2.5% of patients (for both arms) and death in 0.1 and 0.15% of IO and ODS patients, respectively. Results: ODS costs USD 1,394 per biopsy compared to USD 1,800 for IO inclusive of all complications. IC for ODS remain less when overall complications <20%, major complications <5.5%, and IC per death <USD 1.125 million. ODS remained favored through sensitivity analysis. Conclusion: Outpatient management after PKB for low-risk patients costs less from the institutional perspective compared to IO, inclusive of complications and death. ODS should be considered for low-risk patients undergoing native kidney biopsy.
Cardiac Dysfunction and Noncardiac Dysfunction as Precursors of Heart Failure With Reduced and Preserved Ejection Fraction in the Community
Authors: Lam Carolyn S.P. , Lyass Asya , Kraigher-Krainer Elisabeth , Massaro Joseph M. , Lee Douglas S. , Ho Jennifer E. , Levy Daniel , Redfield Margaret M. , Pieske Burkert M. , Benjamin Emelia J. , Vasan Ramachandran S.
Published: June 2011

Background—

Heart failure (HF) is a clinical syndrome characterized by signs and symptoms involving multiple organ systems. Longitudinal data demonstrating that asymptomatic cardiac dysfunction precedes overt HF are scarce, and the contribution of noncardiac dysfunction to HF progression is unclear. We hypothesized that subclinical cardiac and noncardiac organ dysfunction would accelerate the manifestation of HF.

Methods and Results—

We studied 1038 participants of the Framingham Heart Study original cohort (mean age, 76±5 years; 39% men) with routine assessment of left ventricular systolic and diastolic function. Major noncardiac organ systems were assessed with the use of serum creatinine (renal), serum albumin (hepatic), ratio of forced expiratory volume in 1 second to forced vital capacity (FEV
1
:FVC ratio; pulmonary), hemoglobin concentration (hematologic/oxygen-carrying capacity), and white blood cell count (systemic inflammation). On follow-up (mean, 11 years), there were 248 incident HF events (146 in women). After adjustment for established HF risk factors, antecedent left ventricular systolic dysfunction (hazard ratio, 2.33; 95% confidence interval, 1.43 to 3.78) and diastolic dysfunction (hazard ratio, 1.32; 95% confidence interval, 1.01 to 1.71) were associated with increased HF risk. After adjustment for cardiac dysfunction, higher serum creatinine, lower FEV1:FVC ratios, and lower hemoglobin concentrations were associated with increased HF risk (all
P
<0.05); serum albumin and white blood cell count were not. Subclinical dysfunction in each noncardiac organ system was associated with a 30% increased risk of HF (
P
=0.013).

Conclusions—

Antecedent cardiac dysfunction and noncardiac organ dysfunction are associated with increased incidence of HF, supporting the notion that HF is a progressive syndrome and underscoring the importance of noncardiac factors in its occurrence.
Hepatocyte Growth Factor Attenuates Transforming Growth Factor-β-Angiotensin II Crosstalk Through Inhibition of the PTEN/Akt Pathway
Authors: Iekushi Kazuma , Taniyama Yoshiaki , Kusunoki Hiroshi , Azuma Junya , Sanada Fumihiro , Okayama Keita , Koibuchi Nobutaka , Iwabayashi Masaaki , Rakugi Hiromi , Morishita Ryuichi
Published: June 2011

Both angiotensin II (Ang II) and transforming growth factor (TGF)-β1 are thought to be involved in the progression of chronic kidney disease. In contrast, hepatocyte growth factor (HGF) counteracts the actions of Ang II and TGF-β1. Therefore, in this study, we investigated the molecular mechanisms of how HGF antagonizes the Ang II-TGF-β axis in renal cells. In cultured human mesangial cells, TGF-β1 increased angiotensin type 1 receptor (AT
1
R) mRNA, mainly dependent on the Akt/phosphatidylinositol 3-kinase signaling pathway. Furthermore, TGF-β1 decreased the expression and phosphatase activity of phosphatase and tensin homolog, deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/Akt pathway. These data revealed positive feedback of the Ang II-TGF-β pathway, because Ang II increased TGF-β expression. In contrast, HGF significantly attenuated the increase in AT
1
R gene expression, and inhibited the decrease in PTEN induced by TGF-β1. Of importance, a PTEN-specific inhibitor significantly attenuated the reduction in TGF-β1–induced AT
1
R expression by HGF. These data suggest that HGF attenuated TGF-β1–induced AT
1
R expression through the PTEN/Akt pathway. To investigate this hypothesis, we performed in vivo experiments in mice with increased circulating levels of HGF produced by transgenically expressing HGF under control of a cardiac-specific transgene (HGF-Tg). In HGF-Tg mice, renal injury and fibrosis were significantly decreased, associated with reduction in AT
1
R expression and increase in PTEN after Ang II infusion, as compared with control mice. Moreover, these renal protective effects were abrogated by a neutralizing antibody against HGF. Thus, the present study demonstrated that HGF counteracts the vicious cycle of Ang II-TGF-β1-AT
1
R, mediating the inhibition of PTEN.
Angiotensin (1-7) Induces Mas Receptor Internalization
Authors: Gironacci Mariela M. , Adamo Hugo P. , Corradi Gerardo , Santos Robson A. , Ortiz Pablo , Carretero Oscar A.
Published: June 2011

Angiotensin (Ang) (1-7) is the endogenous ligand for the G protein–coupled receptor Mas, a receptor associated with cardiac, renal, and cerebral protective responses. Physiological evidence suggests that Mas receptor (MasR) undergoes agonist-dependent desensitization, but the underlying molecular mechanism regulating receptor activity is unknown. We investigated the hypothesis that MasR desensitizes and internalizes on stimulation with Ang-(1-7). For this purpose, we generated a chimera between the MasR and the yellow fluorescent protein (YFP; MasR-YFP). MasR-YFP–transfected HEK 293T cells were incubated with Ang-(1-7), and the relative cellular distribution of MasR-YFP was observed by confocal microscopy. In resting cells, MasR-YFP was mostly localized to the cell membrane. Ang-(1-7) induced a redistribution of MasR-YFP to intracellular vesicles of various sizes after 5 minutes. Following the time course of [
125
I]Ang-(1-7) endocytosis, we observed that half of MasR-YFP underwent endocytosis after 10 minutes, and this was blocked by a MasR antagonist. MasR-YFP colocalized with Rab5, the early endosome antigen 1, and the adaptor protein complex 2, indicating that the R is internalized through a clathrin-mediated pathway and targeted to early endosomes after Ang-(1-7) stimulation. A fraction of MasR-YFP also colocalized with caveolin 1, suggesting that at some point MasR-YFP traverses caveolin 1–positive compartments. In conclusion, MasR undergoes endocytosis on stimulation with Ang-(1-7), and this event may explain the desensitization of MasR responsiveness. In this way, MasR activity and density may be tightly controlled by the cell.
The Vascular Endothelial Growth Factor Receptor Inhibitor Sunitinib Causes a Preeclampsia-Like Syndrome With Activation of the Endothelin System
Authors: Kappers Mariëtte H.W. , Smedts Frank M.M. , Horn Thomas , van Esch Joep H.M. , Sleijfer Stefan , Leijten Frank , Wesseling Sebastiaan , Strevens Helena , Jan Danser A.H. , van den Meiracker Anton H.
Published: June 2011

Angiogenesis inhibition is an established treatment for several tumor types. Unfortunately, this therapy is associated with adverse effects, including hypertension and renal toxicity, referred to as “preeclampsia.” Recently, we demonstrated in patients and in rats that the multitarget tyrosine kinase inhibitor sunitinib induces a rise in blood pressure (BP), renal dysfunction, and proteinuria associated with activation of the endothelin system. In the current study we investigated the effects of sunitinib on rat renal histology, including the resemblance with preeclampsia, as well as the roles of endothelin 1, decreased nitric oxide (NO) bioavailability, and increased oxidative stress in the development of sunitinib-induced hypertension and renal toxicity. In rats on sunitinib, light and electron microscopic examination revealed marked glomerular endotheliosis, a characteristic histological feature of preeclampsia, which was partly reversible after sunitinib discontinuation. The histological abnormalities were accompanied by an increase in urinary excretion of endothelin 1 and diminished NO metabolite excretion. In rats on sunitinib alone, BP increased (ΔBP: 31.6±0.9 mm Hg). This rise could largely be prevented with the endothelin receptor antagonist macitentan (ΔBP: 12.3±1.5 mm Hg) and only mildly with Tempol, a superoxide dismutase mimetic (ΔBP: 25.9±2.3 mm Hg). Both compounds could not prevent the sunitinib-induced rise in serum creatinine or renal histological abnormalities and had no effect on urine nitrates but decreased proteinuria and urinary endothelin 1 excretion. Our findings indicate that both the endothelin system and oxidative stress play important roles in the development of sunitinib-induced proteinuria and that the endothelin system rather than oxidative stress is important for the development of sunitinib-induced hypertension.
Acute Change in Vascular Tone Alters Intima-Media Thickness
Authors: Thijssen Dick H.J. , Scholten Ralph R. , van den Munckhof Inge C.L. , Benda Nathalie , Green Daniel J. , Hopman Maria T.E.
Published: June 2011

Atherosclerosis is a lifelong process involving artery wall thickening. Increased wall thickness has been widely adopted as a preclinical surrogate marker of atherosclerosis. A prerequisite for such a surrogate marker is that it is a structural characteristic of the vessel wall that is not subject to acute changes. The purpose of this study was to examine the acute effects of vasodilator drug administration on wall thickness of the carotid and superficial femoral arteries. High-resolution ultrasound was used to examine carotid and femoral artery diameters and wall thickness in 15 young (25±4 years of age) and 15 older (70±6 years of age) healthy men who were administered sublingual glyceryl trinitrate. Diameter and wall thickness were collected before and across a 10-minute period after glyceryl trinitrate administration. Glyceryl trinitrate induced a significant increase in carotid and femoral artery diameter and a decrease in wall thickness in both young and older men (both
P
<0.001). The latter was significantly larger than in young men (both
P
<0.01). The changes in carotid artery wall thickness in both young (35±23 μm) and older men (71±46 μm) approximate those considered prognostically relevant. Collectively, our data suggest that vasodilator drug administration induces a rapid and marked decrease in wall thickness, which mirrors conduit artery vasodilation in both young and older men. This finding confirms the presence of acute changes in wall thickness and has important implications for future studies that assess artery wall characteristics as a surrogate measure of atherosclerosis.
Climatological Characteristics of Arctic and Antarctic Surface-Based Inversions
Authors: Zhang Yehui , Seidel Dian J. , Golaz Jean-Christophe , Deser Clara , Tomas Robert A.
Published: June 2011

Surface-based inversions (SBIs) are frequent features of the Arctic and Antarctic atmospheric boundary layer. They influence vertical mixing of energy, moisture and pollutants, cloud formation, and surface ozone destruction. Their climatic variability is related to that of sea ice and planetary albedo, important factors in climate feedback mechanisms. However, climatological polar SBI properties have not been fully characterized nor have climate model simulations of SBIs been compared comprehensively to observations. Using 20 years of twice-daily observations from 39 Arctic and 6 Antarctic radiosonde stations, this study examines the spatial and temporal variability of three SBI characteristic—frequency of occurrence, depth (from the surface to the inversion top), and intensity (temperature difference over the SBI depth)—and relationships among them. In both polar regions, SBIs are more frequent, deeper, and stronger in winter and autumn than in summer and spring. In the Arctic, these tendencies increase from the Norwegian Sea eastward toward the East Siberian Sea, associated both with (seasonal and diurnal) variations in solar elevation angle at the standard radiosonde observation times and with differences between continental and maritime climates. Two state-of-the-art climate models and one reanalysis dataset show similar seasonal patterns and spatial distributions of SBI properties as the radiosonde observations, but with biases in their magnitudes that differ among the models and that are smaller in winter and autumn than in spring and summer. SBI frequency, depth, and intensity are positively correlated, both spatially and temporally, and all three are anticorrelated with surface temperature.
Persistent Weakening Trend in the Spring Sensible Heat Source over the Tibetan Plateau and Its Impact on the Asian Summer Monsoon
Authors: Duan Anmin , Li Fei , Wang Meirong , Wu Guoxiong
Published: June 2011

Using a dataset extended by the addition of data for 2004–08, this study reexamined the trend in the sensible heating (SH) flux at 73 meteorological stations over the Tibetan Plateau (TP) during 1980–2008 and investigated its impact on monsoon precipitation in the surrounding region. In contrast to ongoing climate warming, a weakening trend in SH is persistent over most of the plateau, despite a sharp increase in the ground–air temperature difference in 2004–08. The weakening trend in SH over the TP is primarily a response to the spatial nonuniformity of large-scale warming over the East Asian continent, which is characterized by much greater warming amplitude at mid- and high latitudes than over the tropics and subtropics. Furthermore, the suppressed air pump effect, which is driven by SH over the TP and acts as a strong forcing source, gives rise to reduced precipitation along the southern and eastern slopes of the plateau, and increased rainfall over northeastern India and the Bay of Bengal. No significantly stable correlation exists between the SH source over the TP and the overall trend or interdecadal variability in the East Asian or South Asian summer monsoon.
Prospects for Improving Subseasonal Predictions
Authors: Pegion Kathy , Sardeshmukh Prashant D.
Published: June 2011

Extending atmospheric prediction skill beyond the predictability limit of about 10 days for daily weather rests on the hope that some time-averaged aspects of anomalous circulations remain predictable at longer forecast lead times, both because of the existence of natural low-frequency modes of atmospheric variability and coupling to the ocean with larger thermal inertia. In this paper the week-2 and week-3 forecast skill of two global coupled atmosphere–ocean models recently developed at NASA and NOAA is compared with that of much simpler linear inverse models (LIMs) based on the observed time-lag correlations of atmospheric circulation anomalies in the Northern Hemisphere and outgoing longwave radiation (OLR) anomalies in the tropics. The coupled models are found to beat the LIMs only slightly, and only if an ensemble prediction methodology is employed. To assess the potential for further skill improvement, a predictability analysis based on the relative magnitudes of forecast signal and forecast noise in the LIM framework is conducted. Estimating potential skill by such a method is argued to be superior to using the ensemble-mean and ensemble-spread information in the coupled model ensemble prediction system. The LIM-based predictability analysis yields relatively conservative estimates of the potential skill, and suggests that outside the tropics the average coupled model skill may already be close to the potential skill, although there may still be room for improvement in the tropical forecast skill.