bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammatory Myofibroblastic Tumor of the Breast
Authors: Markopoulos Christos , Charalampoudis Petros , Karagiannis Evangelia , Antonopoulou Zoh , Mantas Dimitrios
Published: February 2015

Inflammatory myofibroblastic tumors (IMTs) of the breast represent extremely rare lesions. Due to the scarcity of reports, their natural history, recurrence, and metastatic potential remain poorly defined. We report on a case of a primary breast IMT in a postmenopausal female patient treated successfully with breast conserving surgery and review the literature pertaining to this rare entity.
Elevated Troponin Serum Levels in Adult Onset Still’s Disease
Authors: Manzini Carlo Umberto , Brugioni Lucio , Colaci Michele , Tognetti Maurizio , Spinella Amelia , Sebastiani Marco , Giuggioli Dilia , Ferri Clodoveo
Published: February 2015

Adult onset Still’s disease (AOSD) is a rare inflammatory systemic disease that occasionally may affect myocardium. Diagnosis is based on typical AOSD symptoms after the exclusion of well-known infectious, neoplastic, or autoimmune/autoinflammatory disorders. In the case of abrupt, recent onset AOSD, it could be particularly difficult to make the differential diagnosis and in particular to early detect the possible heart involvement. This latter event is suggested by the clinical history of the four patients described here, incidentally observed at our emergency room. All cases were referred because of acute illness (high fever, malaise, polyarthralgias, skin rash, and sore throat), successively classified as AOSD, and they presented abnormally high levels of serum troponin without overt symptoms of cardiac involvement. The timely treatment with steroids (3 cases) or ibuprofen (1 case) leads to the remission of clinicoserological manifestations within few weeks. These observations suggest that early myocardial injury might be underestimated or entirely overlooked in patients with AOSD; routine cardiac assessment including troponin evaluation should be mandatory in all patients with suspected AOSD.
Effects of Storage Time on Total Protein and Globulin Concentrations in Bovine Fresh Frozen Plasma Obtained for Transfusion
Authors: Proverbio D. , Spada E. , Baggiani L. , Bagnagatti De Giorgi G. , Roggero N. , Belloli A. , Pravettoni D. , Perego R.
Published: February 2015

To evaluate the effects of storage conditions on total protein (TP) and globulin fractions in fresh frozen bovine plasma units prepared and stored for transfusion, TP and globulin fractions were evaluated in fresh plasma and at 1 month and 6 and 12 months after blood collection in plasma stored at −20°C. Significant differences in concentrations were found in the median concentration of total protein (P = 0.0336), between 0 months and 1 month (P = 0.0108), 0 and 6 months (P = 0.0023), and 0 and 12 months (P = 0.0027), in mean concentration (g/dL) of albumin (P = 0.0394), between 0 months and 1 month (P = 0.0131), 0 and 6 months (P = 0.0035), and 0 and 12 months (P = 0.0038), and beta‐2 fraction (P = 0.0401), between 0 and 6 months (P = 0.0401) and 0 and 12 months (P = 0.0230). This study suggests that total gamma globulin concentration in bovine frozen plasma is stable for 12 months at −20°C. Total protein, ALB, and beta‐2 fraction have significantly different concentrations (g/dL) when compared to prestorage. This study has shown IgG protein fraction stability in bovine fresh frozen plasma collected for transfusion; therefore, bovine fresh frozen plasma seems to be suitable for the treatment of hypogammaglobulinemia (failure of passive transfer) in calves when stored for 12 months at −20°C.
Joint Preservation of the Wrist Using Articulated Distraction Arthroplasty: A Case Report of a Novel Technique
Authors: Fletcher Matt D. A.
Published: February 2015

Distraction arthroplasty of the ankle, elbow, and hip has become widely accepted and used within the orthopaedic community with excellent initial results which appear sustained. To date it has not been applied to the wrist in the same manner. A novel technique, drawn upon past success of articulated ankle distraction and static wrist distraction, was devised and evaluated by application of articulated wrist distraction performed over a 12-week period in a patient with poor functional outcome following limited wrist fusion. Posttreatment results showed improvement in range of motion (100-degree arc), subjective pain, and functional outcome measures (DASH 21.7, Mayo Wrist Score 80) comparable or better than either limited wrist fusion or proximal row carpectomy. Articulated wrist distraction initially appears to be a promising therapeutic option for the management of the stiff and painful wrist to maintain maximal function for which formal wrist arthrodesis may be the only alternative.
Matrix Metalloproteinase 9 Secreted by Hypoxia Cardiac Fibroblasts Triggers Cardiac Stem Cell Migration In Vitro
Authors: Gao Qing , Guo Maojuan , Zeng Wenyun , Wang Yijing , Yang Lin , Pang Xiaoli , Li Huhu , Suo Yanrong , Jiang Xijuan , Yu Chunquan
Published: February 2015

Cessation of blood supply due to myocardial infarction (MI) leads to complicated pathological alteration in the affected regions. Cardiac stem cells (CSCs) migration plays a major role in promoting recovery of cardiac function and protecting cardiomyocytes in post-MI remodeling. Despite being the most abundant cell type in the mammalian heart, cardiac fibroblasts (CFs) were underestimated in the mechanism of CSCs migration. Our objective in this study is therefore to investigate the migration related factors secreted by hypoxia CFs in vitro and the degree that they contribute to CSCs migration. We found that supernatant from hypoxia induced CFs could accelerate CSCs migration. Four migration-related cytokines were reported upregulated both in mRNA and protein levels. Upon adding antagonists of these cytokines, the number of migration cells significantly declined. When the cocktail antagonists of all above four cytokines were added, the migration cells number reduced to the minimum level. Besides, MMP-9 had an important effect on triggering CSCs migration. As shown in our results, MMP-9 induced CSCs migration and the underlying mechanism might involve TNF-α signaling which induced VEGF and MMP-9 expression.
The Impact of Migraine on Posterior Ocular Structures
Authors: Demircan Süleyman , Ataş Mustafa , Arık Yüksel Sevgi , Ulusoy Melek D. , Yuvacı İsa , Arifoğlu Hasan Basri , Başkan Burhan , Zararsız Gökmen
Published: February 2015

Purpose. To investigate the thickness of the retinal nerve fiber layer (RNFL) and choroid in patients who have migraines in comparison to healthy controls.Methods. This study included 76 eyes and patients in the migraine group, 36 with aura (MWA group) and 40 without (MWoA group), and 38 eyes as control subjects. The RNFL and macular thicknesses were analysed with standard OCT protocol while choroidal thickness was analysed with EDI protocol in all subjects. Choroidal thickness was measured at the fovea, 1500 µm nasal and 1500 µm temporal to the fovea in a horizontal section.Results. The mean RNFL thickness for nasal and nasal inferior sectors was significantly thinner (P≤0.018) in the migraineurs’ eyes than in those of the controls, as was the mean choroid thickness at the fovea and measured points (P<0.0001). However, the mean macular thickness was not significantly different between the groups.Conclusions. This study suggests that migraine leads to a reduction in the peripapillary RNFL thickness and to thinning in choroidal structures. These findings can be explained by a chronic ischemic insult related to migraine pathogenic mechanisms and these findings are considered supportive of the relationship between glaucoma and migraine.
Protection against Multiple Subtypes of Influenza Viruses by Virus-Like Particle Vaccines Based on a Hemagglutinin Conserved Epitope
Authors: Chen Shaoheng , Zheng Dan , Li Changgui , Zhang Wenjie , Xu Wenting , Liu Xueying , Fang Fang , Chen Ze
Published: February 2015

We selected the conserved sequence in the stalk region of influenza virus hemagglutinin (HA) trimmer, the long alpha helix (LAH), as the vaccine candidate sequence, and inserted it into the major immunodominant region (MIR) of hepatitis B virus core protein (HBc), and, by using theE. coliexpression system, we prepared a recombinant protein vaccine LAH-HBc in the form of virus-like particles (VLP). Intranasal immunization of mice with this LAH-HBc VLP plus cholera toxin B subunit with 0.2% of cholera toxin (CTB*) adjuvant could effectively elicit humoral and cellular immune responses and protect mice against a lethal challenge of homologous influenza viruses (A/Puerto Rico/8/1934 (PR8) (H1N1)). In addition, passage of the immune sera containing specific antibodies to naïve mice rendered them resistant against a lethal homologous challenge. Immunization with LAH-HBc VLP vaccine plus CTB*adjuvant could also fully protect mice against a lethal challenge of the 2009 pandemic H1N1 influenza virus or the avian H9N2 virus and could partially protect mice against a lethal challenge of the avian H5N1 influenza virus. This study demonstrated that the LAH-HBc VLP vaccine based on a conserved sequence of the HA trimmer stalk region is a promising candidate vaccine for developing a universal influenza vaccine against multiple influenza viruses infections.
A Two-Stage Range-Free Localization Method for Wireless Sensor Networks
Authors: Yingyou Wen , Zhi Li , Yinghui Meng , Dazhe Zhao
Published: February 2015

Range-free localization plays an important role in low-cost and large scale wireless sensor networks. Many existing range-free localization methods encounter high localization error, especially for the network with a coverage hole. One reason for high localization error is unreasonable distance estimation method. Another reason is that unknown nodes use the shortest distance which has large cumulative distance error to estimate their positions. In this paper, a two-stage centralized range-free localization algorithm (TCRL) is proposed. In the first stage, we design a novel rational distance estimation method to alleviate the distance estimation error between neighbor nodes based on the connectivity information and geometric features. In the second stage, a novel neighborhood function is derived from the estimated distances between neighbor nodes. Then a new localization strategy is proposed based on greedy idea. Finally, the proposed algorithm is compared with the same type algorithms in two network scenarios, namely, random deployment and random deployment with a coverage hole. The simulation results show that TCRL achieves more accurate and reliable results than most of existing range-free methods in the two network scenarios.
Nanosuspension: An Emerging Trend for Bioavailability Enhancement of Etodolac
Authors: Afifi Samar A. , Hassan Maha A. , Abdelhameed Ali S. , Elkhodairy Kadria A.
Published: February 2015

Etodolac (ET) (poorly soluble drug) nanosuspensions were prepared by both pH shift method and antisolvent techniques in order to increase its dissolution rate. Various stabilizers were used, namely, Tween 20 and 80, HPMC, PVP K44, PVA, PEG 400, NaCMC, andβ-cyclodextrin. The prepared nanosuspensions were characterized by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM) and evaluated for their particle size, particle size distribution, andin vitrodissolution rate. In general, it was found that the antisolvent method for the preparation of ET nanosuspensions reduced the drug particle size to a higher extent compared to the pH shift method. The dissolution rate of ET in distilled water was markedly enhanced in the nanosized system, as more than 65% of drug dissolved in 10 min from all the nanosuspension formulations except F5 (stabilized with PVP K44) and F8 (stabilized with Tween 20), as compared to less than 20% of crude drug. Nanoparticles prepared by antisolvent method using Tween 80 as a stabilizer were selected for furtherin vivostudy. Thein vivotest demonstrated that nanoparticles of ET were well absorbed with a percentage drug absorption value 2.7 times more than that of micrometric size of crude ET.
Fan-Shaped Complete Block on Helical Tomotherapy for Esophageal Cancer: A Phantom Study
Authors: Chang Chiu-Han , Mok Greta S. P. , Shueng Pei-Wei , Yeh Hsin-Pei , Shiau An-Cheng , Tien Hui-Ju , Lin Chi-Ta , Wu Tung-Hsin
Published: February 2015

Radiation pneumonitis (RP) is a common complication for radiotherapy of esophageal cancer and is associated with the low dose irradiated lung volume. This study aims to reduce the mean lung dose (MLD) and the relative lung volume at 20 Gy (V20) and at low dose region using various designs of the fan-shaped complete block (FSCB) in helical tomotherapy. Hypothetical esophageal tumor was delineated on an anthropomorphic phantom. The FSCB was defined as the fan-shaped radiation restricted area located in both lungs. Seven treatment plans were performed with nonblock design and FSCB with different fan angles, that is, from 90° to 140°, with increment of 10°. The homogeneous index, conformation number, MLD, and the relative lung volume receiving more than 5, 10, 15, and 20 Gy (V5,V10,V15, andV20) were determined for each treatment scheme. There was a substantial reduction in the MLD,V5,V10,V15, andV20when using different types of FSCB as compared to the nonblock design. The reduction ofV20,V15,V10, andV5was 6.3%–8.6%, 16%–23%, 42%–57%, and 42%–66% for FSCB 90°–140°, respectively. The use of FSCB in helical tomotherapy is a promising method to reduce the MLD,V20, and relative lung volume in low dose region, especially inV5andV10for esophageal cancer.
Insects’ RNA Profiling Reveals Absence of “Hidden Break” in 28S Ribosomal RNA Molecule of Onion Thrips,Thrips tabaci
Authors: Macharia Rosaline Wanjiru , Ombura Fidelis Levi , Aroko Erick Onyango
Published: February 2015

With an exception of aphids, insects’ 28S rRNA is thought to harbor a “hidden break” which cleaves under denaturing conditions to comigrate with 18S rRNA band to exhibit a degraded appearance on native agarose gels. The degraded appearance confounds determination of RNA integrity in laboratories that rely on gel electrophoresis. To provide guidelines for RNA profiles, RNA from five major insect orders, namely, Diptera, Hemiptera, Thysanoptera, Hymenoptera, and Lepidoptera, was compared under denaturing and nondenaturing conditions. This study confirmed that although present in most of insect’s RNA, the “hidden break” is absent in the 28S rRNA of onion thrips,Thrips tabaci. On the other hand, presence of “hidden break” was depicted in whiteflies’ 28S rRNA despite their evolutionary grouping under same order with aphids. Divergence of 28S rRNA sequences confirms variation of both size and composition of gap region among insect species. However, phylogeny reconstruction does not support speciation as a possible source of the hidden break in insect’s 28S rRNA. In conclusion, we show that RNA from a given insect order does not conform to a particular banding profile and therefore this approach cannot be reliably used to characterize newly discovered species.
Exploring the Biomechanical Properties of Brain Malignancies and Their Pathologic Determinants In Vivo with Magnetic Resonance Elastography
Authors: Jamin Yann , Boult Jessica K.R. , Li Jin , Popov Sergey , Garteiser Philippe , Ulloa Jose L. , Cummings Craig , Box Gary , Eccles Suzanne A. , Jones Chris , Waterton John C. , Bamber Jeffrey C. , Sinkus Ralph , Robinson Simon P.
Published: February 2015

Malignant tumors are typically associated with altered rigidity relative to normal host tissue. Magnetic resonance elastography (MRE) enables the noninvasive quantitation of the mechanical properties of deep-seated tissue following application of an external vibrational mechanical stress to that tissue. In this preclinical study, we used MRE to quantify (kPa) the elasticity modulus Gd and viscosity modulus Gl of three intracranially implanted glioma and breast metastatic tumor models. In all these brain tumors, we found a notable softness characterized by lower elasticity and viscosity than normal brain parenchyma, enabling their detection on Gd and Gl parametric maps. The most circumscribed tumor (U-87 MG glioma) was the stiffest, whereas the most infiltrative tumor (MDA-MB-231 metastatic breast carcinoma) was the softest. Tumor cell density and microvessel density correlated significantly and positively with elasticity and viscosity, whereas there was no association with the extent of collagen deposition or myelin fiber entrapment. In conclusion, although malignant tumors tend to exhibit increased rigidity, intracranial tumors presented as remarkably softer than normal brain parenchyma. Our findings reinforce the case for MRE use in diagnosing and staging brain malignancies, based on the association of different tumor phenotypes with different mechanical properties. Cancer Res; 75(7); 1216–24. ©2015 AACR.
Transcriptomic and Protein Expression Analysis Reveals Clinicopathological Significance of Bloom Syndrome Helicase (BLM) in Breast Cancer
Authors: Arora Arvind , Abdel-Fatah Tarek M.A. , Agarwal Devika , Doherty Rachel , Moseley Paul M. , Aleskandarany Mohammed A. , Green Andrew R. , Ball Graham , Alshareeda Alaa T. , Rakha Emad A. , Chan Stephen Y.T. , Ellis Ian O. , Madhusudan Srinivasan
Published: February 2015

Bloom syndrome helicase (BLM) has key roles in homologous recombination repair, telomere maintenance, and DNA replication. Germ-line mutations in the BLM gene causes Bloom syndrome, a rare disorder characterized by premature aging and predisposition to multiple cancers, including breast cancer. The clinicopathologic significance of BLM in sporadic breast cancers is unknown. We investigated BLM mRNA expression in the Molecular Taxonomy of Breast Cancer International Consortium cohort (n = 1,950) and validated in an external dataset of 2,413 tumors. BLM protein level was evaluated in the Nottingham Tenovus series comprising 1,650 breast tumors. BLM mRNA overexpression was significantly associated with high histologic grade, larger tumor size, estrogen receptor–negative (ER−), progesterone receptor–negative (PR−), and triple-negative phenotypes (ps < 0.0001). BLM mRNA overexpression was also linked to aggressive molecular phenotypes, including PAM50.Her2 (P < 0.0001), PAM50.Basal (P < 0.0001), and PAM50.LumB (P < 0.0001) and Genufu subtype (ER+/Her2−/high proliferation; P < 0.0001). PAM50.LumA tumors and Genufu subtype (ER+/Her2−/low proliferation) were more likely to express low levels of BLM mRNA (ps < 0.0001). Integrative molecular clusters (intClust) intClust.1 (P < 0.0001), intClust.5 (P < 0.0001), intClust.9 (P < 0.0001), and intClust.10 (P < 0.0001) were also more likely in tumors with high BLM mRNA expression. BLM mRNA overexpression was associated with poor breast cancer–specific survival (BCSS; ps < 0.000001). At the protein level, altered subcellular localization with high cytoplasmic BLM and low nuclear BLM was linked to aggressive phenotypes. In multivariate analysis, BLM mRNA and BLM protein levels independently influenced BCSS. This is the first and the largest study to provide evidence that BLM is a promising biomarker in breast cancer. Mol Cancer Ther; 14(4); 1057–65. ©2015 AACR.
FGFR-Mediated Reactivation of MAPK Signaling Attenuates Antitumor Effects of Imatinib in Gastrointestinal Stromal Tumors
Authors: Li Fang , Huynh Hung , Li Xiaoyan , Ruddy David A. , Wang Youzhen , Ong Richard , Chow Pierce , Qiu Shumei , Tam Angela , Rakiec Daniel P. , Schlegel Robert , Monahan John E. , Huang Alan
Published: February 2015

Activating mutations in either KIT or PDGFRA are present in approximately 90% of gastrointestinal stromal tumors (GIST). Although treatment with the KIT and PDGFR inhibitor imatinib can control advanced disease in about 80% of GIST patients, the beneficial effect is not durable. Here, we report that ligands from the FGF family reduced the effectiveness of imatinib in GIST cells, and FGF2 and FGFR1 are highly expressed in all primary GIST samples examined. The combination of KIT and FGFR inhibition showed increased growth inhibition in imatinib-sensitive GIST cell lines and improved efficacy in patient-derived GIST xenografts. In addition, inhibition of MAPK signaling by imatinib was not sustained in GIST cells. An ERK rebound occurred through activation of FGF signaling, and was repressed by FGFR1 inhibition. Downregulation of Sprouty proteins played a role in the imatinib-induced feedback activation of FGF signaling in GIST cells.

Significance: We here show that FGFR-mediated reactivation of the MAPK pathway attenuates the antiproliferation effects of imatinib in GISTs. The imatinib-induced ERK rebound can be repressed by the FGFR inhibitor BGJ398, and combined KIT and FGFR inhibition leads to increased efficacy in vitro and in patient-derived xenografts. Cancer Discov; 5(4); 438–51. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 333
Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations
Authors: Ahronian Leanne G. , Sennott Erin M. , Van Allen Eliezer M. , Wagle Nikhil , Kwak Eunice L. , Faris Jason E. , Godfrey Jason T. , Nishimura Koki , Lynch Kerry D. , Mermel Craig H. , Lockerman Elizabeth L. , Kalsy Anuj , Gurski Joseph M. , Bahl Samira , Anderka Kristin , Green Lisa M. , Lennon Niall J. , Huynh Tiffany G. , Mino-Kenudson Mari , Getz Gad , Dias-Santagata Dora , Iafrate A. John , Engelman Jeffrey A. , Garraway Levi A. , Corcoran Ryan B.
Published: February 2015

BRAF mutations occur in approximately 10% of colorectal cancers. Although RAF inhibitor monotherapy is highly effective in BRAF-mutant melanoma, response rates in BRAF-mutant colorectal cancer are poor. Recent clinical trials of combined RAF/EGFR or RAF/MEK inhibition have produced improved efficacy, but patients ultimately develop resistance. To identify molecular alterations driving clinical acquired resistance, we performed whole-exome sequencing on paired pretreatment and postprogression tumor biopsies from patients with BRAF-mutant colorectal cancer treated with RAF inhibitor combinations. We identified alterations in MAPK pathway genes in resistant tumors not present in matched pretreatment tumors, including KRAS amplification, BRAF amplification, and a MEK1 mutation. These alterations conferred resistance to RAF/EGFR or RAF/MEK combinations through sustained MAPK pathway activity, but an ERK inhibitor could suppress MAPK activity and overcome resistance. Identification of MAPK pathway reactivating alterations upon clinical acquired resistance underscores the MAPK pathway as a critical target in BRAF-mutant colorectal cancer and suggests therapeutic options to overcome resistance.

Significance: RAF inhibitor combinations represent promising approaches in clinical development for BRAF-mutant colorectal cancer. Initial characterization of clinical acquired resistance mechanisms to these regimens identified several MAPK pathway alterations driving resistance by reactivating MAPK signaling, highlighting the critical dependence of BRAF-mutant colorectal cancers on MAPK signaling and offering potential strategies to overcome resistance. Cancer Discov; 5(4); 358–67. ©2015 AACR.

See related commentary by Meador and Pao, p. 348

This article is highlighted in the In This Issue feature, p. 333
Generation of Mouse Pluripotent Stem Cell–Derived Proliferating Myeloid Cells as an Unlimited Source of Functional Antigen-Presenting Cells
Authors: Zhang Rong , Liu Tian-Yi , Senju Satoru , Haruta Miwa , Hirosawa Narumi , Suzuki Motoharu , Tatsumi Minako , Ueda Norihiro , Maki Hiroyuki , Nakatsuka Ryusuke , Matsuoka Yoshikazu , Sasaki Yutaka , Tsuzuki Shinobu , Nakanishi Hayao , Araki Ryoko , Abe Masumi , Akatsuka Yoshiki , Sakamoto Yasushi , Sonoda Yoshiaki , Nishimura Yasuharu , Kuzushima Kiyotaka , Uemura Yasushi
Published: February 2015

The use of dendritic cells (DC) to prime tumor-associated antigen-specific T-cell responses provides a promising approach to cancer immunotherapy. Embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) can differentiate into functional DCs, thus providing an unlimited source of DCs. However, the previously established methods of generating practical volumes of DCs from pluripotent stem cells (PSC) require a large number of PSCs at the start of the differentiation culture. In this study, we generated mouse proliferating myeloid cells (pMC) as a source of antigen-presenting cells (APC) using lentivirus-mediated transduction of the c-Myc gene into mouse PSC-derived myeloid cells. The pMCs could propagate almost indefinitely in a cytokine-dependent manner, while retaining their potential to differentiate into functional APCs. After treatment with IL4 plus GM-CSF, the pMCs showed impaired proliferation and differentiated into immature DC-like cells (pMC-DC) expressing low levels of major histocompatibility complex (MHC)-I, MHC-II, CD40, CD80, and CD86. In addition, exposure to maturation stimuli induced the production of TNFα and IL12p70, and enhanced the expression of MHC-II, CD40, and CD86, which is thus suggestive of typical DC maturation. Similar to bone marrow–derived DCs, they stimulated a primary mixed lymphocyte reaction. Furthermore, the in vivo transfer of pMC-DCs pulsed with H-2Kb-restricted OVA257-264 peptide primed OVA-specific cytotoxic T cells and elicited protection in mice against challenge with OVA-expressing melanoma. Overall, myeloid cells exhibiting cytokine-dependent proliferation and DC-like differentiation may be used to address issues associated with the preparation of DCs. Cancer Immunol Res; 3(6); 668–77. ©2015 AACR.
Targeting Interleukin-2 to the Bone Marrow Stroma for Therapy of Acute Myeloid Leukemia Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Schliemann Christoph , Gutbrodt Katrin L. , Kerkhoff Andrea , Pohlen Michele , Wiebe Stefanie , Silling Gerda , Angenendt Linus , Kessler Torsten , Mesters Rolf M. , Giovannoni Leonardo , Schäfers Michael , Altvater Bianca , Rossig Claudia , Grünewald Inga , Wardelmann Eva , Köhler Gabriele , Neri Dario , Stelljes Matthias , Berdel Wolfgang E.
Published: February 2015

The antibody-based delivery of IL2 to extracellular targets expressed in the easily accessible tumor-associated vasculature has shown potent antileukemic activity in xenograft and immunocompetent murine models of acute myelogenous leukemia (AML), especially in combination with cytarabine. Here, we report our experience with 4 patients with relapsed AML after allogeneic hematopoietic stem cell transplantation (allo-HSCT), who were treated with the immunocytokine F16-IL2, in combination with low-dose cytarabine. One patient with disseminated extramedullary AML lesions achieved a complete metabolic response identified by PET/CT, which lasted 3 months. Two of 3 patients with bone marrow relapse achieved a blast reduction with transient molecular negativity. One of the 2 patients enjoyed a short complete remission before AML relapse occurred 2 months after the first infusion of F16-IL2. In line with a site-directed delivery of the cytokine, F16-IL2 led to an extensive infiltration of immune effector cells in the bone marrow. Grade 2 fevers were the only nonhematologic side effects in 2 patients. Grade 3 cytokine-release syndrome developed in the other 2 patients but was manageable in both cases with glucocorticoids. The concept of specifically targeting IL2 to the leukemia-associated stroma deserves further evaluation in clinical trials, especially in patients who relapse after allo-HSCT. Cancer Immunol Res; 3(5); 547–56. ©2015 AACR.
Intra-Arterial Chemotherapy for Muscle-Invasive Bladder Cancer Following Transurethral Resection
Authors: Liang Shengjie , Zou Qingsong , Han Bangmin , Jing Yifeng , Cui Di , An Xiao , Gao Yuan , Hu Jiawei , Xia Shujie
Published: February 2015

Purpose: To assess the efficacy of intra-arterial chemotherapy as a bladder-preservation treatment in patients with muscle-invasive bladder cancer (MIBC) following transurethral resection of bladder tumors (TURBT). Materials and Methods: From 2005 June to 2012 November, 46 patients diagnosed with MIBC (clinical stage T2-T3N0M0) underwent three courses of cisplatin-based intra-arterial chemotherapy as a remedial approach for bladder preservation after TURBT. All patients also received intravesical instillation of chemotherapy as a maintenance strategy. Results: All 46 patients completed the treatment with minor complications. The median follow-up time was 34.5 months (range, 8-87 months). Thirty-two patients (69.6%) demonstrated complete response. The three-year and five-year overall survival was 70.65 and 61.23%, and the disease-specific survival over the same periods was 78.03 and 67.62%, respectively. During the entire follow-up period, more than 80% preserved their bladder. Conclusions: Intra-arterial chemotherapy can be performed as a remedial treatment for MIBC patient following TURBT. Combined with TURBT, it offers an option for bladder preservation therapy on patients who are unable or unwilling to undergo radical cystectomy.
Rehabilitation in Patients with Chronic Respiratory Disease Other than Chronic Obstructive Pulmonary Disease: Exercise and Physical Activity Interventions in Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis
Authors: Burtin Chris , Hebestreit Helge
Published: February 2015

A relevant proportion of children and adults with cystic fibrosis (CF) have a marked decrease in exercise tolerance, which can be partly related to impaired muscle function and decreased physical activity levels in daily life, in addition to lung disease. Preliminary findings suggest that patients with non-CF bronchiectasis face the same problems. These patients might be excellent candidates for exercise and physical activity interventions. This review elaborates on the rationale for exercise training and activity behaviour changes and summarizes the existing evidence for these rehabilitation strategies in patients with bronchiectasis, both CF and non-CF bronchiectasis. Furthermore, practical considerations and safety aspects are discussed.
Evidence that Neurokinin B Controls Basal Gonadotropin-Releasing Hormone Secretion but Is Not Critical for Estrogen-Positive Feedback in Sheep
Authors: Li Qun , Millar Robert P. , Clarke Iain J. , Smith Jeremy T.
Published: February 2015

Background: Loss-of-function mutations in genes encoding kisspeptin or neurokinin B (NKB) or their receptors cause infertility. NKB is coproduced in kisspeptin neurons in the arcuate nucleus (ARC), and these neurons also produce the NKB receptor (NK3R), allowing autosynaptic function. We tested the hypothesis that NKB action in ARC kisspeptin neurons is aligned with increased pulsatile secretion of luteinizing hormone (LH) and/or activation of the estrogen-induced LH surge in ewes. Methods: Using in situ hybridization and immunohistochemistry, we examined NKB expression in kisspeptin neurons during the ovine estrous cycle. We infused kisspeptin, senktide (an NK3R agonist), or dynorphin into the lateral ventricle during the luteal phase of the estrous cycle to determine effects on pulsatile LH secretion. Finally, we examined the effect of an NK3R antagonist (MRK-08) in ovariectomized ewes. Results: NKB (Tac3) mRNA expression in mid-ARC kisspeptin neurons was elevated during the mid-to-late follicular phase of the estrous cycle. The number of NKB-immunoreactive cells and NKB/kisspeptin terminals in the median eminence was similar during the estrous cycle. Kisspeptin and senktide increased LH pulse frequency and mean LH levels. Central MRK-08 infusion eliminated the LH pulses but did not prevent an estrogen-positive feedback on LH secretion. Conclusions: NKB expression in ARC kisspeptin neurons is upregulated during the late follicular phase of the estrous cycle, when the pulsatile secretion of gonadotropin-releasing hormone (GnRH)/LH is maximal. When GnRH/LH secretion is minimal, central senktide infusion induces LH secretion, similar to the response to kisspeptin. Although the increase in LH in response to senktide appeared surge-like, we did not observe any change in the surge following NK3R antagonist treatment. We conclude that NKB plays a role in increasing basal GnRH/LH pulsatility in the follicular phase of the cycle but is not essential for estrogen-induced positive feedback.
Catecholamine-Synthesizing Enzymes Are Expressed in Parasympathetic Head and Neck Paraganglioma Tissue
Authors: Osinga Thamara E. , Korpershoek Esther , de Krijger Ronald R. , Kerstens Michiel N. , Dullaart Robin P.F. , Kema Ido P. , van der Laan Bernard F.A.M. , van der Horst-Schrivers Anouk N.A. , Links Thera P.
Published: February 2015

Background/Aim: Increased dopamine production may be a feature of head and neck paraganglioma (HNPGL). 18F-fluorodihydroxyphenylalanine positron emission tomography scintigraphy has a high sensitivity for detecting HNPGLs. These observations strongly suggest that HNPGLs have the capacity for L-3,4-dihydroxyphenylalanine uptake and conversion towards dopamine. Therefore, our aim was to demonstrate the presence of catecholamine-synthesizing enzymes, i.e. tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC) and dopamine β-hydroxylase (DBH) in HNPGL tissue. Methods: A single-center study was performed among patients who underwent surgery for HNPGL at a single university referral center between 1994 and 2012. HNPGL tissue was immunohistochemically stained for TH, AADC and DBH. Data on paraganglioma-associated germline mutations, preoperative biochemical phenotype and imaging studies were retrieved. Catecholamine excess was defined as preoperative plasma and/or urinary levels of metanephrine, normetanephrine or 3-methoxytyramine above the upper reference limit. Results: Nineteen HNPGLs from 18 patients were evaluated. All tumor tissues (100%) stained positive for AADC, 6 (32%) for TH and 2 (11%) for DBH. Of 3 HNPGLs staining positive for DBH, 2 were also positive for AADC and TH. Catecholamine excess was only present in 1 patient (5%). The HNPGLs of this single patient only showed positive staining for AADC. Conclusions: Catecholamine-synthesizing enzymes, in particular AADC, are expressed in the majority of HNPGL tissues.
Medical Treatment of Acromegaly with Dopamine Agonists or Somatostatin Analogs
Authors: Chanson Philippe
Published: February 2015

Treatment of acromegaly aims to correct (or prevent) tumor compression of surrounding tissues by excising the disease-causing lesion and reduce growth hormone (GH) and IGF-1 levels to normal values. When surgery (the usual first-line treatment) fails to correct GH/IGF-1 hypersecretion, medical treatment with dopamine agonists (DAs; particularly cabergoline) or somatostatin analogs (SAs) can be used. The GH receptor antagonist pegvisomant is helpful in patients who are totally or partially resistant to SAs and can be given in association with both SAs and/or DAs. Thanks to this multistep therapeutic strategy, adequate hormonal disease control is achieved in most patients, giving them normal life expectancy. Comorbidities associated with acromegaly generally improve after treatment, but persistent sequelae may nonetheless impair quality of life.
Investigating the Transcriptional Control of Cardiovascular Development
Authors: Kathiriya Irfan S. , Nora Elphège P. , Bruneau Benoit G.
Published: February 2015

Transcriptional regulation of thousands of genes instructs complex morphogenetic and molecular events for heart development. Cardiac transcription factors choreograph gene expression at each stage of differentiation by interacting with cofactors, including chromatin-modifying enzymes, and by binding to a constellation of regulatory DNA elements. Here, we present salient examples relevant to cardiovascular development and heart disease, and review techniques that can sharpen our understanding of cardiovascular biology. We discuss the interplay between cardiac transcription factors,
cis
-regulatory elements, and chromatin as dynamic regulatory networks, to orchestrate sequential deployment of the cardiac gene expression program.
Epigenetics and Metabolism
Authors: Keating Samuel T. , El-Osta Assam
Published: February 2015

The molecular signatures of epigenetic regulation and chromatin architectures are fundamental to genetically determined biological processes. Covalent and post-translational chemical modification of the chromatin template can sensitize the genome to changing environmental conditions to establish diverse functional states. Recent interest and research focus surrounds the direct connections between metabolism and chromatin dynamics, which now represents an important conceptual challenge to explain many aspects of metabolic dysfunction. Several components of the epigenetic machinery require intermediates of cellular metabolism for enzymatic function. Furthermore, changes to intracellular metabolism can alter the expression of specific histone methyltransferases and acetyltransferases conferring widespread variations in epigenetic modification patterns. Specific epigenetic influences of dietary glucose and lipid consumption, as well as undernutrition, are observed across numerous organs and pathways associated with metabolism. Studies have started to define the chromatin-dependent mechanisms underlying persistent and pathophysiological changes induced by altered metabolism. Importantly, numerous recent studies demonstrate that gene regulation underlying phenotypic determinants of adult metabolic health is influenced by maternal and early postnatal diet. These emerging concepts open new perspectives to combat the rising global epidemic of metabolic disorders.
Molecular Basis of Cardioprotection
Authors: Heusch Gerd
Published: February 2015

Reperfusion is mandatory to salvage ischemic myocardium from infarction, but reperfusion per se contributes to injury and ultimate infarct size. Therefore, cardioprotection beyond that by timely reperfusion is needed to reduce infarct size and improve the prognosis of patients with acute myocardial infarction. The conditioning phenomena provide such cardioprotection, insofar as brief episodes of coronary occlusion/reperfusion preceding (ischemic preconditioning) or following (ischemic postconditioning) sustained myocardial ischemia with reperfusion reduce infarct size. Even ischemia/reperfusion in organs remote from the heart provides cardioprotection (remote ischemic conditioning). The present review characterizes the signal transduction underlying the conditioning phenomena, including their physical and chemical triggers, intracellular signal transduction, and effector mechanisms, notably in the mitochondria. Cardioprotective signal transduction appears as a highly concerted spatiotemporal program. Although the translation of ischemic postconditioning and remote ischemic conditioning protocols to patients with acute myocardial infarction has been fairly successful, the pharmacological recruitment of cardioprotective signaling has been largely disappointing to date.
Racial Disparities in Outcomes of Adult Heart Transplantation
Authors: Kilic Arman , Higgins Robert S. D. , Whitson Bryan A. , Kilic Ahmet
Published: February 2015

Background—

This study evaluated whether minority orthotopic heart transplant (OHT) recipients tend to be transplanted at worse performing centers.

Methods and Results—

OHT recipients between 2000 and 2010 were identified in the United Network for Organ Sharing database and stratified by race. Center performance was evaluated using observed-to-expected mortality ratios that were calculated using validated indexes for recipient and donor risk in OHT. The primary outcome was 1-year post-OHT mortality. A total of 102 centers performed OHT in 18 085 patients. Blacks had higher unadjusted 1-year mortality, which was confirmed after risk adjustment. Blacks had increased risk-adjusted mortality at poor performing centers (observed-to-expected mortality ratio, >1.2; odds ratio, 1.37 [95% confidence interval, 1.12–1.69];
P
=0.002) and a strong trend toward increased mortality at excellent performing centers (observed-to-expected mortality ratio, <0.8; odds ratio, 1.42 [95% confidence interval, 0.99–2.02];
P
=0.06). A higher proportion of blacks were treated at centers with higher-than-expected mortality (56.4% versus 47.1% whites versus 48.1% Hispanics;
P
<0.001), a finding that persisted after adjusting for insurance type and highest education level. In addition, there was a positive correlation between the percentage of blacks and observed-to-expected mortality ratios at the center level (
r
=0.32;
P
=0.001). In multivariable analysis incorporating immunologic and socioeconomic variables, there was no clear dominant source for the disparities in outcomes of OHT between races.

Conclusions—

Blacks have a propensity to be transplanted at worse performing centers; however, center effect alone does not explain the mortality difference between ethnicities. Although referral of minorities to better performing centers would improve absolute survival, it would not likely eliminate the racial disparities that exist in OHT outcomes.
Rapid and Body Weight–Independent Improvement of Endothelial and High-Density Lipoprotein Function After Roux-en-Y Gastric Bypass
Authors: Osto Elena , Doytcheva Petia , Corteville Caroline , Bueter Marco , Dörig Claudia , Stivala Simona , Buhmann Helena , Colin Sophie , Rohrer Lucia , Hasballa Reda , Tailleux Anne , Wolfrum Christian , Tona Francesco , Manz Jasmin , Vetter Diana , Spliethoff Kerstin , Vanhoutte Paul M. , Landmesser Ulf , Pattou Francois , Staels Bart , Matter Christian M. , Lutz Thomas A. , Lüscher Thomas F.
Published: February 2015

Background—

Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight loss–independent manner. The present study investigated in rats and patients whether obesity-induced endothelial and high-density lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1–dependent mechanism.

Methods and Results—

Eight days after RYGB in diet-induced obese rats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin
9-39
(10 μg·kg
−1
·h
−1
). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDL-mediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB.

Conclusions—

RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1–mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity.
Drip and Ship Thrombolytic Therapy for Acute Ischemic Stroke
Authors: Sheth Kevin N. , Smith Eric E. , Grau-Sepulveda Maria V. , Kleindorfer Dawn , Fonarow Gregg C. , Schwamm Lee H.
Published: February 2015

Background and Purpose—

Interhospital transfer after use of intravenous tissue-type plasminogen activator (tPA) in acute stroke (drip and ship) is increasingly frequent. Small studies have suggested that drip and ship tPA is safe and increases rates of tPA use; however, little is known about real-world practice patterns. We sought to evaluate temporal trends in drip and ship tPA use and to compare the patient and hospital characteristics with that of conventional (front door) thrombolysis.

Methods—

We analyzed data from 44 667 patients with ischemic stroke treated with intravenous tPA ≤3 hours of symptom onset in the Get With The Guidelines-Stroke program from April 2003 to October 2010 in 1440 hospitals. The main outcomes were the frequency of drip and ship tPA use over time, the characteristics of patients treated, and in-hospital outcomes, treatments, and complications.

Results—

Among 44 667 patients treated with tPA, the drip and ship method was a common method (n=10 475; 23.5%), the use of which increased in parallel with the traditional tPA method over time. Patients treated by the drip and ship method differed significantly from front-door patients, with lower National Institutes of Health Stroke Scale scores when recorded (n=35 467). Crude in-hospital mortality (10.9%) and symptomatic intracranial hemorrhage (5.7%) in patients treated by the drip and ship method were slightly higher compared with those in front-door patients, and these differences persisted after risk adjustment.

Conclusions—

Drip and ship tPA is common, used in 1 in 4 patients treated with tPA in the United States. Modest differences in mortality and symptomatic intracranial hemorrhage may be because of patient selection bias, post-tPA care differences, or unmeasured confounding. The drip and ship paradigm may facilitate widespread tPA use in patients with acute stroke.
Policies and Influence
Authors: Sellheim Nikolas
Published: February 2015

The European Union’s ban on trade in seal products prohibits the placing on the market of seal products stemming from commercial hunts. It is based on the assumption that the commercial seal hunt is inherently inhumane, although the design of the ban does not contribute to alleviating this concern. This article takes the perceived problems in eu documents relating to the seal hunt under closer scrutiny and analyses the composition and characteristics of the stakeholders involved. While political processes are marginally touched upon, it is the ban’s underlying principles and effects that the article considers and it embeds the crafting process and the ban itself in a normative and discursive environment.
Water Rights: Fragmented Rights?
Authors: Ambrus Mónika
Published: February 2015

Historically, global water law has developed in fragments. The fragmented nature of water law mainly originates from the fact that water can be seen as an economic, ecological and social unit (horizontal fragmentation). Within the clusters that these units constitute, water law is also seen as fragmented, given that a particular cluster is composed of different levels (vertical fragmentation). This article will scrutinise the social justice cluster, or the right to water, and examine whether and to what extent vertical fragmentation in water law leads to divergent approaches among the different levels, while placing the discussion within the general context of fragmentation in international law. For that purpose the elaboration of the human right to water by the Committee on Economic, Social and Cultural Rights, functioning at the international level, will be compared with the practice of the European Court of Human Rights (ECTHR), a regional court.