bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Agents in CML Therapy: Tyrosine Kinase Inhibitors and Beyond
Authors: Melo Junia V. , Chuah Charles
Published: December 2008

The emergence of resistance to imatinib has become a significant problem despite the remarkable clinical results achieved with this tyrosine kinase inhibitor in the treatment of chronic myeloid leukaemia. The most common cause of imatinib resistance is the selection of leukemic clones with point mutations in the Abl kinase domain. These mutations lead to amino acid substitutions and prevent the appropriate binding of imatinib. Genomic amplification of BCR-ABL, modulation of drug efflux or influx transporters, and Bcr-Abl–independent mechanisms also play important roles in the development of resistance. Persistent disease is another therapeutic challenge and may in part, be due to the inability of imatinib to eradicate primitive stem cell progenitors. A multitude of novel agents have been developed and have shown in vitro and in vivo efficacy in overcoming imatinib resistance. In this review, we will discuss the current status of the ATP-competitive and non-ATP–competitive Bcr-Abl tyrosine kinase inhibitors. We will also describe inhibitors acting on targets found in signaling pathways downstream of Bcr-Abl, such as the Ras-Raf-mitogen-activated protein kinase and phosphatidylinositol-3 kinase-Akt-mammalian target of rapamycin pathways, and targets without established links with Bcr-Abl.
Pleiotrophin produced by multiple myeloma induces transdifferentiation of monocytes into vascular endothelial cells: a novel mechanism of tumor-induced vasculogenesis
Authors: Chen Haiming , Campbell Richard A. , Chang Yunchao , Li Mingjie , Wang Cathy S. , Li Jennifer , Sanchez Eric , Share Michael , Steinberg Jeffrey , Berenson Ariana , Shalitin Dror , Zeng Zhaohui , Gui Dorina , Perez-Pinera Pablo , Berenson Ronald J. , Said Jonathan , Bonavida Benjamin , Deuel Thomas F. , Berenson James R.
Published: December 2008

Enhanced angiogenesis is a hallmark of cancer. Pleiotrophin (PTN) is an angiogenic factor that is produced by many different human cancers and stimulates tumor blood vessel formation when it is expressed in malignant cancer cells. Recent studies show that monocytes may give rise to vascular endothelium. In these studies, we show that PTN combined with macrophage colony-stimulating factor (M-CSF) induces expression of vascular endothelial cell (VEC) genes and proteins in human monocyte cell lines and monocytes from human peripheral blood (PB). Monocytes induce VEC gene expression and develop tube-like structures when they are exposed to serum or cultured with bone marrow (BM) from patients with multiple myeloma (MM) that express PTN, effects specifically blocked with antiPTN antibodies. When coinjected with human MM cells into severe combined immunodeficient (SCID) mice, green fluorescent protein (GFP)–marked human monocytes were found incorporated into tumor blood vessels and expressed human VEC protein markers and genes that were blocked by anti-PTN antibody. Our results suggest that vasculogenesis in human MM may develop from tumoral production of PTN, which orchestrates the transdifferentiation of monocytes into VECs.
Activity of the BH3 mimetic ABT-737 on polycythemia vera erythroid precursor cells
Authors: Zeuner Ann , Pedini Francesca , Francescangeli Federica , Signore Michele , Girelli Gabriella , Tafuri Agostino , De Maria Ruggero
Published: December 2008

An increased expression of antiapoptotic molecules is often found in malignant cells, where it contributes to their clonal expansion by conferring an improved survival ability. We found that erythroid precurors derived from patients with polycythemia vera (PV) with medium and high JAK2V617F mutation rates often express elevated levels of the antiapoptotic molecules Bcl-2 and Bcl-XL (5 of 12 patients with 3 to 7 times Bcl-2 and 3 of 12 patients with 4 to 7 times Bcl-XL than average normal controls) and are more resistant to myelosuppressive drugs than normal erythroblasts. ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-XL, and Bcl-W, induced apoptosis preferentially in JAK2V617F-high PV erythroid precursors as compared with JAK2V617F-low or normal erythroblasts. ABT-737 inhibited also the proliferation of PV erythroblasts and interfered with the formation of endogenous erythroid colonies by PV hematopoietic progenitors. Altogether, these results suggest that small-molecule inhibitors of Bcl-2/Bcl-XL may be used in the treatment of patients with PV with high JAK2V617F allele burden.
Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy
Authors: Jabbour Elias , Kantarjian Hagop M. , Jones Dan , Shan Jenny , O'Brien Susan , Reddy Neeli , Wierda William G. , Faderl Stefan , Garcia-Manero Guillermo , Verstovsek Srdan , Rios Mary Beth , Cortes Jorge
Published: December 2008

We assessed the long-term efficacy of imatinib dose escalation in 84 patients with chronic myeloid leukemia in chronic phase who met the criteria of failure to standard-dose imatinib. Twenty-one patients with hematologic failure and 63 with cytogenetic failure had their imatinib dose escalated from 400 to 800 mg daily (n = 72) or from 300 to 600 mg daily (n = 12). After a median follow-up of 61 months from dose escalation, 69% remained alive. Complete cytogenetic responses were achieved in 40%; including 52% of patients with cytogenetic failure and 5% of those with hematologic failure. The estimated 2- and 3-year event-free survival and overall survival rates were 57% and 47%, and 84% and 76%, respectively. Responses were long-lasting; 88% of patients with major cytogenetic response sustained their response beyond 2 years. Treatment was well tolerated, with 76% of patients, at 12 months, continuing to receive imatinib at 100% of the intended dose. In conclusion, imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic failure and a previous cytogenetic response to standard-dose imatinib.
Stem cell factor and interleukin-2/15 combine to enhance MAPK-mediated proliferation of human natural killer cells
Authors: Benson Don M. , Yu Jianhua , Becknell Brian , Wei Min , Freud Aharon G. , Ferketich Amy K. , Trotta Rossana , Perrotti Danilo , Briesewitz Roger , Caligiuri Michael A.
Published: December 2008

Stem cell factor (SCF) promotes synergistic cellular proliferation in combination with several growth factors, and appears important for normal natural killer (NK)–cell development. CD34+ hematopoietic precursor cells (HPCs) require interleukin-15 (IL-15) for differentiation into human NK cells, and this effect can be mimicked by IL-2. Culture of CD34+ HPCs or some primary human NK cells in IL-2/15 and SCF results in enhanced growth compared with either cytokine alone. The molecular mechanisms responsible for this are unknown and were investigated in the present work. Activation of NK cells by IL-2/15 increases expression of c-kit whose kinase activity is required for synergy with IL-2/15 signaling. Mitogen-activated protein kinase (MAPK) signaling intermediaries that are activated both by SCF and IL-2/15 are enhanced in combination to facilitate earlier cell-cycle entry. The effect results at least in part via enhanced MAPK-mediated modulation of p27 and CDK4. Collectively the data reveal a novel mechanism by which SCF enhances cellular proliferation in combination with IL-2/15 in primary human NK cells.
The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316M mutation
Authors: Jackson Shannon C. , Sinclair Gary D. , Cloutier Stephanie , Duan Zhaoxia , Rand Margaret L. , Poon Man-Chiu
Published: December 2008

Montreal platelet syndrome (MPS), hitherto described in only one kindred, is a hereditary thrombocytopenia associated with mucocutaneous bleeding, giant platelets, and spontaneous platelet aggregation in vitro. These are features shared with some forms of type 2B von Willebrand disease (VWD); however, the MPS kindred had not been investigated for VWD. We found that all affected MPS family members had borderline to normal von Willebrand factor antigen (VWF:Ag; 0.43-0.75 U/mL), discrepantly low ristocetin cofactor activity (VWF:RCo; 0.16-0.29 U/mL), and normal factor VIII coagulant activity (FVIII:C; 0.57-1.04 U/mL). Unaffected family members all had normal VWF:Ag, VWF:RCo, and FVIII:C levels. In addition, persons with MPS, but not unaffected family members, had loss of plasma (but not platelet) high molecular weight VWF multimers, and were heterozygous for the previously reported V1316M type 2B VWD mutation. Thus, in reevaluating this kindred, we determined that patients with MPS have type 2B VWD with the V1316M VWF mutation.
Vascular endothelial growth factor-D transgenic mice show enhanced blood capillary density, improved postischemic muscle regeneration, and increased susceptibility to tumor formation
Authors: Kärkkäinen Anna-Mari , Kotimaa Antti , Huusko Jenni , Kholova Ivana , Heinonen Suvi Elina , Stefanska Anna , Dijkstra Marike Hinke , Purhonen Hanna , Hämäläinen Eveliina , Mäkinen Petri Ilmari , Turunen Mikko Petri , Ylä-Herttuala Seppo
Published: December 2008

Vascular endothelial growth factor-D (VEGF-D) has angiogenic and lymphangiogenic activity, but its biologic role has remained unclear because knockout mice showed no clear phenotype. Transgenic (TG) mice expressing the mature form of human VEGF-D (hVEGF-D) were produced by lentiviral (LV) transgenesis using the perivitelline injection method. Several viable founders showed a macroscopically normal phenotype and the transgene transmitted through germ line. Expression of hVEGF-D mRNA was high in skeletal muscles, skin, pancreas, heart, and spleen. A significant increase was found in capillary density of skeletal muscles and myocardium, whereas no changes were observed in lymphatic capillary density. After induction of hindlimb ischemia, the TG mice showed enhanced capacity for muscle regeneration. However, on aging the TG mice had significantly increased mortality from malignant tumors, of which half were breast adenocarcinomas characterized with the absence of periductal muscle cells. Some tumors metastasized into the lungs. In addition, lung and skin tumors were found, but no blood- or lymphatic vessel–derived malignancies were detected. We conclude that in mice hVEGF-D is an angiogenic factor associated with improved muscle regeneration after ischemic injury but also with increased incidence of tumor formation with a preference for mammary gland tumors.
Donor-derived oral squamous cell carcinoma after allogeneic bone marrow transplantation
Authors: Janin Anne , Murata Hideyuki , Leboeuf Christophe , Cayuela Jean-Michel , Gluckman Eliane , Legrès Luc , Desveaux Allison , Varna Mariana , Ratajczak Philippe , Soulier Jean , de Thé Hugues , Bertheau Philippe , Socié Gérard
Published: December 2008

In animal models, tissue stem cells were proposed to exhibit an unexpected level of plasticity, although issues on cell fusions have lead to some controversies. Only transplantation experiments using genetically distinct recipients and donors can unequivocally show these changes in cell fate. We have analyzed oral squamous cell carcinomas arising in 8 long-term survivors of allogeneic bone marrow transplantation, in whom chronic graft-versus-host disease greatly favors development of squamous cell carcinomas, possibly as a consequence of lichenoid mucosal inflammation. With the use of 2 independent methods, (1) combined immunostaining and fluorescent in situ hybridization (FISH) analysis for X and Y chromosomes sequences in sex-mismatched grafts and (2) comparison of microsatellite typing of laser-microdissected tumor, donor, and recipient cells, in all tumors, we showed that 4 of these 8 epithelial tumors actually arose from the engrafted allogeneic bone marrow. Thus, donor-derived bone marrow cells, whether hematopoietic or mesenchymal, recruited to sites of chronic mucosal inflammation yielded epithelial tumors. Our observations therefore show that marrow cells in humans have a major role in epithelial cancer formation after allogeneic transplantation.
Analysis of EGFR, HER2, and TOP2A gene status and chromosomal polysomy in gastric adenocarcinoma from Chinese patients
Authors: Liang Zhiyong , Zeng Xuan , Gao Jie , Wu Shafei , Wang Peng , Shi Xiaohua , Zhang Jing , Liu Tonghua
Published: December 2008

Background

The EGFR and HER2 genes are located on chromosomes 7 and 17, respectively. They are therapeutic targets in some tumors. The TOP2A gene, which is located near HER2 on chromosome 17, is the target of many chemotherapeutic agents, and co-amplification of HER2 and TOP2A has been described in several tumor types. Herein, we investigated the gene status of EGFR, HER2, and TOP2A in Chinese gastric carcinoma patients. We determined the rate of polysomy for chromosomes 7 and 17, and we attempted to clarify the relationship between EGFR, HER2, and TOP2A gene copy number and increased expression of their encoded proteins. Furthermore, we tried to address the relationship between alterations in EGFR, HER2, and TOP2A and chromosome polysomy.

Methods

One hundred cases of formalin fixed and paraffin embedded tumor tissues from Chinese gastric carcinoma patients were investigated by immunohistochemistry and fluorescence in situ hybridization (FISH) methods.

Results

Forty-two percent of the cases showed EGFR overexpression; 16% showed EGFR FISH positive; 6% showed HER2 overexpression; and 11% showed HER2 gene amplification, including all six HER2 overexpression cases. TOP2A nuclear staining (nuclear index, NI) was determined in all 100 tumors: NI values ranged from 0.5 – 90%. Three percent of the tumors showed TOP2A gene amplification, which were all accompanied by HER2 gene amplification. Nineteen percent of the tumors showed chromosome 7 polysomy, and 16% showed chromosome 17 polysomy. Chromosome 7 polysomy correlated significantly with EGFR FISH-positivity, but was not associated with EGFR overexpression. HER2 overexpression associated significantly with HER2 gene amplification. TOP2A gene amplification was significantly associated with HER2 gene amplification. No relationship was found between alterations in the EGFR, HER2, and TOP2A genes and clinicopathologic variables of gastric carcinoma.

Conclusion

The data from our study suggest that chromosome 7 polysomy may be responsible for increased EGFR gene copy number in gastric carcinomas, and that HER2 gene amplification may be the major reason for HER2 protein overexpression. A combined investigation of the gene status of EGFR, HER2, and TOP2A should facilitate the identification of a target therapeutic regimen for gastric carcinoma patients.
Adherence to highly active antiretroviral therapy and its correlates among HIV infected pediatric patients in Ethiopia
Authors: Biadgilign Sibhatu , Deribew Amare , Amberbir Alemayehu , Deribe Kebede
Published: December 2008

Background

The introduction of combination antiretroviral therapy (ART) has resulted in striking reductions in HIV-related mortality. Despite increased availability of ART, children remain a neglected population. This may be due to concerns that failure to adhere appears to be related to continued viral replication, treatment failure and the emergence of drug-resistant strains of HIV. This study determines the rates and factors associated with adherence to Antiretroviral (ARV) Drug therapy in HIV-infected children who were receiving Highly Active Antiretroviral Therapy (HAART) in Addis Ababa, Ethiopia in 2008.

Methods

A cross-sectional study was conducted in five hospitals in Addis Ababa from February 18 – April 28, 2008. The study population entailed parents/caretaker and index children who were following ART in the health facilities. A structured questionnaire was used for data collection.

Results

A total of 390 children respondents were included in the study with a response rate of 91%. The majority, equaling 205 (52.6%) of the children, were greater than 9 years of age. Fifty five percent of the children were girls. A total of 339 children (86.9%) as reported by caregivers were adherent to antiretroviral drugs for the past 7 days before the interview. Numerous variables were found to be significantly associated with adherence: children whose parents did not pay a fee for treatment [OR = 0.39 (95%CI: 0.16, 0.92)], children who had ever received any nutritional support from the clinic [OR = 0.34 (95%CI: 0.14, 0.79)] were less likely to adhere. Whereas children who took co-trimoxazole medication/syrup besides ARVs [OR = 3.65 (95%CI: 1.24, 10.74)], children who did not know their sero-status [OR = 2.53 (95%CI: 1.24, 5.19)] and children who were not aware of their caregiver's health problem [OR = 2.45 (95%CI: 1.25, 4.81)] were more likely to adhere than their counterparts.

Conclusion

Adherence to HAART in children in Addis Ababa was higher than other similar setups. However, there are still significant numbers of children who are non-adherent to HAART.
Mosquito larvicidal and antimicrobial activity of protein of Solanum villosum leaves
Authors: Chowdhury Nandita , Laskar Subrata , Chandra Goutam
Published: December 2008

Background

Mosquitoes are associated with the transmission of malaria, dengue, Japanese encephalitis, filariasis and other viral diseases throughout the globe, apart from being a nuisance pest. Biological control alone or as a part of integrated vector management stands to be a better alternative to the chemical controls aimed against pest mosquitoes. At the same time it is necessary to control bacteria by synthetic or natural means (plant products). Hence the present study was designed to screen the effect of mosquito larvicidal and antimicrobial activitiy of protein isolated from matured leaves of Solanum villosum against mosquito immatures and some pathogenic bacteria.

Methods

Aqueous solvent extract of fresh mature leaves of S. villosum was tested against 3rd instar larvae of Anopheles stephensi, Culex quinquefasciatus and Stegomyia aegypti mosquitoes and against four pathogenic bacteria. The protein fraction was isolated and tested for mosquitocidal and antibacterial activities. Amino acid analysis was performed on isolated protein using PICO.TAG amino acid system. SDS-PAGE was also done to detect the bands of amino acid on the basis of their molecular weights.

Results

Proteins isolated from mature leaves of S. villosum were found to have larvicidal and antimicrobial properties. Analysis of the isolated protein identified fifteen amino acids of which eight were essential amino acids. SDS-PAGE detected seven bands corresponding to different molecular weights in the range of 69–109 KDa.

Conclusion

Proteins of mature leaves of S. villosum exhibited moderate larvicidal and antimicrobial activities. The study provides considerable scope in exploiting local indigenous resources for isolation of antimicrobial and mosquito larvicidal proteins.
Pericardial effusion – an unusual manifestation of salmonellosis: a case report
Authors: Sahu Manisa , Sujatha Sistla , DR Chaya , Parija Subhash Chandra
Published: December 2008

Background

Nontyphoidal salmonellae are important food-borne pathogens that are usually associated with self-limiting gastroenteritis. Occurrence of extra-intestinal non-typhoidal salmonellosis in humans is increasing in many developing countries. The risk of extra-intestinal nontyphoidal salmonellosis is higher in patients with impaired cell mediated immunity, lympho-proliferative disorders and IL-12 deficiencies. Pericardial involvement is one of the rare manifestations accounting for <2% cases but the mortality is very high.

Case presentation

A 23 year old male was admitted in the medicine ward with complaints of fever, chest pain with non-productive cough, not associated with hemoptysis for past 3 weeks. He was a known case of Hodgkin's lymphoma and was treated with complete course of chemotherapy. Cardiovascular examination, chest X-ray and ECG findings suggested this to be a case of pericardial effusion. The causative agent of this purulent pericardial effusion was identified as Group B Salmonella following isolation from the pericardial fluid.
Enterobius Vermicularis infection of the appendix as a cause of acute appendicitis in a Greek adolescent: a case report
Authors: Efraimidou Eleni , Gatopoulou Anthia , Stamos Charilaos , Lirantzopoulos Nikolaos , Kouklakis George
Published: December 2008

Gastrointestinal infection due to Enterobius vermicularis occurs worldwide and is considered to be the most common helminth infection. The simple presence of E. vermicularis in the appendix usually produces symptoms of acute appendicitis. The association of this parasitic infestation with acute appendicitis varies from 0.2%–41.8% worldwide. We present a case of a 15 year old female with enterobiasis of appendix presented with clinical features of acute appendicitis. The appendix was surgically removed and the specimen was pathologically diagnosed to contain of E. vermicularis in non-inflamed and histologically normal appendix. Even if this condition is not uncommon in the Greek population, to the best of our knowledge this is the first report presented in the English literature.
The Response of Household Saving to the Large Shock of German Reunification
Authors: Fuchs-Schündeln Nicola
Published: December 2008

German reunification was a large, unexpected shock for East Germans. Exploiting German reunification as a natural experiment, I analyze the validity of the life-cycle consumption model. I derive three stylized features concerning the saving behavior of East versus West Germans after reunification: (i) East Germans have higher saving rates than West Germans; (ii) this East-West gap is increasing in age at reunification; and (iii) for every cohort, this gap is declining over time. I show that a comprehensive life-cycle model can replicate these features. The precautionary saving motive is essential for the success of the model. (JEL D14, D91, E21)
Principles of Long-Term Dynamics of Dendritic Spines
Authors: Yasumatsu Nobuaki , Matsuzaki Masanori , Miyazaki Takashi , Noguchi Jun , Kasai Haruo
Published: December 2008

Long-term potentiation of synapse strength requires enlargement of dendritic spines on cerebral pyramidal neurons. Long-term depression is linked to spine shrinkage. Indeed, spines are dynamic structures: they form, change their shapes and volumes, or can disappear in the space of hours. Do all such changes result from synaptic activity, or do some changes result from intrinsic processes? How do enlargement and shrinkage of spines relate to elimination and generation of spines, and how do these processes contribute to the stationary distribution of spine volumes? To answer these questions, we recorded the volumes of many individual spines daily for several days using two-photon imaging of CA1 pyramidal neurons in cultured slices of rat hippocampus between postnatal days 17 and 23. With normal synaptic transmission, spines often changed volume or were created or eliminated, thereby showing activity-dependent plasticity. However, we found that spines changed volume even after we blocked synaptic activity, reflecting a native instability of these small structures over the long term. Such “intrinsic fluctuations” showed unique dependence on spine volume. A mathematical model constructed from these data and the theory of random fluctuations explains population behaviors of spines, such as rates of elimination and generation, stationary distribution of volumes, and the long-term persistence of large spines. Our study finds that generation and elimination of spines are more prevalent than previously believed, and spine volume shows significant correlation with its age and life expectancy. The population dynamics of spines also predict key psychological features of memory.
Matrix Metalloproteinase-9 Facilitates Glial Scar Formation in the Injured Spinal Cord
Authors: Hsu Jung-Yu C. , Bourguignon Lilly Y. W. , Adams Christen M. , Peyrollier Karine , Zhang Haoqian , Fandel Thomas , Cun Christine L. , Werb Zena , Noble-Haeusslein Linda J.
Published: December 2008

In the injured spinal cord, a glial scar forms and becomes a major obstacle to axonal regeneration. Formation of the glial scar involves migration of astrocytes toward the lesion. Matrix metalloproteinases (MMPs), including MMP-9 and MMP-2, govern cell migration through their ability to degrade constituents of the extracellular matrix. Although MMP-9 is expressed in reactive astrocytes, its involvement in astrocyte migration and formation of a glial scar is unknown. Here we found that spinal cord injured, wild-type mice expressing MMPs developed a more severe glial scar and enhanced expression of chondroitin sulfate proteoglycans, indicative of a more inhibitory environment for axonal regeneration/plasticity, than MMP-9 null mice. To determine whether MMP-9 mediates astrocyte migration, we conducted a scratch wound assay using astrocytes cultured from MMP-9 null, MMP-2 null, and wild-type mice. Gelatin zymography confirmed the expression of MMP-9 and MMP-2 in wild-type cultures. MMP-9 null astrocytes and wild-type astrocytes, treated with an MMP-9 inhibitor, exhibited impaired migration relative to untreated wild-type controls. MMP-9 null astrocytes showed abnormalities in the actin cytoskeletal organization and function but no detectable untoward effects on proliferation, cellular viability, or adhesion. Interestingly, MMP-2 null astrocytes showed increased migration, which could be attenuated in the presence of an MMP-9 inhibitor. Collectively, our studies provide explicit evidence that MMP-9 is integral to the formation of an inhibitory glial scar and cytoskeleton-mediated astrocyte migration. MMP-9 may thus be a promising therapeutic target to reduce glial scarring during wound healing after spinal cord injury.
Distinctive Quantal Properties of Neurotransmission at Excitatory and Inhibitory Autapses Revealed Using Variance–Mean Analysis
Authors: Ikeda Kaori , Yanagawa Yuchio , Bekkers John M.
Published: December 2008

Normal brain function depends on an interplay between glutamatergic and GABAergic synaptic transmission, yet questions remain about the biophysical differences between these two classes of synapse. By taking advantage of a simple culture system, we present here a detailed comparison of excitatory and inhibitory neurotransmission under identical conditions using the variance–mean (V–M) method of quantal analysis. First, we validateV–Manalysis for glutamatergic autapses formed by isolated hippocampal pyramidal neurons in culture, confirming that the analysis accurately predicts the quantal amplitude (Q). We also show thatV–Manalysis is only weakly sensitive to intersite and intrasite quantal variance and to the known inhomogeneities in release probability (Pr). Next, by repeating the experiments with GABAergic autapses, we confirm thatV–Manalysis provides an accurate account of inhibitory neurotransmission in this system. MeanPr, provided byV–Manalysis, shows a dependence on extracellular Ca2+concentration that is nearly identical for both excitatory and inhibitory autapses. Finally, theV–Mmethod allows us to compare the locus of short-term synaptic plasticity at these connections. Glutamatergic autapses exhibit paired-pulse depression that depends mainly on changes inPr, whereas depression at GABAergic autapses appears to depend primarily on changes in the number of release sites. We conclude that, apart from differences in the mechanisms of short-term plasticity, the basic quantal properties of excitatory and inhibitory connections in this hippocampal system are remarkably similar.
Intact Retinal Pigment Epithelium Maintained by Nok Is Essential for Retinal Epithelial Polarity and Cellular Patterning in Zebrafish
Authors: Zou Jian , Lathrop Kira L. , Sun Ming , Wei Xiangyun
Published: December 2008

Within the vertebrate eye, the retinal pigment epithelium (RPE) juxtaposes with the retina, but how the RPE plays a role in retinal morphogenesis remains elusive. It has been shown that the loss of function of the polarity proteins, such as Nagie oko (Nok), disrupts RPE integrity and retinal lamination. However, it is unclear whether or not such defects are caused in a tissue-autonomous manner. Here, by taking advantage of thenokmutation, we have generated a transgenic model to restore the Nok function in the RPE, but not in the retina. With this model, we show that Nok is required for RPE integrity in a tissue-autonomous manner. However, proper retinal epithelial polarity does not require retinal expression of Nok before embryonic photoreceptor genesis; rather, it requires a Nok-mediated intact RPE. Interestingly, sporadic wild-type RPE donor cells are not sufficient to maintain proper retinal polarity. We further show that RPE-mediated retinal epithelial polarity underlies proper patterning of retinal ganglion cells and the cells of the inner nuclear layer. Nevertheless, during embryonic photoreceptor genesis, an intact RPE is not sufficient to maintain retinal epithelial polarity and retinal cellular pattern formation. Our results show that the subcellular architecture and cellular pattern formation of a tissue may be regulated by neighboring tissues through tissue–tissue interactions.
Expression patterns and role of prostaglandin-endoperoxide synthases, prostaglandin E synthases, prostacyclin synthase, prostacyclin receptor, peroxisome proliferator-activated receptor delta and retinoid x receptor alpha in rat endometrium during artificially-induced decidualization
Authors: Gillio-Meina Carolina , Phang Sen Han , Mather James P , Knight Brian S , Kennedy Thomas G
Published: December 2008

To determine if changes in endometrial expression of the enzymes and receptors involved in prostaglandin (PG) synthesis and action might provide insights into the PGs involved in the initiation of decidualization, ovariectomized steroid-treated rats at the equivalent of day 5 of pseudopregnancy were given a deciduogenic stimulus and killed at various times up to 32 h thereafter. The expression of PG-endoperoxide synthases (PTGS1 and PTGS2), microsomal PGE synthases (PTGES and PTGES2), cytosolic PGE synthase (PTGES3), prostacyclin synthase (PTGIS), prostacyclin receptor, peroxisome proliferator-activated receptor δ (PPARD) and retinoid x receptor α (RXRA) in endometrium was assessed by semiquantitative RT-PCR, western blot analyses and immunohistochemistry. In addition, to determine which PG is involved in mediating decidualization, we compared the ability of PGE2, stable analogues of PGI2, L165041 (an agonist of PPARD), and docasahexanoic acid (an agonist of RXRA) to increase endometrial vascular permeability (EVP, an early event in decidualization), and decidualization when infused into the uterine horns of rats sensitized for the decidual cell reaction (DCR). EVP was assessed by uterine concentrations of Evans blue 10 h after initiation of infusions. DCR was assessed by the uterine mass 5 days after the initiation of the infusions. Because enzymes associated with the synthesis of PGE2, including PTGS2, are up-regulated in response to a deciduogenic stimulus and because PGE2 was more effective than the PGI2 analogues and PPARD and RXRA agonists in increasing EVP and inducing decidualization, we suggest that PGE2 is most likely the PG involved in the initiation of decidualization in the rat.
Enhanced focal adhesion assembly reflects increased mechanosensation and mechanotransduction at maternal–conceptus interface and uterine wall during ovine pregnancy
Authors: Burghardt Robert C , Burghardt James R , Taylor James D , Reeder Adele T , Nguen Bar T , Spencer Thomas E , Bayless Kayla J , Johnson Greg A
Published: December 2008

The integrity of the fetal–maternal interface is critical for proper fetal nourishment during pregnancy. Integrins are important adhesion molecules present at the interface during implantation; however,in vivoevidence for integrin activation and focal adhesion formation at the maternal–conceptus interface is limited. We hypothesized that focal adhesion assembly in uterine luminal epithelium (LE) and conceptus trophectoderm (Tr) results from integrin binding of extracellular matrix (ECM) at this interface to provide increased tensile forces and signaling to coordinate utero-placental development. An ovine model of unilateral pregnancy was used to evaluate mechanotransduction events leading to focal adhesion assembly at the maternal–conceptus interface and within the uterine wall. Animals were hysterectomized on days 40, 80, or 120 of pregnancy, and uteri immunostained for integrins (ITGAV, ITGA4, ITGA5, ITGB1, ITGB3, and ITGB5), ECM proteins (SPP1, LGALS15, fibronectin (FN), and vitronectin (VTN)), cytoskeletal molecules (ACTN and TLN1), and a signal generator (PTK2). Focal adhesion assembly in myometrium and stroma was also studied to provide a frame of reference for mechanical stretch of the uterine wall. Large focal adhesions containing aggregates of ITGAV, ITGA4, ITGA5, ITGB1, ITGB5, ACTN, and PTK2 were detected in interplacentomal uterine LE and Tr of gravid but not non-gravid uterine horns and increased during pregnancy. SPP1 and LGALS15, but not FN or VTN, were present along LE and Tr interfaces in both uterine horns. These data support the idea that focal adhesion assembly at the maternal–conceptus interface reflects adaptation to increasing forces caused by the growing fetus. Cooperative binding of multiple integrins to SPP1 deposited at the maternal–conceptus interface forms an adhesive mosaic to maintain a tight connection between uterine and placental surfaces along regions of epitheliochorial placentation in sheep.
Progesterone and interferon tau regulate leukemia inhibitory factor receptor and IL6ST in the ovine uterus during early pregnancy
Authors: Song Gwonhwa , Satterfield M Carey , Kim Jinyoung , Bazer Fuller W , Spencer Thomas E
Published: December 2008

The actions of leukemia inhibitory factor (LIF) via LIF receptor (LIFR) and its co-receptor, IL6 signal transducer (IL6ST), are implicated in uterine receptivity to conceptus implantation in a number of species including sheep. The present study determined the effects of the estrous cycle, pregnancy, progesterone (P4), and interferon tau (IFNT) on the expression ofLIFRandIL6STin the ovine uterus.LIFRmRNA and protein were localized to the endometrial luminal (LE) and superficial glandular epithelia (sGE), whereasIL6STmRNA and protein were localized primarily in the middle to deep GE. BothLIFRandIL6STmRNAs and protein were more abundant in pregnant than cyclic ewes and increased from days 10 to 20 of pregnancy. Treatment of ovariectomized ewes with P4 and/or infusion of ovine IFNT increasedLIFRandIL6STin endometrial LE/sGE and GE respectively. Co-expression ofLIFRandIL6STas well as phosphorylated STAT3 was observed only in the upper GE of the endometrium as well as in the conceptus trophectoderm on days 18 and 20. In mononuclear trophectoderm and GE cells, LIF elicited an increase in phosphorylated STAT3 and MAPK3/1 MAPK proteins. Collectively, these results suggest thatLIFRandIL6STare both stimulated by IFNT and regulated by P4 in a complex stage- and cell-specific manner, and support the hypothesis that LIF exerts effects on the endometrial GE as well as conceptus trophectoderm during early pregnancy in sheep. Thus, LIF and STAT3 may have biological roles in endometrial function and trophectoderm growth and differentiation.
Good Response to Gefitinib in Lung Adenocarcinoma of Complex Epidermal Growth Factor Receptor (EGFR) Mutations with the Classical Mutation Pattern
Authors: Wu Shang-Gin , Chang Yih-Leong , Hsu Ya-Chieh , Wu Jenn-Yu , Yang Chih-Hsin , Yu Chong-Jen , Tsai Meng-Feng , Shih Jin-Yuan , Yang Pan-Chyr
Published: December 2008

Background.

Epidermal growth factor receptor (EGFR) mutations are usually detected in lung adenocarcinoma and are associated with a response to EGFR tyrosine kinase inhibitors (TKIs). However, not all EGFR mutations have similarly high clinical response rates. This study aimed to investigate the clinical characteristics and response to gefitinib in lung adenocarcinoma patients with complex EGFR mutations.

Materials and Methods.

Three hundred thirty-nine specimens of lung adenocarcinoma from patients treated with gefitinib were collected for EGFR sequencing. Nineteen patients with complex EGFR mutations were enrolled for the study after excluding three patients with the EGFR T790M mutation, which confers resistance to gefitinib.

Results.

Among the 19 patients, 12 had complex mutations with the classical mutation pattern (L858R or deletion in exon 19). When compared with those without the classical mutation pattern, patients with this mutation pattern had a higher response rate (83% versus 29%), longer progression-free survival duration (median, 12.7 months versus 4.9 months), and longer overall survival time (median, 24.7 months versus 12.3 months) after gefitinib treatment.

Comparing patients harboring complex EGFR mutations with a classical mutation pattern with those harboring single classical mutations, there were no statistical differences in the response rate (83% versus 73%), progression-free survival time (median, 12.7 months versus 8.1 months,) or overall survival time (median, 24.7 months versus 16.4 months).

Conclusion.

Patients with complex EGFR mutations with the classical mutation pattern had the same response rate, progression-free survival duration, and overall survival time as those with single classical mutations. EGFR TKIs may be the choice of treatment for this type of lung adenocarcinoma.
Persistence, Up to 18 Months of Follow-Up, of Epirubicin-Induced Myocardial Dysfunction Detected Early by Serial Tissue Doppler Echocardiography: Correlation with Inflammatory and Oxidative Stress Markers
Authors: Mantovani Giovanni , Madeddu Clelia , Cadeddu Christian , Dessì Mariele , Piras Alessandra , Massa Elena , Serpe Roberto , Antoni Giorgia , Mercuro Giuseppe
Published: December 2008

A phase II, open, nonrandomized trial was carried out in a group of epirubicin-treated cancer patients with the aim of detecting early preclinical changes that are predictive of the risk for heart failure. Thirty-one patients (male/female ratio, 8/23; mean age ± standard deviation, 59 ± 14 years) with tumors at different sites and scheduled to be treated with an epirubicin-based chemotherapy regimen, were enrolled. We prospectively evaluated the acute (1 week after) and late (3, 6, 12, and 18 months of follow-up) effects of epirubicin administration. A significant impairment in systolic left ventricular (LV) function was observed at a cumulative epirubicin dose of 200 mg/m2. This was shown by a reduction in the strain rate (SR) peak in comparison with baseline and persisted throughout the treatment and follow-up, up to 18 months; strain (Σ) remained unchanged. The Sm wave showed a progressive reduction that became significant only at the 18-month follow-up. On TDI the Em/Am ratio declined at the 200-mg/m2 cumulative epirubicin dose versus baseline and persisted throughout the treatment and up to the 18-month follow-up. On conventional echocardiography the E/A ratio declined significantly only at the 300-mg/m2 cumulative epirubicin dose. Interleukin (IL)-6, soluble IL-6 receptor, and reactive oxygen species (ROS) increased significantly at the 200-mg/m2 dose, and IL-6 was persistently high at the 300- and 400-mg/m2 doses, returning to within baseline values during follow-up. ROS, after the peak reached at the 200-mg/m2 dose, returned to within baseline values. A significant inverse correlation between ΔSR and the increase in both IL-6 and ROS was observed. A multiple regression analysis showed that both the IL-6 and ROS variables were independent and strongly predictive of ΔSR. The clinical meaningfulness of our findings warrants further investigations on a larger number of patients for a longer period of follow-up.
Expression and regulation of glucocorticoid-induced leucine zipper in the developing anterior pituitary gland
Authors: Ellestad Laura E , Malkiewicz Stefanie A , Guthrie H David , Welch Glenn R , Porter Tom E
Published: December 2008

The expression profile of glucocorticoid-induced leucine zipper (GILZ) in the anterior pituitary during the second half of embryonic development in the chick is consistent with in vivo regulation by circulating corticosteroids. However, nothing else has been reported about the presence of GILZ in the neuroendocrine system. We sought to characterize expression and regulation of GILZ in the chicken embryonic pituitary gland and determine the effect of GILZ overexpression on anterior pituitary hormone levels. Pituitary GILZ mRNA levels increased during embryogenesis to a maximum on the day of hatch, and decreased through the first week after hatch. GILZ expression was rapidly upregulated by corticosterone in embryonic pituitary cells. To determine whether GILZ regulates hormone gene expression in the developing anterior pituitary, we overexpressed GILZ in embryonic pituitary cells and measured mRNA for the major pituitary hormones. Exogenous GILZ increased prolactin mRNA above basal levels, but not as high as that in corticosterone-treated cells, indicating that GILZ may play a small role in lactotroph differentiation. The largest effect we observed was a twofold increase in FSH β subunit in cells transfected with GILZ but not treated with corticosterone, suggesting that GILZ may positively regulate gonadotroph development in a manner not involving glucocorticoids. In conclusion, this is the first report to characterize avian GILZ and examine its regulation in the developing neuroendocrine system. We have shown that GILZ is upregulated by glucocorticoids in the embryonic pituitary gland and may regulate expression of several pituitary hormones.
Retinoic acid-mediated down-regulation of ENO1/MBP-1 gene products caused decreased invasiveness of the follicular thyroid carcinoma cell lines
Authors: Trojanowicz Bogusz , Winkler Anja , Hammje Kathrin , Chen Zhouxun , Sekulla Carsten , Glanz Dagobert , Schmutzler Cornelia , Mentrup Birgit , Hombach-Klonisch Sabine , Klonisch Thomas , Finke Rainer , Köhrle Josef , Dralle Henning , Hoang-Vu Cuong
Published: December 2008

Retinoic acid (RA) acts as an anti-proliferative and redifferentiation agent in the therapy of thyroid carcinoma. Our previous studies demonstrated that pretreatment of follicular thyroid carcinoma cell lines FTC-133 and FTC-238 resulted in decreased in vitro proliferation rates and reduced tumor cell growth of xenotransplants. In addition to the previous results, we found that RA led to decreased vitality and invasiveness of FTC-133 and FTC-238 cells as they reacted with reduction of intracellular ATP levels and number of migrated cells respectively. However, the molecular mechanisms by which RA mediates these effects are not well understood. Two-dimensional (2D) screening of the proteins related to ATP metabolism and western blot analysis revealed α-enolase (ENO1) to be down-regulated in FTC-133 and FTC-238 cells after RA treatment. 2D gel detection and mass spectrometric analysis revealed that ENO1 existed as three separate protein spots of distinct pIs (ENO1–A1–A3). Comparative 2D difference gel electrophoresis analysis of fluorescently labeled protein samples of RA-treated and untreated FTC-133 demonstrated a selective down-regulation of ENO1-A1 which we identified as a phosphoprotein. RA caused the dephosphorylation of ENO1-A1. Both, RA-mediated and specific knock-down of ENO1/MBP-1 resulted in the reduction of MYC oncoprotein, and simultaneously decreased proliferation rates of FTC-133 and FTC-238 cell lines. In summary, the RA-mediated down-regulation of the ENO1 gene products and MYC oncoprotein provides a novel molecular mechanism facilitating the anti-proliferative effect of RA in human thyroid carcinoma cells and suggests new pathways for supportive RA therapies.
Role of the E3 ubiquitin ligase gene related to anergy in lymphocytes in glucose and lipid metabolism in the liver
Authors: Nakamichi Sachie , Senga Yoko , Inoue Hiroshi , Emi Aki , Matsuki Yasushi , Watanabe Eijiro , Hiramatsu Ryuji , Ogawa Wataru , Kasuga Masato
Published: December 2008

Gene related to anergy in lymphocytes (GRAIL) is an E3 ubiquitin ligase that regulates energy in T-lymphocytes. Whereas, the relevance of GRAIL to T lymphocyte function is well established, the role of this protein in other cell types remains unknown. Given that GRAIL is abundant in the liver, we investigated the potential function of GRAIL in nutrient metabolism by generating mice in which the expression of GRAIL is reduced specifically in the liver. Adenovirus-mediated transfer of a short hairpin RNA specific for GRAIL mRNA markedly reduced the amounts of GRAIL mRNA and protein in the liver. Blood glucose levels of the mice with hepatic GRAIL deficiency did not differ from those of control animals in the fasted or fed states. However, these mice manifested glucose intolerance in association with a normal increase in plasma insulin levels during glucose challenge. The mice also manifested an increase in the serum concentration of free fatty acids, whereas the serum levels of cholesterol and triglyceride were unchanged. The hepatic abundance of mRNAs for glucose-6-phosphatase, catalytic (a key enzyme in hepatic glucose production) and for sterol regulatory element-binding transcription factor 1 (an important transcriptional regulator of lipogenesis) was increased in the mice with hepatic GRAIL deficiency, possibly contributing to the metabolic abnormalities of these animals. Our results thus demonstrate that GRAIL in the liver is essential for maintenance of normal glucose and lipid metabolism in living animals.
How to study lipidomes
Authors: Seppänen-Laakso Tuulikki , Orešič Matej
Published: December 2008

Lipidome is loosely defined as the entire spectrum of lipids in a biological system. Given the modern lipidomics platforms for the first time empower us with the ability to obtain a snapshot of complete cellular/organismal lipidome, many surprises and discoveries are likely awaiting us in the area of lipids as related to cellular/organismal physiology. The lipidomics approaches can be applied both as the phenotyping platform and for the hypothesis-driven research aiming to elucidate, e.g., a specific pathway or gene function. Modern lipidomics methods combine the latest mass spectrometry technology and bioinformatics methods with traditional methods such as for sample preparation and lipid extraction.
Hexose-6-phosphate dehydrogenase: linking endocrinology and metabolism in the endoplasmic reticulum
Authors: Bánhegyi Gábor , Csala Miklós , Benedetti Angelo
Published: December 2008

Hexose-6-phosphate dehydrogenase (H6PD) got into the focus of interest due to its role in the prereceptorial activation of glucocorticoids, which has been implicated in the pathomechanism of metabolic syndrome. Genetic observations, results gained in H6PD knockout mice, and studies on differentiating adipocytes demonstrated the importance of the enzyme in metabolic regulation. A nutrient-sensing function can be postulated for the enzyme, which links metabolism to endocrinology in the endoplasmic reticulum. This review provides an overview of the recent developments concerning the enzyme and its impact on various branches of the intermediary metabolism, which make it an important subject for the research on obesity, diabetes, and metabolic syndrome.