bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of flexible-heteroarotinoids for kidney cancer
Authors: Liu Tongzu , Masamha Chioniso Patience , Chengedza Shylet , Berlin K. Darrell , Lightfoot Stan , He Feng , Benbrook Doris Mangiaracina 
Published: May 2009

Abstract
Potential chemopreventive and therapeutic value of the lead Flexible Heteroarotinoid (Flex-Het), SHetA2, was indicated by growth inhibition of multiple cancer cell lines. The objective of this study was to evaluate the SHetA2 mechanism and in vivo activity in kidney cancer. SHetA2 induced apoptosis in the Caki-1 kidney cancer cell line through reduction of Bcl-2 protein and induction of PARP-1 and caspase 3 cleavages, whereas normal kidney epithelial cells exhibited resistance. Both normal and cancerous cells underwent G1 arrest and loss of Cyclin D1. Tubule differentiation was induced in organotypic cultures and xenograft tumors in association with increases in E-Cadherin mRNA and protein expression. SHetA2 repressed activity of nuclear factor-κB, a transcription factor that regulates apoptosis, Bcl-2, growth, Cyclin D1, differentiation, and E-Cadherin in the opposite manner as SHetA2. Glutathione binding and generation of reactive oxygen species were not required for these activities. Oral SHetA2 inhibited growth in one of two renal cancer xenograft models without causing mortality or weight loss. Structure function analysis of related Flex-Hets for potential improvement of SHetA2 pharmaceutical properties showed that compounds with increased hydrophilicity slightly reduced the growth inhibition efficacy, but retained the differential effect on cancer over normal cells. Flex-Hets and metabolites were not mutagenic in the Ames test. In conclusion, SHetA2 regulates growth, differentiation, and apoptosis in kidney cancer cells through multiple molecular events downstream of nuclear factor-κB repression. Increasing the hydrophilicity of Flex-Hets does not attenuate the differential effect on cancer cells over normal cells, thus offering alternatives for improvement of therapeutic value.[Mol Cancer Ther 2009;8(5):OF1–12]
Transcriptional induction of GRP78/BiP by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor–induced apoptosis
Authors: Baumeister Peter , Dong Dezheng , Fu Yong , Lee Amy S. 
Published: May 2009

AbstractHistone deacetylase (HDAC) inhibitors are emerging as effective therapies in the treatment of cancer, and the role of HDACs in the regulation of promoters is rapidly expanding. GRP78/BiP is a stress inducible endoplasmic reticulum (ER) chaperone with antiapoptotic properties. We present here the mechanism for repression of the Grp78 promoter by HDAC1. Our studies reveal that HDAC inhibitors specifically induce GRP78, and the induction level is amplified by ER stress. Through mutational analysis, we have identified the minimal Grp78 promoter and specific elements responsible for HDAC-mediated repression. We show the involvement of HDAC1 in the negative regulation of the Grp78 promoter not only by its induction in the presence of the HDAC inhibitors trichostatin A and MS-275 but also by exogenous overexpression and small interfering RNA knockdown of specific HDACs. We present the results of chromatin immunoprecipitation analysis that reveals the binding of HDAC1 to the Grp78 promoter before, but not after, ER stress. Furthermore, overexpression of GRP78 confers resistance to HDAC inhibitor–induced apoptosis in cancer cells, and conversely, suppression of GRP78 sensitizes them to HDAC inhibitors. These results define HDAC inhibitors as new agents that up-regulate GRP78 without concomitantly inducing the ER or heat shock stress response, and suppression of GRP78 in tumors may provide a novel, adjunctive option to enhance anticancer therapies that use these compounds. [Mol Cancer Ther 2009;8(5):1086–94]
Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin
Authors: LeBeau Aaron M. , Brennen W. Nathaniel , Aggarwal Saurabh , Denmeade Samuel R. 
Published: May 2009

Abstract
Fibroblast-Activation Protein-α (FAP) is a membrane-bound serine protease that is expressed on the surface of reactive stromal fibroblasts present within the majority of human epithelial tumors but is not expressed by normal tissues. FAP is a postprolyl peptidase that differs from other dipeptidyl prolyl peptidases such as diprolylpeptidase 4 in that it also has gelatinase and collagenase endopeptidase activity. Therefore, FAP represents a potential pan-tumor target whose enzymatic activity can be exploited for the intratumoral activation of prodrugs and protoxins. To evaluate FAP as a tumor-specific target, putative FAP-selective peptide protoxins were constructed through modification of the prodomain of melittin, a 26 amino acid amphipathic cytolytic peptide that is the main toxic component in the venom of the common European honeybee Apis milefera. Melittin is synthesized as promelittin, containing a 22 amino acid NH2-terminal prodomain rich in the amino acids proline and alanine. In this study, peptides containing truncated melittin prodomain sequences were tested on erythrocytes to determine the optimal prodomain length for inhibiting cytolytic activity. Once optimized, modified promelittin peptides were generated in which previously identified FAP substrate sequences were introduced into the prodomain. Peptide protoxins were identified that were efficiently activated by FAP and selectively toxic to FAP-expressing cell lines with an IC50 value in the low micromolar range that is similar to melittin. Intratumoral injection of an FAP-activated protoxin produced significant lysis and growth inhibition of human breast and prostate cancer xenografts with minimal toxicity to the host animal. [Mol Cancer Ther 2009;8(5):1378–86]
Differences in Physician and Patient Ratings of Items Used to Assess Hip Disorders
Authors: Martin RobRoy L. , Mohtadi Nicholas G. , Safran Marc R. , Leunig Michael , Martin Hal D. , McCarthy Joseph , Guanche Carlos A. , Kelly Bryan T. , Byrd J. W. Thomas , Clohisy John C. , Philippon Marc J. , Sekiya Jon K. 
Published: May 2009

Background The purpose of this study was to determine what issues are important to active individuals with hip lesions and to assess whether these issues are different from those that surgeons think are important. Hypothesis A discrepancy will be noted between what patients and surgeons believe to be important. Study Design Cross-sectional study; Level of evidence, 3. Methods This study comprised 150 consecutive patients (73 men, 77 women) from the international practices of 9 orthopaedic surgeons specializing in the management of hip disorders. All participants were seeking treatment for musculoskeletal hip disease. Average patient age was 42 ± 11 years (range, 18-60). Patients and surgeons rated the importance of 146 potential hip outcome assessment items on a 6-point Likert-type scale. Results Of the 23 items identified as being important to patients, 16 were in the sports and recreation category. The top 11 items that the clinicians thought were most important were rated significantly lower by patients (P <. 0005). Specifically, surgeons rated several items as being important that fell into the symptoms, functional limitations, and occupational issues categories, whereas patients did not. That is, a difference was found between patients and clinicians in how they rated items related to symptoms, functional limitations, and occupation (P <. 01). A difference was not found between patients and surgeons in how they rated items related to sports and recreation and social-emotional lifestyle (P >. 01). Conclusion The hypothesis of this study was affirmed: a discrepancy was found between what issues patients believe are important and what surgeons perceive as being important to patients. This information may be particularly important when assessing treatment outcomes from a patient's perspective. Clinicians must be careful in presuming that the issues that they are attempting to improve with treatment are issues that are important to patients. These findings also emphasize the importance of discussing appropriate postoperative expectations for those considering surgery.
Mitochondrial clearance is regulated by Atg7-dependent and -independent mechanisms during reticulocyte maturation
Authors: Zhang Ji , Randall Mindy S. , Loyd Melanie R. , Dorsey Frank C. , Kundu Mondira , Cleveland John L. , Ney Paul A. 
Published: May 2009

AbstractMitochondrial clearance is a well recognized but poorly understood biologic process, and reticulocytes, which undergo programmed mitochondrial clearance, provide a useful model to study this phenomenon. At the ultrastructural level, mitochondrial clearance resembles an autophagy-related process; however, the role of autophagy in mitochondrial clearance has not been established. Here we provide genetic evidence that autophagy pathways, initially identified in yeast, are involved in mitochondrial clearance from reticulocytes. Atg7 is an autophagy protein and an E1-like enzyme, which is required for the activity of dual ubiquitin-like conjugation pathways. Atg7 is required for the conjugation of Atg12 to Atg5, and Atg8 to phosphatidylethanolamine (PE), and is essential for autophagosome formation. In the absence of Atg7, mitochondrial clearance from reticulocytes is diminished but not completely blocked. Mammalian homologs of Atg8 are unmodified in Atg7−/− erythroid cells, indicating that canonical autophagy pathways are inactive. Thus, mitochondrial clearance is regulated by both autophagy-dependent and -independent mechanisms. In addition, mitochondria, which depolarize in wild-type cells before elimination, remain polarized in Atg7−/− reticulocytes in culture. This suggests that mitochondrial depolarization is a consequence rather than a cause of autophagosome formation in reticulocytes.
Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3
Authors: Fukuda Seiji , Singh Pratibha , Moh Akira , Abe Mariko , Conway Edward M. , Boswell H. Scott , Yamaguchi Seiji , Fu Xin-Yuan , Pelus Louis M. 
Published: May 2009

Abstract
Internal tandem duplication mutations in the Flt3 tyrosine kinase gene (ITD-Flt3) and overexpression of Survivin are frequently found in patients with acute myeloid leukemia (AML). We investigated whether Survivin mediates the enhanced survival of primary hematopoietic progenitor cells (HPCs) resulting from ITD-Flt3 signaling. Ectopic ITD-Flt3 mutants increased Survivin expression in Ba/F3 cells downstream of PI3-kinase/Akt. Treatment of ITD-Flt3+ human MV4-11 leukemia cells with the ITD-Flt3 inhibitor SU5416 reduced Survivin expression and inhibited cell proliferation. ITD-Flt3 dramatically increased the number of primary mouse marrow c-kit+, Sca-1+, LinNeg cells and colony-forming unit granulocyte-macrophages (CFU-GMs) able to proliferate in the absence of growth factors, whereas Survivin deletion significantly reduced growth factor–independent proliferation and increased apoptosis, which was further accentuated by SU5416. Ectopic ITD-Flt3 reduced differentiation of LinNeg marrow cells cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) plus stem cell factor, which was partially blocked by Survivin deletion. In addition, Survivin deletion decreased secondary colony formation induced by ITD-Flt3. Dominant-negative (dn)–Survivin delayed development of acute leukemia in mice that received a transplant of Ba/F3 cells expressing ITD-Flt3. These results suggest that Survivin regulates expansion of ITD-Flt3–transformed HPCs with self-renewal capability and development of ITD-Flt3+ acute leukemia and that antagonizing Survivin may provide therapeutic benefit for patients with acute leukemia expressing ITD-Flt3.
Thrombin-cleaved osteopontin regulates hemopoietic stem and progenitor cell functions through interactions with α9β1 and α4β1 integrins
Authors: Grassinger Jochen , Haylock David N. , Storan Melonie J. , Haines Gemma O. , Williams Brenda , Whitty Genevieve A. , Vinson Andrew R. , Be Cheang Ly , Li Songhui , Sørensen Esben S. , Tam Patrick P.L. , Denhardt David T. , Sheppard Dean , Choong Peter F. , Nilsson Susan K. 
Published: May 2009

AbstractOsteopontin (OPN), a multifunctional acidic glycoprotein, expressed by osteoblasts within the endosteal region of the bone marrow (BM) suppresses the proliferation of hemopoietic stem and progenitor cells and also regulates their lodgment within the BM after transplantation. Herein we demonstrate that OPN cleavage fragments are the most abundant forms of this protein within the BM. Studies aimed to determine how hemopoietic stem cells (HSCs) interact with OPN revealed for the first time that murine and human HSCs express α9β1 integrin. The N-terminal thrombin cleavage fragment of OPN through its binding to the α9β1 and α4β1 integrins plays a key role in the attraction, retention, regulation, and release of hemopoietic stem and progenitor cells to, in, and from their BM niche. Thrombin-cleaved OPN (trOPN) acts as a chemoattractant for stem and progenitor cells, mediating their migration in a manner that involves interaction with α9β1 and α4β1 integrins. In addition, in the absence of OPN, there is an increased number of white blood cells and, specifically, stem and progenitor cells in the peripheral circulation.
Immunomodulatory drugs reorganize cytoskeleton by modulating Rho GTPases
Authors: Xu Yibing , Li Jianwu , Ferguson Gregory D. , Mercurio Frank , Khambatta Gody , Morrison Lisa , Lopez-Girona Antonia , Corral Laura G. , Webb David R. , Bennett Brydon L. , Xie Weilin 
Published: May 2009

AbstractIMiDs immunomodulatory drugs, including lenalidomide and pomalidomide represent a novel class of small molecule anticancer and anti-inflammatory drugs with broad biologic activities. However, the molecular mechanism through which these drugs exert their effects is largely undefined. Using pomalidomide and primary human monocytes, we report that pomalidomide rapidly and selectively activated RhoA and Rac1, but not Cdc42 or Ras, in the absence of any costimulation. Consistent with the activation of Rho GTPases, we found that pomalidomide enhanced F-actin formation, stabilized microtubules, and increased cell migration, all of which were blocked by selective inhibitors of ROCK1 and Rac1. Further, we showed that in Swiss 3T3 cells, pomalidomide only activated RhoA, not Rac1 or Cdc42, and potently induced stress fiber formation. The pomalidomide effect on actin cytoskeleton was blocked by the ROCK1 inhibitor, but not Rac1 inhibitor. Finally, we demonstrated that pomalidomide was able to regulate the activity of Rho GTPases and the formation of F-actin in primary human T cells as it did in monocytes and showed that the activation of RhoA was essential for pomalidomide-induced interleukin-2 expression in T cells. These novel activities provide what we believe a critical mechanism by which IMiDs drugs function as therapeutic immunomodulatory agents.
The relationship between the serum free light chain assay and serum immunofixation electrophoresis, and the definition of concordant and discordant free light chain ratios
Authors: Singhal Seema , Vickrey Eric , Krishnamurthy Jairam , Singh Veerpal , Allen Sharon , Mehta Jayesh 
Published: May 2009

Abstract“Stringent” complete remission in myeloma has been defined by a normal serum free light chain ratio (SFLCR) in addition to the standard criteria for CR. 2648 serial samples from 122 IgG or IgA myeloma patients were studied to explore the relationship between SFLCR and serum immunofixation electrophoresis (SIFE). SFLCR was normal in 34% of cases with positive SIFE and abnormal in 66%. SFLCR was normal in 69% of cases with negative SIFE and abnormal in 31%. When evaluated with SIFE as the benchmark, the sensitivity of SFLCR was 66% and specificity was 69%. These findings were unchanged when abnormal SFLCR values were classified as concordant (< 0.26 for λ disease and > 1.65 for κ) or discordant (< 0.26 for κ disease and > 1.65 for λ). Additional studies are required to determine the temporal relationship between SFLCR normalization and paraprotein clearance. Until then, the role of SFLCR in defining response remains controversial.
Cellular senescence of white blood cells in very long-term survivors after allogeneic hematopoietic stem cell transplantation: the role of chronic graft-versus-host disease and female donor sex
Authors: Baerlocher Gabriela M. , Rovó Alicia , Müller Astrid , Matthey Sybille , Stern Martin , Halter Jörg , Heim Dominik , Rischewski Johannes , Gratwohl Alois , Tichelli André 
Published: May 2009

Abstract
In this single-center, cross-sectional study, we evaluated 44 very long-term survivors with a median follow-up of 17.5 years (range, 11-26 years) after hematopoietic stem cell transplantation. We assessed the telomere length difference in human leukocyte antigen-identical donor and recipient sibling pairs and searched for its relationship with clinical factors. The telomere length (in kb, mean ± SD) was significantly shorter in all recipient blood cells compared with their donors' blood cells (P < .01): granulocytes (6.5 ± 0.9 vs 7.1 ± 0.9), naive/memory T cells (5.7 ± 1.2 vs 6.6 ± 1.2; 5.2 ± 1.0 vs 5.7 ± 0.9), B cells (7.1 ± 1.1 vs 7.8 ± 1.1), and natural killer/natural killer T cells (4.8 ± 1.0 vs 5.6 ± 1.3). Chronic graft-versus-host disease (P < .04) and a female donor (P < .04) were associated with a greater difference in telomere length between donor and recipient. Critically short telomeres have been described in degenerative diseases and secondary malignancies. If this hypothesis can be confirmed, identification of recipients at risk for cellular senescence could become part of monitoring long-term survivors after hematopoietic stem cell transplantation.
Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats
Authors: Hsu Hsao-Hsun , Ko Wen-Je , Hsu Jo-Yu , Chen Jin-Shing , Lee Yung-Chie , Lai I-Rue , Chen Chau-Fong 
Published: May 2009

AbstractBackgroundSimvastatin has been shown to ameliorate pulmonary hypertension by several mechanisms in experimental animal models. In this study, we hypothesized that the major benefits of simvastatin in pulmonary hypertension occur via the heme oxygenase-1 pathway.MethodsSimvastatin (10 mg/kgw/day) was tested in two rat models of pulmonary hypertension (PH): monocrotaline administration and chronic hypoxia. The hemodynamic changes, right heart hypertrophy, HO-1 protein expression, and heme oxygenase (HO) activity in lungs were measured in both models with and without simvastatin treatment. Tin-protoporphyrin (SnPP, 20 μmol/kg w/day), a potent inhibitor of HO activity, was used to confirm the role of HO-1.ResultsSimvastatin significantly ameliorated pulmonary arterial hypertension from 38.0 ± 2.2 mm Hg to 22.1 ± 1.9 mm Hg in monocrotaline-induced PH (MCT-PH) and from 33.3 ± 0.8 mm Hg to 17.5 ± 2.9 mm Hg in chronic hypoxia-induced PH (CH-PH) rats. The severity of right ventricular hypertrophy was significantly reduced by simvastatin in MCT-PH and CH-PH rats. Co-administration with SnPP abolished the benefits of simvastatin. Simvastatin significantly increased HO-1 protein expression and HO activity in the lungs of rats with PH; however co-administration of SnPP reduced HO-1 activity only. These observations indicate that the simvastatin-induced amelioration of pulmonary hypertension was directly related to the activity of HO-1, rather than its expression.ConclusionThis study demonstrated that simvastatin treatment ameliorates established pulmonary hypertension primarily through an HO-1-dependent pathway.
Puromycin-based vectors promote a ROS-dependent recruitment of PML to nuclear inclusions enriched with HSP70 and Proteasomes
Authors: Moran Diarmuid M , Shen Hong , Maki Carl G 
Published: May 2009

Abstract

Background
Promyelocytic Leukemia (PML) protein can interact with a multitude of cellular factors and has been implicated in the regulation of various processes, including protein sequestration, cell cycle regulation and DNA damage responses. Previous studies reported that misfolded proteins or proteins containing polyglutamine tracts form aggregates with PML, chaperones, and components of the proteasome, supporting a role for PML in misfolded protein degradation.

Results
In the current study, we have identified a reactive oxygen species (ROS) dependent aggregation of PML, small ubiquitin-like modifier 1 (SUMO-1), heat shock protein 70 (HSP70) and 20S proteasomes in human cell lines that have been transiently transfected with vectors expressing the puromycin resistance gene, puromycin n-acetyl transferase (pac). Immunofluorescent studies demonstrated that PML, SUMO-1, HSP70 and 20S proteasomes aggregated to form nuclear inclusions in multiple cell lines transfected with vectors expressing puromycin (puro) resistance in regions distinct from nucleoli. This effect does not occur in cells transfected with identical vectors expressing other antibiotic resistance genes or with vectors from which the pac sequence has been deleted. Furthermore, ROS scavengers were shown to ablate the effect of puro vectors on protein aggregation in transfected cells demonstrating a dependency of this effect on the redox state of transfected cells.

Conclusion
Taken together we propose that puromycin vectors may elicit an unexpected misfolded protein response, associated with the formation of nuclear aggresome like structures in human cell lines. This effect has broad implications for cellular behavior and experimental design.
Genome-wide identification and characterization of cytochrome P450 monooxygenase genes in the ciliate Tetrahymena thermophila
Authors: Fu Chengjie , Xiong Jie , Miao Wei 
Published: May 2009

Abstract

Background
Cytochrome P450 monooxygenases play key roles in the metabolism of a wide variety of substrates and they are closely associated with endocellular physiological processes or detoxification metabolism under environmental exposure. To date, however, none has been systematically characterized in the phylum Ciliophora. T. thermophila possess many advantages as a eukaryotic model organism and it exhibits rapid and sensitive responses to xenobiotics, making it an ideal model system to study the evolutionary and functional diversity of the P450 monooxygenase gene family.

Results
A total of 44 putative functional cytochrome P450 genes were identified and could be classified into 13 families and 21 sub-families according to standard nomenclature. The characteristics of both the conserved intron-exon organization and scaffold localization of tandem repeats within each P450 family clade suggested that the enlargement of T. thermophila P450 families probably resulted from recent separate small duplication events. Gene expression patterns of all T. thermophila P450s during three important cell physiological stages (vegetative growth, starvation and conjugation) were analyzed based on EST and microarray data, and three main categories of expression patterns were postulated. Evolutionary analysis including codon usage preference, site-specific selection and gene-expression evolution patterns were investigated and the results indicated remarkable divergences among the T. thermophila P450 genes.

Conclusion
The characterization, expression and evolutionary analysis of T. thermophila P450 monooxygenase genes in the current study provides useful information for understanding the characteristics and diversities of the P450 genes in the Ciliophora, and provides the baseline for functional analyses of individual P450 isoforms in this model ciliate species.