bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endoconidioma populifrom aspen and alder: phylogeny, and variations in cleistopycnidial morphology and their ecological implications
Authors: Tsuneda A. , Hambleton S. , Currah R. S. 
Published: July 2010

Cleistopycnidial ontogeny and sequences of nuclear internal transcribed spacers (ITS) and large subunits (LSU) were compared for five strains of Endoconidioma populi Tsuneda et al.: three from trembling aspen and two from alder. The cleistopycnidia of two of the aspen strains, including the type strain, were subglobose to flask-shaped (mostly 35–100 µm × 30–60 µm), and consisted solely of meristematic cells with thick cell walls that were heavily impregnated with melanin granules. Peridial cells were not visibly differentiated from locular cells and were also capable of forming endoconidia. Endoconidia were released from one to several sites of the cleistopycnidium by the dissolution of peridial cell wall. The alder strains shared these characteristics, except that their cleistopycnidia released both endoconidia and conidiogenous cells. Unlike those four strains, cleistopycnidia of the third aspen strain were cylindrical, often exceeding 500 µm in length, branched, and possessed a peridium of textura angularis that developed from short, determinate hyphae. Conidiogenous cells contained abundant lipid bodies that were not mobilized until the onset of endoconidiogenesis. The peridium at the basal area was prone to breakage by external forces, indicating that the individual cleistopycnidium, as a whole, functions as a dispersal unit. A small number of ITS nucleotide differences among strains corresponded to their observed morphological differences and host association. Phylogenetic analyses suggested a close relationship of E. populi with Hormonema carpetanum Bills, Peláez & Ruibal, and Coniozyma leucospermi (Crous & Denman) Crous.
Antimycobacterial screening of traditional medicinal plants using the microplate resazurin assay
Authors: Webster Duncan , Lee Timothy D.G. , Moore Jill , Manning Tracy , Kunimoto Dennis , LeBlanc Darren , Johnson John A. , Gray Christopher A. 
Published: July 2010

Multidrug-resistant Mycobacterium tuberculosis strains have rapidly become a global health concern. North American First Nations communities have used traditional medicines for generations to treat many pulmonary infections. In this study, we evaluated the antimycobacterial activity of 5 medicinal plants traditionally used as general therapeutics for pulmonary illnesses and specifically as treatments for tuberculosis. Aqueous extracts of Aralia nudicaulis , Symplocarpus foetidus , Heracleum maximum , Juniperus communis, and Acorus calamus were screened for antimycobacterial activity against Bacillus Calmette–Guérin, Mycobacterium avium, and M. tuberculosis H37Ra using the colorimetric microplate resazurin assay. Extracts of Acorus calamus and H. maximum root demonstrated significant antimycobacterial activity comparable to that of the rifampin control (2 µg/mL). Evaluation of the cytotoxicity of these 2 extracts using the MTT assay also showed that the extracts were less toxic to 3 human cell lines than was the DMSO positive control. This study demonstrates that aqueous extracts of the roots of H. maximum and Acorus calamus possess strong in vitro antimycobacterial activity, validates traditional knowledge, and provides potential for the development of urgently needed novel antituberculous therapeutics.
ET-1 plasma levels and ocular blood flow in retinitis pigmentosaThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.
Authors: Cellini Mauro , Strobbe Ernesto , Gizzi Corrado , Campos Emilio C. 
Published: July 2010

Retinitis pigmentosa (RP) is an inherited retinal disorder clinically characterized by a pale, waxy optic nerve head, attenuated retinal blood vessels, and bone spicule pigment in the retina. Hemodynamic studies have demonstrated that RP is associated with a reduction in the retinal and choroidal blood flow. Retinal hemodynamic impairment is also present in early stages of RP, and various hypotheses have been advanced as to the cause. The authors studied 20 patients, 12 males and 8 females, aged 26–42 years (mean 35.1 years) and affected by simplex RP. The patients had a visual acuity of 0.9 ± 0.1, visual field mean defect of –6.52 ± 3.58 dB, and b-wave electroretinogram amplitude of 260.08 ± 8.24 µV. An increase in plasma levels of endothelin-1 (ET-1) was found: 1.910 ± 0.317 pg/mL versus 1.180 ± 0.210 pg/mL in non-RP controls (p < 0.02). Moreover both an ocular and systemic vascular impairment was detected by means of color Doppler imaging and laser Doppler flowmetry performed during a cold pressor test. We found a correlation between the increase of ET-1 plasma levels in RP and the decrease of peak systolic velocity in the ophthalmic artery (p < 0.03) and in the posterior ciliary arteries (p < 0.006). It is thought that an increase of ET-1 and retinal oxygen levels in RP could lead to vasoconstriction and a decrease of the retinal blood flow, worsening the abiotrophic process.
Remarkably long-lasting tachyphylaxis of pain responses to ET-1: evidence against central nervous system involvementThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.
Authors: Khodorova Alla , Strichartz Gary R. 
Published: July 2010

A profound tachyphylaxis of the acute nocifensive flinching (pain) response to subcutaneous injection of endothelin-1 (ET-1) into the hind paw footpad is shown by the reduced response to a second injection. Flinching from the second injection was 20% ± 5%, 57% ± 18%, 79% ± 35%, and 100% ± 17% of that from the first injection (both 200 µmol/L, 2 nmol) at respective intervals of 24, 30, 48, and 72 h. Inhibition of afferent impulses by local anesthesia of the sciatic nerve, reducing initial flinching to 6%–13% of control, did not affect the tachyphylaxis for the second injection at 24 h. There was no cross-desensitization between formalin and ET-1 injected sequentially into the same paw. Suppression of descending inhibitory effects from endogenous opiates by naloxone (5–8 mg/kg, i.p.), given 30 min before the second ET-1 injection, did not prevent tachyphylaxis. Diffuse effects caused by an initial subcutaneous ET-1 injection into the tail or forepaw resulted in sensitization of the response to ET-1 in the hind paw, rather than tachyphylaxis. In contrast, selective inhibition of local ETAreceptors during the initial administration of ET-1, by the antagonist BQ-123 (3.2 mmol/L), reduced tachyphylaxis of nocifensive flinching. Therefore, prolonged pain tachyphylaxis is not due to reduced responsiveness of the CNS, but rather depends on the functional sensitivity or availability of peripheral ETAreceptors.
A Chemosensitization Screen Identifies TP53RK, a Kinase that Restrains Apoptosis after Mitotic Stress
Authors: Peterson David , Lee James , Lei Xingye C. , Forrest William F. , Davis David P. , Jackson Peter K. , Belmont Lisa D. 
Published: July 2010

Abstract
Taxanes are very effective at causing mitotic arrest; however, there is variability among cancer cells in the apoptotic response to mitotic arrest. The variability in clinical efficacy of taxane-based therapy is likely a reflection of this variability in apoptotic response, thus elucidation of the molecular mechanism of the apoptotic response to mitotic stress could lead to improved clinical strategies. To identify genes whose expression influences the rate and extent of apoptosis after mitotic arrest, we screened a kinase-enriched small interfering RNA library for effects on caspase activation in response to maximally effective doses of paclitaxel, a PLK1 inhibitor, or cisplatin. Small interfering RNA oligonucleotides directed against an atypical protein kinase, TP53RK, caused the greatest increase in caspase-3/7 activation in response to antimitotic agents. Time-lapse microscopy revealed that cells entered mitosis with normal kinetics, but died after entry into mitosis in the presence of paclitaxel more rapidly when TP53RK was depleted. Because expression levels of TP53RK vary in cancers, TP53RK levels could provide a molecular marker to predict response to antimitotic agents. TP53RK inhibition may also sensitize cancers to taxanes. Cancer Res; 70(15); 6325–35. ©2010 AACR.
Single-Cell Analysis of T-Cell Receptor Repertoire of HTLV-1 Tax-Specific Cytotoxic T Cells in Allogeneic Transplant Recipients with Adult T-Cell Leukemia/Lymphoma
Authors: Tanaka Yukie , Nakasone Hideki , Yamazaki Rie , Sato Ken , Sato Miki , Terasako Kiriko , Kimura Shun-ichi , Okuda Shinya , Kako Shinichi , Oshima Kumi , Tanihara Aki , Nishida Junji , Yoshikawa Toshiaki , Nakatsura Tetsuya , Sugiyama Haruo , Kanda Yoshinobu 
Published: July 2010

AbstractAdult T-cell leukemia (ATL) is a lymphoproliferative malignancy associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection. Recently, it has been shown that allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for ATL, and that HTLV-1 Tax-specific CD8+ cytotoxic T cells (CTL) contribute to the graft-versus-ATL effect. In the present study, we, for the first time, analyzed the T-cell receptor (TCR) repertoire of isolated Tax301–309 (SFHSLHLLF)-specific CTLs in HLA-A*2402+ ATL patients before and after allo-HSCT by single-cell reverse transcription-PCR. The Tax301–309-specific CTLs in bone marrow and peripheral blood showed highly restricted oligoclonal diversity. In addition, a unique conserved amino acid motif of “P-D/P-R” in TCR-β complementarity-determining region 3 in either BV7- or BV18-expressing CTLs was observed not only in all of the samples from ATL patients, but also in samples from the same patient before and after HSCT. Furthermore, the P-D/P-R motif–bearing CTL clones established from peripheral blood samples after HSCT exhibited strong killing activity against the HTLV-1–infected T cells of the patient. CTL clones were not established in vitro from samples prior to allo-HSCT. In addition, CTL clones with a strong killing activity were enriched in vivo after HSCT in the patient. Hence, Tax301–309-specific CTLs in ATL patients might have a preference for TCR construction and induce strong immune responses against the HTLV-1–infected T cells of patients, which contribute to the graft-versus-ATL effects after allo-HSCT. However, further analyses with a larger number of patients and more frequent sampling after allo-HSCT is required to confirm these findings. Cancer Res; 70(15); 6181–92. ©2010 AACR.
Interaction of TAp73 and Breast Cancer–Associated Gene 3 Enhances the Sensitivity of Cervical Cancer Cells in Response to Irradiation-Induced Apoptosis
Authors: Leung Thomas Ho-Yin , Ngan Hextan Yuen-Sheung 
Published: July 2010

Abstract
Identification of proteins that are involved in the sensitivity of radiotherapy of cancers is important to enhance the response to cancer treatment. Expression of TAp73 is associated with the sensitivity of radiotherapy in cervical cancer patients, suggesting it plays an important role in controlling radiosensitivity. Here, by using yeast two-hybrid system, we identify breast cancer–associated gene 3 (BCA3) as the first and novel protein interacting partner of TAp73. By coimmunoprecipitation and Western blot analysis, we confirm that TAp73 binds with and stabilizes BCA3 in cervical cancer cell line HeLa. Immunofluorescence staining indicates that BCA3 is localized in the cytoplasm and nucleus. Interestingly, when coexpressed with TAp73, BCA3 interacts and colocalizes with TAp73 at the mitochondria. Mutagenesis reveals that the oligomerization domain of TAp73 is responsible for the interaction with BCA3. Furthermore, BCA3 augments the transactivation activity of TAp73 on bax promoter and protein expression. In addition, the expression of BCA3 also increases the sensitivity of TAp73-transfected cells in response to γ-irradiation–induced apoptosis. Western blot analysis also shows that TAp73 and BCA3 induce activation of caspase-7 and caspase-9. In summary, these findings suggested that BCA3 is a novel protein partner of TAp73, and they cooperate with each other to exert tumor-suppressive functions and sensitize the response of cervical cancer cells to radiotherapy. Cancer Res; 70(16); 6486–96. ©2010 AACR.
Tumor-Specific CD8+ T Cells Expressing Interleukin-12 Eradicate Established Cancers in Lymphodepleted Hosts
Authors: Kerkar Sid P. , Muranski Pawel , Kaiser Andrew , Boni Andrea , Sanchez-Perez Luis , Yu Zhiya , Palmer Douglas C. , Reger Robert N. , Borman Zachary A. , Zhang Ling , Morgan Richard A. , Gattinoni Luca , Rosenberg Steven A. , Trinchieri Giorgio , Restifo Nicholas P. 
Published: July 2010

AbstractT-cell–based immunotherapies can be effective in the treatment of large vascularized tumors, but they rely on adoptive transfer of substantial numbers (∼20 million) of tumor-specific T cells administered together with vaccination and high-dose interleukin (IL)-2. In this study, we report that ∼10,000 T cells gene-engineered to express a single-chain IL-12 molecule can be therapeutically effective against established tumors in the absence of exogenous IL-2 and vaccine. Although IL-12–engineered cells did not perist long-term in hosts, they exhibited enhanced functionality and were detected in higher numbers intratumorally along with increased numbers of endogenous natural killer and CD8+ T cells just before regression. Importantly, transferred T cells isolated from tumors stably overproduced supraphysiologic amounts of IL-12, and the therapeutic effect of IL-12 produced within the tumor microenvironment could not be mimicked with high doses of exogenously provided IL-12. Furthermore, antitumor effects could be recapitulated by engineering wild-type open-repertoire splenocytes to express both the single-chain IL-12 and a recombinant tumor-specific T-cell receptor (TCR), but only when individual cells expressed both the TCR and IL-12, indicating that arrested migration of T cells at the tumor site was required for their activities. Successful tumor eradication was dependent on a lymphodepleting preconditioning regimen that reduced the number of intratumoral CD4+ Foxp3+ T regulatory cells. Our findings reveal an approach to genetically modify T cells to reduce the cell number needed, eliminate the need for vaccines or systemic IL-2, and improve immunotherapy efficacy based on adoptive transfer of gene-engineered T cells. Cancer Res; 70(17); 6725–34. ©2010 AACR.
Overcoming Persistent Dependency on Androgen Signaling after Progression to Castration-Resistant Prostate Cancer
Authors: Yamaoka Masuo , Hara Takahito , Kusaka Masami 
Published: July 2010

Abstract
Prostate cancer is the most common form of cancer in males in the United States, and the second leading cause of cancer death. Initially, most cases of prostate cancer respond well to hormone therapy; however, resistance often develops rapidly, leading to castration-resistant prostate cancer (CRPC). Several mechanisms for castration resistance have been proposed, of which the most significant seems to be the “intracrine” production of androgens from adrenal androgen or intratumorally via the de novo route. This mechanism stimulates disease progression through reactivation of androgen receptor signaling in patients who have previously undergone castration therapy. 17,20-lyase is essential for androgen synthesis in both the adrenal glands and CRPC tissue, and some 17,20-lyase inhibitors and second-generation anti-androgens that were developed to treat CRPC are currently under clinical investigation, with encouraging preliminary data reported so far. However, resistance to some of these therapies has already been noted. The study of circulating tumor cells will likely be important not only to identify patients likely to receive benefit from this therapeutic approach, but also to further understand the molecular mechanisms of resistance. Clin Cancer Res; 16(17); 4319–24. ©2010 AACR.
A Single-Dose, Crossover, Placebo- and Moxifloxacin-Controlled Study to Assess the Effects of Neratinib (HKI-272) on Cardiac Repolarization in Healthy Adult Subjects
Authors: Hug Bruce , Abbas Richat , Leister Cathie , Burns Jaime , Sonnichsen Daryl 
Published: July 2010

Abstract
Purpose: Neratinib is an orally administered, small-molecule, irreversible pan-ErbB inhibitor in development for the treatment of ErbB2-positive breast cancer. This study assessed the effects of therapeutic and supratherapeutic neratinib concentrations on cardiac repolarization, in accordance with current regulatory guidance.
Experimental Design: This was a two-part study in healthy subjects. In part 1, subjects were randomized to receive placebo, 400 mg moxifloxacin, or 240 mg neratinib (therapeutic dose) following a high-fat meal. In part 2, after a washout period, subjects received placebo plus 400 mg ketoconazole or 240 mg neratinib plus ketoconazole (supratherapeutic dose). ANOVA was used to compare the baseline-adjusted QTc interval for neratinib with that of placebo (reference), and for neratinib plus ketoconazole with that of placebo plus ketoconazole (reference). Pharmacokinetic/pharmacodynamic analyses and categorical summaries of interval data were done. Assay sensitivity was evaluated by the effect of moxifloxacin on QTc compared with placebo.
Results: Sixty healthy subjects were enrolled in this study. The upper bounds of the 90% confidence interval for baseline-adjusted QTcN (population-specific corrected QT) were ≤10 milliseconds greater than the corresponding reference at all postdose time points under conditions of both therapeutic and supratherapeutic plasma concentrations of neratinib. Pharmacokinetic/pharmacodynamic analysis revealed no relationship between neratinib concentrations and QTc interval. No subjects had QTcI, QTcF, or QTcN intervals &gt;450 milliseconds or change from baseline &gt;30 milliseconds. Moxifloxacin produced a significant increase in QTcN compared with placebo (P &lt; 0.05).
Conclusions: Therapeutic and supratherapeutic plasma concentrations of neratinib do not prolong the QTc interval in healthy subjects. Clin Cancer Res; 16(15); 4016–23. ©2010 AACR.
miR-192/miR-215 Influence 5-Fluorouracil Resistance through Cell Cycle-Mediated Mechanisms Complementary to Its Post-transcriptional Thymidilate Synthase Regulation
Authors: Boni Valentina , Bitarte Nerea , Cristobal Ion , Zarate Ruth , Rodriguez Javier , Maiello Evaristo , Garcia-Foncillas Jesus , Bandres Eva 
Published: July 2010

AbstractThymidylate synthase (TYMS) is a target of the most widely used chemotherapeutic agents against gastrointestinal malignancies, the fluoropyrimidine-based therapy. TYMS expression levels have been identified as predictive biomarkers for 5-fluoruracil (FU) response in colorectal cancer, but their clinical utility remains controversial. The complexity of fluoropyrimidine response must require more mechanisms that currently have not been completely elucidated. In this context, microRNAs (miRNA) may play a role in modulating chemosensitivity. By carrying out an in silico analysis coupled to experimental validation, we detected that miR-192 and miR-215 target TYMS expression in colorectal cancer cell lines. However, downregulation of TYMS by these miRNAs does not sensitize colorectal cancer cell lines to FU treatment. The overexpression of miR-192/215 significantly reduces cell proliferation by targeting cell cycle progression. This effect was partially associated with p53 status, because reduction of cell proliferation and cell cycle arrest was associated with p21 and p27 induction. The decrease of S-phase cells by these miRNAs mitigates the effects of S phase–specific drugs and suggests that other mechanisms different from TYMS overexpression are essential to direct FU resistance. Finally, ectopic expression of miR-192/215 might have stronger impact to predict FU response than TYMS inhibition. Prospective studies to elucidate the role of these miRNAs as predictive biomarkers to FU are necessary. Mol Cancer Ther; 9(8); 2265–75. ©2010 AACR.
p53-Dependent Induction of Prostate Cancer Cell Senescence by the PIM1 Protein Kinase
Authors: Zemskova Marina , Lilly Michael B. , Lin Ying-Wei , Song Jin H. , Kraft Andrew S. 
Published: July 2010

Abstract
The PIM family of serine threonine protein kinases plays an important role in regulating both the growth and transformation of malignant cells. However, in a cell line–dependent manner, overexpression of PIM1 can inhibit cell and tumor growth. In 22Rv1 human prostate cells, but not in Du145 or RWPE-2, PIM1 overexpression was associated with marked increases in cellular senescence, as shown by changes in the levels of β-galactosidase (SA-β-Gal), p21, interleukin (IL)-6 and IL-8 mRNA and protein. During early cell passages, PIM1 induced cellular polyploidy. As the passage number increased, markers of DNA damage, including the level of γH2AX and CHK2 phosphorylation, were seen. Coincident with these DNA damage markers, the level of p53 protein and genes transcriptionally activated by p53, such as p21, TP53INP1, and DDIT4, increased. In these 22Rv1 cells, the induction of p53 protein was associated not only with senescence but also with a significant level of apoptosis. The importance of the p53 pathway to PIM1-driven cellular senescence was further shown by the observation that expression of dominant-negative p53 or shRNA targeting p21 blocked the PIM1-induced changes in the DNA damage response and increases in SA-β-Gal activity. Likewise, in a subcutaneous tumor model, PIM1-induced senescence was rescued when the p53-p21 pathways are inactivated. Based on these results, PIM1 will have its most profound effects on tumorigenesis in situations where the senescence response is inactivated. Mol Cancer Res; 8(8); 1126–41. ©2010 AACR.
Molecular characterisation of Tyr530Ser and IVS16–1G>T mutations causing severe factor V deficiency
Authors: Zheng Weidong , Liu Yanhui , Luo Ying , Chen Zhihong , Wang Yan , Zhang Liyan , Gao Guoquan , Yao Zhibin 
Published: July 2010

SummaryOur previous study reported a missense mutation (Tyr530Ser) and a splicing site mutation (IVS16–1G>T) in blood coagulation factor V (FV) gene in a two-year-old Chinese boy. However, the linkage between the mutations and severe FV deficiency and the underlying mechanism has not been elucidated. The present study was designed to investigate the effect of the two mutations and the possible pathogenetic mechanism. FV procoagulant activity showed tremendous decrease in the patient with two mutations. The bioinformatics analyses predicted that IVS16–1G>T mutation may cause the entire exon 17 of FV to be skipped in transcription and thereby result in a deletion mutant. To confirm the predicted results, the fragment of exon 16 to exon 18 containing IVS16–1G>T mutation was obtained by PCR and site-directed mutagenesis. IVS16–1G>T mutant and wild-type constructs were transfected into COS-7 cells. Sequence analysis showed that mutant transcript lacked the entire 180-bp length of exon 17. Moreover, compared to wild-type, the expression of the two mutant proteins was decreased and the procoagulant activity was also reduced when the deletion mutant cDNA and Tyr530Ser site mutant cDNA were transfected into COS-7 cells, respectively. Our results indicate that Tyr530Ser and IVS16–1G>T could be separately responsible for severe FV deficiency, while the phenotype in the proband could be caused by the combination effect of the two defects.