bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stereotyped B-Cell Receptor Is an Independent Risk Factor of Chronic Lymphocytic Leukemia Transformation to Richter Syndrome
Authors: Rossi Davide , Spina Valeria , Cerri Michaela , Rasi Silvia , Deambrogi Clara , De Paoli Lorenzo , Laurenti Luca , Maffei Rossana , Forconi Francesco , Bertoni Francesco , Zucca Emanuele , Agostinelli Claudio , Cabras Antonello , Lucioni Marco , Martini Maurizio , Magni Michele , Deaglio Silvia , Ladetto Marco , Nomdedeu Josep F. , Besson Caroline , Ramponi Antonio , Canzonieri Vincenzo , Paulli Marco , Marasca Roberto , Larocca Luigi M. , Carbone Antonino , Pileri Stefano A. , Gattei Valter , Gaidano Gianluca 
Published: June 2009

AbstractPurpose: Few biological prognosticators are useful for prediction of Richter syndrome (RS), representing the transformation of chronic lymphocytic leukemia (CLL) to aggressive lymphoma. Stereotyped B-cell receptors (BCR) may have prognostic effect in CLL progression. We tested the prognostic effect of stereotyped BCR for predicting RS transformation.Experimental Design: The prevalence of stereotyped BCR was compared in RS (n = 69) versus nontransformed CLL (n = 714) by a case-control analysis. Subsequently, the effect of stereotyped BCR at CLL diagnosis on risk of RS transformation was actuarially assessed in a consecutive CLL series (n = 753).Results: RS (n = 69) displayed a higher prevalence of stereotyped BCR (P &lt; 0.001) compared with nontransformed CLL. The actuarial risk of RS transformation was significantly higher in CLL carrying stereotyped BCR (P &lt; 0.001). Among BCR subsets most represented in CLL, subset 8 using IGHV4-39/IGHD6-13/IGHJ5 carried the highest risk of RS transformation [hazard ratio (HR), 24.50; P &lt; 0.001]. Multivariate analysis selected stereotyped BCR (HR, 3.33; P = 0.001) and IGHV4-39 usage (HR, 4.03; P = 0.004) as independent predictors of RS transformation. The combination of IGHV4-39 usage and stereotyped BCR in the same patient identified CLL with a very high risk of RS transformation (5-year risk, 68.7%). The risk carried by stereotyped BCR and IGHV4-39 usage was specific for RS transformation and had no effect on CLL progression without transformation.Conclusions: Analysis of BCR features may help identify CLL patients at risk of RS. A close monitoring and a careful biopsy policy may help early recognition of RS in CLL patients using stereotyped BCR, particularly if combined with IGHV4-39.
Antitumor Activity of NK012 Combined with Cisplatin against Small Cell Lung Cancer and Intestinal Mucosal Changes in Tumor-Bearing Mouse after Treatment
Authors: Nagano Tatsuya , Yasunaga Masahiro , Goto Koichi , Kenmotsu Hirotsugu , Koga Yoshikatsu , Kuroda Jun-ichiro , Nishimura Yoshihiro , Sugino Takashi , Nishiwaki Yutaka , Matsumura Yasuhiro 
Published: June 2009

AbstractPurpose: To investigate the advantages of treatment with the SN-38–incorporating polymeric micelles NK012 over CPT-11 in combination with cisplatin [cis-dichlorodiammineplatinum (II) (CDDP)] in mice bearing a small cell lung cancer xenograft in terms of antitumor activity and toxicity, particularly intestinal toxicity.Experimental Design: Cytotoxic effects were evaluated in human small cell lung cancer cell lines [H69, H82, and vascular endothelial growth factor (VEGF)–secreting cells (SBC-3/VEGF and its mock transfectant SBC-3/Neo)]. In vivo antitumor effects were evaluated in SBC-3/Neo–bearing and SBC-3/VEGF–bearing mice after NK012/CDDP or CPT-11/CDDP administration on days 0, 7, and 14. Drug distribution was analyzed by high-performance liquid chromatography or fluorescence microscopy, and the small intestine was pathologically examined.Results: The in vitro growth-inhibitory effects of NK012 were 198- to 532-fold more potent than those of CPT-11. A significant difference in the relative tumor volume on day 30 was found between NK012/CDDP and CPT-11/CDDP treatments (P = 0.0058). Inflammatory changes in the small intestinal mucosa were rare in all NK012-treated mice but were commonly observed in CPT-11–treated mice. Moreover, a large amount of CPT-11 was excreted into the feces and high CPT-11 concentration was detected in the small intestinal epithelium. On the other hand, a small amount of NK012 was found in the feces and NK012 was weakly and uniformly distributed in the mucosal interstitium.Conclusions: NK012/CDDP combination may be a promising candidate regimen against lung cancer without severe diarrhea toxicity and therefore warrants further clinical evaluation.
Immune-Mediated Antitumor Activity of Reovirus Is Required for Therapy and Is Independent of Direct Viral Oncolysis and Replication
Authors: Prestwich Robin J. , Ilett Elizabeth J. , Errington Fiona , Diaz Rosa M. , Steele Lynette P. , Kottke Tim , Thompson Jill , Galivo Feorillo , Harrington Kevin J. , Pandha Hardev S. , Selby Peter J. , Vile Richard G. , Melcher Alan A. 
Published: June 2009

Abstract
Purpose: Reovirus is a naturally occurring oncolytic virus in clinical trials. Although tumor infection by reovirus can generate adaptive antitumor immunity, its therapeutic importance versus direct viral oncolysis is undefined. This study addresses the requirement for viral oncolysis and replication, and the relative importance of antitumor immunity and direct oncolysis in therapy.
Experimental Design: Nonantigen specific T cells loaded with reovirus were delivered i.v. to C57BL/6 and severe combined immunodeficient mice bearing lymph node and splenic metastases from the murine melanoma, B16ova, with assessment of viral replication, metastatic clearance by tumor colony outgrowth, and immune priming. Human cytotoxic lymphocyte priming assays were done with dendritic cells loaded with Mel888 cells before the addition of reovirus.
Results: B16ova was resistant to direct oncolysis in vitro, and failed to support reovirus replication in vitro or in vivo. Nevertheless, reovirus purged lymph node and splenic metastases in C57BL/6 mice and generated antitumor immunity. In contrast, reovirus failed to reduce tumor burden in severe combined immunodeficient mice bearing either B16ova or reovirus-sensitive B16tk metastases. In the human system, reovirus acted solely as an adjuvant when added to dendritic cells already loaded with Mel888, supporting priming of specific antitumor cytotoxic lymphocyte, in the absence of significant direct tumor oncolysis; UV-treated nonreplicating reovirus was similarly immunogenic.
Conclusion: The immune response is critical in mediating the efficacy of reovirus, and does not depend upon direct viral oncolysis or replication. The findings are of direct relevance to fulfilling the potential of this novel anticancer agent.
Rapid Immune Recovery and Graft-versus-Host Disease–like Engraftment Syndrome following Adoptive Transfer of Costimulated Autologous T Cells
Authors: Rapoport Aaron P. , Stadtmauer Edward A. , Aqui Nicole , Vogl Dan , Chew Anne , Fang Hong-Bin , Janofsky Stephen , Yager Kelly , Veloso Elizabeth , Zheng Zhaohui , Milliron Todd , Westphal Sandra , Cotte Julio , Huynh Hong , Cannon Andrea , Yanovich Saul , Akpek Gorgun , Tan Ming , Virts Kristen , Ruehle Kathleen , Harris Carolynn , Philip Sunita , Vonderheide Robert H. , Levine Bruce L. , June Carl H. 
Published: June 2009

AbstractPurpose: Previously, we showed that adoptive transfer of in vivo vaccine-primed and ex vivo (anti-CD3/anti-CD28) costimulated autologous T cells (ex-T) at day +12 after transplant increased CD4 and CD8 T-cell counts at day +42 and augmented vaccine-specific immune responses in patients with myeloma. Here, we investigated the safety and kinetics of T-cell recovery after infusing ex-T at day +2 after transplant.Experimental Design: In this phase I/II two-arm clinical trial, 50 patients with myeloma received autografts after high-dose melphalan followed by infusions of ex-T at day +2 after transplant. Patients also received pretransplant and posttransplant immunizations using a pneumococcal conjugate vaccine only (arm B; n = 24) or the pneumococcal conjugate vaccine plus an HLA-A2–restricted multipeptide vaccine for HLA-A2+ patients (arm A; n = 26).Results: The mean number of T cells infused was 4.26 × 1010 (range, 1.59-5.0). At day 14 after transplant, the median CD3, CD4, and CD8 counts were 4,198, 1,545, and 2,858 cells/μL, respectively. Interleukin (IL)-6 and IL-15 levels increased early after transplant and IL-15 levels correlated significantly to day 14 T-cell counts. Robust vaccine-specific B- and T-cell responses were generated. T-cell infusions were well tolerated with no effect on hematopoietic recovery. Eight patients (16%) developed a T-cell “engraftment syndrome” characterized by diarrhea and fever that was clinically and histopathologically indistinguishable from grade 1 to 3 acute graft-versus-host disease (GVHD) of the gastrointestinal tract (seven patients) and/or grade 1 to 2 cutaneous GVHD (four patients).Conclusions: Adoptive T-cell transfers achieve robust T-cell recovery early after transplant and induce moderate-to-severe autologous GVHD in a subset of patients.
Inflexinol inhibits colon cancer cell growth through inhibition of nuclear factor-κB activity via direct interaction with p50
Authors: Ban Jung Ok , Oh Ju Hoon , Hwang Bang Yeon , Moon Dong Cheul , Jeong Heon-Sang , Lee Seram , Kim Soyoun , Lee Hyosung , Kim Kyung-Bo , Han Sang Bae , Hong Jin Tae 
Published: June 2009

Abstract
Kaurane diterpene compounds have been known to be cytotoxic against several cancer cells through inhibition of nuclear factor-κB (NF-κB) activity. Here, we showed that inflexinol, a novel kaurane diterpene compound, inhibited the activity of NF-κB and its target gene expression as well as cancer cell growth through induction of apoptotic cell death in vitro and in vivo. These inhibitory effects on NF-κB activity and on cancer cell growth were suppressed by the reducing agents DTT and glutathione and were abrogated in the cells transfected with mutant p50 (C62S). Sol-gel biochip and surface plasmon resonance analysis showed that inflexinol binds to the p50 subunit of NF-κB. These results suggest that inflexinol inhibits colon cancer cell growth via induction of apoptotic cell death through inactivation of NF-κB by a direct modification of cysteine residue in the p50 subunit of NF-κB. [Mol Cancer Ther 2009;8(6):1613–24]
Consensus transcriptome signature of perineural invasion in pancreatic carcinoma
Authors: Abiatari Ivane , DeOliveira Tiago , Kerkadze Vachtang , Schwager Christian , Esposito Irene , Giese Nathalia A. , Huber Peter , Bergman Frank , Abdollahi Amir , Friess Helmut , Kleeff Jörg 
Published: June 2009

Abstract
Perineural invasion, the growth of tumor cells along nerves, is a key feature of pancreatic cancer. The cardinal symptom of pancreatic cancer, abdominal pain often radiating to the back, as well as the high frequency of local tumor recurrence following resection are both attributed to the unique ability of pancreatic tumor cells to invade the neuronal system. The molecular mechanisms underlying the neuroaffinity of pancreatic tumors are not completely understood. In this study, we developed a novel method to monitor ex vivo perineural invasion into surgically resected rat vagal nerves by different human pancreatic tumor cell lines. Genome-wide transcriptional analyses were employed to identify the consensus set of genes differentially regulated in all highly nerve-invasive (nerve invasion passage 3) versus less invasive (nerve invasion passage 0) pancreatic tumor cells. The critical involvement of kinesin family member 14 (KIF14) and Rho-GDP dissociation inhibitor β (ARHGDIβ) in perineural invasion was confirmed on RNA and protein levels in human pancreatic tumor specimens. We found significant up-regulation of KIF14 and ARHGDIβ mRNA levels in patients with pancreatic cancer, and both proteins were differentially expressed in tumor cells invading the perineural niche of pancreatic cancer patients as detected by immunohistochemistry. Moreover, functional knockdown of KIF14 and ARHGDIβ using small interfering RNA resulted in altered basal and/or perineural invasion of pancreatic tumor cells. Our work provides novel insights into the molecular determinants of perineural invasion in pancreatic cancer. The established nerve invasion model and the consensus signature of perineural invasion could be instrumental in the identification of novel therapeutic targets of pancreatic cancer as exemplified by KIF14 and ARHGDIβ. [Mol Cancer Ther 2009;8(6):1494–1504]
SHP and Sin3A expression are essential for adamantyl-substituted retinoid-related molecule–mediated nuclear factor-κB activation, c-Fos/c-Jun expression, and cellular apoptosis
Authors: Farhana Lulu , Dawson Marcia I. , Xu Liping , Dannenberg Jan-Hermen , Fontana Joseph A. 
Published: June 2009

Abstract
We previously found that the adamantyl-substituted retinoid-related molecules bind to the small heterodimer partner (SHP) as well as the Sin3A complex. In this report, we delineated the role of SHP and the Sin3A complex in 4-[3′-(1-adamantyl)-4′-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC)–mediated inhibition of cell growth and apoptosis. We examined the effect of loss of SHP and Sin3A expression in a number of cell types on 3-Cl-AHPC–mediated growth inhibition and apoptosis induction, 3-Cl-AHPC–mediated nuclear factor-κB (NF-κB) activation, and 3-Cl-AHPC–mediated increase in c-Fos and c-Jun expression. We found that loss of SHP or Sin3A expression, while blocking 3-Cl-AHPC–mediated apoptosis, had little effect on 3-Cl-AHPC inhibition of cellular proliferation. We have previously shown that 3-Cl-AHPC–mediated NF-κB activation is necessary for apoptosis induction. We have now shown that 3-Cl-AHPC–enhanced c-Fos and c-Jun expression is also essential for maximal 3-Cl-AHPC–mediated apoptosis. 3-Cl-AHPC induction of c-Fos and c-Jun expression as well as NF-κB activation was dependent on SHP protein levels. In turn, SHP levels are regulated by Sin3A because ablation of Sin3A resulted in a decrease in SHP expression. Thus, SHP and Sin3A play an important role in adamantyl-substituted retinoid-related induction of cellular apoptosis. [Mol Cancer Ther 2009;8(6):1625–35]
Luteinizing hormone-releasing hormone receptor–targeted deslorelin-docetaxel conjugate enhances efficacy of docetaxel in prostate cancer therapy
Authors: Sundaram Sneha , Durairaj Chandrasekar , Kadam Rajendra , Kompella Uday B. 
Published: June 2009

Abstract
Docetaxel, a chemotherapeutic agent currently used for improving survival of prostate cancer patients, suffers from low therapeutic index. The objective of this study was to prepare a new docetaxel derivative conjugated to deslorelin, a luteinizing hormone-releasing hormone (LHRH) superagonist, and to determine whether it enhances docetaxel potency in vitro and in vivo. Because docetaxel is not amenable for conjugation with peptides, we introduced a -COOH group in docetaxel, forming docetaxel-hemiglutarate, and subsequently conjugated this to serine in deslorelin, forming deslorelin-docetaxel. Fourier-transform IR, 1H-nuclear magnetic resonance, and liquid chromatography-mass spectrometry analyses confirmed deslorelin-docetaxel formation. Antiproliferative efficacy in LNCaP and PC-3 cell lines over 24, 48, and 72 hours exhibited the order deslorelin-docetaxel &gt; docetaxel, whereas deslorelin alone had no effect, with deslorelin-docetaxel potency being 15-fold greater than docetaxel at 72 h. Further, cells pretreated with antisense oligonucleotide against LHRH receptor exhibited decreased deslorelin-docetaxel efficacy, without any change in docetaxel efficacy. Thus, deslorelin-docetaxel efficacy is likely mediated via LHRH receptor. Cell cycle analysis showed that docetaxel treatment led to arrest in G2-M phase, whereas deslorelin-docetaxel treatment allowed greater progression to apoptosis in both cell lines, with deslorelin-docetaxel exerting 5-fold greater apoptosis compared with docetaxel in prostate cancer cell lines. Antitumor efficacy studies in PC-3 prostate xenograft-bearing mice indicated the efficacy order deslorelin-docetaxel &gt; docetaxel ≫ deslorelin &gt; PBS, with deslorelin-docetaxel exerting ∼5.5-fold greater tumor growth inhibition than docetaxel alone. Thus, deslorelin-docetaxel prepared in this study retains pharmacologic effects of both docetaxel and deslorelin while enhancing the antiproliferative, apoptotic, and antitumor efficacy of docetaxel by several folds in prostate cancer therapy. [Mol Cancer Ther 2009;8(6):1655–65]
Suberoylanilide hydroxamic acid (Zolinza/vorinostat) sensitizes TRAIL-resistant breast cancer cells orthotopically implanted in BALB/c nude mice
Authors: Shankar Sharmila , Davis Rachel , Singh Karan P. , Kurzrock Razelle , Ross Douglas D. , Srivastava Rakesh K. 
Published: June 2009

Abstract
The purpose of this study was to examine whether histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA; Zolinza/vorinostat) could sensitize tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant breast carcinoma in vivo. BALB/c nude mice were orthotopically implanted with TRAIL-resistant MDA-MB-468 cells and treated i.v. with SAHA, TRAIL, or SAHA followed by TRAIL for four times during first 3 weeks. The effects of drugs on tumor growth and markers of apoptosis, metastasis, and angiogenesis were examined. SAHA sensitized TRAIL-resistant xenografts to undergo apoptosis through multiple mechanisms. Whereas TRAIL alone was ineffective, SAHA inhibited growth of MDA-MB-468 xenografts in nude mice by inhibiting markers of tumor cell proliferation, angiogenesis, and metastasis and inducing cell cycle arrest and apoptosis. The sequential treatment of nude mice with SAHA followed by TRAIL was more effective in inhibiting tumor growth, angiogenesis, and metastasis and inducing apoptosis than SAHA alone, without overt toxicity. Treatment of nude mice with SAHA resulted in down-regulation of nuclear factor-κB and its gene products (cyclin D1, Bcl-2, Bcl-XL, vascular endothelial growth factor, hypoxia-inducible factor-1α, interleukin-6, interleukin-8, matrix metalloproteinase-2, and matrix metalloproteinase-9) and up-regulation of DR4, DR5, Bak, Bax, Bim, Noxa, PUMA, p21CIP1, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2 in tumor cells. Furthermore, control mice showing increased rate of tumor growth had increased numbers of CD31+ or von Willebrand factor-positive blood vessels and increased circulating vascular endothelial growth factor receptor 2-positive endothelial cells compared with SAHA-treated or SAHA plus TRAIL-treated mice. In conclusion, sequential treatment with SAHA followed by TRAIL may target multiple pathways in tumor progression, angiogenesis, and metastasis and represents a novel therapeutic approach to treat breast cancer. [Mol Cancer Ther 2009;8(6):1596–69]
Novel benzylidene-thiazolidine-2,4-diones inhibit Pim protein kinase activity and induce cell cycle arrest in leukemia and prostate cancer cells
Authors: Beharry Zanna , Zemskova Marina , Mahajan Sandeep , Zhang Fengxue , Ma Jian , Xia Zuping , Lilly Michael , Smith Charles D. , Kraft Andrew S. 
Published: June 2009

Abstract
The Pim protein kinases play important roles in cancer development and progression, including prostate tumors and hematologic malignancies. To investigate the potential role of these enzymes as anticancer drug targets, we have synthesized novel benzylidene-thiazolidine-2,4-diones that function as potent Pim protein kinase inhibitors. With IC50 values in the nanomolar range, these compounds block the ability of Pim to phosphorylate peptides and proteins in vitro and, when added to DU145 prostate cancer cells overexpressing Pim, inhibit the ability of this enzyme to phosphorylate a known substrate, the BH3 protein BAD. When added to prostate cancer cell lines, including PC3, DU145, and CWR22Rv1, and human leukemic cells, MV4;11, K562, and U937 cells, these compounds induce G1-S cell cycle arrest and block the antiapoptotic effect of the Pim protein kinase. The cell cycle arrest induced by these compounds is associated with an inhibition of cyclin-dependent kinase 2 and activity and translocation of the Pim-1 substrate p27Kip1, a cyclin-dependent kinase 2 inhibitory protein, to the nucleus. Furthermore, when added to leukemic cells, these compounds synergize with the mammalian target of rapamycin inhibitor rapamycin to decrease the phosphorylation level of the translational repressor 4E-BP1 at sites phosphorylated by mammalian target of rapamycin. Combinations of rapamycin and the benzylidene-thiazolidine-2,4-diones synergistically block the growth of leukemic cells. Thus, these agents represent novel Pim inhibitors and point to an important role for the Pim protein kinases in cell cycle control in multiple types of cancer cells. [Mol Cancer Ther 2009;8(6):1473–83]
Expression levels of p18INK4C modify the cellular efficacy of cyclin-dependent kinase inhibitors via regulation of Mcl-1 expression in tumor cell lines
Authors: Eguchi Tomohiro , Itadani Hiraku , Shimomura Toshiyasu , Kawanishi Nobuhiko , Hirai Hiroshi , Kotani Hidehito 
Published: June 2009

Abstract
Because cyclin-dependent kinases (CDK) play a pivotal role in cancer progression, the development of CDK inhibitors has attracted attention in antitumor therapy. However, despite significant preclinical and clinical developments, CDK inhibition biomarkers for predicting efficacy against certain cancers in individual patients have not been identified. Here, we characterized a macrocyclic quinoxalin-2-one CDK inhibitor, compound A, and identified a gene biomarker for predicting its efficacy. Compound A showed 100-fold selectivity for CDK family proteins over other kinases and inhibited both E2F transcriptional activity and RNA polymerase II phosphorylation. Compound A treatment resulted in decreased proliferation in various tumor cell lines; however, the apoptosis induction rate differed significantly among the cell lines examined, which was consistent with roscovitine. By comparing the mRNA expression profiles of sensitive and resistant cell lines, we found that expression levels of an endogenous CDK inhibitor, p18INK4C, showed a strong negative correlation to the sensitivity. In fact, p18 status was correlated with the response to CDK inhibitor in an independent data set of multiple myeloma cell lines and silencing p18 expression increased the susceptibility of resistant cells to CDK inhibitors. The analysis of molecular mechanisms revealed that cells with lowered p18 had aberrant CDK6 and E2F activities, which resulted in a transcriptional down-regulation of Mcl-1, a key molecule associated with flavopiridol-induced apoptosis, thereby leading to susceptibility to therapeutic intervention with CDK inhibitors. These results identified a molecular basis for CDK inhibitors to exert an antitumor effect in p18-deficient cancers and support the clinical use of CDK inhibitors. [Mol Cancer Ther 2009;8(6):1460–72]