bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiviral Immunity following Smallpox Virus Infection: a Case-Control Study
Authors: Hammarlund Erika , Lewis Matthew W. , Hanifin Jon M. , Mori Motomi , Koudelka Caroline W. , Slifka Mark K. 
Published: October 2010

ABSTRACT

Outbreaks of smallpox (i.e., caused by variola virus) resulted in up to 30% mortality, but those who survived smallpox infection were regarded as immune for life. Early studies described the levels of neutralizing antibodies induced after infection, but smallpox was eradicated before contemporary methods for quantifying T-cell memory were developed. To better understand the levels and duration of immunity after smallpox infection, we performed a case-control study comparing antiviral CD4
+
and CD8
+
T-cell responses and neutralizing antibody levels of 24 smallpox survivors with the antiviral immunity observed in 60 smallpox-vaccinated (i.e., vaccinia virus-immune) control subjects. We found that the duration of immunity following smallpox infection was remarkably similar to that observed after smallpox vaccination, with antiviral T-cell responses that declined slowly over time and antiviral antibody responses that remained stable for decades after recovery from infection. These results indicate that severe, potentially life-threatening disease is not required for the development of sustainable long-term immunity. This study shows that the levels of immunity induced following smallpox vaccination are comparable in magnitude to that achieved through natural variola virus infection, and this may explain the notable success of vaccination in eradicating smallpox, one of the world's most lethal diseases.
Amphipathic α-Helix AH2 Is a Major Determinant for the Oligomerization of Hepatitis C Virus Nonstructural Protein 4B
Authors: Gouttenoire Jérôme , Roingeard Philippe , Penin François , Moradpour Darius 
Published: October 2010

ABSTRACT
Nonstructural protein 4B (NS4B) is a key organizer of hepatitis C virus (HCV) replication complex formation. It induces a specific membrane rearrangement, designated membranous web, that serves as a scaffold for the HCV replication complex. However, the mechanisms underlying membranous web formation are poorly understood. Based on fluorescence resonance energy transfer (FRET) and confirmatory coimmunoprecipitation analyses, we provide evidence for an oligomerization of NS4B in the membrane environment of intact cells. Several conserved determinants were found to be involved in NS4B oligomerization, through homotypic and heterotypic interactions. N-terminal amphipathic α-helix AH2, comprising amino acids 42 to 66, was identified as a major determinant for NS4B oligomerization. Mutations that affected the oligomerization of NS4B disrupted membranous web formation and HCV RNA replication, implying that oligomerization of NS4B is required for the creation of a functional replication complex. These findings enhance our understanding of the functional architecture of the HCV replication complex and may provide new angles for therapeutic intervention. At the same time, they expand the list of positive-strand RNA virus replicase components acting as oligomers.
Evolved Variants of the Membrane Protein Can Partially Replace the Envelope Protein in Murine Coronavirus Assembly
Authors: Kuo Lili , Masters Paul S. 
Published: October 2010

ABSTRACT
The coronavirus small envelope (E) protein plays a crucial, but poorly defined, role in the assembly of virions. To investigate E protein function, we previously generated E gene point mutants of mouse hepatitis virus (MHV) that were defective in growth and assembled virions with anomalous morphologies. We subsequently constructed an E gene deletion (ΔE) mutant that was only minimally viable. The ΔE virus formed tiny plaques and reached optimal infectious titers many orders of magnitude below those of wild-type virus. We have now characterized highly aberrant viral transcription patterns that developed in some stocks of the ΔE mutant. Extensive analysis of three independent stocks revealed that, in each, a faster-growing virus harboring a genomic duplication had been selected. Remarkably, the net result of each duplication was the creation of a variant version of the membrane protein (M) gene that was situated upstream of the native copy of the M gene. Each different variant M gene encoded an expressed protein (M*) containing a truncated endodomain. Reconstruction of one variant M gene in a ΔE background showed that expression of the M* protein markedly enhanced the growth of the ΔE mutant and that the M* protein was incorporated into assembled virions. These findings suggest that M* proteins were repeatedly selected as surrogates for the E protein and that one role of E is to mediate interactions between transmembrane domains of M protein monomers. Our results provide a demonstration of the capability of coronaviruses to evolve new gene functions through recombination.
eIF2α Kinase PKR Modulates the Hypoxic Response by Stat3-Dependent Transcriptional Suppression of HIF-1α
Authors: Papadakis Andreas I. , Paraskeva Efrosyni , Peidis Philippos , Muaddi Hala , Li Suiyang , Raptis Leda , Pantopoulos Kostas , Simos George , Koromilas Antonis E. 
Published: October 2010

Abstract
Hypoxia within the tumor microenvironment promotes angiogenesis, metabolic reprogramming, and tumor progression. In addition to activating hypoxia-inducible factor-1α (HIF-1α), cells also respond to hypoxia by globally inhibiting protein synthesis via serine 51 phosphorylation of translation eukaryotic initiation factor 2α (eIF2α). In this study, we investigated potential roles for stress-activated eIF2α kinases in regulation of HIF-1α. Our investigations revealed that the double-stranded RNA–dependent protein kinase R (PKR) plays a significant role in suppressing HIF-1α expression, acting specifically at the level of transcription. HIF-1α transcriptional repression by PKR was sufficient to impair the hypoxia-induced accumulation of HIF-1α and transcriptional induction of HIF-1α–dependent target genes. Inhibition of HIF-1A transcription by PKR was independent of eIF2α phosphorylation but dependent on inhibition of the signal transducer and activator of transcription 3 (Stat3). Furthermore, HIF-1A repression required the T-cell protein tyrosine phosphatase, which acts downstream of PKR, to suppress Stat3. Our findings reveal a novel tumor suppressor function for PKR, which inhibits HIF-1α expression through Stat3 but is independent of eIF2α phosphorylation. Cancer Res; 70(20); 7820–9. ©2010 AACR.
Role of LIM and SH3 Protein 1 (LASP1) in the Metastatic Dissemination of Medulloblastoma
Authors: Traenka Christopher , Remke Marc , Korshunov Andrey , Bender Sebastian , Hielscher Thomas , Northcott Paul A. , Witt Hendrik , Ryzhova Marina , Felsberg Jörg , Benner Axel , Riester Stephanie , Scheurlen Wolfram , Grunewald Thomas G.P. , von Deimling Andreas , Kulozik Andreas E. , Reifenberger Guido , Taylor Michael D. , Lichter Peter , Butt Elke , Pfister Stefan M. 
Published: October 2010

Abstract
Medulloblastoma is the most common malignant pediatric brain tumor and is one of the leading causes of cancer-related mortality in children. Treatment failure mainly occurs in children harboring metastatic tumors, which typically carry an isochromosome 17 or gain of 17q, a common hallmark of intermediate and high-risk medulloblastoma. Through mRNA expression profiling, we identified LIM and SH3 protein 1 (LASP1) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. In an independent validation cohort of 101 medulloblastoma samples, the abundance of LASP1 mRNA was significantly associated with 17q gain, metastatic dissemination, and unfavorable outcome. LASP1 protein expression was analyzed by immunohistochemistry in a large cohort of patients (n = 207), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival. In vitro experiments in medulloblastoma cell lines showed a strong reduction of cell migration, increased adhesion, and decreased proliferation upon LASP1 knockdown by small interfering RNA–mediated silencing, further indicating a functional role for LASP1 in the progression and metastatic dissemination of medulloblastoma. Cancer Res; 70(20); 8003–14. ©2010 AACR.
Impact of Stromal Sensitivity on Radiation Response of Tumors Implanted in SCID Hosts Revisited
Authors: García-Barros Mónica , Thin Tin Htwe , Maj Jerzy , Cordon-Cardo Carlos , Haimovitz-Friedman Adriana , Fuks Zvi , Kolesnick Richard 
Published: October 2010

Abstract
Severe combined immunodeficient (SCID) mice carry a germ-line mutation in DNA-PK, associated with deficiency in recognition and repair DNA double-strand breaks. Thus, SCID cells and tissues display increased sensitivity to radiation-induced postmitotic (clonogenic) cell death. Nonetheless, the single-radiation doses required for 50% permanent local control (TCD50) of tumors implanted in SCID mice are not significantly different from the TCD50 values of the same tumors in wild-type hosts. Whereas the tumor stroma is derived from the host, the observation that tumors implanted in SCID mice do not exhibit hypersensitivity to radiation might imply that stromal endothelial elements do not contribute substantially to tumor cure by ionizing radiation. Here, we challenge this notion, testing the hypothesis that ASMase-mediated endothelial apoptosis, which results from plasma membrane alterations, not DNA damage, is a crucial element in the cure of tumors in SCID mice by single-dose radiotherapy (SDRT). We show that the endothelium in MCA/129 fibrosarcomas and B16 melanomas exhibits a wild-type apoptotic phenotype in SCID hosts, abrogated in tumors in SCIDasmase−/− littermates, which also acquire resistance to SDRT. Conversion into a radioresistant tumor phenotype when implanted in SCIDasmase−/− hosts provides compelling evidence that cell membrane ASMase-mediated microvascular dysfunction, rather than DNA damage–mediated endothelial clonogenic lethality, plays a mandatory role in the complex pathophysiologic mechanism of tumor cure by SDRT, and provides an explanation for the wild-type SDRT responses reported in tumors implanted in SCID mice. Cancer Res; 70(20); 8179–86. ©2010 AACR.
Clld7, A Candidate Tumor Suppressor on Chromosome 13q14, Regulates Pathways of DNA Damage/Repair and Apoptosis
Authors: Zhou Xiaobo , Münger Karl 
Published: October 2010

Abstract
Chronic lymphocytic leukemia deletion gene 7 (Clld7) is a candidate tumor suppressor on chromosome 13q14. Clld7 encodes an evolutionarily conserved protein that contains an RCC1 domain plus broad complex, tramtrack, bric-a-brac (BTB), and POZ domains. In this study, we investigated the biological functions of Clld7 protein in inducible osteosarcoma cell lines. Clld7 induction inhibited cell growth, decreased cell viability, and increased γ-H2AX staining under conditions of caspase inhibition, indicating activation of the DNA damage/repair pathway. Real-time PCR analysis in tumor cells and normal human epithelial cells revealed Clld7 target genes that regulate DNA repair responses. Furthermore, depletion of Clld7 in normal human epithelial cells conferred resistance to apoptosis triggered by DNA damage. Taken together, the biological actions of Clld7 are consistent with those of a tumor suppressor. Cancer Res; 70(22); 9434–43. ©2010 AACR.
Multiple Injections of Electroporated Autologous T Cells Expressing a Chimeric Antigen Receptor Mediate Regression of Human Disseminated Tumor
Authors: Zhao Yangbing , Moon Edmund , Carpenito Carmine , Paulos Chrystal M. , Liu Xiaojun , Brennan Andrea L. , Chew Anne , Carroll Richard G. , Scholler John , Levine Bruce L. , Albelda Steven M. , June Carl H. 
Published: October 2010

AbstractRedirecting T lymphocyte antigen specificity by gene transfer can provide large numbers of tumor-reactive T lymphocytes for adoptive immunotherapy. However, safety concerns associated with viral vector production have limited clinical application of T cells expressing chimeric antigen receptors (CAR). T lymphocytes can be gene modified by RNA electroporation without integration-associated safety concerns. To establish a safe platform for adoptive immunotherapy, we first optimized the vector backbone for RNA in vitro transcription to achieve high-level transgene expression. CAR expression and function of RNA-electroporated T cells could be detected up to a week after electroporation. Multiple injections of RNA CAR–electroporated T cells mediated regression of large vascularized flank mesothelioma tumors in NOD/scid/γc(−/−) mice. Dramatic tumor reduction also occurred when the preexisting intraperitoneal human-derived tumors, which had been growing in vivo for &gt;50 days, were treated by multiple injections of autologous human T cells electroporated with anti-mesothelin CAR mRNA. This is the first report using matched patient tumor and lymphocytes showing that autologous T cells from cancer patients can be engineered to provide an effective therapy for a disseminated tumor in a robust preclinical model. Multiple injections of RNA-engineered T cells are a novel approach for adoptive cell transfer, providing flexible platform for the treatment of cancer that may complement the use of retroviral and lentiviral engineered T cells. This approach may increase the therapeutic index of T cells engineered to express powerful activation domains without the associated safety concerns of integrating viral vectors. Cancer Res; 70(22); 9053–61. ©2010 AACR.
Fecal DNA for Noninvasive Diagnosis of Colorectal Cancer in Immunochemical Fecal Occult Blood Test–Positive Individuals
Authors: Calistri Daniele , Rengucci Claudia , Casadei Gardini Andrea , Frassineti Giovanni Luca , Scarpi Emanuela , Zoli Wainer , Falcini Fabio , Silvestrini Rosella , Amadori Dino 
Published: October 2010

Abstract
Background: We aimed to define the potential of the fecal DNA assay as an alternative or in addition to the currently used immunochemical fecal occult blood test (iFOBT) for the early diagnosis of colorectal cancer.
Methods: A total of 560 individuals aged 50 to 69 years with a positive iFOBT were recruited from an Italian FOBT regional screening program. Twenty-six were diagnosed with adenocarcinoma, 264 with high-risk adenoma, and 54 with low-risk adenoma, whereas 216 subjects did not have premalignant or malignant lesions. Fecal DNA integrity was analyzed blindly by the fluorescence long DNA (FL-DNA) test.
Results: iFOBT and FL-DNA were largely independent variables (rs = 0.036, P = 0.42), with values ranging from 101 to 5,826 ng/mL and from 0 to 515 ng, respectively. Median values of both variables were significantly higher in cancer patients than in patients with noncancerous lesions or in healthy individuals. Moreover, iFOBT and FL-DNA values were individually associated with a number of pathologic parameters. Sequential use of the diagnostic iFOBT and FL-DNA methods showed that fecal DNA provided more accurate diagnostic information and was able to identify subgroups at different risk of cancer in iFOBT-positive individuals.
Conclusions: A combined approach based on FL-DNA and iFOBT evaluation could help to better identify colorectal cancers and to determine a patient's risk of harboring a preneoplastic or neoplastic lesion. Further evaluation in a screening setting is needed to confirm this hypothesis.
Impact: Fecal DNA could be a useful tool to better predict cancer risk in FOBT-positive individuals. Cancer Epidemiol Biomarkers Prev; 19(10); 2647–54. ©2010 AACR.
High Levels of Expression of Human Stromal Cell–Derived Factor-1 Are Associated with Worse Prognosis in Patients with Stage II Pancreatic Ductal Adenocarcinoma
Authors: Liang John J. , Zhu Shaobo , Bruggeman Richard , Zaino Richard J. , Evans Douglas B. , Fleming Jason B. , Gomez Henry F. , Zander Dani S. , Wang Huamin 
Published: October 2010

AbstractBackground: Stromal cell–derived factor-1 (SDF-1) and its receptor, CXCR4, have been shown to mediate invasiveness and metastatic behavior in a number of cancers, including ovarian, prostate, bladder, breast, and pancreatic cancers. The expression and significance of SDF-1 in pancreatic ductal adenocarcinoma (PDA) have not been systematically studied.Methods: We examined the expression of SDF-1 by immunohistochemistry using a mouse anti-human SDF-1/CXCL12 antibody (dilution 1:300) and a tissue microarray consisting of 72 stage II PDAs from pancreaticoduodenectomy specimens. The staining results were categorized as SDF-1-high (SDF-1-H; cytoplasmic staining of ≥10% of tumor cells) or SDF-1-low (SDF-1-L; no staining or staining of &lt;10% of tumor cells). The results of SDF-1 expression were correlated with clinicopathologic parameters and survival. Statistical analyses were done using SPSS software.Result: Of the 72 stage II PDAs, 25 (35%) showed high levels of SDF-1 expression. The median overall and recurrence-free survival for patients with SDF-1-H PDAs were 26.1 and 11.1 months, respectively, compared with 44.3 and 22.3 months for patients with SDF-1-L tumors (log-rank test, P = 0.047 and P = 0.021). In multivariate analysis, high SDF-1 expression correlated with poor overall and disease-free survival (P = 0.02 and P = 0.02) independent of tumor size, differentiation, and lymph node status.Conclusion: High levels of SDF-1 expression were associated with poor overall and disease-free survival in patients with stage II PDA. SDF-1 may serve as a useful prognostic marker for stage II PDA.Impact: Our results suggest that SDF-1-CXCR4 or SDF-1-CXCR7 pathways may represent a potential target for therapeutic intervention as well as prediction of prognosis in PDA. Cancer Epidemiol Biomarkers Prev; 19(10); 2598–604. ©2010 AACR.
Reproductive Factors, Hormone Use, and Risk for Lung Cancer in Postmenopausal Women, the Nurses' Health Study
Authors: Baik Christina S. , Strauss Gary M. , Speizer Frank E. , Feskanich Diane 
Published: October 2010

Abstract
Background: There is increasing evidence suggesting that female hormones may play a significant role in lung cancer development. We evaluated the associations between reproductive factors, exogenous hormone use, and lung cancer incidence in the Nurses' Health Study.
Methods: We assessed age at menopause, age at menarche, type of menopause, parity, age at first birth, postmenopausal hormone (PMH) use, and past oral contraceptive use in 107,171 postmenopausal women. Cox models were used to estimate the hazard ratios for each exposure, adjusting for smoking and other covariates.
Results: We identified 1,729 lung cancer cases during follow-up from 1984 to 2006. Menopause onset before 44 years of age (hazard ratio, 1.39; 95% confidence interval, 1.14-1.70) and past oral contraceptive use for &gt;5 years (hazard ratio, 1.22; 95% confidence interval, 1.05-1.42) were associated with increased lung cancer risk. These associations were strongest in current smokers and small cell histology. In never smokers, increased parity was associated with decreased risk among parous women (P trend = 0.03), whereas in current smokers, older age at first birth was associated with increased risk (P trend = 0.02). PMH use was not associated with overall lung cancer incidence. However, nonsignificant results of increased risk in adenocarcinoma were seen with current PMH use.
Conclusions: Our findings suggest female hormones may influence lung carcinogenesis, although the effect is likely modest, varied by histologic subtype, and altered by smoking.
Impact: Further investigation of the pathophysiology of female hormones in lung cancer subtypes and their interaction with smoking will lead to better understanding of lung carcinogenesis. Cancer Epidemiol Biomarkers Prev; 19(10); 2525–33. ©2010 AACR.
Effect of Long-term Storage in TRIzol on Microarray-Based Gene Expression Profiling
Authors: Ma Wencai , Wang Michael , Wang Zhi-Qiang , Sun Luhong , Graber David , Matthews Jairo , Champlin Richard , Yi Qing , Orlowski Robert Z. , Kwak Larry W. , Weber Donna M. , Thomas Sheeba K. , Shah Jatin , Kornblau Steven , Davis Richard E. 
Published: October 2010

Abstract
Background: Although TRIzol is widely used for preservation and isolation of RNA, there is suspicion that prolonged sample storage in TRIzol may affect array-based gene expression profiling (GEP) through premature termination during reverse transcription.
Methods: GEP on Illumina arrays compared paired aliquots (cryopreserved or stored in TRIzol) of primary samples of multiple myeloma (MM) and acute myeloid leukemia (AML). Data were analyzed at the “probe level” (a single consensus value) or “bead level” (multiple measurements provided by individual beads).
Results: TRIzol storage does not affect standard probe-level comparisons between sample groups: different preservation methods did not generate differentially expressed probes (DEP) within MM or AML sample groups, or substantially affect the many DEPs distinguishing between these groups. Differences were found by gene set enrichment analysis, but these were dismissible because of instability with permutation of sample labels, unbalanced restriction to TRIzol aliquots, inconsistency between MM and AML groups, and lack of biological plausibility. Bead-level comparisons found many DEPs within sample pairs, but most (73%) were &lt;2-fold changed. There was no consistent evidence that TRIzol causes premature reverse transcription termination. Instead, a subset of DEPs were systematically due to increased signals in TRIzol-preserved samples from probes near the 5′ end of transcripts, suggesting better mRNA preservation with TRIzol.
Conclusions: TRIzol preserves RNA quality well, without a deleterious effect on GEP. Samples stored frozen with and without TRIzol may be compared by GEP with only minor concern for systematic artifacts.
Impact: The standard practice of prolonged sample storage in TRIzol is suitable for GEP. Cancer Epidemiol Biomarkers Prev; 19(10); 2445–52. ©2010 AACR.
Dietary Factors and Risk of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: A Pooled Analysis of Two Prospective Studies
Authors: Tsai Huei-Ting , Cross Amanda J. , Graubard Barry I. , Oken Martin , Schatzkin Arthur , Caporaso Neil E. 
Published: October 2010

AbstractBackground: Other than male sex, family history, advanced age, and race, risk factors for chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) are unknown. Very few studies have investigated diet in relation to these leukemias, and no consistent associations are known.Methods: Using two large prospective population-based studies, we evaluated the relationship between diet and CLL/SLL risk. Among 525,982 men and women free of cancer at enrollment, we identified 1,129 incident CLL/SLL cases during 11.2 years of follow-up.Results: We found no associations between total fat, saturated fat, fiber, red meat, processed meat, fruit, or vegetable intake and risk of CLL/SLL. We noted a suggestive positive association between body mass index and CLL/SLL (hazard ratio, 1.30; 95% confidence interval, 0.99-1.36).Conclusion: We did not find any associations between food or nutrient intake and CLL/SLL.Impact: Our large prospective study indicates that diet may not play a role in CLL/SLL development. Cancer Epidemiol Biomarkers Prev; 19(10); 2680–4. ©2010 AACR.