bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct Algorithm for Bernstein Enclosure Boundary of Polynomials
Authors: Hamadneh Tareq , Al Zoubi Hassan , Abu Falahah Ibraheem , Al-Sabbagh Mutaz
Published: June 2022

Multivariate polynomials of finite degree can be expanded into Bernstein form over a given simplex domain. The minimum and maximum Bernstein control points optimize the polynomial curve over the same domain. In this paper, we address methods for computing these control points in the simplicial case of maximum degree L. To this end, we provide arithmetic operations and properties for obtaining a fast computational method of Bernstein coefficients. Furthermore, we give an algorithm for direct determination of the minimum and maximum Bernstein coefficients (enclosure boundary) in the simplicial multivariate case. Subsequently, the implicit form, monotonicity, and dominance cases are investigated.
Exosomal Circular RNA hsa_circ_0046060 of Umbilical Cord Mesenchymal Stromal Cell Ameliorates Glucose Metabolism and Insulin Resistance in Gestational Diabetes Mellitus via the miR-338-3p/G6PC2 Axis
Authors: Cao Minkai , Bu Chaozhi , Zhang Jingjing , Ren Yongwei , Zhou Guanlun , Chen Chao , Han Guorong , Jiang Shi-Wen , Wen Juan
Published: June 2022

Background. Impaired glucose metabolism and insulin sensitivity have been linked to the pathogenesis of gestational diabetes mellitus (GDM). Exosomes secreted by the umbilical cord mesenchymal stromal cells (UMSCs) and circular RNAs (circRNAs) derived from exosomes have been shown to be associated with the progression of GDM-related complications. Methods. UMSCs were isolated from umbilical cords and identified through flow cytometry. Exosomes were isolated from UMSCs and were then characterized. The expression levels of RNA of hsa_circ_0046060, mmu_circ_0002819, and miR-338-3p were determined by quantitative real-time polymerase chain reaction (RT-qPCR). The intracellular glucose intake and glycogen content were measured using a High Sensitivity Glucose Assay Kit and Glycogen Assay Kit, respectively. Bioinformatics analysis and luciferase reporter assay were used to validate interactions among hsa_circ_0046060, miR-338-3p, and G6PC2. The expression of insulin receptor substrate-1 (IRS-1) and its phosphorylated form, (p-IRS-1), as well as G6PC2, was determined through western blotting. Results. UMSCs and exosomes were successfully isolated and identified. The upregulation of hsa_circ_0046060 decreased the intracellular glucose content in L-02 cells (43.45 vs. 16.87 pM/mg,

P
=
0.0002

), whereas shRNA-mediated downregulation reversed this effect (16.87 vs. 33.16 pM/mg,

P
=
0.0011

). Mmu_circ_0002819 in mice aggravated dysregulated glucose metabolism (49.88 vs. 21.69 pM/mg,

P
=
0.0031

) and insulin sensitivity (0.20 vs. 0.11 mg/mL,

P
=
0.03

) in GDM mice, which was abrogated by the knockdown of mmu_circ_0002819. The results of luciferase reporter assay revealed that miR-338-3p and G6PC2 were the potential targets of has_circ_0046060. Western blotting results showed that the reduced activation of IRS-1 induced by GDM (1.25 vs. 0.54,

P
=
0.0001

) could be rescued by the administration of si-circ-G-UMSC-EXOs (0.54 vs. 1.17,

P
=
0.0001

). Conclusion. Taken together, the inhibition of hsa_circ_0046060 expression in exosomes from GDM-derived UMSCs can alleviate GDM by reversing abnormal glucose metabolism and insulin resistance in vivo and in vitro.
Research on Parameter Estimation and Prediction of Sports Financial Market Volatility Model
Authors: Song Shaoyang , Jing Feiyue
Published: June 2022

At present, the utility function of the financial system in the sports industry has not been brought into full play. Volatility reflects the uncertainty of asset price changes and plays an important role in asset pricing, portfolio, risk management, and asset allocation. Volatility has the characteristics of thick tail, leverage, market linkage, long memory, and aggregation. There are differences between different markets and countries. Therefore, according to the complex characteristics of volatility, this paper uses the feature-oriented research method to study several volatility prediction models, namely, random volatility model, realized volatility model, and multivariate volatility model. In order to promote capital formation and alleviate the financing constraints of sports finance, it provides reference value for reducing transaction costs, improving the quality and efficiency of sports industry, and realizing sustainable and rapid development.
Multifactorial Analysis of Clinical Prognosis of Liver Metastasis and Vascular Intervention Combined with Ablation in Colorectal Cancer
Authors: Lin WenJi , Zhu CongHui , Yao JiaDi , Liu YuHuang , Lin HuiYu , Liu Yan
Published: June 2022

Colorectal cancer is one of the leading causes of deaths in China. The initial stages of colorectal cancer can be treated by surgery, radiation, and chemotherapy. However, in the advanced stages, it warrants an application of multimodality treatment. With advances in the medical field, there are applications of new modality of treatment that could possibly provide the appropriate treatment for the advanced stage tumours. The first site of metastasis after colorectal cancer is the liver and the conventional treatment to cure the metastatic lesion involves the administration of chemotherapy. With further advancement, chemotherapy has been directly administered at the thorough transarterial chemoembolization (TACE) which is a vascular intervention. With further advancement, the nonvascular intervention, such as radiofrequency ablations (RFAs), has been administered to the patients. A large amount of data support the use of vascular intervention (TACE) with ablation for hepatic carcinoma; there is no sufficient literature to support the application of the modality in the metastatic liver lesion. In this prospective observational study, we have enrolled 80 patients with metastatic liver lesion from the adenocarcinoma of colon or rectum, treated the patients with a combination of the TACE and ablation therapy, and followed up the patients for a period of 3 years. A multivariate analysis of the various factors that influence the prognosis and outcome has been studied and it has been concluded that the combination therapy is medically beneficial for individuals with aggressive liver lesions, improving overall as well as progression-free life span.
The Effect of Particle Size of Copper Oxide (CuO) on the Heat‐Induced Catalysis Decomposition of Molecular Perovskite‐Based Energetic Material DAP‐4
Authors: Fu Yuping , Deng Peng , Li Xiaoxia
Published: June 2022

In this study, the effect of copper oxide (CuO) with different sizes on the heat‐induced catalysis decomposition of typical molecular perovskite‐based energetic material DAP‐4 was studied. Pure CuO with different sizes and DAP‐4 are characterized by X‐ray diffraction (XRD) and scanning electron microscopy (SEM). Heat‐induced catalysis decomposition performances of DAP‐4 with adding CuO were investigated by differential scanning calorimeter (DSC). Results demonstrated that with a lower‐addition CuO at the nanoscale added (1 wt%), DAP‐4 had decreased at least by 36°C with the heating rate of 10°C/min, compared with pure DAP‐4. With the CuO particle size of 50 nm, the Ea of DAP‐4 heat‐induced decomposition in DAP‐4/CuO‐50 had reduced from 159.8 kJ/mol to 120.2 kJ/mol, which is lower than DAP‐4/CuO‐150. The heat‐induced catalysis decomposition mechanism of DAP‐4 by using CuO as a nanoadditive was proposed.
Privacy-Preserving Outsourcing Scheme for SVM on Vertically Partitioned Data
Authors: Qiu Guowei , Huo Hua , Gui Xiaolin , Dai Huijun
Published: June 2022

Support vector machine (SVM) is an important technique for data classification. Traditional SVM assumes free access to data. If the data are split and held by different users, for privacy reasons, users are likely unwilling to submit their data to a third party for classification. In this paper, by using additive homomorphic encryption and random transformations (matrix transformation and vector decomposition), we design a privacy-preserving outsourcing scheme for conducting Least Squares SVM (LS-SVM) classification on vertically partitioned data. In our system, multiple data owners (users) submit their encrypted data to two non-colluding service providers, which conduct SVM algorithm on it. During the execution of our algorithm, neither service provider learns anything about the input data, the intermediate results, or the predicted result. In other words, our algorithm is encrypted in the whole process. Extensive theoretical analysis and experimental evaluation demonstrate the correctness, security, and efficiency of the method.
Aberrant Expression and Potency as a Cancer Immunotherapy Target of Inhibitor of Apoptosis Protein Family, Livin/ML-IAP in Lung Cancer
Authors: Hariu Hiroyuki , Hirohashi Yoshihiko , Torigoe Toshihiko , Asanuma Hiroko , Hariu Midori , Tamura Yasuaki , Aketa Katsuyuki , Nabeta Chika , Nakanishi Katsuya , Kamiguchi Kenjiro , Mano Yoshinori , Kitamura Hiroshi , Kobayashi Junichi , Tsukahara Tomohide , Shijubo Noriharu , Sato Noriyuki
Published: June 2022

CD8+ CTLs have an essential role in immune response against tumor. Although an increasing number of tumor-associated antigens that can be recognized by CTLs have been identified from human tumors, a limited number of tumor-associated antigens is known in lung cancer. In addition, because some of them are expressed in noncancerous tissues, there exist limitations in their application to tumor immunotherapy. Livin/ML-IAP is one of recently identified inhibitor of apoptosis protein (IAP) family, which is overexpressed in melanoma cells. In this report, we show that Livin/ML-IAP is aberrantly expressed in many lung cancer cell lines and primary lung cancer tissues, whereas it is not detectable in normal tissues, including lung by reverse transcription-PCR methods. To identify HLA-A24-restricted T-cell epitopes of Livin/ML-IAP, eight peptides were selected from the amino acid sequence of this protein and screened for their binding affinity to HLA-A24. It was revealed that Livin7 peptide (amino acid sequence, KWFPSCQFLL) had the highest affinity to HLA-A24. By stimulating peripheral blood lymphocytes of HLA-A24-positive lung cancer patients with Livin7 peptide in vitro, the peptide-specific CTLs were successfully induced from four of five patients with Livin/ML-IAP-positive lung cancer but not from any of four patients without Livin/ML-IAP expression in their cancer tissues. Furthermore, the CTLs induced by Livin7 peptide showed cytotoxicity against Livin/ML-IAP+ lung cancer cell lines in an HLA-A24-restricted manner. Our data suggest that Livin/ML-IAP may be an excellent target antigen in immunotherapy for lung cancer and Livin7 peptide may serve as a potent peptide vaccine for HLA-A*2402+/Livin+ lung cancer patients.
Fas Ligand–Positive Membranous Vesicles Isolated from Sera of Patients with Oral Cancer Induce Apoptosis of Activated T Lymphocytes
Authors: Kim Jeong Whun , Wieckowski Eva , Taylor Douglas D. , Reichert Torsten E. , Watkins Simon , Whiteside Theresa L.
Published: June 2022

Objective: In patients with oral squamous cell carcinoma, a high proportion of T cells in the tumor undergo apoptosis, which correlates with Fas ligand (FasL) expression on tumor cells. The present study was done to identify mechanisms responsible for apoptosis of T cells seen in the peripheral circulation of these patients.

Methods: Sera of 27 patients, normal donor sera, and supernatants of cultured normal or tumor cells were fractionated by size exclusion chromatography and ultracentrifugation to isolate microvesicles. The presence of microvesicle-associated FasL was studied by Western blots, blocking with anti-Fas reagents, and immunoelectron microscopy. Biological activities of microvesicles were tested including the ability to induce apoptosis of Jurkat and T-cell blasts. Semiquantitative analysis of FasL in microvesicles was correlated with caspase-3 activity, DNA fragmentation, cytochrome c release, loss of mitochondrial membrane potential, and TCR-ζ chain expression in lymphocytes.

Results: FasL-positive (FasL+) microvesicles were detected in sera of 21 of 27 patients. Microvesicles contained 42 kDa FasL. These microvesicles induced caspase-3 cleavage, cytochrome c release, loss of mitochondrial membrane potential, and reduced TCR-ζ chain expression in target lymphocytes. Biological activity of the FasL+ microvesicles was partially blocked by ZB4 anti-Fas monoclonal antibody. Microvesicle-associated FasL levels correlated with the patients' tumor burden and nodal involvement.

Conclusion: Sera of patients with active oral squamous cell carcinoma contain FasL+ microvesicles, which induce the receptor and mitochondrial apoptotic pathways in Jurkat and activated T cells.
Aberrant Methylation and Silencing of theBNIP3Gene in Colorectal and Gastric Cancer
Authors: Murai Masafumi , Toyota Minoru , Suzuki Hiromu , Satoh Ayumi , Sasaki Yasushi , Akino Kimishige , Ueno Masako , Takahashi Fumihiko , Kusano Masanobu , Mita Hiroaki , Yanagihara Kazuyoshi , Endo Takao , Hinoda Yuji , Tokino Takashi , Imai Kohzoh
Published: June 2022

BNIP3 protein is a proapoptotic member of the Bcl-2 family that is expressed in hypoxic regions of tumors. To examine its role in the progression of gastrointestinal cancer, we examined the expression and DNA methylation status of BNIP3 gene in a panel of colorectal and gastric cancer cell lines. BNIP3 was not expressed in 14 of the 24 cell lines tested, and its absence was not caused by gene mutation or by altered expression of hypoxia inducible factor-1, a key transcription factor that regulates BNIP3 expression. On the other hand, methylation of the 5′ CpG island of BNIP3 was closely correlated with silencing the gene. Moreover, treating methylated cells with the methyltransferase inhibitor 5-aza-2′-deoxycytidine restored hypoxia-induced expression of BNIP3 mRNA and protein, which in turn led to cell death. Aberrant methylation of BNIP3 was also detected in 66% of primary colorectal and 49% of primary gastric cancers, but not in normal tissue samples collected from areas adjacent to the tumors. Apparently, epigenetic alteration of BNIP3 is a frequent and cancer-specific event, which suggests that inactivation of BNIP3 likely plays a key role in the progression of some gastrointestinal cancers and that it may be a useful molecular target for therapy.
Quantitative Analysis of Melanoma-Induced Cytokine-Mediated Immunosuppression in Melanoma Sentinel Nodes
Authors: Lee Jonathan H. , Torisu-Itakara Hitoe , Cochran Alistair J. , Kadison Alan , Huynh Young , Morton Donald L. , Essner Richard
Published: June 2022

Purpose: Melanoma sentinel nodes (SN) show evidence of immunosuppression prior to tumor metastasis. Interleukin (IL)-10 and IFN-γ can induce dendritic cells (DC) that express immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO). The goals of this study are to evaluate the role of melanoma in SN immunosuppression and to assess reversibility of SN immunosuppression by a cytokine therapy.

Experimental Design: Fifty-seven clinical stage I/II melanoma patients underwent wide local excision and sentinel lymphadenectomy (WLE/SL), with removal of non-SN. In 21 patients, nodal RNA was analyzed by quantitative real-time PCR for expression levels of IL-2, IL-10, IL-12, IFN-γ, and IDO genes. Among the remaining 36 patients, 15 received peritumoral injection of recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF) 2 to 5 days prior to WLE/SL. Lymph nodes (LN) from these 36 patients were assessed for T-cell area, DC area, and DC density.

Results: Of 21 patients whose nodal RNA was analyzed, 13 had residual melanoma at the primary site or a tumor-positive SN. In these patients, expression levels of IL-10 (P = 0.05), IFN-γ (P < 0.05), and IDO (P = 0.06) were dramatically higher in SNs than non-SNs. This difference was not evident in the 8 patients without residual melanoma or SN metastasis. Of the 36 patients whose LNs were examined for histologic features, the 15 patients who received rhGM-CSF had significantly higher SN values of T-cell area, DC area, and DC density than those who did not receive rhGM-CSF.

Conclusions: Our data provide molecular evidence of cytokine-mediated SN immunosuppression that is associated with presence of melanoma. Furthermore, SN immunosuppression can potentially be reversed by a cytokine therapy.
Serum Levels of an Isoform of Apolipoprotein A-II as a Potential Marker for Prostate Cancer
Authors: Malik Gunjan , Ward Michael D. , Gupta Saurabh K. , Trosset Michael W. , Grizzle William E. , Adam Bao-Ling , Diaz Jose I. , Semmes O. John
Published: June 2022

Purpose: We recently showed that protein expression profiling of serum using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) has potential as a diagnostic approach for detection of prostate cancer. As a parallel effort, we have been pursuing the identification of the protein(s) comprising the individual discriminatory “peaks” and evaluating their utility as potential biomarkers for prostate disease.

Experimental Design: We employed liquid chromatography, gel electrophoresis and tandem mass spectroscopy to isolate and identify a protein that correlates with observed SELDI-TOF MS mass/charge (m/z) values. Immunodepletion, immunoassay, and Western analysis were used to verify that the identified protein generated the observed SELDI peak. Subsequent immunohistochemistry was used to examine the expression of the proteins in prostate tumors.

Results: An 8,946 m/z SELDI-TOF MS peak was found to retain discriminatory value in each of two separate data sets with an increased expression in the diseased state. Sequence identification by liquid chromatography-MS/MS and subsequent immunoassays verified that an isoform of apolipoprotein A-II (ApoA-II) is the observed 8,946 m/z SELDI peak. Immunohistochemistry revealed that ApoA-II is overexpressed in prostate tumors. SELDI-based immunoassay revealed that an 8.9-kDa isoform of ApoA-II is specifically overexpressed in serum from individuals with prostate cancer. ApoA-II was also overexpressed in the serum of individuals with prostate cancer who have normal prostate-specific antigen (0-4.0 ng/mL).

Conclusions: We have identified an isoform of ApoA-II giving rise to an 8.9K m/z SELDI “peak” that is specifically overexpressed in prostate disease. The ability of ApoA-II to detect disease in patients with normal prostate-specific antigen suggests potential utility of the marker in identifying indolent disease.
The Relationship between Epidermal Growth Factor Receptor Mutations and Clinicopathologic Features in Non–Small Cell Lung Cancers
Authors: Tokumo Masaki , Toyooka Shinichi , Kiura Katsuyuki , Shigematsu Hisayuki , Tomii Kunitoshi , Aoe Motoi , Ichimura Kouichi , Tsuda Toshihide , Yano Masaaki , Tsukuda Kazunori , Tabata Masahiro , Ueoka Hiroshi , Tanimoto Mitsune , Date Hiroshi , Gazdar Adi F. , Shimizu Nobuyoshi
Published: June 2022

Purpose: Recent studies reported that clinical responsiveness to gefitinib was associated with somatic mutation of epidermal growth factor receptor (EGFR) gene in non–small cell lung cancers (NSCLC). Here, we investigated the relationship between EGFR mutation and clinicopathologic features.

Experimental Design: EGFR mutational status of 120 NSCLCs was determined mainly in EGFR exons 18 to 21 by direct sequence and correlated with clinicopathologic parameters.

Results: EGFR mutations were present in 38 cases (32%) and the majority of mutations were in-frame deletions of exon 19 (19 cases) and a missense mutation in exon 21 (18cases). EGFR mutations were frequently associated with adenocarcinoma (P < 0.0001), never smoker (P < 0.0001), and female gender (P = 0.0001). Of interest, increasing smoke exposure was inversely related to the rate of EGFR mutation (P < 0.0001). Multivariate analysis showed that smoking and histology were independent variables. Furthermore, gender difference was observed for the mutational location (P = 0.01) dominance of exon 19 for males and exon 21 for females. Twenty-one cases were treated with gefitinib and found that EGFR mutation was significantly related to gefitinib responsiveness (P = 0.002). In addition, median survival times of patients with and without EGFR mutations treated with gefitinib were 25.1 and 14.0 months, respectively. Patients with EGFR mutations had approximately 2-fold survival advantage; however, the difference was not significant.

Conclusions: We show that EGFR mutations were significantly related to histology and smoke exposure and were a strong predictive factor for gefitinib responsiveness in NSCLC.
Slug Expression in the E-cadherin Preserved Tumors Is Related to Prognosis in Patients with Esophageal Squamous Cell Carcinoma
Authors: Uchikado Yasuto , Natsugoe Shoji , Okumura Hiroshi , Setoyama Tetsuro , Matsumoto Masataka , Ishigami Sumiya , Aikou Takashi
Published: June 2022

Purpose: The expression of E-cadherin correlates with the development, progression, and metastasis of esophageal squamous cell carcinoma (ESCC). Slug, a member of the snail family of transcriptional factors, is a newly identified suppressive transcriptional factor of E-cadherin. The purpose of the present study was to evaluate the clinical significance of E-cadherin and Slug expression in ESCC.

Experimental Design: Immunohistochemistry was used to investigate the expression of E-cadherin and Slug proteins in 203 patients with ESCC. The relationships between expression of these proteins and clinicopathologic factors, including prognosis, were analyzed.

Results: Positive expression of E-cadherin and Slug was observed in 43% and 48% of cases, respectively. The tumors with reduced E-cadherin expression or positive Slug expression invaded deeper, had more lymph node metastasis, and had more lymphatic invasion than the tumors with preserved E-cadherin expression or negative Slug expression. Slug expression significantly correlated with reduced E-cadherin expression. Sixty-seven of the 98 (68.4%) tumors with positive Slug expression had reduced E-cadherin expression (P = 0.0011). Patients with reduced E-cadherin expression or positive Slug expression had poor clinical outcomes. In the preserved E-cadherin group, the 5-year survival rate was better for patients who were negative for Slug expression than for those who were positive for Slug expression (P = 0.035). Multivariate analysis indicated that E-cadherin expression and Slug expression were not independent prognostic factors.

Conclusions: Evaluation of not only the expression of E-cadherin but also the co-expression of E-cadherin and Slug in preserved E-cadherin group is useful for predicting malignant properties of ESCC.
The L1 Cell Adhesion Molecule Is Induced in Renal Cancer Cells and Correlates with Metastasis in Clear Cell Carcinomas
Authors: Allory Yves , Matsuoka Yasuko , Bazille Céline , Christensen Erik Ilsø , Ronco Pierre , Debiec Hanna
Published: June 2022

Purpose: The L1 cell adhesion molecule is overexpressed in many human carcinomas. The objectives of the study were to provide a comprehensive description of L1 distribution in human kidney and to establish the prognostic relevance of L1 expression in renal cell carcinomas (RCC).

Experimental Design: Using two antibodies to the extracellular part and the cytoplasmic domain, respectively, we first compared L1 expression in normal kidney and renal tumors of diverse histopathologic origin, then we studied L1 expression together with tumor stage, grade, molecular prognostic biomarkers, and metastatic behavior.

Results: In normal kidney, L1 immunoreactive with both antibodies was expressed in all epithelial cells originating from the ureteric bud except for intercalated cells. In renal tumors, L1 was mainly detected in those originating from cells that do not express L1 in the normal kidney [i.e., 33 of 72 clear cell RCC (ccRCC) and 25 of 88 papillary RCC (papRCC)]. Both in ccRCC and papRCC, L1 reacted only with the antibody to the extracellular domain, suggesting that the protein was truncated. In these carcinomas, L1 expression was strongly correlated with Ki-67 proliferation index (ccRCC, P = 0.0059; papRCC, P = 0.0039), but only in ccRCC, the presence of L1 was associated with the risk of metastasis (P = 0.0121). This risk was higher if cyclin D1 was concurrently absent in tumor cells (P < 0.0001). The L1+/cyclin D1− profile was an independent prognostic factor of metastasis occurrence in multivariate analysis (P = 0.0023).

Conclusion: We have found a combination of markers that can serve to identify a subgroup of high-risk patients with ccRCC that may require more aggressive therapies.
Aberrantly Methylated CDKN2A, MGMT, and MLH1 in Colon Polyps and in Fecal DNA from Patients with Colorectal Polyps
Authors: Petko Zsolt , Ghiassi Mahan , Shuber Anthony , Gorham Janice , Smalley Walter , Washington M. Kay , Schultenover Stephen , Gautam Shiva , Markowitz Sanford D. , Grady William M.
Published: June 2022

Colon cancer is the third leading cause of cancer-related death in the United States, affecting ∼147,000 people each year. Most colon cancers arise from benign neoplasms and evolve into adenocarcinomas through a stepwise histologic progression sequence that starts from adenomas or hyperplastic polyps/serrated adenomas. Genetic alterations and, more recently, epigenetic alterations have been associated with specific steps in this polyp-adenocarcinoma sequence and likely drive the histologic progression of colon cancer. Consequently, we have assessed in colon adenomas and hyperplastic polyps the methylation status of MGMT, CDKN2A, and MLH1 to determine the timing and frequency of these events in the polyp-carcinoma progression sequence and subsequently to analyze the potential for these methylated genes to be molecular markers for adenomas and hyperplastic polyps. We have found that methylated MGMT, CDKN2A, and MLH1 occur in 49%, 34%, and 7% of adenomas and in 5%, 10%, and 7% of hyperplastic polyps, respectively, and that they are more common in histologically advanced adenomas. Furthermore, analysis of fecal DNA from persons who have undergone colonoscopic exams revealed methylated CDKN2A, MGMT, and MLH1 in fecal DNA from 31%, 48%, and 0% of individuals with adenomas and from 16%, 27%, and 10% of individuals with no detectable polyps, respectively. These results show that aberrant methylated genes can be detected frequently in sporadic colon polyps and that they can be detected in fecal DNA. Notably, improvements in the specificity and sensitivity of the fecal DNA-based assays will be needed to make them clinically useful diagnostic tests for polyps.
Early Lymphocyte Recovery Predicts Superior Survival after Autologous Hematopoietic Stem Cell Transplantation for Patients with Primary Systemic Amyloidosis
Authors: Porrata Luis F. , Gertz Morie A. , Litzow Mark R. , Lacy Martha Q. , Dispenzieri Angela , Inwards David J. , Ansell Stephen M. , Micallef Ivanna N.M. , Gastineau Dennis A. , Elliott Michele , Hogan William J. , Hayman Suzanne R. , Tefferi Ayalew , Markovic Svetomir N.
Published: June 2022

Purpose: Absolute lymphocyte count recovery at day 15 (ALC-15) post-autologous stem cell transplantation (ASCT) is a powerful prognostic indicator for survival for multiple hematologic malignancies and metastatic breast cancer. The relationship of ALC-15 with clinical outcomes in primary systemic amyloidosis is unknown.

Experimental Design: We evaluated 145 consecutive patients with primary systemic amyloidosis who underwent ASCT at the Mayo Clinic from 1996 to 2003. The ALC-15 threshold was set at 500 cells/μL based on our previous observations.

Results: The median patient follow-up was 22 months (range, 3-87 months). Higher hematologic complete response was observed in patients with an ALC-15 ≥ 500 cells/μL compared with patients with an ALC-15 < 500 cells/μL (41% versus 21%, P < 0.0008, respectively). The median overall survival and progression-free survival times were significantly better for the 59 patients that achieved an ALC-15 ≥ 500 cells/μL compared with 86 patients with ALC-15 < 500 cells/μL (not reached versus 53 months, P < 0.0003 and not reached versus 27 months, P < 0.0001, respectively). Multivariate analysis showed ALC-15 to be an independent prognostic factor for overall survival and progression-free survival.

Conclusions: ALC-15 ≥ 500 cells/μL is associated with significantly improved clinical outcomes following ASCT in patients with primary systemic amyloidosis.
Combination of IFN-α and 5-Fluorouracil Induces Apoptosis through IFN-α/β Receptor in Human Hepatocellular Carcinoma Cells
Authors: Kondo Motoi , Nagano Hiroaki , Wada Hiroshi , Damdinsuren Bazarragchaa , Yamamoto Hirofumi , Hiraoka Nobuaki , Eguchi Hidetoshi , Miyamoto Atsushi , Yamamoto Tameyoshi , Ota Hideo , Nakamura Masato , Marubashi Shigeru , Dono Keizo , Umeshita Koji , Nakamori Shoji , Sakon Masato , Monden Morito
Published: June 2022

Purpose: Several studies showed the effectiveness of combination therapy with IFN-α and 5-fluorouracil (5-FU) for advanced hepatocellular carcinoma. However, only little is known about the underlying mechanism of combination therapy. In the present study, we examined whether apoptosis through IFN-α/β receptor (IFN-α/βR) was associated with the effects of combination therapy.

Experimental Design: HuH7, PLC/PRF/5, HLE, and HLF were treated with IFN- (500 units/mL), 5-FU (0.5 μg/mL), or their combination for 10 days. In addition, IFN-α/βR gene transfer with combination therapy was done.

Results: Ten-day treatment by combination therapy resulted in >80% cell growth inhibition. Terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling analysis showed synergistic effects for combination therapy on PLC/PRF/5, HLE, and HLF. Concordant results were obtained with DNA fragmentation. Moreover, there was an evidence showing that changes in the expression of Bcl-2 family lead to apoptosis. On the other hand, the expression of IFN-α/βR and up-regulation of α-phospho–signal transducer and activator of transcription 1, IFN regulatory factor-1 by combination therapy were observed in all cell lines. Furthermore, IFN-α/type 2 IFN receptor long form–transfected HuH7 cells treated with combination therapy showed strong DNA fragmentation compared with nontransfected or transfected with IFN-α- and 5-FU-treated HuH7.

Conclusions: Our results showed that combination of IFN-α plus 5-FU strongly induced cell growth inhibition of human hepatocellular carcinoma cells and indicated that oneof the direct mechanisms of combination therapy may in part be attributable to alterations in induction of apoptosis through IFN-α/βR.
A Fiber-Modified, Secretory Leukoprotease Inhibitor Promoter-Based Conditionally Replicating Adenovirus for Treatment of Ovarian Cancer
Authors: Rein Daniel T. , Breidenbach Martina , Kirby Tyler O. , Han Tie , Siegal Gene P. , Bauerschmitz Gerd J. , Wang Minghui , Nettelbeck Dirk M. , Tsuruta Yuko , Yamamoto Masato , Dall Peter , Hemminki Akseli , Curiel David T.
Published: June 2022

Purpose: The use of conditionally replicating adenoviruses (CRAD) is dependent on molecular differences between tumor cells and nontumor cells. Transcriptional targeting of CRAD replication via tumor-specific promoters is an effective way to control replication regulation. Genetic fiber pseudotyping is an approach for circumventing low expression of the primary adenovirus serotype 5 (Ad5) receptor by using the distinct adenovirus serotype 3 (Ad3) receptor for entry into and subsequent killing of ovarian cancer cells.

Experimental Design: In this study, we constructed a fiber-modified CRAD containing the secretory leukoprotease inhibitor (SLPI) promoter to control viral replication via the E1A gene (Ad5/3SLPI). To evaluate the liver toxicity of chimeric 5/3 fiber-modified CRADs, we compared Ad5/3SLPI with Ad5/3Cox-2L, a CRAD with E1A under control of the Cox-2 promoter, and Ad5/3Δ24, a CRAD that replicates in cancer cells inactive in the retinoblastoma/p16 pathway by use of an in vivo hepatotoxicity model and by a model system that uses slices of human liver.

Results: We show efficient viral replication and oncolysis of Ad5/3SLPI in both multiple ovarian cancer cell lines and primary tumor cell spheroids as well as therapeutic efficacy in an orthotopic mouse model of peritoneal carcinomatosis. Ad5/3SLPI showed significantly decreased liver toxicity compared with other 5/3 fiber-modified control vectors examined.

Conclusions: In summary, Ad5/3SLPI is a promising vector candidate for treating metastatic ovarian cancer and showed robust virus replication, oncolysis, and in vivo therapeutic efficacy. Ad5/3SLPI showed comparatively low liver toxicity and therefore holds potential for patient use in the clinic.
Increased Vascularization Predicts Favorable Outcome in Follicular Lymphoma
Authors: Koster Ad , van Krieken Joannes H.J.M. , MacKenzie Marius A. , Schraders Margit , Borm George F. , van der Laak Jeroen A.W.M. , Leenders William , Hebeda Konnie , Raemaekers John M.M.
Published: June 2022

Purpose: In malignant lymphoma, angiogenesis has been associated with adverse outcome or more aggressive clinical behavior. This correlation has been established in groups of patients with a large heterogeneity regarding lymphoma subtypes and treatment regimens. The aim of this study is to investigate the significance of vascularization in patients with follicular lymphoma receiving uniform first-line treatment.

Experimental Design: We assessed microvessel density (MVD) in pretreatment lymph node biopsies of 46 previously untreated patients with follicular lymphoma using anti-CD34 immunohistochemical staining and interactive quantification. In a selection of cases, vascular endothelial growth factor (VEGF)-RNA in situ hybridization was done. Patients were treated with cyclophosphamide-vincristine-prednisone induction chemotherapy combined with IFN-α2b. Thirty-six patients responded and received IFN-α as maintenance therapy.

Results: MVD ranged from 10 to 70 per measurement field of 0.19 mm2 (median, 38). Median progression-free survival was 47 months in patients with MVD in the highest tertile and only 13 months in patients with lower MVD. Overall survival in patients with low vessel density was 59 months. In patients with high vessel density, median overall survival was not reached. Multivariate analysis indicated that MVD was independently associated with overall survival. There was a lack of correlation between VEGF-RNA expression and vessel density.

Conclusion: This study shows that in follicular lymphoma increased vascularization is associated with improved clinical outcome. Furthermore, VEGF-A expression seems not to be involved in follicular lymphoma angiogenesis.
Prognostic Relevance of Fragile Histidine Triad Protein Expression in Patients with Small Cell Lung Cancer
Authors: Rohr Ulrich-Peter , Rehfeld Nina , Geddert Helene , Pflugfelder Lucy , Bruns Ingmar , Neukirch Judith , Rohrbeck Astrid , Grote Hans J. , Steidl Ulrich , Fenk Roland , Opalka Bertram , Gabbert Helmut E. , Kronenwett Ralf , Haas Rainer
Published: June 2022

Purpose: The fragile histidine triad protein (FHIT) is a putative tumor suppressor in patients with lung cancer. In this study, we examined the prognostic value of FHIT expression for survival in patients with small cell lung cancer (SCLC).

Experimental Design: As assessed by immunohistochemistry using formalin-fixed, paraffin-embedded tissue sections, tumors of 225 patients with SCLC were retrospectively evaluated for FHIT expression. The influence of FHIT staining intensities as well as the proportion of FHIT-positive cells within a tumor was taken into consideration for univariate and multivariate survival analysis.

Results: FHIT expression was observed in 61.8% of the SCLC tumors. Lack of FHIT was significantly associated with a shorter survival time for the patients with a median of 157 ± 18 days compared with 210 ± 18 days for those patients with FHIT-positive tumors (P = 0.0061). Furthermore, the proportion of FHIT-positive cells within the tumor was related to survival. Patients with tumors of <25% FHIT-positive cells had the worst survival of 155 ± 21 days compared with 217 ± 19 days for patients with a proportion of ≥25% of FHIT-expressing tumor cells (P = 0.0016). In contrast to the proportion of FHIT-positive cells within the tumor, no significant difference in survival was observed when different FHIT staining intensities (weak versus strong) were considered (median survival of 208 ± 17 versus 234 ± 34 days, P=0.665). Multivariate analysis using Cox regression including 11 variables confirmed the prognostic significance of FHIT expression next to performance status, tumor stage, and lactate dehydrogenase.

Conclusion: The presence of FHIT was correlated with a better prognosis for patients with SCLC.
The Expression of Fascin, an Actin-Bundling Motility Protein, Correlates with Hormone Receptor–Negative Breast Cancer and a More Aggressive Clinical Course
Authors: Yoder Brian J. , Tso Elisa , Skacel Marek , Pettay Jim , Tarr Shannon , Budd Thomas , Tubbs Raymond R. , Adams Josephine C. , Hicks David G.
Published: June 2022

The invasion and metastasis of tumor cells is a major cause of mortality in cancer patients. In the current study, we investigated the expression of fascin, an actin-bundling motility-associated protein, in 210 invasive breast carcinomas with corresponding 5-year clinical follow-up. Fascin expression was compared with hormone receptor (ER/PR) status, HER2 status, cancer grade, cancer stage, metastasis pattern, disease-free survival, and overall survival. Fascin expression was seen in 16% (33/210) of the cases and correlated with ER negativity (22/33, P < 0.001), PR negativity (21/33, P < 0.001), Bloom-Richardson grade 3 (19/29, P < 0.001), and advanced stage (stage 3 or 4, P=0.04).There was no correlation between fascin expression and HER2 status or pattern of metastases. Patients whose tumors were positive for fascin showed both a decreased mean disease-free survival (74.44 versus 100.52 months, P = 0.002) and mean overall survival (77.58 versus 98.98 months, P = 0.002), independent of tumor stage and HER2 status, but not independent of ER/PR status or cancer grade. Given fascin's role in altering cell motility, overexpression may contribute to a more aggressive clinical course in ER/PR-negative breast cancers. If so, then fascin may represent a new molecular target for therapeutic intervention in patients with ER-negative breast cancer.
Expression of EphA2 is Prognostic of Disease-Free Interval and Overall Survival in Surgically Treated Patients with Renal Cell Carcinoma
Authors: Herrem Christopher J. , Tatsumi Tomohide , Olson Kathleen S. , Shirai Keisuke , Finke James H. , Bukowski Ronald M. , Zhou Ming , Richmond Amy L. , Derweesh Ithaar , Kinch Michael S. , Storkus Walter J.
Published: June 2022

Whereas normally expressed at sites of cell-to-cell contact in adult epithelial tissues, recent studies have shown that the receptor tyrosine kinase EphA2 is overexpressed in numerous epithelial-type carcinomas, with the greatest level of EphA2 expression observed in metastatic lesions. In the current study, we have assessed EphA2 expression in archived renal cell carcinoma (RCC) tissues as it relates to patient disease course.

Using specific anti-EphA2 monoclonal antibody 208 and immunohistochemistry, we evaluated EphA2 protein expression levels in RCC specimens surgically resected from 34 patients (including 30 conventional clear-cell RCC, 3 papillary, and 1 chromophobic RCC cases) resulting in clinical cures.

Regardless of histopathologic subtype, RCC lesions expressing higher levels of EphA2 tended to be of a higher grade (P < 0.05) and larger (P = 0.093), more-highly-vascularized tumors (P = 0.005). Perhaps most notable, the degree of EphA2 overexpression (versus normal matched autologous kidney tissue) seemed predictive of short-term (<1 year) versus longer-term (≥1 year) disease-free interval (P < 0.001) and of overall survival (P < 0.001) among the RCC patients evaluated.

These data suggest that EphA2 expression level may serve as a useful prognostic tool in the clinical management of patients who have been successfully treated with surgery, but who are at greater risk for accelerated disease recurrence and who have a poorer prognosis.
Prognostic Implications of Molecular and Immunohistochemical Profiles of the Rb and p53 Cell Cycle Regulatory Pathways in Primary Non–Small Cell Lung Carcinoma
Authors: Burke Louise , Flieder Douglas B. , Guinee Donald G. , Brambilla Elizabeth , Freedman Andrew N. , Bennett William P. , Jones Raymond T. , Borkowski Andrew , Caporaso Neil A. , Fleming Marian , Trastek Victor , Pairolero Peter , Tazelaar Henry , Midthun David , Jett James R. , Liotta Lance A. , Travis William D. , Harris Curtis C.
Published: June 2022

Purpose: Many studies have highlighted the aberrant expression and prognostic significance of individual proteins in either the Rb (particularly cyclin D1, p16INK4A, and pRb) or the p53 (p53 and p21Waf1) pathways in non–small cell lung cancer. We hypothesize that cumulative abnormalities within each and between these pathways would have significant prognostic potential regarding survival.

Experimental Design: Our study population consisted of 106 consecutive surgically resected cases of predominantly early-stage non–small cell lung cancer from the National Cancer Institute-Mayo Clinic series, and assessment of proteins involved both immunohistochemical (cyclin D1, p21Waf1, pRb, p16INK4A, and p53) and mutational analysis (p53) in relationship to staging and survival.

Results: Cyclin D1 overexpression was noted in 48% of the tumors, p16INK4A negative in 53%, pRb negative in 17%, p53 immunopositive in 50%, p53 mutation frequency in 48%, and p21Waf1 overexpression in 47%, none with prognostic significance. Cyclin D1 overexpression in pRb-negative tumors revealed a significantly worse prognosis with a mean survival of 2.3 years (P = 0.004). A simultaneous p53 mutation dramatically reduced the mean survival time to 0.9 years (P = 0.007). Cyclin D1 overexpression with either a p53 mutation or a p53 overexpression was also associated with a significantly poorer prognosis (P = 0.0033 and 0.0063, respectively).

Conclusions: Some cumulative abnormalities in the Rb and p53 pathways (e.g., cyclin D1 overexpression and p53 mutations) significantly cooperate to predict a poor prognosis; however, the complexity of the cell cycle protein interaction in any given tumor warrants caution in interpreting survival results when specific protein abnormalities are taken in isolation.
Minichromosome Maintenance Protein 3 Elicits a Cancer-Restricted Immune Response in Patients with Brain Malignancies and Is a Strong Independent Predictor of Survival in Patients with Anaplastic Astrocytoma
Authors: Söling Ariane , Sackewitz Mirko , Volkmar Michael , Schaarschmidt Daniel , Jacob Roland , Holzhausen Hans-Jürgen , Rainov Nikolai G.
Published: June 2022

Purpose: The identification of new molecular markers in astrocytic tumors may help to understand the biology of these tumors in more detail. Informative tumor markers may represent prognostic factors for response to therapy and outcome as well as potential targets for novel anticancer therapies.

Experimental Design: Tumor-associated antigens were identified by immunoscreening of a human glioma cDNA expression library with allogeneic sera from patients with diffuse astrocytoma (WHO grades 2-4). The expression of one of the identified antigens, the replication licensing factor minichromosome maintenance protein 3 (MCM3), was analyzed by immunohistochemistry in 142 primary and 27 recurrent astrocytomas (WHO grades 2-4). In addition, 98 serum specimens from patients with primary and secondary brain malignancies and 30 serum specimens from healthy controls were examined by serologic immunoscreening for immunoreactivity with MCM3.

Results: MCM3 is overexpressed in human astrocytic tumors and elicits a cancer-restricted humoral immune response in 9.3% (9 of 97) of patients with brain tumors (n = 95) and brain metastases (n = 2) but not in healthy controls. Expression of MCM3 in diffuse astrocytoma is significantly associated with age (P < 0.001), histologic grade (P < 0.001), time to recurrence (P = 0.01), and expression of the proliferation marker Ki-67 (P < 0.001) but not with sex (P = 0.800). Univariate and multivariate Cox regression analysis confirmed MCM3 expression as an independent predictor of poor outcome in astrocytoma patients (P < 0.001 for both).

Conclusions: MCM3 may represent a glioma-associated antigen with significant prognostic role as well as have some potential as a target for cancer-directed therapy.
Prognostic Significance of Jab1 Expression in Laryngeal Squamous Cell Carcinomas
Authors: Dong Youyi , Sui Li , Watanabe Yasuo , Yamaguchi Fuminori , Hatano Naoya , Tokuda Masaaki
Published: June 2022

Purpose: Jun activation domain-binding protein 1 (Jab1) is known as a coactivator of AP1 transcription factor, which contributes to tumor progression by degrading the p27kip1 protein. The purpose of this study is to investigate whether Jab1 expression is correlated with p27kip1 level and cell proliferation, as well as whether Jab1 expression is associated with clinicopathologic variables and prognosis of laryngeal squamous cell carcinoma (LSCC).

Experimental Design: Immunohistochemical and/or Western blot analysis was done in HEp-2 cells and 102 cases of LSCCs.

Results: Jab1 expression was negatively associated with p27kip1 expression and was positively associated with cell proliferation both in HEp-2 cells and LSCCs. Jab1 overexpression was detected in 51% LSCCs and was significantly associated with unfavorable clinicopathologic variables. Survival analysis revealed that Jab1 overexpression is significantly associated with short disease-free and overall survival (P = 0.0036 and P = 0.0001, respectively). When Jab1 and p27kip1 are combined, patients with Jab1(+)/p27kip1(−) revealed poor disease-free and overall survival (P= 0.0008 and P < 0.0001, respectively). When Jab1 expression and lymph node status are combined, patients with Jab1(+)/lymph node(+) revealed poorer disease-free andoverall survival than others (P < 0.0001 and P < 0.0001, respectively). Furthermore, patients with the phenotype of Jab1(+)/p27kip1(−)/lymph node(+) revealed the worst disease-free and overall survival (P < 0.0001 and P < 0.0001, respectively). Multivariate analysis revealed that Jab1 protein is an independent prognostic indicator for overall survival.

Conclusions: These findings suggested that Jab1 protein may contribute to the tumor progression and represent a novel prognostic indicator for LSCCs.