bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

AbstractPurpose: 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 &lt; 500 cells/μL (41% versus 21%, P &lt; 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 &lt; 500 cells/μL (not reached versus 53 months, P &lt; 0.0003 and not reached versus 27 months, P &lt; 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

Abstract
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 &gt;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

Abstract
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

Abstract
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

Abstract
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 &lt;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

Abstract
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 &lt; 0.001), PR negativity (21/33, P &lt; 0.001), Bloom-Richardson grade 3 (19/29, P &lt; 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

Abstract
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 &lt; 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 (&lt;1 year) versus longer-term (≥1 year) disease-free interval (P &lt; 0.001) and of overall survival (P &lt; 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

Abstract
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

Abstract
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 &lt; 0.001), histologic grade (P &lt; 0.001), time to recurrence (P = 0.01), and expression of the proliferation marker Ki-67 (P &lt; 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 &lt; 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

Abstract
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 &lt; 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 &lt; 0.0001 and P &lt; 0.0001, respectively). Furthermore, patients with the phenotype of Jab1(+)/p27kip1(−)/lymph node(+) revealed the worst disease-free and overall survival (P &lt; 0.0001 and P &lt; 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.