bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence of CD44+/CD24−/low Cells in Breast Cancer May Not Be Associated with Clinical Outcome but May Favor Distant Metastasis
Authors: Abraham Benny K. , Fritz Peter , McClellan Monika , Hauptvogel Petra , Athelogou Maria , Brauch Hiltrud 
Published: June 2022

Abstract
Purpose: Breast cancer is composed of phenotypically diverse populations of cancer cells. The ability to form breast tumors has been shown by in vitro/in vivo studies to be restricted to epithelial tumor cells with CD44+/CD24−/low characteristics. Validation of these findings with respect to detection in clinical samples, prognosis, and clinical relevance is in demand.
Experimental Design: We investigated breast cancer tissues for the prevalence of CD44+/CD24−/low tumor cells and their prognostic value. The study included paraffin-embedded tissues of 136 patients with and without recurrences. In addition, a breast cancer progression array with normal, carcinoma in situ, and carcinoma tissues was analyzed. We applied double-staining immunohistochemistry for the detection of CD44+/CD24−/low cells. Evaluation was by microscopic pathologic inspection and automated image analysis.
Results: CD44+/CD24−/low cells ranged from 0% to 40% in normal breast and from 0% to 80% in breast tumor tissues. The prevalence of CD44+/CD24−/low tumor cells in 122 tumors was ≤10% in the majority (78%) of cases and &gt;10% in the remainder. There was no significant correlation between CD44+/CD24−/low tumor cell prevalence and tumor progression. Although recurrences of tumors with high percentages of CD44+/CD24−/low tumor cells were mainly distant, preferably osseous metastasis, there was no correlation with the event-free and overall survival. There was no influence on the response to different treatment modalities.
Conclusions: Our findings suggest that the prevalence of CD44+/CD24−/low tumor cells in breast cancer may not be associated with clinical outcome and survival but may favor distant metastasis.
Expression of MDA-7/IL-24 and Its Clinical Significance in Resected Non–Small Cell Lung Cancer
Authors: Ishikawa Shinya , Nakagawa Tatsuo , Miyahara Ryo , Kawano Yozo , Takenaka Kazumasa , Yanagihara Kazuhiro , Otake Yosuke , Katakura Hiromichi , Wada Hiromi , Tanaka Fumihiro 
Published: June 2022

Abstract
Purpose: The melanoma differentiation-associated gene-7 (MDA-7) protein, also known as interleukin (IL)-24, is a novel candidate of tumor suppressor that can induce apoptosis experimentally in a variety of human malignant cells including lung cancer cells. However, only one clinical study has documented that MDA-7/IL-24 expression is down-regulated with progression of melanoma. Thus, the present study was conducted to assess the clinical significance of MDA-7/IL-24 expression in non–small cell lung cancer.
Experimental Design: A total of 183 consecutive patients with resected pathologic stage I-IIIA, non–small cell lung cancer were retrospectively reviewed, and immunohistochemical staining was used to detect MDA-7/IL-24 expression.
Results: MDA-7/IL-24 expression was high in 97 (53.0%) patients and low in the other patients. There was no significant correlation between MDA-7/IL-24 status and any patients' characteristic including pathologic stage. There was no significant difference in tumor angiogenesis or proliferative activity according to MDA-7/IL-24 status, but MDA-7/IL-24-high adenocarcinoma showed a significantly higher incidence of apoptotic tumor cell death than MDA-7/IL-24-low adenocarcinoma. MDA-7/IL-24-high patients seemed to show a favorable postoperative prognosis as compared with MDA-7/IL-24-low patients (5-year survival rates, 75.9% and 62.0%, respectively), although the difference did not reach a statistical significance (P = 0.061). Subset analyses showed that positive MDA-7/IL-24 expression was a significant factor to predict a favorable prognosis in adenocarcinoma (P = 0.033), which was confirmed by a multivariate analysis; there was no difference in the prognosis according to MDA-7/IL-24 status in squamous cell carcinoma.
Conclusions: MDA-7/IL-24 status was a significant prognostic factor in lung adenocarcinoma, not in lung squamous cell carcinoma.
The Evolution of Antibodies into Versatile Tumor-Targeting Agents
Authors: Lin Michael Z. , Teitell Michael A. , Schiller Gary J. 
Published: June 2022

Abstract
In recent years, monoclonal antibodies have become important weapons in the arsenal of anticancer drugs, and in select cases are now the drugs of choice due to their favorable toxicity profiles. Originally developed to confer passive immunity against tumor-specific antigens, clinical uses of monoclonal antibodies are expanding to include growth factor sequestration, signal transduction modulation, and tumor-specific drug delivery. In this review, we shall present the origins of antibody therapeutics within the field of immunotherapy and their evolution into effective anticancer agents, then discuss their multiple mechanisms of action, the basis of their tumor selectivity, and their therapeutic properties compared with traditional therapies. Antibodies are complex molecules whose efficacy and toxicity depend on the antigen, the antibody, any conjugated groups, and even the patient. Finally, we shall present new technologies being developed to increase the efficacy and selectivity of antibody-based therapeutics. Interestingly, many of the new approaches straddle the middle ground between immunotherapy and the traditional modalities of chemotherapy and radiotherapy, and can be seen as ways of combining the selectivity of the former with the efficacy of the latter.
Human Monocyte-Derived Dendritic Cells Pulsed with Wild-Type p53 Protein Efficiently Induce CTLs against p53 Overexpressing Human Cancer Cells
Authors: Tokunaga Naoyuki , Murakami Takayoshi , Endo Yoshikatsu , Nishizaki Masahiko , Kagawa Shunsuke , Tanaka Noriaki , Fujiwara Toshiyoshi 
Published: June 2022

Abstract
Purpose: Dendritic cells are the most potent antigen-presenting cells for initiating cellular immune responses. Dendritic cells are attractive immunoregulatory cells for cancer immunotherapy, and their efficacy has been investigated in clinical trials. The tumor suppressor gene p53 is pivotal in the regulation of apoptosis, and p53-based immunization is an attractive approach to cancer immunotherapy because of the accumulation of p53 protein in malignant but not in normal cells. It has been shown that dendritic cells transduced with an adenoviral wild-type p53 (wt-p53) construct mediate the antitumor immune responses against p53-overexpressing tumor cells. We examined whether monocyte-derived human dendritic cells pulsed with the purified full-length wt-p53 protein were also capable of inducing the specific antitumor responses against p53-overexpressing tumors in vitro.
Experimental Design: Immature dendritic cells generated in the presence of interleukin-4 and granulocyte/macrophage colony-stimulating factor from monocytes of HLA-A2- or HLA-A24-positive healthy individuals were pulsed with the purified p53 protein. Uptake of p53 protein by human dendritic cells was assessed by Western blotting and immunohistochemical staining using anti-p53 antibody. Induction of p53-specific CTL response was also evaluated by the cytotoxic assay against p53-overexpressing human tumor cells.
Results: Both Western blot and immunohistochemical analysis showed the accumulation of p53 protein in human immature dendritic cells. T cells obtained from HLA-A2- or HLA-A24-positive healthy donors were stimulated twice with p53 protein-pulsed dendritic cells and then applied to the cytotoxicity assay against p53-overexpressing target cells. The CTL activity was specific for p53-overexpressing tumor cells and MHC class I restricted. Moreover, the CTL activity generated by p53 protein-pulsed dendritic cells was nearly identical with that induced by adenoviral wt-p53-transduced dendritic cells.
Conclusions: Our results indicate that monocyte-derived human dendritic cells pulsed with the wt-p53 protein could induce the specific antitumor effect against p53-overexpressing tumors and that this in vitro model offers a new and more simple approach to the development of p53-based immunotherapy.
Prognosis of Non–Small Cell Lung Cancer Patients by Detecting Circulating Cancer Cells in the Peripheral Blood with Multiple Marker Genes
Authors: Sher Yuh-Pyng , Shih Jin-Yuan , Yang Pan-Chyr , Roffler Steve R. , Chu Yi-Wen , Wu Cheng-Wen , Yu Chia-Li , Peck Konan 
Published: June 2022

Abstract
Purpose: Current lung cancer staging and prognosis methods are based on imaging methods, which may not be sensitive enough for early and accurate detection of metastasis. This study aims to validate the use of a panel of markers for circulating cancer cell detection to improve the accuracy of cancer staging, prognosis, and as a rapid assessment of therapeutic response.
Experimental Design: We analyzed the National Cancer Institute-Cancer Genome Anatomy Project database to identify potential marker genes for the detection of circulating cancer cells in peripheral blood. Nested real-time quantitative PCR and a scoring method using cancer cell load Lc were employed to correlate the amount of circulating cancer cells with clinical outcomes in 54 non–small cell lung cancer (NSCLC) patients. The Kaplan-Meier method was employed for analysis of prognostic variables.
Results: A panel of four marker genes was identified and experimentally validated. With these marker genes, we achieved an overall positive detection rate of 72% for circulating cancer cells in the peripheral blood of NSCLC patients. Patients who had higher Lc values had worse outcomes and shorter survival times. Patients with poor therapeutic response were revealed by positive detection of circulating cancer cells after therapy. The results correlated well with the patients' survival time.
Conclusion: Circulating cancer cell detection by a panel of markers and the Lc scoring method can supplement the current tumor, node, metastasis staging method for improved prognosis and for rapid assessment of therapeutic response. Together, they may facilitate the design of better therapeutic strategies for the treatment of NSCLC patients.
Erythropoietin and Erythropoietin Receptor Expression in Head and Neck Cancer: Relationship to Tumor Hypoxia
Authors: Arcasoy Murat O. , Amin Khalid , Chou Shu-Chuan , Haroon Zishan A. , Varia Mahesh , Raleigh James A. 
Published: June 2022

Abstract
Purpose: Erythropoietin, an oxygen-regulated glycoprotein hormone, is a hematopoietic cytokine that stimulates erythropoiesis by binding to its cellular receptor [erythropoietin receptor (EPOR)]. The recombinant form of human erythropoietin is used to prevent or treat anemia in cancer patients. However, in a recent randomized, placebo-controlled trial involving patients receiving curative radiotherapy for squamous cell carcinoma of the head and neck, erythropoietin treatment was associated with poorer locoregional progression-free survival. The purpose of our study was to determine whether EPOR and its ligand erythropoietin are expressed in primary head and neck cancer. We also investigated the hypothesis that erythropoietin expression in malignant cells may be associated with the presence of tumor hypoxia, an important factor involved in resistance to radiation treatment, tumor aggressiveness, and poor prognosis.
Experimental Design: Twenty-one patients received an i.v. infusion of the hypoxia marker pimonidazole hydrochloride before multiple tumor biopsies. Contiguous sections from 74 biopsies were analyzed by immunohistochemistry for EPOR and erythropoietin expression and pimonidazole binding.
Results: EPOR expression was present in tumor cells in 97% of the biopsies. Coexpression of erythropoietin was observed in 90% of biopsies. Erythropoietin and pimonidazole adduct staining did not always colocalize within tumors, but there was a significant positive correlation between levels of microregional erythropoietin expression and pimonidazole binding.
Conclusions: The coexpression of erythropoietin and EPOR in tumor cells suggests that erythropoietin may potentially function as an autocrine or paracrine factor in head and neck cancer. The expression of the hypoxia-inducible protein erythropoietin in tumor cells correlates with levels of tumor hypoxia.
Insulin-Like Growth Factor Type 1 Receptor Expression Correlates to Good Prognosis in Highly Malignant Soft Tissue Sarcoma
Authors: Åhlén Jan , Wejde Johan , Brosjö Otte , von Rosen Anette , Weng Wen-Hui , Girnita Leonard , Larsson Olle , Larsson Catharina 
Published: June 2022

Abstract
Purpose: To evaluate known and suggested prognostic markers, especially insulin-like growth factor type 1 receptor (IGF-1R), in highly malignant soft tissue sarcomas (STS).
Experimental Design: A cohort of 101 patients with primary STS of high malignancy grade was studied with respect to development of metastasis, local recurrence, and survival during a minimum of 5 years follow-up. All tumors were analyzed by immunohistochemistry for expression of Ki-67, p53, p27, Bcl-2, IGF-1R, and microvessel density. The traditional clinical variables size, malignancy grade (3 or 4), necrosis, mitotic frequency, infiltrative tumor growth, vascular invasion, depth, and surgical margins were also evaluated.
Results: A significant association was shown between high expression of IGF-1R and favorable outcome. Among STS with positive IGF-1R immunoreactivity, cases with high expression (76-100% positive cells) had the best outcome, whereas cases with the lowest expression (1-25% positive cells) had the worst. As expected, large tumor size (&gt;11 cm), presence of necrosis, high mitotic count, intralesional surgery, and deep location were all significantly associated with poor outcome, both in univariate and multivariate analyses. No difference in outcome was observed between cases of malignancy grade 3 versus 4, whereas the included and more objective variables necrosis and mitotic count were found to be reliable prognostic markers.
Conclusion: IGF-1R expression is a common feature of highly malignant STS. Further elucidation of the role of IGF-1R and the IGF system in STS may both provide a basis for development of new prognostic tools in STS, as well as shed light on the basic mechanisms of the STS development.
Loss of the AP-2α Transcription Factor Is Associated with the Grade of Human Gliomas
Authors: Heimberger Amy B. , McGary Eric C. , Suki Dima , Ruiz Maribelis , Wang Huamin , Fuller Gregory N. , Bar-Eli Menashe 
Published: June 2022

Abstract
Purpose: The activator protein (AP)-2α transcription factor plays a crucial role in the progression of several human tumors, including malignant melanoma, prostate, and breast cancer. Loss of AP-2α results in deregulation of several genes with AP-2α binding motifs such as E-cadherin, p21WAF1, MMP-2, MCAM/MUC18, VEGF, and c-KIT. The purpose of our study was to determine AP-2α expression distribution among grades of gliomas and any possible effect on prognosis.
Experimental Design: A tissue microarray was assembled from all surgical glioma cases with available tissue samples at M.D. Anderson Cancer Center since 1986 to include 72 glioblastomas, 49 anaplastic astrocytomas, 9 low-grade astrocytoma, 37 oligodendrogliomas, 37 anaplastic oligodendrogliomas, 15 mixed oligoastrocytomas, 20 anaplastic mixed oligoastrocytomas, and 7 gliosarcomas. The microarray included normal brain tissue, and AP-2α expression was determined by immunohistochemistry.
Results: AP-2α expression was lost on 99% (P &lt; 0.001) and 98% (P &lt; 0.001) of glioblastomas and anaplastic astrocytomas, respectively, compared with grade 2 astrocytomas and normal brain, all of which (100%) maintained expression of AP-2α. The loss of AP-2α was a negative prognostic indicator within the overall category of gliomas by univariate analysis (rate ratio, 4.30; 95% confidence interval, 2.60-7.10; P &lt; 0.001). However, there was no significant effect of loss of AP-2α expression on survival observed after adjustment for patient age, Karnofsky Performance Scale score, tumor grade, and extent of resection (rate ratio, 1.2; 95% confidence interval, 0.6-2.2; P = 0.6).
Conclusions: AP-2α expression correlates inversely with glioma grade, suggesting a direct role in glioma tumorigenicity, possibly through subsequent deregulation of target genes. Of all the previously characterized markers of progression, the loss of AP-2α would be the most common (96.2%) molecular marker as an astrocytic tumor evolves from grade 2 to 3.
Inhibition of Platelet-Derived Growth Factor Receptor Signaling Restricts the Growth of Human Breast Cancer in the Bone of Nude Mice
Authors: Lev Dina Chelouche , Kim Sun Jin , Onn Amir , Stone Valerie , Nam Do-Hyun , Yazici Sertac , Fidler Isaiah J. , Price Janet E. 
Published: June 2022

Abstract
Purpose: Bone is a common site for breast cancer metastasis. Platelet-derived growth factor (PDGF) and PDGF receptors (PDGFR) are involved in the regulation of bone resorption. This study examined the effects of STI571 (imatinib mesylate), which inhibits PDGFR tyrosine kinase signaling, on the growth of human breast cancer cells in the bone of nude mice with consequent osteolysis.
Experimental Design: Human breast cancer MDA-MB-435 cells were injected into the tibia of female nude mice. Two weeks later the mice were treated with p.o. and injected water (control), daily p.o. STI571, weekly injection of paclitaxel, or daily STI571, plus weekly paclitaxel, for up to 8 weeks. Growth of tumors in bones and osteolysis were monitored by digital radiography and tumors were collected for histochemical analysis.
Results: Mice treated with STI571 or STI571 plus paclitaxel had smaller bone tumors with less lytic bone destruction than did mice treated with water or paclitaxel alone. The results of treatment with paclitaxel plus STI571 did not differ from those with STI571 alone. Immunohistochemistry showed that PDGF-A, PDGF-B, PDGFRα, and PDGFRβ were expressed in the bone tumors. STI571 treatment inhibited PDGFR phosphorylation in tumor cells and tumor-associated endothelial cells, coincident with increased apoptosis, reduced proliferation, and lower microvessel density in the tumors.
Conclusions: Activated PDGFRs are expressed by endothelial and tumor cells in breast cancer tumors growing in the bone of nude mice. Interfering with PDGFR signaling may be an approach to control the progressive growth of breast cancer cells and thus reduce bone lysis.
Growth Suppression of Ovarian Cancer Xenografts in Nude Mice by Vitamin D Analogue EB1089
Authors: Zhang Xiaohui , Jiang Feng , Li Pengfei , Li Chunrong , Ma Qiuping , Nicosia Santo V. , Bai Wenlong 
Published: June 2022

Abstract
Purpose: The poor response of advanced epithelial ovarian cancer to current treatments necessitates the development of alternative therapeutic strategies. Inhibition of cancer growth by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] compounds represents an innovative approach for cancer therapy. The current study evaluated the therapeutic potential of a synthetic 1,25(OH)2D3 analogue EB1089 in the treatment of ovarian cancer.
Experimental Design: The response of human ovarian cancer cells to 1,25(OH)2D3 and EB1089 were first compared in cell growth, gene transcription, and apoptotic assays. Then, nude mice bearing OVCAR3 tumor xenografts were treated with EB1089 at different dosages, and tumor volumes were monitored. The effect of EB1089 and 1,25(OH)2D3 on the level of serum calcium was also examined. After the treatment, tumors were excised and processed for histologic examination, Ki-67 staining, and tissue terminal deoxynucleotide transferase–mediated dUTP nick end labeling (TUNEL) assays to evaluate the morphologic, proliferative, and apoptotic changes induced by EB1089, respectively.
Results: The study shows that EB1089 suppresses the in vitro growth of ovarian cancer cells and transcriptionally activates the GADD45 reporter gene more effectively than 1,25(OH)2D3. Clinically more importantly, EB1089 suppresses the growth of OVCAR3 tumor xenografts in nude mice without inducing hypercalcemia. Ki-67 staining and tissue TUNEL assays showed that both inhibition of cell proliferation and induction of apoptosis contribute to the EB1089-induced tumor suppression in vivo.
Conclusions: This study is the first demonstration that ovarian cancer responds positively in vivo to treatment with a 1,25(OH)2D3 compound and thus supports continued development of 1,25(OH)2D3 analogues for possible use as an alternative or complementary therapy for human ovarian cancer.
Herstatin, an Autoinhibitor of the Epidermal Growth Factor (EGF) Receptor Family, Blocks the Intracranial Growth of Glioblastoma
Authors: Staverosky Julia A. , Muldoon Leslie L. , Guo Shuhua , Evans Adam J. , Neuwelt Edward A. , Clinton Gail M. 
Published: June 2022

Abstract
Purpose: Herstatin, an autoinhibitor of the epidermal growth factor (EGF) receptor family, was evaluated for efficacy against human glioblastoma in vitro and in vivo in a rat intracranial model.
Experimental Design: Glioblastoma controlled by EGF receptor (EGFR; U87MG) or by the truncated mutant, ΔEGFR (U87MG/Δ), were transfected with Herstatin and evaluated for in vitro and in vivo growth in nude rat brain. Cells treated with purified Herstatin in vitro were evaluated for growth and signal transduction.
Results: Herstatin expression prevented tumor formation by U87MG and purified Herstatin inhibited their growth in vitro in a dose-responsive fashion, whereas in vivo and in vitro growth of U87MG/Δ was resistant to Herstatin. Inhibition of U87MG growth correlated with suppressed EGF activation of EGFR and of Akt but not mitogen-activated protein kinase signaling pathways, whereas ΔEGFR activity and intracellular signaling in U87MG/Δ were unaffected by Herstatin treatment.
Conclusions: Herstatin may have utility against glioblastoma driven by the EGFR but not the mutant ΔEGFR. Blockade of Akt but not the mitogen-activated protein kinase signaling cascade appears to be critical for suppression of intracranial tumor growth.
A Novel Assay to Assess Primary Human Cancer Infectibility by Replication-Selective Oncolytic Adenoviruses
Authors: Wang Yaohe , Thorne Stephen , Hannock Joseph , Francis Jennelle , Au Tina , Reid Tony , Lemoine Nick , Kirn David , Halldén Gunnel 
Published: June 2022

Abstract
Purpose: Replication-selective oncolytic adenoviruses hold promise for cancer treatment, but the predictive use of cell lines, dissociated tumor tissue, and animal models for efficacy against primary cancers are unclear. To further evaluate cytotoxicity and the potential for efficacy of replication-competent adenoviruses we therefore developed a novel methodology using primary human cancer specimens ex vivo; ovarian, colon, rectal, and breast carcinomas were included.
Experimental Design: Tissue culture conditions were developed to maintain viability of adenocarcinomas ex vivo for 48 hours postsurgery. Explants were infected by replication-competent (wild type 5 and E1A mutant dl922-947) and replication-defective (dl312) adenoviruses; early (E1A) and late (hexon) viral gene expression, αv integrins, coxsackievirus and adenovirus receptor (CAR) and tissue viability were assessed by immunohistochemistry and histopathology. Viral replication was verified by replication assays on selected samples.
Results: Viral gene expression varied dramatically among cancer specimens (n = 41). With Ad5, hexon expression was high in 8 of 11 tested specimens, whereas E1A levels were detectable in 16 of 27 tumor explants. Viral gene expression, distribution, and cytopathic effects were greater postinfection with dl922-947. Specimens that supported early gene expression (E1A) also supported viral replication in 13 of 14 tested cases, determined by recovery of infectious units. As predicted, the replication-defective adenovirus dl312 was not associated with viral gene expression.
Conclusions: Primary human tumor tissue remained viable when cultured ex vivo enabling evaluation of viral mutants in tissue with intact morphology. This assay may have great use in determining treatment-sensitive cancers and assess specific oncolytic mutants in individual cases.