bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibitory Effect of Antagonists of Bombesin and Growth Hormone-Releasing Hormone on Orthotopic and Intraosseous Growth and Invasiveness of PC-3 Human Prostate Cancer in Nude Mice
Authors: Stangelberger Anton , Schally Andrew V. , Varga Jozsef L. , Zarandi Marta , Szepeshazi Karoly , Armatis Patricia , Halmos Gabor
Published: June 2022

Purpose: To determine whether antagonists of growth hormone-releasing hormone (GHRH) and bombesin/gastrin-releasing peptide (BN/GRP) can inhibit the orthotopic and metastatic growth of PC-3 human androgen-independent prostate cancers.

Experimental Design: The effects of administration of GHRH antagonist MZ-J-7-118, BN/GRP antagonist RC-3940-II, and their combination on the growth and metastatic spread of PC-3 tumors implanted orthotopically into nude mice were evaluated. The efficacy of this treatment on PC-3 tumors implanted intratibially and s.c. was also determined.

Results: Treatment with MZ-J-7-118, RC-3940-II, or their combination significantly inhibited the growth of PC-3 tumors implanted orthotopically, intraosseously, and s.c. The combination of the two antagonists had the greatest effect, inhibiting orthotopic tumor growth by 77%, intratibially implanted tumors by 86%, and s.c. tumors by 86%. The therapy with BN/GRP and GHRH antagonists, especially in combination, also reduced the local tumor spread and distant metastases in animals bearing orthotopic tumors. Combination therapy was likewise the most effective in reducing the incidence and severity of tibial osteolytic lesions and pathologic fractures in intraosseously implanted tumors. High-affinity binding sites for BN/GRP and GHRH were found in s.c. and orthotopic PC-3 tumor samples. MZ-J-7-118, RC-3940-II, and the combination of both compounds inhibited in vitro growth of PC-3 cells.

Conclusions: Our findings show the efficacy of BN/GRP antagonists and GHRH antagonists for the treatment of advanced prostate cancer in preclinical metastatic models. As BN/GRP antagonists are already in clinical trials and GHRH antagonists are effective in androgen-independent prostate cancer models, these analogues could be considered for the management of advanced prostate carcinoma.
Involvement of Chemokine Receptor 4/Stromal Cell–Derived Factor 1 System during Osteosarcoma Tumor Progression
Authors: Perissinotto Eliana , Cavalloni Giuliana , Leone Francesco , Fonsato Valentina , Mitola Stefania , Grignani Giovanni , Surrenti Nadia , Sangiolo Dario , Bussolino Federico , Piacibello Wanda , Aglietta Massimo
Published: June 2022

Despite intensive chemotherapy and surgery treatment, lung and bone metastasis develop in about 30% of patients with osteosarcoma. Mechanisms for this preferential metastatic behavior are largely unknown. We investigated the role of the chemokine receptor 4 (CXCR4)/stromal cell–derived factor 1 (SDF-1) system to drive the homing of osteosarcoma cells. We analyzed the expression of the CXCR4 and SDF-1 proteins on several osteosarcoma cell lines and the effects of SDF-1 on migration, adhesion, and proliferation of these cancer cells. In vitro assays showed that the migration of osteosarcoma cells expressing CXCR4 receptor follows an SDF-1 gradient and that their adhesion to endothelial and bone marrow stromal cells is promoted by SDF-1 treatment. Moreover, the production of matrix metalloproteinase-9 is increased after SDF-1 exposure. We finally proved in a mouse model our hypothesis of the CXCR4/SDF-1 axis involvement in the metastatic process of osteosarcoma cells. Development of lung metastasis after injection of osteosarcoma cells was prevented by the administration of a CXCR4 inhibitor, the T134 peptide. These data show a possible explanation for the preferential osteosarcoma metastatic development into the lung, where SDF-1 concentration is high, and suggest that molecular strategies aimed at inhibiting the CXCR4/SDF-1 pathway, such as small-molecule inhibitors or anti-CXCR4 antibodies, might prevent the dissemination of osteosarcoma cells.
Mutations and Deletions of the CBP Gene in Human Lung Cancer
Authors: Kishimoto Masahiro , Kohno Takashi , Okudela Koji , Otsuka Ayaka , Sasaki Hiroki , Tanabe Chikako , Sakiyama Tokuki , Hirama Chie , Kitabayashi Issay , Minna John D. , Takenoshita Seiichi , Yokota Jun
Published: June 2022

Purpose: Microarray-based comparative genomic hybridization analysis led us to detect a homozygous deletion at the cyclic AMP response element binding protein-binding protein (CBP) locus in a lung cancer cell line. Oncogenic roles of CBP had been suggested by functional and genetic studies; thus, involvement of CBP gene alterations in lung carcinogenesis was investigated by undertaking comprehensive analysis of genetic CBP alterations in human lung cancer.

Experimental Design: Fifty-nine cell lines and 95 surgical specimens of lung cancer were analyzed for mutations, homozygous and hemizygous deletions, and expression of the CBP gene.

Results: Homozygous CBP deletions, including two intragenic deletions, were detected in three (5.1%) lung cancer cell lines. CBP mutations, including missense, nonsense, and frame-shift mutations, were detected in six (10.2 %) cell lines and five (5.3%) surgical specimens of lung cancer. The wild-type CBP allele was retained in 9 of 11 cases with CBP mutations, and both the wild-type and mutant alleles were expressed in all the six cases with heterozygous CBP mutations examined. Three mutations with amino acid substitutions in the histone acetyltransferase domain caused significant reduction in transcription activation activity of CBP protein in vivo.

Conclusions: A fraction of lung cancers carried mutations and/or deletions of the CBP gene, suggesting that genetic CBP alterations are involved in the genesis and/or progression of a subset of lung cancers.
Methylation of the γ-Catenin Gene Is Associated With Poor Prognosis of Renal Cell Carcinoma
Authors: Breault Julia E. , Shiina Hiroaki , Igawa Mikio , Ribeiro-Filho Leopoldo A. , Deguchi Masao , Enokida Hideki , Urakami Shinji , Terashima Masaharu , Nakagawa Masayuki , Kane Christopher J. , Carroll Peter R. , Dahiya Rajvir
Published: June 2022

Purpose: γ-Catenin is a cell adhesion protein, and its functional loss is associated with tumor invasion and metastasis. We hypothesize that (1) promoter CpG methylation regulates the expression and function of the γ-catenin gene in renal cell carcinoma (RCC) and (2) methylation of the γ-catenin gene is associated with poor prognosis of RCC. To test these hypotheses, we analyzed the CpG methylation status of the γ-catenin gene and its correlation with clinical outcome in RCC.

Experimental Design: Genomic DNA and total RNA were extracted from three renal cancer cell lines (A498, Caki-1, and Caki-2) and 54 RCC tissue samples with their corresponding normal kidney tissue samples. Expression of γ-catenin gene was analyzed by reverse transcription-PCR and immunostaining. Promoter methylation was analyzed by two different methylation-specific PCR (MSP-A and MSP-B), and the results were verified by DNA sequencing.

Results: The demethylating agent (5-aza-2′-deoxycytidine) increased levels of mRNA transcript of the γ-catenin gene in three renal cancer cell lines. γ-Catenin mRNA and protein expression were significantly reduced in RCC samples compared with normal kidney samples, respectively (P < 0.05). MSP-A and MSP-B bands were detected in 45 of 54 (83.3%) and 49 of 54 (90.7%) RCC samples, respectively. In normal kidney, weak products of MSP-A and MSP-B were detected in 5 of 54 (9.3%) and 6 of 54 (11.1%) samples, respectively. Likewise, both MSP-A and MSP-B ratios were significantly higher in RCC samples compared with normal kidney samples, respectively (P < 0.01). Multivariate analysis revealed that the MSP-B ratio was a powerful and independent predictor superior to nuclear grade and Robson stage with respect to survival and disease progression (P = 0.029 and 0.0071, respectively). No mutations in the NH2-terminal region of γ-catenin were found in this study.

Conclusion: Expression of γ-catenin is regulated by promoter CpG methylation, and the balance between methylated and unmethylated RCC cell populations could determine its functional role. Because the conventional nuclear grade and/or staging system have some limitations to predict precise clinical outcome, this is the first report demonstrating that promoter CpG methylation of γ-catenin can be an independent and superior predictor for survival and disease progression.
Prognostic Significance of MMP-1 and MMP-3 Functional Promoter Polymorphisms in Colorectal Cancer
Authors: Zinzindohoué Franck , Lecomte Thierry , Ferraz Jean-Marc , Houllier Anne-Marie , Cugnenc Paul-Henri , Berger Anne , Blons Hélène , Laurent-Puig Pierre
Published: June 2022

Purpose: Matrix metalloproteinase (MMP) belongs to a large group of proteases capable of breaking essentially all components of the extracellular matrix. They are implicated in all steps of tumorogenesis, cancer invasion, and metastasis. Among them, metalloproteinase type 1 (MMP-1) is implicated in tumor invasion and metastasis in different types of cancers including colorectal cancer in which its expression was correlated with poor prognosis. A polymorphism in the promoter region of the MMP-1 gene leads to a variation of its level of transcription.

Study Design: MMP-1 -1607ins/delG and MMP-3 - 1612 ins/delA promoter polymorphisms were genotyped by multiplex PCR from 201 colorectal cancer patients. The median follow-up of patients was 30 months. The MMP genotypes were correlated to clinical outcome.

Results: Patients with the -1607insG/-1607insG MMP-1 genotype had significantly worse specific survival than the others in the whole series (P < 0.04), in stage I to III patients (P < 0.001), and in patients stage I and II (P < 0.01). In multivariate analysis, MMP-1-1607insG allele showed to be an independent poor prognostic factor after adjustment on stage, age, and the use of adjuvant chemotherapy. MMP-3 polymorphism was not associated with survival.

Conclusions: In the subgroups of nondistant metatastic patients (stages I and II, and stages I-III), an inverse relation between the number of MMP-1-1607insG allele and survival was observed suggesting a gene dosage effect. Our results are consistent with the importance of MMP-1-1607ins/delG functional polymorphism in regulating transcription level and with the relationship between MMP-1 expression and cancer invasion, metastasis, and prognosis.
A Phase I and Pharmacokinetic Study of Ecteinascidin-743 (Yondelis) in Children with Refractory Solid Tumors. A Children's Oncology Group Study
Authors: Lau Loretta , Supko Jeffery G. , Blaney Susan , Hershon Linda , Seibel Nita , Krailo Mark , Qu Wenchun , Malkin David , Jimeno Jose , Bernstein Mark , Baruchel Sylvain ,   for the Children's Oncology Group
Published: June 2022

Purpose: To determine the dose-limiting toxicity (DLT) and the maximum tolerated dose of ecteinascidin-743 (ET-743, Yondelis) in children with refractory solid tumors, to establish the recommended dose for pediatric phase II trials, and to characterize the pharmacokinetics of ET-743 in children.

Experimental Design: ET-743 was administered as a 3-hour i.v. infusion every 21 days. The starting dose was 1,100 μg/m2 with planned dose escalation of 200 μg/m2 increments. Pharmacokinetic sampling was done during the first treatment course.

Results: Twelve evaluable patients received a total of 29 courses. One grade 4 DLT (prolonged grade 4 neutropenia) was noted at the first dose level. At the second dose level (1,300 μg/m2), there were two DLTs (reversible grade 4 elevations of hepatic transaminase); hence the maximum tolerated dose was defined as 1,100 μg/m2. Overall, reversible hepatic toxicity, manifested as grade 3 or 4 elevations in hepatic transaminase, occurred in more than 50% of the patients. No grade 3 or 4 thrombocytopenia was reported at either dose level and only one episode of isolated creatine phosphokinase grade 4 elevation was observed. One complete response was documented after six courses in a patient with metastatic Ewing sarcoma. The pharmacokinetics of ET-743 in 8 children was characterized by a terminal disposition phase with a mean half-life of 43.8 ± 18.4 hours, a total body clearance of 28.2 ± 10.5 L/h/m2, and a 959 ± 807 L/m2 steady-state apparent volume of distribution.

Conclusion: ET-743 is safe. The phase II recommended dose of ET-743 administered as a 3-hour i.v. infusion following premedication with dexamethasone is 1,100 μg/m2.
Phase I and Pharmacokinetic Study of DE-310 in Patients with Advanced Solid Tumors
Authors: Soepenberg Otto , de Jonge Maja J. A. , Sparreboom Alex , de Bruin Peter , Eskens Ferry A. L. M. , de Heus Gerda , Wanders Jantien , Cheverton Peter , Ducharme Murray P. , Verweij Jaap
Published: June 2022

Purpose: To assess the maximum-tolerated dose, toxicity, and pharmacokinetics of DE-310, a macromolecular prodrug of the topoisomerase I inhibitor exatecan (DX-8951f). in patients with advanced solid tumors.

Experimental Design: Patients received DE-310 as a 3-hour infusion once every 2 weeks (dose, 1.0-2.0 mg/m2) or once every 6 weeks (dose, 6.0-9.0 mg/m2). Because pharmacokinetics revealed a drug terminal half-life exceeding the 2 weeks administration interval, the protocol was amended to a 6-week interval between administrations also based on available information from a parallel trial using an every 4 weeks schedule. Conjugated DX-8951 (the carrier-linked molecule), and the metabolites DX-8951 and glycyl-DX-8951 were assayed in various matrices up to 35 days post first and second dose.

Results: Twenty-seven patients were enrolled into the study and received a total of 86 administrations. Neutropenia and grade 3 thrombocytopenia, and grade 3 hepatotoxicity with veno-occlusive disease, were dose-limiting toxicities. Other hematologic and nonhematologic toxicities were mild to moderate and reversible. The apparent half-life of conjugated DX-8951, glycyl-DX-8951, and DX-8951 was 13 days. The area under the curve ratio for conjugated DX-8951 to DX-8951 was 600. No drug concentration was detectable in erythrocytes, skin, and saliva, although low levels of glycyl-DX-8951 and DX-8951 were detectable in tumor biopsies. One patient with metastatic adenocarcinoma of unknown primary achieved a histologically proven complete remission. One confirmed partial remission was observed in a patient with metastatic pancreatic cancer and disease stabilization was noted in 14 additional patients.

Conclusions: The recommended phase II dose of DE-310 is 7.5 mg/m2 given once every 6 weeks. The active moiety DX-8951 is released slowly from DE-310 and over an extended period, achieving the desired prolonged exposure to this topoisomerase I inhibitor.
Targeting Cyclooxygenase-2 Reduces Overt Toxicity toward Low-Dose Vinblastine and Extends Survival of Juvenile Mice with Friend Disease
Authors: Cervi Dave , Klement Giannoula , Stempak Diana , Baruchel Sylvain , Koki Alane , Ben-David Yaacov
Published: June 2022

Purpose: To test the efficacy of selective therapy against cyclooxygenase-2 in combination with a low-dose regimen of a cytotoxic agent in the treatment of juvenile hematopoietic malignancies in the experimental model, Friend disease.

Experimental Design: Juvenile erythroleukemic mice (n = 8) received no treatment, celecoxib (1600 mg/kg/d), vinblastine (0.5 μg/g twice weekly), vehicle controls, or celecoxib + vinblastine combination (n = 9) over a 6-month period from time of tumor induction. Overt toxicity was assessed daily and recorded weekly.

Results: Among randomly selected mice from celecoxib treatment groups, plasma concentrations ranged from 2 to 6 μmol/L. As a single agent, celecoxib was not associated with any apparent toxicity. Monotherapy with vinblastine, however, caused early mortality marked by severe diarrhea, lethargy, and weight loss. At the tested doses, neither vinblastine nor celecoxib enhanced survival as monotherapies. Coadministration of these two drugs alleviated the overt toxicity associated with vinblastine and resulted in a significant increase in survival (P < 0.05). Survivors sampled throughout the study showed a trend to decreased weight loss and hematocrit levels among all groups, but significance was evidenced earlier in the vinblastine monotherapy group overall (P < 0.05). Despite similar degree of splenomegaly, histologic analysis revealed preserved splenic mantle architecture from mice given combination therapy compared with those sampled from mice on all other monotherapies, exhibiting a more diffuse burden of blasts and destruction of germinal centers.

Conclusion: We propose that addition of a selective cyclooxygenase-2 inhibitor to a modified low-dose conventional chemotherapeutic regimen protects juvenile mice with Friend disease from succumbing to low-dose cytotoxicity, in part, by neutralizing acute inflammatory responses.
Effect of Tumor Host Microenvironment on Photodynamic Therapy in a Rat Prostate Tumor Model
Authors: Chen Bin , Pogue Brian W. , Zhou Xiaodong , O'Hara Julia A. , Solban Nicolas , Demidenko Eugene , Hoopes P. Jack , Hasan Tayyaba
Published: June 2022

Purpose: Tumor host microenvironment plays an important role in tumor growth, metastasis, and response to cancer therapy. In this study, the influence of tumor host environment on tumor pathophysiology, photosensitizer distribution, and photodynamic therapy (PDT) treatment effect was examined in the metastatic at lymph node and lung (MatLyLu) rat prostate tumor.

Experimental Design: MatLyLu tumors implanted in different host environment [i.e., orthotopically (in the prostate) or s.c.] were compared for difference in vessel density, average vessel size, vascular permeability, tumor vascular endothelial growth factor production, and tumor oxygenation. Uptake of photosensitizer verteporfin in tumors in both sites was determined by fluorescence microscopy. To compare tumor response to PDT, both orthotopic and s.c. MatLyLu tumors were given the same doses of verteporfin and laser light treatment, and PDT-induced tumor necrotic area was measured histologically.

Results: Orthotopic MatLyLu tumors were found to grow faster, have higher vessel density and more permeable vasculature, have higher vascular endothelial growth factor protein levels, and have lower tumor hypoxic fraction than the s.c. tumors. Uptake of photosensitizer verteporfin in the orthotopic tumor was higher than in the s.c. tumors at 15 minutes after injection (1 mg/kg, i.v.), and became similar at 3 hours after injection. For the vascular targeting PDT treatment (0.25 mg/kg verteporfin, 50 J/cm2 at 50 mW/cm2, 15 minutes drug-light interval), there was no significant difference in PDT-induced tumor necrotic area between the orthotopic and s.c. tumors, with 85% to 90% necrosis in both types of tumors. However, tumor necrosis induced by the cellular targeting PDT (1 mg/kg verteporfin, 50 J/cm2 at 50 mW/cm2, 3 hours drug-light interval) was significantly different in the orthotopic (64%) versus the s.c. (29%) tumors.

Conclusions: Tumor host environment can significantly affect photosensitizer verteporfin distribution and PDT treatment effect. Verteporfin-PDT regimen targeting tumor cells is more sensitive to such influence than the vascular targeting PDT. Our study showed the importance of tumor host environment in determining tumor physiologic properties and tumor response to PDT. To obtain clinically relevant information, orthotopic tumor model should be used in the experimental studies.
Expression of Vascular Endothelial Growth Factor in Uveal Melanoma Is Independent of 6p21-Region Copy Number
Authors: Abdel-Rahman Mohamed H. , Craig Elson L. , Davidorf Frederick H. , Eng Charis
Published: June 2022

Purpose: Overexpression of vascular endothelial growth factor (VEGF) and overrepresentation of the 6p region have been reported with a wide variation in uveal melanoma. The aim of the current study is to identify the frequency of copy number alteration in the 6p21 region and its correlation with the expression of VEGF in uveal melanoma.

Experimental Design: We studied 88 uveal melanomas for copy number change in the 6p region by comparative genomic hybridization and/or chromogenic in situ hybridization. Expression of VEGF protein was estimated by immunohistochemistry. In 15 tumors, VEGF mRNA expression was also studied by quantitative reverse transcription–PCR (RT-PCR) and VEGF splice variants were detected by RT-PCR.

Results: Copy number of the 6p21 region was successfully estimated in 37 tumors. In 10 (27%) of those, overrepresentation of the 6p21 region was detected. There was no statistically significant difference in VEGF expression between tumors with and without gain of 6p21 (P = 0.82). VEGF expression was not confined to the tumors and was also detected in the surrounding normal tissue. Expression of VEGF, detected by quantitative RT-PCR, was concordant with expression of VEGF protein. Different VEGF isoforms were expressed in different tumors with no obvious correlation with disease status.

Conclusion: VEGF is overexpressed in a significant number of uveal melanomas. It should be noted that VEGF is not a candidate oncogene in uveal melanoma with 6p gain/amplification. VEGF overexpression other than structural amplification is probably significant in the pathogenesis of uveal melanomas, and its mechanism must be sought.
Determination of Genes Related to Gastrointestinal Tract Origin Cancer Cells Using a cDNA Microarray
Authors: Kim Tae Moon , Jeong Ha Jin , Seo Min Young , Kim Sang Chul , Cho Gabee , Park Chan Hee , Kim Tae Soo , Park Kyu Hyun , Chung Hyun Cheol , Rha Sun Young
Published: June 2022

Purpose: We evaluated the genome-wide gene expression profiles of various cancer cell lines to identify the gastrointestinal tract cancer cell–related genes.

Experimental Design: Gene expression profilings of 27 cancer cell lines and 9 tissues using 7.5K human cDNA microarrays in indirect design with Yonsei reference RNA composed of 11 cancer cell line RNAs were done. The significant genes were selected using significant analysis of microarray in various sets of data. The selected genes were validated using real-time PCR analysis.

Results: After intensity-dependent, within-print-tip normalization by loess method, we observed that expression patterns of cell lines and tissues were substantially different, divided in two discrete clusters. Next, we selected 115 genes that discriminate gastrointestinal cancer cell lines from others using significant analysis of microarray. Among the expression profiles of five gastric cancer cell lines, 66 genes were identified as differentially expressed genes related to metastatic phenotype. YCC-16, which was established from the peripheral blood of one advanced gastric cancer patient, produced a unique gene expression pattern resembling the profiles of lymphoid cell lines. Quantitative real-time reverse transcription-PCR results of selected genes, including PXN, KRT8, and ITGB5, were correlated to microarray data and successfully discriminate the gastrointestinal tract cancer cell lines from hematologic malignant cell lines.

Conclusions: A gene expression database could serve as a useful source for the further investigation of cancer biology using the cell lines.
Effect of the Tumor Vascular-Damaging Agent, ZD6126, on the Radioresponse of U87 Glioblastoma
Authors: Wachsberger Phyllis R. , Burd Randy , Marero Nichol , Daskalakis Constantine , Ryan Anderson , McCue Peter , Dicker Adam P.
Published: June 2022

Purpose: The effect of ZD6126 on tumor oxygen tension and tumor growth delay in combination with ionizing radiation was examined in the human U87 glioblastoma tumor model. Resistance to ZD6126 treatment was investigated with the nitric oxide synthase inhibitor, l-NG-nitroarginine methyl ester (hydrochloride; l-NAME/active form, l-NNA).

Methods: U87 human xenografts were grown in athymic nude mice. ZD6126 was given with or without l-NNA. Tumor oxygen tension was measured using the Oxford Oxylite (Oxford, England) fiberoptic probe system. Tumor volume was determined by direct measurement with calipers and calculated by the formula [(smallest diameter2 × widest diameter)/2].

Results: Multiple doses of ZD6126 treatment (three doses) had a significant effect on tumor growth delay, reducing the average daily tumor growth rate from 29% to 16%. When given 1 hour before radiation, ZD6126 caused an acute increase in hypoxia in U87 tumors, and reduced tumor growth delay compared with that of radiation alone. The combination of ZD6126 given after radiation, either as a single dose or in multiple doses, had greater or similar antitumor activity compared with radiation alone. Twenty-four hours after administration, a single dose of ZD6126 induced little (10 ± 8%) necrosis in U87 xenografts. l-NNA, when given in combination with ZD6126, significantly enhanced the effectiveness of ZD6126 in inducing tumor necrosis.

Conclusions: Our observation that ZD6126-induced tumor hypoxia can decrease radiation response when ZD6126 is given prior to radiation indicates the importance of scheduling. Our findings suggest that the optimal therapeutic benefit of ZD6126 plus radiation in human glioblastoma may require multiple dosing in combination with a nitric oxide synthase inhibitor, to be scheduled following radiotherapy.
A Third-Generation Bisphosphonate, Minodronic Acid (YM529), Augments the Interferon α/β-Mediated Inhibition of Renal Cell Cancer Cell Growth Both In vitro and In vivo
Authors: Yuasa Takeshi , Nogawa Masaki , Kimura Shinya , Yokota Asumi , Sato Kiyoshi , Segawa Hidekazu , Kuroda Junya , Maekawa Taira
Published: June 2022

Purpose: Minodronic acid (YM529) is a third-generation nitrogen-containing bisphosphonate. Here, we have investigated the therapeutic efficacy of YM529 against renal cell cancer (RCC) alone or in combination with IFN both in vitro and in vivo.

Experimental Design: One murine and eight human RCC cell lines were used for the in vitro studies and were subjected to a modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Western blotting. Luciferase-labeled murine RCC cells (RENCALuc) were transplanted into the s.c. tissue or the renal subcapsule of syngeneic BALB/c mice. These mice were treated with YM529 and/or murine IFN and the growth of the cancer cells was monitored by an in vivo imaging system.

Results: YM529 inhibited the growth of RCC cells in a dose- and time-dependent manner and enhanced the growth inhibitory potential of IFN in vitro. In the in vivo mouse models, YM529 did not markedly inhibit the RCC cell growth on its own but it augmented the anticancer effect of IFN (P < 0.05). The YM529-treated mice (with or without IFN) did not alter the γ/δ T-lymphocyte numbers. The various treatment regimens were also not associated with any adverse effects. However, YM529 combined with IFN reduced the serum vascular endothelial growth factor levels.

Conclusions: Our study suggests that YM529 may be a potent anticancer agent for RCC. The efficacy and safety of IFN plus YM529 as a therapy for RCC should be verified by early-phase clinical trials.
Crosstalk between Estrogen Receptor and Growth Factor Receptor Pathways as a Cause for Endocrine Therapy Resistance in Breast Cancer
Authors: Osborne C. Kent , Shou Jiang , Massarweh Suleiman , Schiff Rachel
Published: June 2022

Data suggest that breast cancer growth is regulated by coordinated actions of the estrogen receptor (ER) and various growth factor receptor signaling pathways. In tumors with active growth factor receptor signaling (e.g., HER2 amplification), tamoxifen may lose its estrogen antagonist activity and may acquire more agonist-like activity, resulting in tumor growth stimulation. Because treatments designed to deprive the ER of its ligand estrogen will reduce signaling from both nuclear and membrane ER, aromatase inhibitors might be expected to be superior to tamoxifen in tumors with high growth factor receptor content, such as those overexpressing HER2. Recent clinical studies suggest that this is the case in humans, as trials of aromatase inhibitors show superior results compared with tamoxifen, especially in tumors overexpressing HER2. Although estrogen deprivation therapy is often effective in ER-positive breast cancer, de novo and acquired resistance are still problematic. Experimental models suggest that in one form of resistance to estrogen deprivation therapy, the tumor becomes supersensitive to low residual estrogen concentrations perhaps because of activation of mitogen-activated protein kinase. Such tumors respond to additional treatment with fulvestrant or even tamoxifen. On the other hand, in tumors overexpressing HER2, acquired resistance to estrogen deprivation therapy involves the loss of ER and ER-regulated genes and further up-regulation of growth factor signaling rendering the tumor hormonal therapy resistant. This process can be delayed or reversed by simultaneous treatment with growth factor pathway inhibitors. This strategy is now being tested in clinical trials.
Combinations of Endocrine and Biological Agents: Present Status of Therapeutic and Presurgical Investigations
Authors: Johnston Stephen RD
Published: June 2022

There is an increasing rationale to develop effective combinations of endocrine agents with novel therapeutics that target aberrant signal transduction pathways in estrogen receptor–positive breast cancer. Acquired resistance to endocrine therapy is associated with an increase in peptide growth factor signaling that results in crosstalk activation of estrogen receptor, and various signal transduction inhibitors (STI) can target these pathways to inhibit hormone-resistant growth. In experimental models of hormone-sensitive breast cancer, combinations of endocrine agents with STIs provide significantly greater growth inhibition than either alone, delaying the emergence of resistance. There are now several trials assessing the efficacy of combinations of tyrosine kinase inhibitors with various endocrine agents in the tamoxifen-resistant/second-line setting, together with five randomized phase II/III trials in the first-line setting. Similar work is ongoing with both farnesyltransferase inhibitors and mTOR antagonists where there are strong preclinical data to suggest additive or synergistic effects for either of these agents in combination with tamoxifen or estrogen deprivation therapies. More recently, presurgical studies with biological primary end points are being utilized as an alternative approach to investigate whether combined endocrine/STI therapy is a more effective strategy than endocrine therapy alone. This article reviews the rationale and current status of clinical trials in this area as well as the challenges that lie ahead for the development of these therapeutic combinations for breast cancer.
Short-Term Changes in Ki-67 during Neoadjuvant Treatment of Primary Breast Cancer with Anastrozole or Tamoxifen Alone or Combined Correlate with Recurrence-Free Survival
Authors: Dowsett Mitch , Smith Ian E. , Ebbs Steve R. , Dixon J. Michael , Skene Anthony , Griffith Clive , Boeddinghaus Irene , Salter Janine , Detre Simone , Hills Margaret , Ashley Susan , Francis Stephen , Walsh Geraldine ,   on behalf of the IMPACT Trialists
Published: June 2022

Purpose: Neoadjuvant (preoperative) therapy for breast cancer may allow for the development of intermediate markers of treatment benefit, thereby circumventing the need for efficacy trials of adjuvant therapy, which require much larger patient numbers and longer follow-up. The aim of this study—as part of the Immediate Preoperative “Arimidex” (anastrozole), Tamoxifen, or Arimidex Combined with Tamoxifen (IMPACT) trial (n = 330)—was to test the hypotheses that changes in Ki-67 after 2 weeks and/or 12 weeks: (i) differed between treatments, (ii) predicted clinical tumor response, and/or (iii) may predict long-term outcome differences between treatments in adjuvant therapy.

Experimental Design: The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared these same agents in the adjuvant setting. Biomarkers were measured in biopsy specimens taken before and after 2 and 12 weeks of treatment.

Results: Suppression of the proliferation marker Ki-67 after 2 and 12 weeks was significantly greater with anastrozole than with tamoxifen (P = 0.004 and P < 0.001) but was similar between tamoxifen and the combination (P = 0.600 and P = 0.912). This result closely parallels that seen for the relative recurrence-free survival with the treatments after a median follow-up of 31 months in the ATAC trial in 9,366 patients. Against expectations, apoptosis was not increased in any of the treatment arms.

Conclusions: The data indicate that short-term changes in proliferation in the neoadjuvant setting may be able to predict outcome during adjuvant use of the same treatments. If this can be confirmed, these findings could lead to a profound change in approaches to drug development in breast cancer. The data indicate that estrogen is not an important survival factor for human breast cancer cells.
Colocalization of Carbonic Anhydrase 9 Expression and Cell Proliferation in Human Head and Neck Squamous Cell Carcinoma
Authors: Hoogsteen Ilse J. , Marres Henri A.M. , Wijffels Karien I.E.M. , Rijken Paul F.J.W. , Peters Johannes P.W. , van den Hoogen Franciscus J.A. , Oosterwijk Egbert , van der Kogel Albert J. , Kaanders Johannes H.A.M.
Published: June 2022

Purpose: Tumor cells undergo a variety of biological changes under sustained hypoxic conditions, allowing cells to survive and retain their clonogenic potential. The purpose of this study is to relate the expression of the hypoxia marker carbonic anhydrase 9 (CA9) to the uptake of iododeoxyuridine (IdUrd), a marker of proliferation, in head and neck squamous cell carcinomas. Colocalization of IdUrd and CA9 may identify an important subpopulation of tumor cells that might be responsible for repopulation and disease progression.

Experimental Design: Expression of CA9, IdUrd labeling, and colocalization between IdUrd and CA9 was examined by immunohistochemistry in biopsies of head and neck squamous cell carcinomas. Biopsies were taken from 51 patients recruited between 1998 and 2001 after administration of the proliferation marker IdUrd.

Results: A large variation was observed between the tumors in CA9 expression (range 0-39%), IdUrd labeling (range 0-81%), and colocalization between IdUrd and CA9 [FId(CA9); range 0-53%]. FId(CA9), the fraction of IdUrd-labeled cells positive for CA9, was highest at an intermediate distance from the blood vessels (100-150 μm). IdUrd labeling was higher in T4 carcinomas relative to lower stage tumors (P = 0.04). High FId(CA9) correlated with the worst disease-free survival rates (P = 0.04).

Conclusions: Colocalization between IdUrd labeling and CA9 expression was observed in head and neck squamous cell carcinomas, suggesting the presence of a population of tumor cells under intermediate hypoxic conditions which still has proliferative capacity. The size of this subpopulation may be indicative of tumor aggressiveness and is associated with the worst disease-free survival rates.
50 Years of Preclinical Anticancer Drug Screening: Empirical to Target-Driven Approaches
Authors: Suggitt Marie , Bibby Michael C.
Published: June 2022

The number of anticancer agents that fail in the clinic far outweighs those considered effective, suggesting that the selection procedure for progression of molecules into the clinic requires improvement. The value of any preclinical model will ultimately depend on its ability to accurately predict clinical response. This review focuses on the major contributions of preclinical screening models to anticancer drug development over the past 50 years. Over time, a general transition has been observed from the empirical drug screening of cytotoxic agents against uncharacterized tumor models to the target-orientated drug screening of agents with defined mechanisms of action. New approaches to anticancer drug development involve the molecular characterization of models along with an appreciation of the pharmacodynamic and pharmacokinetic properties of compounds [e.g., the US National Cancer Institute (NCI) in vitro 60-cell line panel, hollow fiber assay, and s.c. xenograft]. Contributions of other potentially more clinically relevant in vivo tumor models including orthotopic, metastatic, and genetically engineered mouse models are also reviewed. Although this review concentrates on the preclinical screening efforts of the NCI, European efforts are not overlooked. Europe has played a key role in the development of new anticancer agents. The two largest academic drug development groups, the European Organisation for Research and Treatment of Cancer and Cancer Research UK, have been collaborating with the NCI in the acquisition and screening of compounds since the 1970s. As with the drug development process internationally, rational pharmacodynamic approaches have more recently been adopted by these two groups.
Glycogen Synthase Kinase-3 Inhibition Sensitizes Pancreatic Cancer Cells to Chemotherapy by Abrogating the TopBP1/ATR-Mediated DNA Damage Response
Authors: Ding Li , Madamsetty Vijay S. , Kiers Spencer , Alekhina Olga , Ugolkov Andrey , Dube John , Zhang Yu , Zhang Jin-San , Wang Enfeng , Dutta Shamit K. , Schmitt Daniel M. , Giles Francis J. , Kozikowski Alan P. , Mazar Andrew P. , Mukhopadhyay Debabrata , Billadeau Daniel D.
Published: June 2022

Purpose:

Pancreatic ductal adenocarcinoma (PDAC) is a predominantly fatal common malignancy with inadequate treatment options. Glycogen synthase kinase 3β (GSK-3β) is an emerging target in human malignancies including PDAC.

Experimental Design:

Pancreatic cancer cell lines and patient-derived xenografts were treated with a novel GSK-3 inhibitor 9-ING-41 alone or in combination with chemotherapy. Activation of the DNA damage response pathway and S-phase arrest induced by gemcitabine were assessed in pancreatic tumor cells with pharmacologic inhibition or siRNA depletion of GSK-3 kinases by immunoblotting, flow cytometry, and immunofluorescence.

Results:

9-ING-41 treatment significantly increased pancreatic tumor cell killing when combined with chemotherapy. Inhibition of GSK-3 by 9-ING-41 prevented gemcitabine-induced S-phase arrest suggesting an impact on the ATR-mediated DNA damage response. Both 9-ING-41 and siRNA depletion of GSK-3 kinases impaired the activation of ATR leading to the phosphorylation and activation of Chk1. Mechanistically, depletion or knockdown of GSK-3 kinases resulted in the degradation of the ATR-interacting protein TopBP1, thus limiting the activation of ATR in response to single-strand DNA damage.

Conclusions:

These data identify a previously unknown role for GSK-3 kinases in the regulation of the TopBP1/ATR/Chk1 DNA damage response pathway. The data also support the inclusion of patients with PDAC in clinical studies of 9-ING-41 alone and in combination with gemcitabine.
Poor Cortical Venous Opacification on Baseline Computed Tomography Angiography Predicts Parenchymal Hemorrhage After Thrombectomy
Authors: Bala Fouzi , Singh Nishita , Menon Bijoy K. , Demchuk Andrew M. , Poppe Alexandre Y. , McTaggart Ryan A. , Nogueira Raul G. , Buck Brian H. , Goyal Mayank , Hill Michael D. , Almekhlafi Mohammed A. ,   the ESCAPE‐NA1 investigators
Published: June 2022

Background

Although the association between cortical venous opacification (VO) and clinical outcomes has been shown in previous studies, little is known about the relationship between parenchymal hemorrhage (PH) and VO in patients with acute stroke. We aimed to determine whether cortical VO assessed on computed tomography angiography correlates with the risk of PH following endovascular treatment.

Methods

This is a post hoc analysis of the ESCAPE NA‐1 (Efficacy and Safety of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke) trial. Control‐arm patients with adequate venous assessment on computed tomography angiography were included. Any PH and symptomatic intracranial hemorrhage were compared between patients with poor VO (cortical vein opacification score<3) versus good opacification (cortical vein opacification score≥3). The relationships with unfavorable functional outcome (90‐day modified Rankin scale 3–6) and 24‐hour infarct volume were assessed. Multivariable logistic and linear regressions were performed.

Results

Among the 545 patients that met the inclusion criteria, 55 (10.2%) had PH and 21 (3.9%) had symptomatic intracranial hemorrhage. Poor VO was observed in 286 (52.5%) patients (median age, 71 years; 51.4% women). PH was more frequent in the patients with poor VO compared with good VO: 43 of 283 (15.2%) versus 12 of 257 (4.7%) (adjusted odds ratio, 3.43; [95% CI, 1.66–7.10]). Symptomatic intracranial hemorrhage was not significantly higher in the poor versus good opacification groups: 14 of 283 (5.0%) versus 7 of 257 (2.7%). Poor opacification was a predictor of unfavorable functional outcome (adjusted odds ratio, 3.01; [95% CI, 1.95–4.64];
P
<0.001), and larger final infarct volume (adjusted B 0.74; [95% CI, 0.45–1.03];
P
<0.001).

Conclusions

Poor VO on computed tomography angiography is strongly associated with an increased risk of PH and worse clinical outcomes after endovascular treatment, and therefore it may be used as a tool for risk stratification in patients with stroke.
Correlation Between Intolerance of Uncertainty and Post-Operative Regret in Otolaryngology Patients
Authors: Cleveland Chelsea N. , Virgen Celina , Steinman Shari A. , Callaham Sarah , Wanstreet Tyler , Carr Michele M.
Published: June 2022

Objective:

To determine if intolerance of uncertainty, depression, anxiety, worry, or stress are related to post-op regret in otolaryngology patients.

Methods:

Adult patients or parents giving consent for pediatric patients meeting criteria for otolaryngologic surgery were recruited and completed the Intolerance of Uncertainty Scale (IUS-12), Penn State Worry Questionnaire (PSWQ), and Depression, Anxiety and Stress Scale-21 (DASS-21) preop and the Decisional Regret (DR) scale 1-month post-op. Pearson correlations were calculated.

Results:

The cohort included 109 patients, 73 (67%) males and 36 (33.3%) females. 43 (39.5%) were college graduates and 66 (60.9%) were not. Mean IUS-12 score was 22.9 (95% CI 21.0-24.8), mean PSWQ score was 46.9 (95% CI 44.5-49.3). DASS-21 mean score was 11.9 (95% CI 9.6-14.3). Mean DR score was 11.1 (95% CI 8.6-13.6). IUS-12 subscales Prospective Anxiety mean score was 14.2 (95% CI 12.8-15.5) and Inhibitory Anxiety mean score was 16.5 (95% CI 14.5-18.6). The Pearson correlation coefficient for post-op DR and total preop IUS was .188 ( P = .027) and the correlation coefficient for post-op DR and preop Prospective Anxiety subscale of IUS score was .174 ( P = .037). Correlations with PSWQ and DASS-21 scores and DR were not statistically significant.

Conclusion:

Intolerance of uncertainty is a psychological construct that is associated with post-op DR. More work is needed to determine whether screening for IU and behavior modification directed at IU for those with high levels would improve post-op decisional regret.
Context-Sensitivity Influences German and Chinese Preschoolers’ Comprehension of Indirect Communication
Authors: Schulze Cornelia , Buttelmann David , Zhu Liqi , Saalbach Henrik
Published: June 2022

Making inferences in communication is a highly context-dependent endeavor. Previous research found cultural variations for context-sensitivity as well as for communication comprehension. However, the relative impact of culture and context-sensitivity on communication comprehension has not been investigated so far. The current study aimed at investigating this interplay and tested 4- and 6-year-old children from Germany ( n = 132) and China ( n = 129). Context-sensitivity was measured with an adapted version of the Ebbinghaus illusion. In this task, children have to discriminate the size of two target circles that only appear to be of similar size due to context circles surrounding the target circles. As expected, performance scores indicated higher degrees of context-sensitivity in Chinese compared to German children and that 6-year-olds were more context-sensitive than 4-year-olds. Further, in an object-choice communication-comprehension task, children watched videos with puppets performing every-day activities (e.g., pet care) and had to choose between two options (e.g., dog or rabbit). A puppet expressed what she wanted either directly (“I want the rabbit”) or indirectly (“I have a carrot”). The children had to choose one option to give to the puppet. In both cultures, 6-year-olds outperformed 4-year-olds and children understood direct communication better than indirect communication. Culture was found to affect children’s processing speed of direct communication. Moreover, culture influenced children’s context-sensitivity while context-sensitivity influenced children’s accuracy in the indirect (but not the direct) communication task. These findings demonstrate that taking context into account is especially important when we are confronted with indirect communication.
Dentistry and Interoperability
Authors: Rajkumar N.M.R. , Muzoora M.R. , Thun S.
Published: June 2022

Information has become the vital commodity of exchange in recent decades. Medicine is no exception; the importance of patient information in the digital form has been recognized by organizations and health care facilities. Almost all patient information, including medical history, radiographs, and feedback, can be digitally recorded synchronously and asynchronously. Nevertheless, patient information that could be shared and reused to enhance care delivery is not readily available in a format that could be understood by the systems in recipient health care facilities. The systems used in medical and dental clinics today lack the ability to communicate with each other. The critical information is stagnant in isolated silos, unable to be shared, analyzed, and reused. In this article, we propose enabling interoperability in health care systems that could facilitate communication across systems for the benefit of patients and caregivers. We explain in this article the importance of interoperable data, the international interoperability standards available, and the range of benefits and opportunities that interoperability can create in dentistry for providers and patients alike.
Exploring Ductility in Dental Ceramics
Authors: Alves L.M.M. , Rodrigues C.S. , Vardhaman S. , Saunders C. , Schneider J.M. , Lawn B.R. , Zhang Y.
Published: June 2022

Two damage regimes—“brittle” and “ductile”—have been identified in the literature on ceramic grinding, machining, grit blasting, and wear. In the brittle regime, the damage mechanism is essentially crack formation, while in the ductile region, it is quasiplasticity. Onset of the brittle mode poses the greater threat to strength, so it becomes important to understand the mechanics of ductile–brittle thresholds in these materials. Controlled microcontact tests with a sharp indenter are employed to establish such thresholds for a suite of contemporary computer-aided design/computer-aided manufacturing dental ceramics. Plots of flexural strength S versus indentation load P show a steep decline beyond the threshold, consistent with well-established contact mechanics relations. Threshold dimensions occur on a scale of order 1 µm and contact load of order 1 N, values pertinent to practical grit finishing protocols. The ductile side of ceramic shaping is accessed by reducing grit sizes, applied loads, and depths of cut below critical levels. It is advocated that critical conditions for ductile shaping may be most readily quantified on analogous S( P) plots, but with appropriate machining variable (grit size, depths of cut, infeed rate) replacing load P. Working in the ductile region offers the promise of compelling time and cost economies in prosthesis fabrication and preparation.