bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intratumoral injection of interferon‐α and systemic delivery of agonist anti‐CD137 monoclonal antibodies synergize for immunotherapy
Authors: Dubrot Juan , Palazón Asis , Alfaro Carlos , Azpilikueta Arantza , Ochoa María Carmen , Rouzaut Ana , Martinez‐Forero Iván , Teijeira Alvaro , Berraondo Pedro , Le Bon Agnes , Hervás‐Stubbs Sandra , Melero Ignacio 
Published: March 2010

AbstractCD137 artificial costimulation results in complete tumor rejection in several mouse models. Type I interferons (IFN) exert antitumor effects through an array of molecular functions on malignant cells, tumor stroma and immune system cells. The fact that agonist anti‐CD137 mAb induce tumor regressions in mice deficient in the unique receptor for Type I IFNs (IFNAR−/−) indicated potential for treatment combinations. Indeed, combination of intratumor injections of mouse IFN‐α and intraperitoneal injections of anti‐CD137 mAb synergized as seen on subcutaneous lesions derived from the MC38 colon carcinoma, which is resistant to each treatment if given separately. Therapeutic activity was achieved both against lesions directly injected with IFN‐α and against distant concomitant tumors. Experiments in bone marrow chimeras prepared with IFNAR−/− and WT mice concluded that expression of the receptor for Type I interferons is mainly required on cells of the hematopoietic compartment. Synergistic effects correlated with a remarkable cellular hyperplasia of the tumor draining lymph nodes (TDLNs). Enlarged TDLNs contained more plasmacytoid and conventional dendritic cells (DC) that more readily cross‐presented. Importantly, numbers of both DC subtypes inversely correlated with the tumor size. Numbers of CD8 T cells specific for a dominant tumor antigen were increased at TDLNs by each separate treatment but only with slight augments due to the combination. Combined antitumor effects of the therapeutic strategy were also seen on subcutaneous TC‐1 tumors established for 24 days before treatment onset. The described strategy is realistic because (i) agents of each kind are clinically available and (ii) equivalent procedures in humans are feasible.
The leader peptide of a human rec. MnSOD as molecular carrier which delivers high amounts of Cisplatin into tumor cells inducing a fast apoptosis in vitro
Authors: Borrelli Antonella , Schiattarella Antonietta , Mancini Roberto , Morelli Franco , Capasso Clemente , De Luca Viviana , Gori Enrico , Mancini Aldo 
Published: March 2010

AbstractThe leader peptide of a recombinant MnSOD (rMnSOD‐Lp) constitutes the carrier that allows rMnSOD to penetrate tumor cells. A synthetic preparation of rMnSOD‐Lp was 68Ga labeled (rMnSOD‐Lp‐68Ga) and injected into animals bearing spontaneous mammary cancers, followed by PET examinations, which demonstrated unambiguously the tumor sites in all the animals, suggesting that if rMnSOD‐Lp was able to transport the radioisotope into tumor cells, it would also be able to deliver cytotoxic molecules. The rMnSOD‐Lp was, therefore, conjugated to cisplatin (rMnSOD‐Lp‐CC) and added to cultured tumor cells. Equal concentrations of cisplatin were used for the tests. After treating the ovarian cancer cells with 11.1 μg of cisplatin alone, analysis by atomic absorbance spectrophotometry was able to detect only 6 ng of platinum, whereas when the same cells were treated with the same amount of cisplatin conjugated to leader peptide rMnSOD, 387 ng of platinum were detected, i.e., an amount 80 times greater. Only the tumor cells died following treatment with rMnSOD‐Lp‐CC; molecular analysis revealed that its addition generated an increasing expression of Erk‐2 and Bax products, which could be inhibited only by a selective MAP/ERK kinase inhibitor (PD98059), revealing that rMnSOD‐Lp‐CC has an apoptotic function, exactly as occurs when using the cisplatin alone. Data are statistically significant and indicate that by using rMnSOD‐Lp‐CC, the cisplatin can be transformed from an agent with antireplicative activity into a specific and selective antitumor molecule, increasing its therapeutic index. We think that rMnSOD‐Lp‐CC deserves to be considered as a new antitumor agent.
Hsa‐let‐7g inhibits proliferation of hepatocellular carcinoma cells by downregulation of c‐Myc and upregulation of p16INK4A
Authors: Lan Fei‐Fei , Wang Hua , Chen Yang‐Chao , Chan Chu‐Yan , Ng Samuel S. , Li Kui , Xie Dan , He Ming‐Liang , Lin Marie C. , Kung Hsiang‐Fu 
Published: March 2010

AbstractzMicroRNAs (miRNAs) are endogenously expressed small noncoding RNAs that regulate approximately one‐third of human genes at post‐transcription level. Previous studies have shown that miRNAs were implicated in many cellular processes and participated in the progress of various tumors including hepatocellular carcinoma (HCC). Among all miRNAs, the let‐7 family is well recognized to play pivotal roles in tumorigenesis by functioning as potential growth suppressor. In the present study, we aimed to investigate the role of let‐7 family, particularly the hsa‐let‐7g, in the molecular pathogenesis of HCC. By use of MTT, qPCR, Western blotting and 2‐dimensional electrophoresis (2‐DE), over‐expression of hsa‐let‐7g was found to inhibit the proliferation of HCC cell line via negative and positive regulations of c‐Myc and p16INK4A, respectively. The expression of hsa‐let‐7g was noted to be markedly lowered in the HepG2, Hep3B and Huh7 cells, yet higher in the Bel‐7404 HCC cell line. Proliferation of HCC cell line was significantly inhibited after the transfection of hsa‐let‐7g mimics, while hsa‐let‐7g inhibitor transfection exerted an opposite effect. Concurrently, the mRNA and protein levels of c‐Myc were found significantly decreased in HepG2 cells after transfection of hsa‐let‐7g mimics, but obviously increased in Bel‐7404 cells after transfection of hsa‐let‐7g inhibitor. As revealed by 2‐DE, a significant upregulation of p16INK4A was revealed after the gain‐of‐function study using hsa‐let‐7g. Therefore, we suggest that hsa‐let‐7g may act as a tumor suppressor gene that inhibits HCC cell proliferation by downregulating the oncogene, c‐Myc, and upregulating the tumor suppressor gene, p16INK4A.
ABO blood group and incidence of epithelial ovarian cancer
Authors: Gates Margaret A. , Wolpin Brian M. , Cramer Daniel W. , Hankinson Susan E. , Tworoger Shelley S. 
Published: March 2010

AbstractPrevious studies have observed an association between ABO blood group and risk of certain malignancies, including ovarian cancer; however, no prospective studies of the association with ovarian cancer risk are available. Using data from 49,153 women in the Nurses' Health Study, we examined the association between ABO blood group and incidence of epithelial ovarian cancer. Study participants reported their blood type and Rh factor in 1996, and 234 women were diagnosed with incident ovarian cancer during 10 years of follow‐up. We used Cox proportional hazards regression to model the incidence rate ratios (RR) and 95% confidence intervals (CI) of ovarian cancer for each blood group category. Compared to women with blood group O, women with blood group AB or B had a nonsignificant 38% increase in ovarian cancer incidence (95% CI = 0.88–2.16 for blood group AB and 0.96–1.99 for blood group B), whereas blood group A was not associated with risk (RR = 0.95, 95% CI = 0.70–1.30). Combining blood groups AB and B, we observed a statistically significant positive association with presence versus absence of the B antigen overall (RR = 1.41, 95% CI = 1.06–1.88) and for the serous invasive subtype (RR = 1.53, 95% CI = 1.08–2.17). In this large, prospective cohort of women, presence of the B antigen was positively associated with ovarian cancer incidence, whereas blood group A was not associated with risk. Additional studies are needed to confirm this association and to explore the mechanisms through which blood group may influence ovarian cancer risk.
Lysophosphatidic acid‐induced expression of periostin in stromal cells: Prognoistic relevance of periostin expression in epithelial ovarian cancer
Authors: Choi Kyung Un , Yun Jeong Sup , Lee Il Hwan , Heo Soon Chul , Shin Sang Hun , Jeon Eun Su , Choi Yoon Ji , Suh Dong‐Soo , Yoon Man‐Soo , Kim Jae Ho 
Published: March 2010

AbstractLysophosphatidic acid (LPA) is a bioactive lipid crucial for the initiation and progression of ovarian cancer. Identification of LPA‐induced biomarkers is necessary for predicting prognosis of ovarian cancer patients. Here we report periostin, an extracellular matrix protein, as an LPA‐induced protein in stromal cells and as a prognostic marker in patients with epithelial ovarian cancer (EOC). In human EOC tissues, periostin was mainly expressed in cancer‐associated stromal fibroblasts, but not in cancer cells. The expression levels of periostin highly correlated with poor survival and tumor recurrence of ovarian cancer patients. Treatment of human adipose tissue‐derived stromal cells with LPA or conditioned media from human ovarian adenocarcinoma cell lines, such as SK‐OV‐3 and OVCAR‐3, induced expression of periostin. The periostin expression induced by cancer‐conditioned media was abrogated by silencing of the LPA receptor 1 expression using small hairpin RNA lentivirus. Recombinant periostin stimulated adhesion and invasion of SK‐OV‐3 human ovarian adenocarcinoma cells and induced expression of matrix metalloprotease‐2 in the cancer cells. These results suggest that LPA is associated with the expression of periostin in cancer‐associated fibroblasts of EOC.
A potentially functional polymorphism in the promoter region of miR‐34b/c is associated with an increased risk for primary hepatocellular carcinoma
Authors: Xu Yan , Liu Li , Liu Jibin , Zhang Yixin , Zhu Jian , Chen Jianguo , Liu Sheng , Liu Zheng , Shi Haibin , Shen Hongbing , Hu Zhibin 
Published: March 2010

AbstractThe miR‐34 family members are direct transcriptional targets of tumor suppressor p53, and loss of miR‐34 function can impair p53‐mediated cell cycle arrest and apoptosis. A potentially functional SNP rs4938723 (T > C) was found in the promoter region of pri‐miR‐34b/c (423 bp from the transcription start site), located in the CpG island and might affect transcription factor GATA binding and therefore pri‐miR‐34b/c expression. In our study, we hypothesized that SNPs miR‐34b/c rs4938723 and TP53 Arg72Pro may independently or jointly contribute to primary hepatocellular carcinoma (HCC) susceptibility. We then genotyped the 2 SNPs in a case–control study of 501 patients with primary HCC and 548 cancer‐free controls in a Chinese population. We observed that the variant genotypes of miR‐34b/c rs4938723 were associated with significantly increased HCC risks compared with the wild‐type TT genotype (adjusted OR = 1.37, 95% CI =1.06–1.78 for TC; OR = 1.53, 95% CI = 1.02–2.31 for CC and OR = 1.40, 95% CI = 1.10–1.80 for TC/CC). Furthermore, we found a significant interaction between alcohol drinking and SNP rs4938723 on HCC risk (p = 0.05 for multiplicative and p = 0.01 for additive interaction). However, we did not find any main effect of TP53 Arg72Pro on HCC risk in this population. These findings indicate that the potentially functional SNP rs4938723 in the promoter region of pri‐miR‐34b/c may contribute to the susceptibility of HCC in this Chinese population.
p53 transactivation is involved in the antiproliferative activity of the putative tumor suppressor RBM5
Authors: Kobayashi Takahiko , Ishida Junich , Musashi Manabu , Ota Shuichi , Yoshida Takeshi , Shimizu Yuichi , Chuma Makoto , Kawakami Hiroshi , Asaka Masahiro , Tanaka Junji , Imamura Masahiro , Kobayashi Masanobu , Itoh Hiroshi , Edamatsu Hironori , Sutherland Leslie C. , Brachmann Rainer K. 
Published: March 2010

AbstractRBM5 (RNA‐binding motif protein 5) is a nuclear RNA binding protein containing 2 RNA recognition motifs. The RBM5 gene is located at the tumor suppressor locus 3p21.3. Deletion of this locus is the most frequent genetic alteration in lung cancer, but is also found in other human cancers. RBM5 is known to induce apoptosis and cell cycle arrest but the molecular mechanisms of RBM5 function are poorly understood. Here, we show that RBM5 is important for the activity of the tumor suppressor protein p53. Overexpression of RBM5 enhanced p53‐mediated inhibition of cell growth and colony formation. Expression of RBM5 augmented p53 transcriptional activity in reporter gene assays and resulted in increased mRNA and protein levels for endogenous p53 target genes. In contrast, shRNA‐mediated knockdown of endogenous RBM5 led to decreased p53 transcriptional activity and reduced levels of mRNA and protein for endogenous p53 target genes. RBM5 affected protein, but not mRNA, levels of endogenous p53 after DNA damage suggest that RBM5 contributes to p53 activity through post‐transcriptional mechanisms. Our results show that RBM5 contributes to p53 transcriptional activity after DNA damage and that growth suppression and apoptosis mediated by RBM5 are linked to activity of the tumor suppressor protein p53.
Lipid peroxidation in the kidney of rats treated with V and/or Mg in drinking water
Authors: Ścibior Agnieszka , Zaporowska Halina , Niedźwiecka Irmina 
Published: March 2010

AbstractSpontaneous and stimulated lipid peroxidation (LPO) after vanadate and magnesium treatment was studied in kidney supernatants obtained from outbred 5‐month‐old, albino male Wistar rats. The 2‐month‐old animals daily received: group I (control), deionized water to drink; group II, water solution of sodium metavanadate, NaVO3 (SMV, 0.125 mg V ml−1); group III, water solution of magnesium sulfate, MgSO4 (MS, 0.06 mg Mg ml−1); and group IV, water solution of SMV‐MS at the same concentrations as in groups II and III for V and Mg, respectively, over a 12‐week period. FeSO4, NaVO3 and MgSO4 were selected as agents that may modify LPO process in in vitro conditions. Spontaneous malondialdehyde (MDA) levels in kidney supernatants increased significantly in the rats in groups II and IV, compared with groups I and III; and they were also significantly higher in all the groups of rats compared with the liver supernatants. The total antioxidant status (TAS) in groups II and IV tended to be higher too. Vanadium concentration in the kidney of the rats in groups II and IV increased, whereas the kidney Mg content in groups II, III and IV decreased, compared with levels in the liver. As the two‐way ANOVA indicated, the changes in the basal MDA level, TAS and Mg concentration in the liver of rats at combined V and Mg application only resulted from independent action of V. As far as the in vitro results are concerned, in the supernatants obtained from the rats in groups II and IV, a significant increase in MDA level was demonstrated in the presence of 30 µm of exogenous FeSO4 as well as 30, 100, 200 and 400 µm NaVO3 and 100, 200, 400, 600, 800 and 1000 µm MgSO4, compared with groups I and III. The 600, 800 and 1000 µm of exogenous MgSO4 also significantly elevated MDA production in the supernatants obtained from the rats in group III, compared with spontaneously formed MDA in the same supernatants. The three‐way ANOVA showed that the changes in LPO induced by in vitro treatment of kidney supernatants with exogenous Fe or V or Mg (600, 800 and 1000 µm) were a consequence of independent action of those metals and they also resulted from the interactions between exogenous Fe (Feexog) and endogenous V (Vend) and between Vend and exogenous V (Vexog). In conclusion, V (as NaVO3) consumed by the rats with drinking water at a dose of 12.9 mg V kg−1 b.w. per 24 h for 12 weeks increased the basal LPO and markedly enhanced TAS in the renal tissue. Its pro‐oxidant potential was also found in in vitro conditions. The Mg dose (6 mg Mg kg−1 b.w. per 24 h) ingested by the rats together with V (12.7 mg V kg−1 b.w. per 24 h) neither reduced nor intensified the spontaneous LPO, compared with V‐only intoxicated animals; however, the stimulating effect of Mg on LPO was revealed in in vitro conditions.
Response to retreatment of malignant hypercalcemia with the bisphosphonate AHPrBP (APD): Respective role of kidney and bone
Authors: Dr. Thiebaud D. , Jaeger P. , Burckhardt P. 
Published: March 2010

Abstract
Malignant hypercalcemia is caused by both increased bone resorption and enhanced tubular reabsorption of calcium.
First, the response to an infusion of APD was compared in two groups of patients: 23 with breast cancer versus 20 with squamous cell cancer. The decrease in plasma calcium was smaller in the latter group (p &lt; 0.05 at day 14), due to increased tubular reabsorption of calcium (TmCa/GFR 2.20 ± 0.05 versus 2.58 ± 0.06 mmol/liter; p &lt; 0.001), whereas the degree of bone resorption reflected by urinary hydroxyproline was identical. Therefore, at a given initial plasma calcium level, the type of tumor (on which TmCA/GFR depends) seems to be a determinant for the effectiveness of the treatment.
Second, the response to the initial treatment was compared with that to a second treatment with the same dose in 12 patients whose malignant hypercalcemia relapsed. Within 9 days, plasma calcium decreased from 3.46 ± 0.10 to 2.50 ± 0.10 mmol/liter after the first course, but only from 3.37 ± 0.08 to 2.79 ± 0.09 mmol/liter after the second course (p &lt; 0.01). TmCa/GFR was similar before the first and the second treatment and did not vary during the days following the infusion of APD. Initial urinary hydroxyproline was slightly but not significantly higher before the second treatment. It dropped following both APD courses, but to a lesser extent after the second treatment, reflecting higher bone resorption or possible resistance to bisphosphonate.
In conclusion, both the degree of tubular reabsorption of calcium (which depends on tumor type) and that of bone resorption modify the response of malignant hypercalcemia to APD, bone resorption playing the key role for the loss of efficacy in case of retreatment.
A new method for automatic recognition of the radiographic trabecular pattern
Authors: Geraets Wil G. M. , van der Stelt Paul F. , Netelenbos Coen J. , Elders Petra J. M. 
Published: March 2010

Abstract
This study reports a method to describe and analyze the structure of the trabecular pattern seen on radiographs of the distal radius. The structure is measured and related to the bone mineral density (BMD) of the lumbar spine measured by dual-photon absorptiometry.
Radiographs of hand and wrist combined with additional information of the bone mineral density of the vertebrae serve as testing material. With a computer-aided imaging system, a part of the depicted radius is scanned. The image is filtered and segmented into a bilevel picture consisting of a light network with dark meshes. Seven features of the bilevel picture are measured and analyzed.
It is shown that six features correlate significantly with the bone mineral density measured at the lumbar spine, although the correlations between the trabecular pattern and the BMD are too weak to allow precise predictions of BMD values for individuals. Nevertheless, the correlations confirm the existence of a relationship between the radiographic trabecular pattern and the bone mineral density of the lumbar spine. The method is worth being further developed for use on individual patients. It provides a noninvasive tool to make an objective and quantitative assessment of the trabecular pattern.
Serum osteocalcin (BGP) Levels in normal men: A longitudinal evaluation reveals an age-associated increase
Authors: Orwoll Eric S. , Deftos Leonard J. 
Published: March 2010

Abstract
Serum levels of bone gla protein (BGP) have been reported to increase with aging and hence to reflect an age-related increase in bone remodeling activity. To evaluate the relationship between aging and serum BGP levels in a study of longitudinal design, we measured BGP concentrations in 77 normal men at 6 month intervals over a 3 year period. Mean BGP levels at the onset (4.95 ± 1.5 ng/ml) increased significantly during the study (p = 0.004), and the mean of individual BGP slopes was positive (0.38 ± 0.6 ng/ml per year, p = 0.0001). The rate of change in BGP was not related to serum creatinine levels or dietary calcium intake.
Acidosis inhibits 1,25-(OH)2D3 but not cAMP production in response to parathyroid hormone in the rat
Authors: Ro Heung-Kyu , Tembe Vrishali , Krug Thomas , Yang Po-Yao J. , Bushinsky David A. , Dr. Favus Murray J. 
Published: March 2010

Abstract
Parathyroid hormone (PTH) is a major activator of renal proximal tubule 25-hydroxyvitamin D3-1-hydroxylase (1-OHase). Chronic metabolic acidosis (CMA) inhibits 1-OHase and reduces circulating 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] levels in rats fed a low-Ca diet (LCD, 0.002% Ca). To examine the cellular mechanism whereby CMA inhibits 1-OHase, PTH-dependent renal 1-OHase activity and cAMP were measured in proximal tubules isolated from rats fed LCD for 14 days and made acidotic by the addition of 1.5% ammonium chloride to the drinking water. Serum 1,25-(OH)2D3 and proximal tubule 1-OHase activity and cAMP content were lower in acidotic rats. hPTH-(1–34) (10−7 M) in vitro increased cAMP content to equivalent concentrations in tubules from rats with CMA and from nonacidotic controls; however, PTH increased 1-OHase activity only in tubules from nonacidotic animals. Although forskolin increased tubule cAMP content to equivalent levels in tubules from acidotic and nonacidotic rats, 1-OHase activity declined in tubules from nonacidotic rats and remained suppressed in acidotic tubules.
The results suggest that chronic metabolic acidosis inhibits the PTH activation of 1-OHase through alteration of one or more steps in a cAMP-independent messenger system. PTH and forskolin can increase cAMP production by acidotic and nonacidotic proximal tubules; however, 1-OHase activity is not restored to normal in acidotic tubules and nonacidotic tubule 1-OHase may be inhibited.
Aminohydroxybutane bisphosphonate inhibits bone loss due to immobilization in rats
Authors: Thompson David D. , Seedor J. Gregory , Weinreb Miron , Rodan Gideon A. , Rosini Sergio 
Published: March 2010

Abstract
The purpose of this study was to document the effects of aminobutane bisphosphonate (AHBuP) on bone remodeling during immobilization in rats.
Male Sprague-Dawley rats underwent unilateral sciatic neurectomy after receiving two daily subcutaneous injections of 0, 0.01, 0.10, or 1.0 mg P per kg AHBuP. Rats were sacrificed at 24 h or 10 or 20 days postimmobilization. Femora were ashed and tibiae were prepared for histomorphometric analysis.
AHBuP was effective in inhibiting bone loss due to immobilization in a dose-dependent manner. The percentage loss of femoral ash weight due to immobilization decreased in a dose-dependent manner. In vehicle-treated rats, there was a significant decrease in trabecular bone volume (TBV) in the immobilized tibiae compared to the normal tibiae; in AHBuP-treated rats there was a dose-dependent increase in TBV both in the immobilized and control tibiae. The osteoid surface extent was decreased in AHBuP-treated rats in a dose-dependent manner. The mineral apposition rate was altered only in the intact leg of rats treated with 0.1 and 1.0 mg P AHBuP per kg compared to vehicle treated. Osteoclast number per mm was reduced by AHBuP treatment.
In conclusion, aminohydroxybutane bisphosphonate effectively prevented the bone loss due to immobilization in this system.