tbuckley/cabot-search huggingface dataset:
A novel VEGFR2 autophosphorylation inhibitor, Ki23057, prevents progression and liver metastasis of colon cancer
Authors: Katsunobu Sakurai, Nobuya Yamada, Masakazu Yashiro, Midori Komatsu, Tetsuji Sawada, Masaichi Ohira, Atsushi Miwa, Kosei Hirakawa
Journal: Cancer Research (2007)

2129  Background:Although new drugs for colon cancer have been developed and survival is improving, the results are not sufficient. Novel treatment approaches and new drugs are necessary. Vascular endothelial growth factor (VEGF) plays a central role in angiogenesis. Tumor growth and metastasis, including colorectal cancer, are strongly dependent upon VEGF for angiogenesis. Ki23057 is a new small-synthetic tyrosine kinase inhibitor that blocks autophosphorylation of the VEGF receptor2 (VEGFR2). To determine the effect of Ki23057 as an anti-angiogenic agent, we studied the effect of Ki23057 for colon cancer and vascular endothelial cells in vitro and in vivo.   Materials and Methods: The effect of Ki23057 on the proliferation of three colon cancer cell lines (LM-H3, LoVo and LS174T) and human umbilical vein endothelial cells (HUVECs) was examined by means of the MTT assay. Capillary tube formation of endothelial cells was measured by coculture with normal human fibroblasts using an Angiogenesis kit (Kurabo, Osaka Japan). Ki23057 was added at a concentration of 0, 30 or 300 nM, followed by VEGF (10 ng/mL). The cells were cocultured for 11 days and stained with anti-CD31 antibody. The effect of Ki23057 on tyrosine phosphorylation of VEGFR2 in HUVECs was examined with immunoprecipitation. The effect of Ki23057 on the growth of LM-H3 xenografts and liver metastasis was examined in nude mice. Microvessels in the xenografted LM-H3 tumors were stained immunohistochemically using CD31 antibody.  Results: The proliferation of HUVECs was significantly inhibited by Ki23057 (≥10 nM). On the other hand, Ki23057 (1-102 nM) did not inhibit the proliferation of three colon cancer cell lines. Tube formation was inhibited in HUVECs treated with Ki23057 compared with controls. The average numbers of vessels were 4.50±0.71/HPF (without addition of VEGF and Ki23057), 7.94±1.33 /HPF (VEGF 10 ng/mL, without Ki23057), 1.47±0.37/HPF (with 10 ng/mL VEGF and 30 nM Ki23057) and 0.19±0.16/HPF (10 ng/mL VEGF and 300 nM Ki23057). Immunoprecipitation demonstrated that Ki23057 inhibited tyrosine phosphorylation of VEGFR2 in HUVECs. Ki23057 exhibited a significant inhibitory effect on the growth of the xenografted LM-H3 tumors. After day 3, tumor growth was more strongly inhibited in the treatment group compared with controls. Microvessel density in xenografted tumors treated with Ki23057 was less than that in controls. Compared with the control group, the treatment group exhibited significant inhibition of liver metastasis. The weight of the liver was 3.73±1.00 g in the control group and 2.43±0.52 g in the treatment group. The liver weights in the control group were significantly greater than in the treatment group (p  Conclusions:Ki23057 may be a promising new antiangiogenic agent for colon cancer.
Activation of AP-1 signaling pathway by nanosecond pulsed electric field: Inhibition of AP-1 results in increased apoptosis
Authors: Bijaya Nayak, Cynthia Galindo, Susan Weintraub, Karl Schoenbach, Martin Meltz
Journal: Cancer Research (2008)

5755  Nanosecond pulsed electric field (nsPEF) that generates non-ionizing radiation is a potential new technology in development for cancer treatment. Studies from our laboratory and others have shown induction of apoptosis after nsPEF exposure. The present study was undertaken to examine the effects of nsPEF on the gene expression profile using microarray analysis. Microarray analysis revealed changes in the expression of fos/jun transcription factors; which are components of the AP-1 transcription factor. These observations led to the hypothesis that nsPEF exposure can activate the AP-1 signaling pathway and that the inhibition of AP-1 signaling using specific AP-1 inhibitors might increase the apoptotic response of nsPEF. The studies were performed in 244B human lymphoblastoid cells. The cells were exposed to nsPEF pulses with 10 ns pulse duration at an average peak electric field intensity of 200 kV/cm using a Blumlein pulser device. Microarray analysis was performed using Affymetrix HGU133-A chip, which probes for 22,000 genes. The expression of the fos/Jun (AP-1) factors was analyzed using RNase protection assay and Western blotting. The binding of AP-1 complex to the AP-1 consensus element TGACTCA was examined using the electrophoretic mobility shift assay. Induction of apoptosis was examined using different apoptosis markers, including annexin-V binding and caspase activation. Early induction of the members of the fos and jun transcription factors were observed, occurring within 3 hours after the nsPEF exposure. Functional studies using electrophoretic mobility shift assay showed an increased binding of AP-1 transcription factor to the AP-1 binding element after nsPEF exposure. Fos/jun factors were translocated into the nucleus and there was also activation of the AP-1 target genes EGR-1 and EGR-3 following nsPEF exposure. Further, the expression of fos and jun transcription factors and the binding of AP-1 complex were inhibited in the presence of AP-1 inhibitors curcumin and nordihydroguaiaretic acid (NDGA). Inhibition of AP-1 by curcumin and NDGA resulted in increased apoptosis by nsPEF. Our findings suggest that nsPEF, in combination with AP-1 inhibitors, could possibly be used as a new approach to increase apoptosis in cancer treatment. This work was supported by the AFOSR MURI Grant No. F49620-02-10320, and URC grant No. 123953.
Syndromic immune disorder caused by a viable hypomorphic allele of spliceosome component Snrnp40
Authors: Duanwu Zhang, Tao Yue, Jin Huk Choi, Evan Nair-Gill, Xue Zhong, Kuan-wen Wang, Xiaoming Zhan, Xiaohong Li, Mihwa Choi, Miao Tang, Jiexia Quan, Sara Hildebrand, Eva Marie Y. Moresco, Bruce Beutler
Journal: Nature Immunology (2019)
Angiostrongylus cantonensis in North African hedgehogs as vertebrate hosts, Mallorca, Spain, October 2018
Authors: Claudia Paredes-Esquivel, Jessica Sola, Sofía Delgado-Serra, Miguel Puig Riera, Nieves Negre, Miguel Ángel Miranda, José A Jurado-Rivera
Journal: Eurosurveillance (2019)

In October 2018, two Atelerix algirus hedgehogs were admitted to the Wildlife Rehabilitation Hospital in Mallorca (Balearic Islands, Spain) with signs of acute neurological disease. Necropsy detected immature, fully developed nematodes in the subarachnoid space of both hedgehogs, including a gravid female worm. DNA-based molecular tools confirmed the nematode as Angiostrongylus cantonensis , an important aetiological agent of eosinophilic meningitis in humans. So far this zoonotic parasite in has not been reported in western European wildlife.
FOXA proteins regulate MMP7 in collaboration with ETV4 protein in pancreatic cancer
Authors: Yan Song, Howard Crawford
Journal: Cancer Research (2008)

63  The family of forkhead transcription factors (FOX proteins) contains a huge number of members with diverse functions, ranging from embryonic development, organ specification, cell proliferation to energy metabolism. Only recently, however, have their roles in tumorigenesis and cancer metastasis started to emerge. Particularly, FOXA proteins (Class A of FOX proteins) have been demonstrated to be overexpressed in several human cancers; including those of the esophagus, mammary gland and prostate, although their functions are largely unknown. In normal pancreas, FOXA proteins are well-known to be indispensable for organ development and glucose metabolism. Little is known about their roles in pancreatic cancer, a dismal disease with an overall survival rate of less than 4%. Matrix metalloproteinase 7 (MMP7), a member of the family of matrix metalloproteinases, is overexpressed in more than 98% of human pancreatic cancers, in contrast to its quiescence in normal pancreas. It has been proposed as a marker for early detection of pancreatic cancer. In this study, we have found that FOXA1 and FOXA2 protein are overexpressed in human pancreatic cancer samples and pancreatic cancer cell lines, as well as in a mouse model of pancreatic cancer, using immunohistochemistry and immunoblot analysis. Utilizing RNAi knockdown and transient overexpression assays, we showed that FOXA1 and FOXA2 proteins were required for MMP7 expression in pancreatic cancer cell lines. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) demonstrated that FOXA proteins directly bind with the MMP7 promoter region. Luciferase-reporter assays illustrated FOXA proteins are activators of the MMP7 promoter. Mutagenesis of the FOXA binding sites in the MMP7 promoter eliminated their physical interaction, as well as promoter responsiveness to FOXA proteins. Furthermore, E1A enhancer binding protein (ETV4) was characterized as a partner of FOXA proteins, synergistically enhancing FOXA-induced MMP7 expression. In conclusion, our study demonstrates that the overexpressed FOXA1 and FOXA2 proteins, together with ETV4, lead to the abnormal up-regulation of MMP7 in pancreatic cancer. This finding suggests that overexpressed FOXA proteins may have functional roles in pancreatic cancer tumorigenesis or metastasis by regulating MMP7 expression, and likely other target genes.
Similar risk of ACL graft revision for alpine skiers, football and handball players: the graft revision rate is influenced by age and graft choice
Authors: Arne Ekeland, Lars Engebretsen, Anne Marie Fenstad, Stig Heir
Journal: British Journal of Sports Medicine (2019)

The risk of graft revision following ACL reconstruction may depend on the sport type the individuals are engaged in. The purpose of this study was to report the ACL graft revision rate in alpine skiers, football and handball players.Primary ACL reconstructions and graft revision data from 2004 to December 2016 were obtained from the Norwegian Cruciate Ligament Registry. The graft survival rates were calculated for individuals in each of the three sport types, for bone patellar tendon bone (BPTB) and hamstring tendons (HT) grafts separately, and related to age at primary operation and sex.A total of 711 grafts in 14 201 primary ACL reconstructions were revised (5.0%) after median 6 years, 3.8% in alpine skiers, 5.0% in soccer and 6.1% in handball players (p<0.001). Adjusted Cox regression showed similar ACL graft survival rates in the three groups. The HR for graft revision was 5 times higher for individuals aged ≤18 years than for those aged ≥35 years (p<0.001). The corresponding HR for graft type was 1.8 times higher for HT than for BPTB grafts (p<0.001), but 2.8 times higher for individuals aged ≤18 years (p<0.001). The 12 years survival of BPTB grafts was 96% compared with 93% for HT grafts (p <0.001).The revision rate for ACL grafts was similar among alpine skiers, football and handball players, and the results support the use of BPTB grafts in young athletes with closed growth zones in the knee.Cohort study; level of evidence, 2.
Angiogenesis in osteosarcoma is regulated by tumor interstitial fluid pressure
Authors: Saminathan S. Nathan, Jorge E. Casas-Ganem, Rui Yang, Hirotaka Kawano, Rebecca Sowers, Gene R. Diresta, Anders E. Kolb, Andrew G. Huvos, Richard Gorlick, John H. Healey
Journal: Cancer Research (2005)

4549  Aim: We have previously shown that osteosarcomas (OS) have states of increased interstitial fluid pressure (IFP) and that these states correlated with increased proliferation and chemosensitivity. This study investigates the effect of constitutively raised IFP on angiogenesis in OS. . Method: Sixteen patients with the clinical diagnosis of OS underwent IFP readings by the wick-in-needle method at the time of open biopsy. Blood flow readings were made in the location of the biopsy concurrently. Vascularity as determined by capillary density in the biopsied specimens was correlated with interstitial fluid pressure and blood flow. We validated these findings using immunohistochemical staining for VEGF-A, VEGF-C and TPA on paraffin-embedded tissue blocks of the biopsy samples. In addition human OS (HOS and U2OS), osteoblast (OB) and endothelial (HUVEC) cell lines were grown in a pressurized cell culture system designed to replicate the pressure readings found in the clinical study. Quantitative and qualitative PCR were performed on OS and OB samples grown at various levels of pressure. Cell cycle analysis was performed on HUVEC cells grown under pressure. . Results: Interstitial fluid pressures in the tumors (median 32 mmHg ± SD 19 mmHg) was significantly higher than that in normal tissues (3 ± 6 mmHg). Pressure readings were significantly higher in low vascularity tumors compared to high vascularity tumors (p
Role of non-mutational mechanisms in cancer cell drug resistance
Authors: Vasyl' Chekhun, Jody Filkowski, James Meservy, Yaroslav Ilnytskyy, Dmytro Mykytenko, Volodymyr Tryndyak, Igor Pogribny, Olga Kovalchuk
Journal: Cancer Research (2008)

3211  Many chemotherapy regiments are used effectively to treat breast cancer; however, breast cancer cells often become resistant to the drugs, which usually leads to a relapse and worsening of prognosis. The acquisition of drug resistance is a major clinical obstacle to the successful treatment of breast cancer. The causes of cancer-specific drug resistance are currently believed to be linked to: (i) random drug-induced mutational events (genetic hypothesis), (ii) drug-induced non-mutational alterations of gene function (epigenetic hypothesis), and/or (iii) drug-induced karyotypic changes (karyotypic hypothesis). In the present study, we examined the role of non-mutational mechanisms in the development of a multidrug-resistant phenotype of MCF-7 human breast cancer cells induced by doxorubicin (DOX) and cisplatin (cisDDP), two chemotherapeutic drugs with different modes of action. Both of the drug-resistant cell lines were characterized by extensive alterations in gene-specific cytosine methylation, as indicated by the appearance of a number of differentially methylated DNA genes. A detailed analysis of hypo- and hypermethylated DNA sequences revealed that in addition to specific alterations induced by each of the drugs, the acquisition of the drug-resistant phenotype of MCF-7 cells to DOX and cisDDP was characterized by three common features: dysfunction of genes involved in estrogen metabolism (sulfatase 2 and estrogen receptor α), apoptosis (p53, p73, α-tubulin, BCL2-antagonist of cell death, tissue transglutaminase 2, and forkhead box protein K1), and cell-cell contact (leptin, stromal cell derived factor receptor 1, activin A receptor, and E-cadherin). The analysis also showed that two opposing hypo- and hypermethylation processes may enhance and complement each other in the disruption of these pathways.  Another non-mutational mechanism of gene expression control is mediated via the function of small regulatory RNAs, particularly microRNAs (miRNAs). How these miRNAs might be involved in cancer cell drug resistance remains largely unexplored. MCF-7/DOX cells exhibited a considerable dysregulation of the miRNAome profile. In addition, miR-451 was found to regulate the expression of the multidrug resistance 1 (mdr1) gene. More importantly, transfection of the MCF-7/DOX resistant cells with miR-451 resulted in an increased sensitivity of cells to DOX. These results provide evidence that non-mutational mechanisms are an important feature of cancer cells with the acquired drug-resistant phenotype and may be a crucial contributing factor to its development. Furthermore, the potential reversibility of these alterations may have significant implications for novel therapeutic strategies to overcome cancer cell resistance.
AKAP-associated sperm protein over-expression in ovarian cancer.
Authors: Maurizio Chiriva-Internati, Raffaele Ferrari, Yuefei Yu, Marjorie Jenkins, Martin Kast, Everardo Cobos
Journal: Cancer Research (2008)

2027  Annually in the United States, ovarian carcinomas are diagnosed in approximately 22,000 women, causing 16,000 deaths. Most malignant ovarian tumors are epithelial ovarian cystadenocarcinomas. Women from northern and western Europe and North America are affected most frequently, whereas women from Asia, Africa, and Latin America are affected least frequently. AKAP-associated Sperm Protein (ASP), also known as Ropporin-1 like (ROPN1L), is a protein that interacts with the amphipathic helix region of A-kinase anchoring protein 3, 110 (AKAP3, 110); the AKAPs protein family binds to signal transduction molecules, and is responsible for signaling and trafficking within the cell. Even if ASP has yet not been deeply investigated, its role in sperm motility and cytoskeletal reorganization during spermiogenesis has been suggested. Since the expression of ASP has been shown to be restricted to the normal testis and no other normal tissues, we decided to further investigate its presence in ovarian malignancies.   We evaluated ASP presence at the protein level in paraffin-embedded human ovarian cystadenocarcinomas, by immunohistochemistry. Thirty-three different cases of cystiadenocarcinoma were considered: after deparaffining, the slides underwent antigen retrieval in a thermostatic bath (Fisher Scientific) at 98oC for 30 minutes. After 15 minutes blocking in H2O2 3%, the primary antibody anti-ASP (Imgenex, San Diego, CA) was added for 1 hour, followed by 30 minutes exposure to the envision secondary antibody system (Dako, Carpinteria, CA, USA). The reaction result was highlighted through the DAB staining system (Dako).  Eight of the 33 evaluated samples (24.2%) gave evidence of ASP expression. Between the eight positive samples, in six cases (75%) a strong staining was shown, while a weak level of expression was detected in the remaining two (25%).   To our knowledge, this is the first report of an ASP investigation in cases of ovarian cystadencarcinomas. Further studies are needed to consider ASP as a novel Cancer Testis Antigen (CTA) in ovarian malignancies.
Time Horizons in Cost Analyses—Reply
Authors: Anirban Basu, Matthew L. Maciejewski
Journal: JAMA (2019)

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Operative vs Nonoperative Treatment for Atraumatic Rotator Cuff Tears
Authors: Nitin B. Jain, Gregory D. Ayers, Helen Koudelková, Kristin R. Archer, Rebecca Dickinson, Brian Richardson, Marian Derryberry, John E. Kuhn
Journal: JAMA Network Open (2019)

Rotator cuff disorders remain the most common cause of shoulder pain and are among the most common reasons for patients to seek care in primary and specialty settings. Although operative and nonoperative treatments are offered to patients with atraumatic rotator cuff tears, there is a lack of evidence to support operative vs nonoperative treatment. This paucity of evidence has been highlighted by several professional agencies and experts.To perform a pragmatic randomized clinical trial, the Arthroscopic Rotator Cuff trial, comparing pain and functional outcomes in patients undergoing operative vs nonoperative treatment for atraumatic rotator cuff tears, and assessing heterogeneity of treatment effects by age and tear size.Trial protocol of the Arthroscopic Rotator Cuff trial. This pragmatic randomized clinical trial of an estimated 700 patients is adequately powered to accomplish its aims with 488 patients. Primary analysis will be conducted on an intent-to-treat population in the context of a mixed model. The multicenter trial started recruitment in 2018 with a 1-year follow-up duration. Patients aged 50 years or older to younger than 85 years with magnetic resonance imaging-confirmed atraumatic rotator cuff tears that are suitable for either operative or nonoperative treatment will be enrolled. Block randomization will be performed and stratified by site, age, and tear size.Nonoperative treatment consists of an approximately 3-month standardized physical therapy program, whereas operative treatment consists of rotator cuff surgery followed by approximately 4 months of postoperative rehabilitation.The primary outcome is patient-reported Shoulder Pain and Disability Index score, and the secondary outcome is American Shoulder and Elbow Surgeons Standardized Shoulder Form score measured at 1 year of follow-up.The Arthroscopic Rotator Cuff trial is ongoing, and 12 sites with more than 40 physicians are currently recruiting patients. Although there is variation by site, as of May 2, 2019, 13% of all patients screened (787 of 6293) were eligible for the trial, and 9% of eligible patients (74 of 787) were recruited. Results of this study may help patients, clinicians, and policy makers assess the comparative effectiveness of operative vs nonoperative treatment for atraumatic rotator cuff tears.ClinicalTrials.gov identifier: NCT03295994.
Banding Together: A Systematic Comparison of The Cancer Genome Atlas and the Mitelman Databases
Authors: Connor Denomy, Samuel Germain, Bjorn Haave, Frederick S. Vizeacoumar, Andrew Freywald, Beth A. Weaver, Franco J. Vizeacoumar
Journal: Cancer Research (2019)

Abstract Cytogenetic aberrations at the single-cell level represent an important characteristic of cancer cells relevant to tumor evolution and prognosis. However, with the advent of The Cancer Genome Atlas (TCGA), there has been a major shift in cancer research to the use of data from aggregate cell populations. Given that tumor cells harbor hundreds to thousands of biologically relevant genetic alterations that manifest as intratumor heterogeneity, these aggregate analyses may miss alterations readily observable at single-cell resolution. Using the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer, we developed an algorithm to parse International System for Cytogenetic Nomenclature notation for quantitative abnormalities. Comparison of the Mitelman database and TCGA demonstrated that the Mitelman database is a powerful resource, and that cytogenetic aberrations captured by traditional approaches used in Mitelman database are on par with population-based genomic analyses used in TCGA. This algorithm will help nonspecialists to overcome the challenges associated with the format and syntax of the Mitelman database. Significance: A novel in silico approach compares cytogenetic data between the Mitelman database and TCGA, highlighting the advantages and limitations of both datasets.