tbuckley/cabot-search huggingface dataset:
Cadherin-cadherin engagement promotes cell survival via Rac/Cdc42 and Stat3
Authors: Rozanne Arulanandam, Adina Vultur, Jun Cao, Lionel Larue, Helene Feracci, Leda Raptis
Journal: Cancer Research (2008)

2522  Stat3 (signal transducer and activator of transcription-3) is activated by a number of receptor and non-receptor tyrosine kinases, while a constitutively active form of Stat3 alone is sufficient to induce neoplastic transformation. We recently demonstrated a dramatic increase in the activity of Stat3 in breast carcinoma as well as normal epithelial cells and fibroblasts, as a consequence of cell to cell adhesion (Oncogene 23:2600). Given the generally accepted, positive role of Stat3 in proliferation, the Stat3 activity increase observed in post-confluent cells, that is when cells do not divide, was an unexpected observation. In the present report we demonstrate that Stat3 can also be activated through homophilic interactions by E-cadherin and cadherin-11, two members of the classical type I and II cadherin family of surface receptors, responsible for the formation of cell to cell junctions. Furthermore, by plating cells onto surfaces coated with fragments encompassing the two outermost domains of these cadherins, we demonstrate that cadherin engagement can activate Stat3, even in the absence of direct cell to cell contact. Unexpectedly, our results revealed for the first time a dramatic surge in total Rac1 and Cdc42 protein levels by cadherin engagement, and an increase in Rac1 and Cdc42 activity, which is responsible for the Stat3 stimulation observed upon cadherin ligation. Inhibition of cadherin interactions using a peptide, a soluble cadherin fragment or genetic ablation induced apoptosis, pointing to an significant role of this pathway in cell survival signalling, a finding which could also have important therapeutic implications.
Preoperative chemoradiation +/- pazopanib in non-rhabdomyosarcoma soft tissue sarcoma (NRSTS): A report from Children's Oncology Group (COG) and NRG Oncology.
Authors: Aaron R. Weiss, Yueh-Yun Chi, Yen-Lin Chen, Edwin Choy, Jessica L. Davis, Julie Fanburg-Smith, Douglas S. Hawkins, Mark Kayton, Lynn Million, Scott H. Okuno, Andrew Ostrenga, R. Lor Randall, Thomas Scharschmidt, Joel Sorger, Sheri L. Spunt, Jing Tian, Stephanie Alicia Terezakis, Dian Wang, Eduardo Zambrano, Jennifer O. Black
Journal: Journal of Clinical Oncology (2019)

11002 Background: Pazopanib is a multi-targeted tyrosine kinase inhibitor with activity in advanced soft tissue sarcoma. ARST1321 is a phase II study designed to compare the near complete pathologic response rate (≥ 90% necrosis) of preoperative chemoradiation +/- pazopanib in children and adults with intermediate/high risk chemotherapy-sensitive NRSTS. Methods: ARST1321 is a jointly designed COG and NRG Oncology study opened to enrollment in July 2014. Eligible adult (≥18 years) and pediatric ( &lt; 18 years) patients with unresected, newly diagnosed truncal/extremity NRSTS were enrolled into the Chemotherapy Cohort ( &gt; 5 cm, grade 2/3, protocol-designated chemotherapy-sensitive histology). Following a dose-finding phase, patients were randomized to receive (Regimen A) or not receive (Regimen B) pazopanib ( &lt; 18 years: 350 mg/m2/day; ≥ 18 years: 600 mg/day) in combination with ifosfamide (7.5 gm/m2/cycle) and doxorubicin (75 mg/m2/cycle) + 45 Gy preoperative RT followed by primary resection at week 13, then adjuvant chemotherapy. Results: As of June 30, 2018, 81 eligible patients were enrolled and randomized. Week 13 response is available for 42 patients (60% of expected information). The rate of ≥ 90% pathologic necrosis was 58.3% for Regimen A and 22.2% for Regimen B. Based on the significance level of 0.081 (for the second efficacy analysis with overall one-sided significance level of 0.20, power of 0.80, and O’Brien-Fleming-type cumulative error spending function), the 83.8% confidence interval for the difference was between 16.5% and 55.8%. At this predetermined interim analysis, the efficacy bound was crossed indicating that Regimen A is more efficacious than Regimen B. Given these findings, enrollment was stopped. Grade 3/4 toxicities were 73.8% for Regimen A and 29% for Regimen B with neutropenia, thrombocytopenia and febrile neutropenia being the most common toxicities. Conclusions: The rate of near complete pathologic response was significantly greater with the addition of pazopanib to preoperative chemoradiation in children and adults with intermediate/high risk NRSTS. The comparison of survival outcomes requires longer follow-up. Clinical trial information: NCT02180867.
Phagocytosis of damaged 9L glioma cells by microglia/macrophages isolated from adult rat brains
Authors: Nisha V. Kulprathipanja, Carol A. Kruse
Journal: Cancer Research (2004)

1283   The ability of microglia/macrophages to remove damaged tumor cells was examined to better understand the endogenous immune responses that may ensue following brain tumor therapies. 9L rat glioma cells were damaged by exposure to ultraviolet (UV) radiation for 10 minutes, 30 hours before use in phagocytosis assays. The glioma cells were then stained with Annexin-V-APC, which binds to phosphatidylserine (PS) on their cell surfaces and is an indicator of apoptotic death. CD11b+ microglia/macrophages isolated from 9L-bearing adult rat brains were plated two hours prior to their use in phagocytosis assays. Undamaged 9L cells (17.3% PS+) or UV-irradiated 9L cells (72.1% PS+) were then added to the microglia/macrophages at a 1:1 ratio and co-incubated for 3 hours. Cytochalasin D, which prevents phagocytic function by inhibiting actin cytoskeleton polymerization, was added to control wells. The percentage of microglia/macrophages phagocytosing glioma cells was then determined by subtracting the background binding observed in the control wells from the experimental wells. Eight percent of the microglia/macrophages phagocytosed UV-irradiated 9L cells, but none of the undamaged 9L cells were taken up by microglia/macrophages. Furthermore, 14% of the microglia/macrophages isolated from the rat brain were positive for the PS receptor. The addition of Annexin-V-biotin to the UV-irradiated cells 30 minutes prior to the phagocytosis assay blocked phagocytic function by 88%, implicating the interaction of PS and the PS receptor as a signal for the engulfment of damaged glioma cells by microglia/macrophages. Support: NIH F31 NS44074 & RO1 NS56798
Profiling of circulating tumor cells isolated from 105 metastatic gastric cancer patients revealed HER2 overexpression/activation for potential use in clinical setting.
Authors: Saswati Hazra, Jeeyun Lee, Phillip Sangwook Kim, Kyoung-Mee Kim, Limin Liu, Edvelyn Webster, Andrew Fithian, Sharat Singh, WonKi Kang
Journal: Journal of Clinical Oncology (2012)

10535 Background: Gastric cancer (GCA) is the second leading cause of cancer mortality in the world. Survival of patients with advanced GCA treated with chemotherapy remains low. New targeted therapies are urgently needed. There is mounting evidence of the role of HER2 overexpression in patients with GCA, and it has been highly correlated to poor outcomes with more aggressive disease. The ability to accurately determine HER2 status by testing circulating tumor cells (CTCs) may improve patient treatment by allowing ongoing assessment of HER2 status during treatment and/or identifying additional patients who could potentially benefit from HER2- targeted therapy. Methods: The Collaborative Enzyme Enhanced Reactive-immunoassay (CEER) was utilized to determine the expression and activation (phosphorylation) levels of HER2 in CTCs isolated from blood specimens obtained from 105 metastatic GCA patients. Results: Utilizing the CEER platform, the levels of HER2 expression and phosphorylation were determined for CTCs isolated from metastatic GCA patients. Evaluable CTCs were found in 33% (35/105) of enrolled patients. Out of 35 patients, 7 patients (20%) have high HER2 over expression, 6 patients (17%) have moderate HER2 expression and 11 patients (31%) have HER2 activation (phospho positive) with no HER2 over-expression. Conclusions: When CTCs were present, the CEER assay identified varying levels of HER2 involvements in 68% of metastatic GCA patients. HER2 positive CTCs could serve as a prognostic and/or predictive marker in patients with advanced GCA and CTC-HER2 profile shifts can be utilized to monitor the treatment efficacy.
Methods for categorizing a molecular biomarker in early marker studies: A simulation study
Authors: Dongyun Yang, Susan Groshen, Heinz-Josef Lenz
Journal: Cancer Research (2005)

762  Colon cancer is a major cause of cancer deaths in the USA. Global DNA hypomethylation is found in most tumors including colon cancer, suggesting that modulation of this methylation may be used as a surrogate end-point biomarker for chemoprevention. Tumor promoters have been shown to induce DNA hypomethylation that may result from an increase in DNA demethylase activity. Rutin and four bile acids, deoxycholic acid, chenodeoxycholic acid, cholic acid and lithocholic acid that promote colon cancer and ursodeoxycholic acid that prevents colon cancer were administered to male F344 rats for 14 days at 4.0 gm/kg diet except for rutin at 3.0 gm/kg. DNA methylation was determined by Dot Blot Analysis using a mouse monoclonal anti-5-methylcytosine antibody. Rutin and the four bile acids that promote colon cancer caused DNA hypomethylation, while ursodeoxycholic acid did not alter DNA methylation in the colon. The ability of deoxycholic acid and quercetin (a colon tumor promoter and the aglycone of rutin) to induce DNA demethylase activity was determined in rat colon. Since methionine prevented and reversed DNA hypomethylation induced by tumor promoters in mouse liver, we also determined whether it would prevent/reverse DNA demethylase activity and DNA hypomethylation induced by deoxycholic acid and quercetin. Male F344 rats were administered 300 mg/kg deoxycholic acid or 50 mg/kg quercetin by oral gavage for four days and then held for another four days. Some rats were also administered 8.0 gm/kg methionine in their diet either concurrently with the tumor promoters or during the holding period. Rats were sacrificed after 2 and 4 days of exposure to the tumor promoters and after 2 and 4 days of the holding period. The colonic mucosa was obtained and frozen in liquid nitrogen. DNA demethylase activity was determined using a synthetic 383 bp DNA that had its CpG sites radiolabeled with 3H-methyl groups. DNA demethylase activity was determined by the release of the radiolabel as 3H-methanol. The reaction mixture was filtered though an YM 10 membrane and the radioactivity measured by liquid scintillation. Deoxycholic acid and quercetin significantly increased the level of DNA demethylase activity in a nuclear protein extract from the colonic mucosa. Both tumor promoters also caused DNA hypomethylation in the colon. Hence, increased DNA demethylase activity could be one of the possible mechanisms by which colon tumor promoters such as deoxycholic acid and quercetin induce DNA hypomethylation and promote tumor development.
The serological markers TIMP-1, PAI-1, MASP-2 and CRP are independent predictors of colorectal cancer-specific death.
Authors: Anne F. Lomholt, Hans J. Nielsen, Nils Brünner, Ib J. Christensen
Journal: Cancer Research (2006)

5723  Introduction: The prognostic value of serological markers sampled preoperatively in patients with colorectal cancer (CRC) has been established. This study combines a panel of these markers in order to select a prognostic profile independent of the clinical baseline covariates: stage, localization, gender and age at diagnosis. The markers selected for this study are plasminogen activator inhibitor-1 (PAI-1), soluble urokinase plasminogen activator receptor (suPAR), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), tetranectin, YKL-40, soluble vascular endothelial growth factor (VEGF), molecules of the mannan-binding lectin (MBL) pathway of innate immunity and its associated serine protease MASP-2, carcinoembryonic antigen (CEA) and the acute phase response marker C-reactive protein (CRP). Methods: Six-hundred and fifty-four CRC patients undergoing elective surgery were followed for 7.9 years (median, 6.8–9.1 years). The primary end-point was cancer-specific death and 308 patients were registered with CRC as primary cause of death. Multiple imputations were used for missing values and the time to cancer-specific death was subsequently analyzed with the multivariable Cox proportional hazards model. Serological markers were entered into the statistical model as continuous variables on the log scale with the exception of CEA and CRP which were scored using conventional cutpoints. Results: The mannan-binding lectin pathway molecules were not associated to the other markers. Univariable analysis of the serological markers showed all to be significant predictors of cancer-specific death with the exception of MBL (p=0.36). All markers were entered into the multivariable analysis and the final model was selected including only covariates which are significant in the analysis including the baseline clinical characteristics. The final multivariable analysis showed that TIMP-1 (p
A circuit view of deep brain stimulation in Alzheimer’s disease and the possible mechanisms
Authors: Danfang Yu, Huanhuan Yan, Jun Zhou, Xiaodan Yang, Youming Lu, Yunyun Han
Journal: Molecular Neurodegeneration (2019)

Alzheimer's disease (AD) is characterized by chronic progressive cognitive deterioration frequently accompanied by psychopathological symptoms, including changes in personality and social isolation, which severely reduce quality of life. Currently, no viable therapies or present-day drugs developed for the treatment of AD symptoms are able to slow or reverse AD progression or prevent the advance of neurodegeneration. As such, non-drug alternatives are currently being tested, including deep brain stimulation (DBS). DBS is an established therapy for several neurological and psychiatric indications, such as movement disorders. Studies assessing DBS for other disorders have also found improvements in cognitive function, providing the impetus for clinical trials on DBS for AD. Targets of DBS in AD clinical trials and animal model studies include the fornix, entorhinal cortex (EC), nucleus basalis of Meynert (NBM), and vertical limb of diagonal band (VDB). However, there is still no comprehensive theory explaining the effects of DBS on AD symptoms or a consensus on which targets provide optimal benefits. This article reviews the anatomy of memory circuits related to AD, as well as studies on DBS rescue of AD in these circuits and the possible therapeutic mechanisms.
Formation of the depurinating N3adenine and N7guanine adducts by reaction of DNA with hexestrol-3′,4′-quinone or enzyme-activated 3′-hydroxyhexestrol. Implications for a unifying mechanism of tumor initiation by natural and synthetic estrogens
Authors: Sandra J. Gunselman, Muhammad Saeed, Sheila Higginbotham, Eleanor G. Rogan, Ercole L. Cavalieri
Journal: Cancer Research (2004)

1564  The nonsteroidal synthetic estrogen hexestrol (HES), which is diethylstilbestrol hydrogenated at the C-3 –C-4 double bond, is carcinogenic. Its major metabolite is the catechol, 3′-OH-HES, which can be metabolically converted to the catechol quinone, HES-3′,4′-Q. Study of HES was undertaken with the scope to substantiate evidence that natural catechol estrogen-3,4-quinones are endogenous carcinogenic metabolites. HES-3′,4′-Q was previously shown to react with deoxyguanosine to form the depurinating adduct 3′-OH-HES-6′-N7Gua by 1,4-Michael addition. The depurinating adduct 3′-OH-HES-6′-N3Ade is formed by reaction of HES-3′,4′-Q with Ade. The structure of the N3Ade adduct was established by NMR and MS. The depurinating 3′-OH-HES-6′-N7Gua and 3′-OH-HES-6′-N3Ade adducts were also formed by reaction of HES-3′,4′-Q with DNA or by activation of 3′-OH-HES by tyrosinase, lactoperoxidase, prostaglandin H synthase or 3-methylcholanthrene-induced rat liver microsomes at 37°C in the presence of DNA. The N3Ade adduct was released instantaneously from DNA, whereas the N7Gua adduct was released with a half-life of approximately 3 h. Much lower (
Additive effect of selenium and bicalutamide in human prostate cancer cells in vitro
Authors: Vasundara Venkateswaran, Seamus Teahan, Ahmed Haddad, Laurence H. Klotz, Linda M. Sugar, Neil E. Fleshner
Journal: Cancer Research (2006)

3835   Introduction: Prostate cancer (PCa) is the commonest non-cutaneous malignancy and second leading cause of cancer death in males. Evidence from epidemiological and clinical trials indicates that selenium may reduce the risk of PCa. To date, selenium has not been shown to offer a therapeutic benefit in the management of established prostate cancer. We hypothesize that a combination of selenium and bicalutamide could lead to delayed androgen resistance, providing additional therapeutic benefit for the management of advanced PCa. Methods: Human PCa cells {LNCaP and PC3-AR2 (AR positive) and PC3-M (AR negative)} were incubated for 72 h with, varying concentrations of seleneno-DLmethionine (0-200 μM), bicalutamide (0-100 μM) or a combination of both. Cells were fixed and stained with propidium iodide for flow cytometric analysis. Cellular protein and DNA were extracted to determine expression of apoptotic markers. The individual and combined effects of these compounds on cell proliferation were assessed by MTT assay. Results: Data obtained from flow-cytometric analysis demonstrate that significant apoptosis (p
Reduced-Intensity Conditioning Versus Myeloablative Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients with Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis of Randomized Trials
Authors: Ahmad Kamal, Muhammad Abu Zar, Hafiz Muhammad Fazeel, Seren Durer, Ceren Durer, Syed Shabee Hassan, Mustafa Nadeem Malik, Abdul Rafae, Faiqa Ijaz, Shehroz Aslam, Faiz Anwer, Mehdi Hamadani
Journal: Blood (2018)
Array-based comparative genomic hybridization guides identification of novel genes implicated in prostate cancer.
Authors: Karin Hermans, Hetty Van der Korput, Herman Van Dekken, Wytske Van Weerden, Jan Trapman
Journal: Cancer Research (2006)

5686  Prostate cancer is the most common malignancy in men in developed countries. The molecular mechanisms underlying prostate cancer development and progressive growth are still poorly understood. To unravel these mechanisms we analyzed genomic DNA from eleven human prostate cancer xenografts by 1Mb spaced array-based comparative genomic hybridization (array CGH). Xenograft DNA lacks DNA from normal cells of human origin, allowing most accurate genomic studies. Xenografts reflect a variety of clinical stages of prostate cancer. The most frequent small region of chromosomal loss (approx. 3 Mb) was on 21q22.2–q22.3 (4 xenografts). This generates the recently described TMPRSS:ERG fusion gene, linking the TMPRSS2 promoter and exon 1 to exon 4 of the ERG gene. RT-PCR also showed variable levels of expression of the TMPRSS2:ERG fusion gene in three other xenografts. Further genomic analyses indicated two alternative mechanisms of TMPRSS2 to ERG gene fusion. Eleven homozygous deletions in eight different xenografts were detected. Most are predicted to be relevant for tumorigenesis. The most frequent homozygous deletion detected by array CGH was that of PTEN on 10q23.3 (3 xenografts). Novel homozygous deletions on 2q37.1 and 8p23.3-pter need further investigation, because obvious candidate tumor suppressor genes could not be indicated. A homozygous deletion close to fragile site FRA16D on 16q23.1 affected the WWOX gene. The homozygous deletion on 13q13.1 included at least three genes implicated in tumorigenesis: BRCA2, APRIN and DLC2; the one on 13q14.2 included RB1. Other homozygous deletions affected ATBF1 on 16q22.2–q22.3 and MKK4 on 17p12. A homozygous deletion on 17p11.2–p12 encompassed the N-COR transcription co-repressor gene. Detailed analysis of xenograft DNAs by PCR identified a second homozygous deletion of N-COR, which was not visualized by array CGH. Because N-COR has never been implicated in prostate cancer, it was subjected to further structural and functional investigation. Additionally to the two homozygous deletions we detected mutation or loss of one copy of N-COR in four other xenografts. Functional studies, utilizing N-COR specific siRNA, demonstrated stimulated in vitro growth of LNCaP prostate cancer cells. Our observations, as guided by array CGH, add ERG and N-COR to PTEN as novel important genes in prostate cancer.
Gentamicin 240 mg plus azithromycin 2 g vs. ceftriaxone 500 mg plus azithromycin 2 g for treatment of rectal and pharyngeal gonorrhoea: a randomized controlled trial
Authors: F. Rob, B. Klubalová, E. Nyčová, J. Hercogová, M. Unemo
Journal: Clinical Microbiology and Infection (2019)
The natural history of intravascular lymphoma.
Authors: Ekokobe Fonkem, David J Robison, Edwin Lok, Shiva Gautam, Eric Wong
Journal: Journal of Clinical Oncology (2012)

e18541 Background: The diagnosis of IVL is often delayed or found at post-mortem because this disease is rare. Published data consist of case reports or series, which are insufficient to offer a global perspective of this disorder. Methods: We included cases of IVL published between 1957 and 2011, and performed Wilcoxon rank sum test to evaluate survival differences. Results: There were 191 B-cell and 7 T-cell lymphomas. Median age was 65 (range 12-87) years. Central nervous system (CNS) was the first site of disease in 92(47%), skin in 41(21%), and lung in 22(11%) individuals. Forty-five% of CNS IVL was diagnosed at postmortem versus 12% for skin and 27% for lung IVL. Age is a significant prognostic factor and patients &lt;75 years had a median survival of 14.0(range 0.1-165.0) months versus those ≥75 years had a median survival of 6.0(range 0.1-178.0) months (P=0.05). There is a trend favoring women, median survival 14.0(0.3-96) months, over men, median survival 7.0(0.1-178.0) months (P=0.07). Gender, ethnicity, organ site involvement, hemoglobin, LDH, bone marrow involvement and MRI were not significant. There is no difference in patient survival when treated with Adriamycin-based versus non-Adriamycin-based chemotherapies. Among the 12 CNS IVL patients with recurrence, 3(25%) recurred in CNS while 2(14%) recurred in skin and 7(58%) in lungs. Among the 9 patients with skin IVL, 4(45%) recurred in skin while 1(11%) in CNS, 1(11%) in lungs, and 3(33%) in other organs. Two (50%) of 4 patients with lung IVL had recurrence in the lungs and the other 2(50%) recurred in other organs. Conclusions: The treatment of CNS IVL is hampered by lack of timely diagnosis. The prognosis and pattern of relapse of CNS IVL patients is significantly different from those with skin and lung IVL, suggesting variations in the underlying biological mechanism of disease.