tbuckley/cabot-search huggingface dataset:
Abstract #4533: Bortezomib down-regulates phospho-Akt through up-regulation of protein phosphatase 2A activity in hepatocellular carcinoma cells
Authors: Kuen-Feng Chen, Hui-Chuan Yu, Yu-Lung Lee, Tsung-Hao Liu, Pei-Jer Chen, Ann-Lii Cheng
Journal: Cancer Research (2009)

Background: We have previously reported that down-regulation of phospho-Akt (P-Akt) is a major molecular event that determines sensitivity of hepatocellular carcinoma (HCC) cells toward bortezomib, a proteasome inhibitor (Cancer Res 2008; 68:6698-6707). Here, we further demonstrated that protein phosphatase 2A (PP2A) plays a key role in mediating this effect of bortezomib on Akt. Methods: Two HCC cell lines, Sk-Hep1 and PLC5, were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interference RNA (siRNA). Results: Bortezomib induced apoptosis in association with down-regulation of P-Akt in sensitive Sk-Hep1 cells but not in resistant PLC5 cells. We found that okadaic acid, a PP2A inhibitor, reversed down-regulation of P-Akt in bortezomib-treated Sk-Hep1 cells, suggesting that bortezomib might inhibit Akt signals by affecting PP2A. Further biochemical analyses showed that bortezomib up-regulated PP2A phosphatase activity in Sk-Hep1 cells in a dose-dependent manner, but not in PLC5 cells. However, the protein expressions of PP2A complex including subunit A, B and C, were not affected by bortezomib in Sk-Hep1 cells. Moreover, co-immunoprecipitation assay showed that bortezomib did not alter PP2A association to Akt in Sk-Hep1 cells, indicating bortezomib does not affect PP2A via enhancing protein-protein interactions. Finally, silencing the catalytic subunit of PP2A by siRNA reversed bortezomib-induced down-regulation of P-Akt and apoptosis, indicating PP2A is essential in mediating the effect of bortezomib on Akt. Conclusions: Bortezomib down-regulates P-Akt through up-regulation of PP2A phosphatase activity in HCC cells. Supported by NTUH (95-96)A11, NTUH97A07, NSC95-2314-B-002-072, DOH (94-97)-TD-B-111-001  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4533.
Sequential or combination therapy in the management of recurrent ovarian carcinoma: Clinical experience beyond clinical trials
Authors: U. Gueth, E. Wight
Journal: Journal of Clinical Oncology (2009)

e16530 Background: There is a vast amount of literature on the effect of systemic therapy in patients with recurrent ovarian carcinoma (ROC) enrolled in clinical trials. However, there are only a few reports that focus on the treatment during the entire course of disease and its changes and development over time. Methods: We investigated the entire treatment course (all agents administered, number of treatment lines, cumulative time of therapy in relation to survival time) in a population-based cohort of 133 ROC patients. In study group A (n = 63), ROC was diagnosed between 1998 to 2006; in group B, ROC was diagnosed between 1990 to 1997 (n = 70). Results: 7.9% of the patients in group A and 8.6% in group B did not receive any chemotherapy in the palliative setting. Comparison between sub-study groups A and B showed similar overall survival (recurrent disease-specific survival): 19 months (A) vs. 18 months (B); p = 0.549. Compared to group B, the patients in the more recent subgroup A received significantly fewer combination therapies (12% vs. 24.1%, p = 0.0057) but more therapy lines (≥3 lines in 56.1% vs. 31.1%, p = 0.005) and also had significantly longer times of treatment in relation to survival time (mean ratio 57.5% vs. 47.5%, p = 0.014). The distribution of the main agents administered in the course of disease was as follows (A vs. B): carboplatin 31.0% vs. 34.7%; pegylated liposomal doxorubicin (PLD): 19.7% vs. 2.0%; gemcitabine 19.2% vs. 3.0%; paclitaxel: 10.7% vs. 14.6%; topotecan: 9.1% vs. 2.5%; others: 10.3% vs. 43.2%. Conclusions: In the current study group, a similar outcome could be achieved with less aggressive treatment regimens, i.e. with fewer combination therapies and with longer treatment periods. Currently, in a palliative treatment setting, the primary goals of surveillance of ROC patients are maintenance and/or an enhancement of quality of life, which can be achieved using less toxic agents such as gemcitabine and PLD. No significant financial relationships to disclose.
Spk-9001: Adeno-Associated Virus Mediated Gene Transfer for Hemophilia B Achieves Sustained Factor IX with Minimal Immune Response
Authors: Daniel J Hui, Yun Liu, Ruchi Patel, Yifeng Chen, Lindsey A. George, Spencer K. Sullivan, Adam Giermasz, John Rasko, Ben J. Samelson-Jones, Jonathan M. Ducore, Sue Dasen, Marcus E. Carr, Xavier M. Anguela, Katherine A. High
Journal: Blood (2017)
Therapeutic destabilization of ErbB2 transcripts mediated by U-rich mRNA binding proteins and microRNAs.
Authors: Corina Marx, Crystal Berger, Stephen Benz, Michael Mattie, Christopher C. Benz, Gary K. Scott
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

5616 

A screen for small molecule inhibitors of ErbB2 transcription identified two drug classes, histone deacetylase (HDAC) and proteasome inhibitors that, relative to Actinomycin D, accelerate decay of mature ErbB2 transcripts. Elements regulating ErbB2 transcript stability have been mapped to a conserved U-rich region within its endogenous 3' UTR, thought to bind to either the stabilizing protein, HuR, or the destabilizing protein AUF1. Additionally, this U-rich region contains several putative microRNA (miRNA) binding elements which may modulate mature transcript stability by recruitment of cognate miRNAs. To assess ErbB2 mRNA stabilizing mechanisms dependent on miRNAs, AUF1 or HuR proteins that may be sensitive to HDAC and/or proteasome inhibition, SKBr3 cells were pretreated (72 h) with siRNAs targeting Dicer (required for mature miRNA processing), HuR or AUF1 prior to culture treatment (5 h) with either HDAC (LAQ824) or proteasome (PS341) inhibitors. ErbB2 mRNA levels of untreated SKBr3 were increased by Dicer siRNA, which also partially prevented the ErbB2 mRNA decline induced by HDAC inhibition. In contrast, AUF1 siRNA pretreatment partially prevented the ErbB2 mRNA decline induced by proteasome inhibition. Consistent with Dicer siRNA results indicating that miRNAs negatively regulate ErbB2 transcript levels, a novel microarray platform for profiling ∼200 miRNAs demonstrated that HDAC inhibition of SKBr3 cells results in upregulation of three miRNAs that putatively bind to the 3’ UTR of ErbB2: miR125a, miR125b, and miR320. Altogether, these findings point to the potential therapeutic importance of mRNA stability as regulated by miRNAs and U-rich mRNA binding proteins, and suggest that HDAC and proteasome inhibitors accelerate ErbB2 transcript decay by fundamentally different mechanisms.
A Young Woman With Refractory Vasospastic Angina
Authors: Seyedmohammad Saadatagah, Kaveh Hosseini, Ali Bozorgi
Journal: JAMA Cardiology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Response by Mendes-Ferreira et al to Letter Regarding Article, “Bmpr2 Mutant Rats Develop Pulmonary and Cardiac Characteristics of Pulmonary Arterial Hypertension”
Authors: Pedro Mendes-Ferreira, Grégoire Manaud, Frédéric Perros
Journal: Circulation (2019)

In Response:We appreciate the interest from Dr Paulin and colleagues in our paper reporting the generation and the characterization of the first rat model of hereditable pulmonary arterial hypertension related to BMPR2 (bone morphogenetic protein type II receptor) mutation.We thank the authors for their comments, and for corroboration of our findings; 27% of the BMPR2 +/∆71 rats presenting a pulmonary arterial hypertension-relevant increase in the right ventricular systolic pressures at 8 to 18 months of age, similarly to what we have previously described (16-27% at 6-12 months), and to what is reported in the human condition (around 20%). 1 The findings of Paulin et al regarding the development of mammary masses and ulcerations in BMPR2 +/∆71 rats are indeed interesting, and require further investigation.As the authors have noted, mice harboring a dominant-negative mutation in the BMPR2 gene have accelerated mammary carcinoma metastases, 2 associated with inflammatory cell infiltration and proinflammatory cytokine expression in fibroblasts lacking BMPR2. 3These findings could explain the increased perivascular fibrillary collagen and interleukin-6 overexpression we observed in the BMPR2 +/∆71 animals that developed spontaneous pulmonary arterial hypertension. 1npublished data from our group corroborate the presence of mammary masses in old female mutant rats, characterized by a quick development, leading to the discovery of these masses already at advanced stages, despite regular observation of the animals.Coherently, BMPR2 silencing leads to decreased BRCA1 (breast cancer susceptibility gene 1) expression. 4Mutations in BRCA1 are associated with inherited breast cancer development, and decreased expression is associated with sporadic malignancies, accounting to a risk of developing breast cancer as high as 80%. 5 Furthermore, lungs from patients with idiopathic pulmonary arterial hypertension, whose BMPR2 expression is also decreased, show a decreased expression of BRCA1. 4 Taking into account that BMPR2 +/∆71 rats show a 50% decrease in BMPR2 expression, 1 a decrease in BRCA1 expression and increased susceptibility to breast cancer development is expected.We are looking forward to further investigations from our Canadian colleagues in that direction.
Long Noncoding RNA MIR17HG Promotes Colorectal Cancer Progression via miR-17-5p
Authors: Jie Xu, Qingtao Meng, Xiaobo Li, Hongbao Yang, Jin Xu, Na Gao, Hao Sun, Shenshen Wu, Giuseppe Familiari, Michela Relucenti, Haitao Zhu, Jiong Wu, Rui Chen
Journal: Cancer Research (2019)

Immune dysregulation plays a vital role in colorectal cancer initiation and progression. Long noncoding RNAs (lncRNA) exhibit multiple functions including regulation of gene expression. Here, we identified an immune-related lncRNA, MIR17HG, whose expression was gradually upregulated in adjacent, adenoma, and colorectal cancer tissue. MIR17HG promoted tumorigenesis and metastasis in colorectal cancer cells both in vitro and in vivo. Mechanistically, MIR17HG increased the expression of NF-κB/RELA by competitively sponging the microRNA miR-375. In addition, RELA transcriptionally activated MIR17HG in a positive feedback loop by directly binding to its promoter region. Moreover, miR-17-5p, one of the transcribed miRNAs from MIR17HG, reduced the expression of the tumor suppressor B-cell linker (BLNK), resulting in increased migration and invasion of colorectal cancer cells. MIR17HG also upregulated PD-L1, indicating its potential role in immunotherapy. Overall, these findings demonstrate that MIR17HG plays an oncogenic role in colorectal cancer and may serve as a promising therapeutic target. SIGNIFICANCE: These findings provide mechanistic insight into the role of the lncRNA MIR17HG and its miRNA members in regulating colorectal cancer carcinogenesis and progression.
Expression of Rho C, prolactin receptor (PRL-R), PDGF-α, and PPAR-γ is significantly higher in Barrett's Esophagus epithelium compared with esophageal squamous epithelium
Authors: Rona Yaeger, Vibhav S. Rangarajan, Tao Su, Alexa Avila-Bront, John P. Stoutenburg, Xiaomei Wang, John-Paul S. Bellistri, Kevin J. Bukowski, Beverly E. Diamond, Hanina Hibshoosh, Charles A. Powell, Charles J. Lightdale, Andrew K. Joe
Journal: Cancer Research (2006)

861  The G-CSF receptor was recently identified on T lymphocytes. Recent studies have reported a possible direct modulatory effect of G-CSF on T lymphocytes. We compared the immunophenotype pattern and gene expression profile of T cells from G-CSF treated blood with untreated blood from normal healthy donors. Peripheral blood was collected from 19 blood stem cell donors, either during mobilization or, at the latest, 3 weeks after treatment with recombinant G-CSF at 10ug/kg/d for > 5 consecutive days. The control group was blood samples from 20 normal healthy volunteers. Different T cell subsets were analyzed by flow cytometry, employing CD3, CD4, CD8, CD45RO, CD45RA, CD28, CD25, CCR7, CD56 and CD94 in various combinations. Global gene expression in purified T cells was performed using Affymetrix HG-U133 Plus GeneChips. Pure (>95%) T cells were isolated by negative selection from peripheral blood mononuclear cells using a pan-T cell kit and from which total RNA was extracted. A total of 2,245 genes were found to be differentially regulated between the G-CSF treated donors and normal controls (NC), with 460 genes upregulated and 1,785 down-regulated in G-CSF treated donors. Of the 460 genes, 231 had over 3-fold elevated expression in donors, but only 65 out of the 1,785 genes were 3-fold downregulated. The upregulated genes included those encoding for molecules involved in adhesion, migration, apoptosis, transcriptional regulation, as well as chemokines, cytokines, growth factors and their receptors. The downregulated genes were mainly associated with signaling and transcriptional regulation. When the GCSF-treated donors were further divided into two groups, i.e. ‘during G-CSF mobilization’ (DG) versus ‘after G-CSF mobilization’ (AG), marked differences were revealed in both gene profiling and phenotype patterns. 59 genes were found to have elevated expression in DG donors by at least 3-fold compared to AG donors. Most of these were genes involved in immune and inflammatory responses, cell growth and maintenance, as well as growth factor and cytokine receptors. Hierarchical clustering revealed a clear separation between the G-CSF treated samples and NC. In addition, two separate clusters differentiated DG from AG. In immunophenotype profiling, AG donors had significantly higher CD45RO+CD3+CD4+ memory T cells than both DG donors and NC (p
A pharmacodynamic study of JI-101, an orally active inhibitor of VEGF-2, PDGF-β, and EphB4 receptors, in patients with refractory/recurrent ovarian cancer.
Authors: Theresa Louise Werner, Aaron Lynn Luebke, Mark Wade, Nuggehally R Srinivas, Dhiraj J. Abhyankar, Philip Caligiuri, Marta Elise Heilbrun, Sunil Sharma
Journal: Journal of Clinical Oncology (2012)

e13548 Background: JI-101 is an oral multi-kinase inhibitor, which targets VEGFR-2, PDGF-β, and EphB4. By targeting multiple angiogenesis signaling pathways, JI-101 has the potential advantage of inhibiting all vital stages of tumor angiogenesis, reducing tumor resistance, and enhancing anti-tumor efficacy. None of the currently approved angiogenesis inhibitors have any appreciable inhibition of EphB4, and therefore, this represents a novel mechanism of action. JI-101 has preclinical activity in various tumor models and has been well tolerated in phase 1 trials. Methods: Eleven women with refractory/recurrent ovarian cancer were enrolled with a median age of 54 yrs (range 52-76). All patients had adequate organ function and ECOG performance status ≤ 2. Each patient received single agent JI-101 at 200mg BID for 28 day treatment cycles. Toxicity and response were evaluated at two month intervals. Results: Eight of 11 patients were evaluable for response (3 were unevaluable due to inability to complete two cycles). A median of 3 cycles (range 2-6) was given. No grade 4 adverse events (AEs) were seen. The most common grade 2/3 hematological AEs were grade 2 anemia (1) and lymphopenia (1). The most common grade 2/3 non-hematological AEs were grade 3 hypertension (7), grade 3 bowel obstruction (2), grade 3 transaminitis (2), and abdominal pain (2). Six patients had stable disease (SD) at two months and two had progressive disease. Best response was SD at four months. Two-month progression free survival was 71% (90% CI 52-99%). Conclusions: JI-101 is well tolerated in refractory/recurrent ovarian cancer patients with the majority of patients with stable disease at two months. The most common toxicity was hypertension, which was easily controlled with anti-hypertensives. The novel mechanism of action of JI-101 is promising in ovarian cancer treatment and further prospective studies of this agent could be pursued in a less refractory patient population.
Inhibiting TGFβ Signaling in CAR T-Cells May Significantly Enhance Efficacy of Tumor Immunotherapy
Authors: Queenie Vong, Chris Nye, Ron Hause, Chris Clouser, Jon Jones, Stephen Burleigh, Christopher M Borges, Melissa Si Ying Chin, Eugenio Marco, Luis Barrera, Jen Da Silva, Fred Harbinski, Georgia Giannoukos, Vidya Dhanapal, Yue Jiang, Ruth Salmon, Christopher J Wilson, Vic E Myer, Grant G Welstead, Christopher J Bond, Blythe Duke Sather
Journal: Blood (2017)
Mycoplasma hyorhinis expression in patients with carcinoma of the prostate
Authors: Namiki Kazunori, Molly McCullers, Stacy Porvasnik, Masaaki Tachibana, Steve Goodison, Charles Rosser
Journal: Cancer Research (2008)

576  OBJECTIVES: Previously other groups have demonstrated Mycoplasma hyorhinis in gastrointestinal tumors. Recently, our group reported that subjecting human cells to a M. hyorhinis protein, p37 was associated with cellular and genetic changes indicative of a more aggressive malignancy. To help elucidate cause and effect, M. hyorhinis must be present in human prostate specimens. Our objectives were to demonstrate M. hyorhinis in human prostate specimens and to evaluate the association of mycoplasmal expression with the presence of prostatic carcinoma and clinical outcomes.  METHODS: Immunohistochemical staining for M. hyorhinis was performed on archival frozen prostate tissue specimens from 24 normal (BPH) controls and 26 consecutive prostate cancer patients from our tissue bank. M. hyorhinis was considered present when more than 5% of the cells were immunoreactive. As a means to confirm these results, nested PCR was performed utilizing primers for M. hyorhinis.  RESULTS: M. hyorhinis was present in 69% of the tumor specimens vs. 33% of the benign specimens. These results were confirmed with nested PCR. Though not powered to detect such a difference, M hyorhinis immunoreactivity was associated with higher grades and higher stages prostatic carcinomas.  CONCLUSIONS: We report the first experience of detecting M hyrohinis in human prostatic tissue. In addition, a higher correlation of M. hyrohinis immunoreactivity was noted in prostatic tumors compared to benign prostates. Currently a larger study is underway to correlate M hyrohinis infection with prostate cancer, specifically higher grade and higher stage tumors.
Docetaxel and imatinib every 21 days for castration resistant prostate cancer: A phase II trial
Authors: T. L. Gillison, L. J. Appleman, D. M. Friedland, T. L. Evans, P. N. Lara, W. E. Gooding, D. E. Lenzner, H. M. Strausser, J. R. Gingrich, G. S. Chatta
Journal: Journal of Clinical Oncology (2009)

e16086 Background: Docetaxel (D) IV every 21 days, is the only cytotoxic agent that prolongs survival in men with castrate resistant prostate cancer (CRPC). Imatinib (I), a tyrosine kinase inhibitor, modulates PDGFR-ß in tumor vasculature. Based on phase I data from our institution, we hypothesized that D plus I would prolong time to progression (TTP) in patients (pts) with CRPC. Methods: Subjects with CRPC received D 60 mg/m2 IV every 21 days plus I 400 mg PO daily. After 10 pts, the study treatment was modified due to toxicity so that pts received I 400 mg on 10 of 21 days/cycle. The primary endpoint was TTP. Secondary endpoints were rate of PSA response and overall survival (OS). The sample size of 43 pts was designed to provide 90% power to detect an increase in TTP from 5 to 8 months. Results: 43 pts enrolled from 8/05 to 9/08. Age at enrollment ranged from 54–86 years (median 69 years). 14 pts received &lt;1 cycle of D plus I and were unevaluable: 10 had significant toxicity, 4 due to non-treatment related reasons. Primary toxicities were hematologic: 21% G4 neutropenia, 5% G4 anemia, and no G4 thrombocytopenia. Fatigue, nausea, diarrhea, and electrolyte abnormalities were common, but &lt;2 cases each of G3-G4 toxicity occurred. 1 case of G5 non-neutropenic sepsis occurred. 29 pts received &gt;2 cycles of chemotherapy (mean 4.6). 12 pts had PR (41.4%), 9 had SD (31.0%), and 8 had no response (27.6%) by PSA. No objective responses were seen by CT imaging among 10 pts with measurable disease. 3 pts remain on trial. For evaluable pts, overall median TTP was 6.4 months (95% CL: 4.8, 8.4 months) compared with TTP of 5 months seen in previous trials. 23 (79%) pts had PSA progression, 3 pts died before progression, and 3 pts remain on trial. For all evaluable pts who had PR or SD by PSA (N = 21), median TTP was 7.1 months (95% CL: 5.5, 9.1 months). Median OS was 23.1 months (95% CL: 11.61 months, NR), compared with 18.9 months for GC Conclusions: Docetaxel on day 1 plus imatinib 10 days of each 21-day cycle resulted in meaningful improvement in TTP in the subset of pts who showed a response. Toxicity precludes its use in the general population, although its role in select pts with good performance status needs to be explored. [Table: see text]
Lymphatic mimicry in maternal endothelial cells promotes placental spiral artery remodeling
Authors: John B. Pawlak, László Bálint, Lillian Lim, Wanshu Ma, Reema B. Davis, Zoltán Benyó, Michael J. Soares, Guillermo Oliver, Mark L. Kahn, Zoltán Jakus, Kathleen M. Caron
Journal: Journal of Clinical Investigation (2019)

Molecular heterogeneity of endothelial cells underlies their highly specialized functions during changing physiological conditions within diverse vascular beds. For example, placental spiral arteries (SAs) undergo remarkable remodeling to meet the ever-growing demands of the fetus - a process which is deficient in preeclampsia. The extent to which maternal endothelial cells coordinate with immune cells and pregnancy hormones to promote SA remodeling remains largely unknown. Here we found that remodeled SAs expressed the lymphatic markers PROX1, LYVE1, and VEGFR3, mimicking lymphatic identity. Uterine natural killer (uNK) cells, which are required for SA remodeling and secrete VEGFC, were both sufficient and necessary for VEGFR3 activation in vitro and in mice lacking uNK cells, respectively. Using Flt4Chy/+ mice with kinase inactive VEGFR3 and Vegfcfl/fl Vav1-Cre mice, we demonstrated that SA remodeling required VEGFR3 signaling, and that disrupted maternal VEGFR3 signaling contributed to late-gestation fetal growth restriction. Collectively, we identified a novel instance of lymphatic mimicry by which maternal endothelial cells promote SA remodeling, furthering our understanding of the vascular heterogeneity employed for the mitigation of pregnancy complications such as fetal growth restriction and preeclampsia.