tbuckley/cabot-search huggingface dataset:
Targeting Histone Deacetylase 6 (HDAC6) as a Novel Approach to Overcome T-Cell Anergy.
Authors: Fengdong Cheng, Hongwei Wang, Karrune Woan, Jennifer Rock-Klotz, Zi Wang, Oscar Merino, Ajay Gill, Danay Marante, Lianet Vazquez, Edward Seto, Javier Pinilla-Ibarz, Eduardo M. Sotomayor, Alejandro Villagra
Journal: Blood (2010)
Abstract 2682: Melanoma phenotype switching to adapt to BRAF inhibition
Authors: Lidia Robert, Jennifer Tsoi, Angel Garcia Diaz, Blanca Homet Moreno, Nhat Truong, Thomas Graeber, Antoni Ribas
Journal: Cancer Research (2015)

Abstract Melanoma can adapt to several stress factors, such as TNF treatment, by changing its phenotype from a highly differentiated (MITF and MART-1 positive) to undifferentiated (neural crest markers) states. We studied this phenomenon as a mechanism of adaptive resistance to BRAF inhibition since melanomas with both MITF high and low have been reported to result in BRAF inhibitor resistance. We treated 17 BRAFV600E mutant melanoma cell lines with the BRAF inhibitor vemurafenib for short term (3 days) or long term (17 days), and compared them to no treatment or TNF treated conditions. We profiled them phenotypically for MART1 antigen (differentiated phenotype) and nerve growth factor receptor (NGFR, neural crest phenotype) expression by flow cytometry. Results comparing median fluorescence intensity (MFI) showed a wide spectrum of adaptive responses to short term BRAF inhibition, followed by solidification or further evolution of these changes upon long term exposure and development of drug tolerance. According to each cell line distribution, we calculated a (x,y) value that organized the cell lines and conditions in four quadrants according to MART1 (x axis) or NGFR (y axis) expression. Two double negative (MART1-/NGFR-) cell lines that were unaffected by treatment and stayed in the same quadrant. Seven MART1-/NGFR+ and four MART1+/NGFR- cell lines slightly changed phenotype with vemurafenib exposure but stayed in the same quadrant. Four cell lines with MART1+/NGFR+ phenotype were greatly influenced by treatment, showing wide plasticity with cells shifting towards NGFR+/MART1- and others towards NGFR-/MART1+. Changes in position between baseline and tolerance to vemurafenib after 17days treatment were numerically quantified as an inferred number from plasticity. Cell lines with double positive (MART1+/NGFR+) phenotype had a significant change in plasticity compared to the rest of cell lines in other quadrants (p = 0.0004). This arranges cells in a four-quadrant pattern that could be likened to a U-turn toward de-differentiation. Cells that de-differentiated with BRAF inhibition mimicked the effect induced by TNF. This effect was driven by a decrease in MITF activity confirmed with a tyrosinase promoter-luciferase assay. In conclusion, baseline melanoma differentiation phenotypes guide the phenotype switch response, with those double positive for differentiation and neural crest markers being at a semi-stable state that can be prone to different plastic changes upon BRAF inhibition. Citation Format: Lidia Robert, Jennifer Tsoi, Angel Garica Diaz, Blanca Homet Moreno, Nhat Truong, Thomas Graeber, Antoni Ribas. Melanoma phenotype switching to adapt to BRAF inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2682. doi:10.1158/1538-7445.AM2015-2682
Abstract 11806: Not Glycemic Control Using Sitagliptin But Lipid Control is Associated With Change in Coronary Atherosclerosis in Patients With Type 2 Diabetes -A Serial Integrated Backscatter Intravascular Ultrasound Study
Authors: Tsuyoshi Nozue, Kazuki Fukui, Yutaka Koyama, Hiroyuki Fujii, Tomoyuki Kunishima, Hiroyuki Hikita, Kiyoshi Hibi, Akiyoshi Miyazawa, Ichiro Michishita
Journal: Circulation (2015)

Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors have anti-atherogenic effects in an animal model. However, clinical usefulness of DPP-4 inhibitors, particularly effects of these drugs on coronary atherosclerosis has not been fully evaluated. Hypothesis: We assessed the hypothesis that sitagliptin, a DPP-4 inhibitor, has beneficial effects on coronary atherosclerosis beyond its hypoglycemic action. Methods: A prospective, open-labeled, randomized multicenter study was performed at 6 Japanese centers. Twenty-eight patients with type 2 diabetes who have undergone elective percutaneous coronary intervention (PCI) were randomly assigned to either the sitagliptin group (group S) or control group (group C). Neither DPP-4 inhibitors nor glucagon-like peptide-1 analogues have been used in group C during study period. Non- PCI lesions were evaluated by integrated backscatter (IB)-intravascular ultrasound (IVUS) at the time of PCI and at 48-week follow-up. The primary end point was percentage change in plaque volume measured using grayscale IVUS and the secondary end point was changes in plaque compositions measured using IB-IVUS. Results: Grayscale IVUS analysis demonstrated that plaque volume tended to be decreased in both groups (group S: -1.7%; group C: -3.2%), but could not reach statistically significance. In addition, percentage changes in plaque volume did not differ between the 2 groups. On IB-IVUS analysis, a significant decrease in the lipid component (group S: from 200.1 to 179.8 mm3, p=0.02; group C: from 298.3 to 256.6 mm3, p=0.1) and an increase in the calcified component (group S: from 2.1 to 3.2 mm3, p=0.06; group C: from 2.3 to 4.8 mm3, p=0.04) were observed. Univariate and multivariate regression analyses showed that sitagliptin use did not correlate with a decrease in the lipid component, whereas percentage change in serum non high-density lipoprotein cholesterol (HDL-C) was an independent and significant predictor associated with change in the lipid component (β=0.454, p=0.04). Conclusions: Sitagliptin had no effects on coronary atherosclerosis in patients with type 2 diabetes. Not glycemic control but lipid control, particularly a decrease in non-HDL-C was associated with the reduction in lipid component.
The proteasome inhibitor, bortezomib, in combination with gemcitabine (Gem) and carboplatin (Carbo) in advanced non-small cell lung cancer (NSCLC): Final results of a phase I California Cancer Consortium study
Authors: A. M. Davies, P. N. Lara, D. H. Lau, P. C. Mack, P. H. Gumerlock, D. R. Gandara, D. Schenkein, J. H. Doroshow
Journal: Journal of Clinical Oncology (2004)

7106 Background: Bortezomib (Velcade, PS-341), a dipeptidyl boronic acid, is a selective and reversible inhibitor of the 26S proteasome of the ubiquitin protein degradation pathway. Gem/Carbo is an accepted first-line treatment for advanced NSCLC. This NCI-sponsored phase I trial examined the safety and tolerability of bortezomib days 1, 4, 8, & 11; Gem days 1 & 8 and Carbo day 1 on a 21-day cycle. Methods: Three dose levels were tested with the following ranges: bortezomib 1.0 –1.3 mg/m2, Gem 800 –1000 mg/m2, Carbo AUC 5.0. Dose limiting toxicity (DLT) was defined as: grade (GR) 4 platelets (plts) (< 10K), GR3 plts (≤ 50K) with bleeding, febrile neutropenia, GR4 ANC ≥ 7 days, or any ≥ GR3 non-heme toxicity except alopecia or inadequately treated nausea, emesis, or diarrhea. Results: 16 (10 chemonaive) NSCLC patients (pts) were treated. Pt characteristics: Median age: 54; Sex M/F = 8/8; KPS ≤80/>80 = 6/10; stage IIIB/IV = 1/15. One DLT was seen at dose level 2: GR3 plts (26K) with minor hemoptysis. Two DLTs were seen at dose level 3: GR3 plts (27K) with genitourinary bleed and GR4 plts (9K) with no bleeding. Most common GR3/4 toxicities were: GR3 plts in 23/49 cycles, GR4 plts in 3/49 cycles and GR3/4 granulocytopenia in 12/49 cycles. Treatment was generally well tolerated with myelosuppression primarly being asymptomatic. In 10 evaluable pts there were 4 partial responses and 5 pts with stable disease. Conclusions: The recommended phase II doses for this regimen are: bortezomib 1.0 mg/m2, Gem 1000 mg/m2 and Carbo AUC 5. Translational Research Funding (TRF) for ongoing molecular correlates will examine ERCC1 mRNA levels in tumor and ERCC1 polymorphisms in genomic DNA. This study forms the basis for SWOG 0339 a phase II trial of this combination for the first-line treatment of advanced NSCLC. (NCI NO1-CM17101, Millennium) Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Pharmaceuticals Millennium Pharmaceuticals Millennium Pharmaceuticals Eli Lilly
Abstract 431: Active secretion of CXCL10 and CCL5 from colorectal cancer microenvironments associates with GranzymeB+ CD8+ T-cell infiltration
Authors: Timothy J. Zumwalt, C. Richard Boland, Ajay Goel
Journal: Cancer Research (2015)

Abstract T-cell infiltration varies among colorectal tumors and directly impacts patient survival. Chemoattraction and infiltration of CD8+ T-cells are mediated by surface chemokine receptors CXCR3 and CCR5, and are associated with favorable prognosis. Transcriptional expression of these receptors’ cognate chemokines, as well as other inflammation-associated chemokines, correlate with prolonged disease-free survival (DFS). These findings, however, were derived from paraffin embedded tissues, thus little is known about the pattern of secreted T-cell targeting chemokines from colorectal tumors. Therefore, this investigation aimed to determine the secretion pattern of chemokines associated with DFS from immediately excised live tumor tissues. Our results demonstrate the first real functional analysis of chemokine activity in colorectal tumors beyond immunohistochemistry and real-time PCR. Forty-four colorectal tumors were procured immediately after surgery and categorized by transcriptional expression of two T-cell marker genes that represent the magnitude of type-1 T-cell activity. Tumors that more highly co-expressed IFNG and TBX21 consequently have a higher frequency of infiltrating GzmB+ CTLs and IFN-γ+ CD4+ helper T-cells and transcribe a unique pattern of DFS-associated chemokines when compared to normal mucosa. High co-expression of IFNG and TBX21 was bimodally distributed across the tumors collected. Tumors with higher co-expression more strongly secreted two DFS-associated chemokines, CXCR3 ligand, CXCL10 and CCR5 ligand, CCL5. Additional results demonstrate that tumors with higher co-expression are proportionally skewed towards early TMN stages and with mismatch repair-deficiency, confirming that infiltration of CD8+ T-cells are associated with early TNM stages and lack of metastasis. Secreted chemokines were detected using a novel immunoassay that may have implications for future development of immunopotentiating treatments in cancer. Note: This abstract was not presented at the meeting. Citation Format: Timothy J. Zumwalt, C. Richard Boland, Ajay Goel. Active secretion of CXCL10 and CCL5 from colorectal cancer microenvironments associates with GranzymeB+ CD8+ T-cell infiltration. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 431. doi:10.1158/1538-7445.AM2015-431
Stem Cell Transplantation (SCT) Improves Survival in Acute Biphenotypic (ABL) and Acute Undifferentiated Leukemia (AUL): A Single Centre Experience.
Authors: Sujaatha Narayanan, Michael J. Barnett, Yasser R. Abou Mourad, Donna L. Forrest, Donna E. Hogge, Julye C. Lavoie, Stephen H. Nantel, John D. Shepherd, Kevin W. Song, Heather J. Sutherland, Cynthia L. Toze, Clayton A. Smith, Maryse Power, Thomas J. Nevill
Journal: Blood (2007)
Assessment of communication about palliative care between physicians and their cancer patients prior to admission to the palliative care unit (PCU).
Authors: Benjamin Storek, Sebastian Nickel, Janett Markwordt, Asita Behzadi, Peter C. Thuss-Patience, Isrid Sturm
Journal: Journal of Clinical Oncology (2013)

e20575 Background: Discussions on palliative care are particularly challenging for both cancer patients (pts) and their treating physicians. From the pts perspective, prior to their admission to the PCU, information about palliative care is often lacking and their opinions are not adequately respected. In our study, we evaluated 1) whether pts were satisfied with the received information about palliative care prior to admission to the PCU, 2) the pts level of understanding about palliative care options and 3) pts wishes for their stay at the PCU. Methods: n=180 from n=273 pts participated in the study (time period: 12 months). A standardized palliative care assessment was performed on the day of admission. Study interview was performed within 48h after admission; the questionnaire contained free response and multiple-choice questions. Analysis: Likert scaling method with descriptive statistics using SPSS. Results: Baseline characteristics: n=92 male, n=88 female, median age 64 (range 26-89), 53% with an ECOG 3, n=25 hematological and n=155 oncological malignancies. Symptoms: 56% had 8-14 physical symptoms, 36% had 3-4 emotional problems, 38% had high levels of distress. Prior knowledge about palliative care: 38% did not know what a PCU was and 31% believed it was a unit for dying patients. 44% received none, 26% some information about palliative care prior admission. 42% did not feel well informed, 34% felt they received some information on palliative care. Prior information about the disease: 27% felt minimally, 64% felt well informed about their current disease state. The following points were not addressed from the physicians: living will 57%, health care proxy 59%, home care supply 70%, hospice 70%, psychooncological care 52%, prognosis 43%. Wishes of pts on the PCU: improvement in their general condition 47%, pain relief 30%. Conclusions: Our study shows that the majority of pts do not feel sufficiently informed about palliative care prior to the admission at the PCU. A communication barrier between physicians and their pts may explain patient’s views. The data confirm the importance of early integration of palliative care in addition to oncological care.
337. Transient Ultrasound-Mediated Microbubble-Assisted Modulation of Blood-Brain Interface in Adult Common Marmoset to Improve rAAV-Mediated Brain Transduction
Authors: Hironori Okada, Hidetoshi Ishibashi, Chiaki Masuda, Hiromi Hayashita-Kinoh, Tomoko Chiyo, Yuko Nitahara-Kasahara, Yoko Endo-Takahashi, Koichi Kato, Yoichi Negishi, Shin'ichi Takeda, Takashi Okada
Journal: Molecular Therapy (2016)

Background: Non-human primates (NHPs) could provide an appropriate model for neuromuscular diseases because of its cognitive function and physiological resemblance to human. Production of transgenic and knockout NHPs from preimplantation embryos by using genomic modification were reported. However, several decades would be required for establishing homozygous and/or phenotypically stable progenies and for developing the symptoms in case of late onset diseases. In contrast, induction of pathology with recombinant adeno-associated virus (rAAV) has potential to break through this situation, because it is possible to realize with the existing aged animals. In this context, fully maturated blood-brain interface (BBI) significantly limits passive rAAV transport from circulation to the brain. To overcome this issue, we investigated BBI opening as a promising technology to make cerebral capillary open transiently by resonance of i.v. injected microbubble (MB) locally excited with ultrasound irradiation (UI). Methods: Evans blue (EB) and aminoisobutyric acid (AIB) were used for a tracer that has high affinity for serum albumin (ALB). MB and EB were i.v. injected as bolus into the femoral vein of the anesthetized adult marmosets. Transcranial (TC) UI to the brain was performed for 5 minutes, and the brain was examined one day after the UI. To verify the leakage, cryosections were immunostained against ALB and CD31. For live imaging analysis, MB, carbon 11-labeled AIB, and rAAV1 were i.v. injected into the tail vein. Subsequently, TCUI and PET scan were performed. At two days after TCUI, rAAV1 with distinguishable another vector genome was i.v. injected again. At one week after TCUI, the brain was sampled, and pieced into various parts. Then relative rAAV genome copies were measured by qPCR. Results: Macroscopically, ALB leakage was recognized in temporal cortex and hippocampus when TCUI was performed towards the temporal region. When TCUI was performed towards all direction, it was found in whole brain except for white matter. Microscopically, the blood vessels of 10-50 µm in diameter especially in the hippocampus were sensitive to BBI opening. From live image, leakage in the hippocampus, anterior cingulate cortex, basal ganglia, optic tract, amygdala, and superior temporal gyrus started just after TCUI. Lower genome copies of the secondary injected rAAV1 at two days after TCUI revealed that the BBI opening was transient. Conclusion: UI-mediated MB-assisted TC-BBI opening is a promising approach to generate the disease model based on adult common marmoset.
BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas
Authors: Noémie Leblay, Frédéric Leprêtre, Nolwenn Le Stang, Amandine Gautier-Stein, Laurent Villeneuve, Sylvie Isaac, Denis Maillet, Françoise Galateau-Sallé, Céline Villenet, Shéhérazade Sebda, Alexandra Goracci, Graham Byrnes, James D McKay, Martin Figeac, Olivier Glehen, François-Noël Gilly, Matthieu Foll, Lynnette Fernandez-Cuesta, Marie Brevet
Journal: Journal of Thoracic Oncology (2016)
Abstract 4153: Investigating the role of Fn14 in EGFRvIII-driven glioblastoma
Authors: Alison Roos, Zachary Mayo, Michael Pineda, Jeffery A. Winkles, Michael E. Berens, Nhan L. Tran
Journal: Cancer Research (2015)

Abstract Glioblastoma Multiforme (GBM) is the most common malignant brain tumor in adults. Most GBM patients succumb to the disease less than one-year post diagnosis due to the highly invasive nature of the tumor, which prevents complete surgical resection and gives rise to tumor recurrence. The invasive phenotype also confers radio-and chemoresistant properties to the tumor cells; therefore, there is a need to develop new therapeutics that target drivers of GBM invasion. Amplification of EGFR is observed in over 50% of GBM tumors, of which half concurrently overexpress the variant EGFRvIII, and expression of both receptors confers a worse prognosis. EGFR and EGFRvIII cooperate to promote tumor progression and invasion, in part, through activation of the JAK/STAT-signaling pathway. Here we report that GBM cells expressing EGFRvIII show increased expression of a previously established mediator of glioma cell invasion and survival, fibroblast growth factor-inducible 14 (Fn14), at the mRNA and protein level. Treatment with a STAT3, STAT5, or JAK inhibitor decreased Fn14 mRNA and protein expression. Finally, knockdown of Fn14 levels in the EGFRvIII-expressing glioma cells decreased both cell survival after temozolomide (TMZ) treatment and cell invasion, which suggests that Fn14, in part, mediates the oncogenic phenotypes conferred by EGFRvIII signaling. Since EGFR inhibitors display limited therapeutic efficacy in GBM patients, we hypothesize that Fn14-targeted therapies could potentially limit invasiveness and chemoresistance in these tumor subtypes. Citation Format: Alison Roos, Zachary Mayo, Michael Pineda, Jeffery A. Winkles, Michael E. Berens, Nhan L. Tran. Investigating the role of Fn14 in EGFRvIII-driven glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4153. doi:10.1158/1538-7445.AM2015-4153
Plasma Circulating Levels of Soluble P-Selectin and Thrombospondin-1 (TSP1) Are Elevated in Patients with Cancer and a Shortened Activated Partial Thromboplastin Time (APTT) without Clinical Evidence of Thrombosis: An Inexpensive and Simple Test (APTT) To Be Considered for Its Clinical Value.
Authors: Fabiola E. Del Carpio-Cano, Diana Zamora-Rangel, Miguel A. Rosales-Manoatl, Maria R. Rivas-Gonzalez, Eduardo Cervera-Ceballos, Raul A. De La Cadena
Journal: Blood (2006)
Three-dimensional evaluation of subclinical extension of extramammary Paget disease: visualization of the histological border and its comparison to the clinical border
Authors: T. Murata, T. Honda, G. Egawa, A. Kitoh, T. Dainichi, A. Otsuka, S. Nakajima, S. Kore-eda, Y. Kaku, S. Nakamizo, Y. Endo, A. Fujisawa, Y. Miyachi, K. Kabashima
Journal: British Journal of Dermatology (2016)

In extramammary Paget disease (EMPD), Paget cells are sometimes detected outside the clinical border (subclinical extension). However, the spreading pattern of Paget cells in subclinical extension remains unclear. In addition, the macroscopic appearances of lesions accompanied by subclinical extension are totally unknown.To characterize the spreading pattern of Paget cells as well as the macroscopic appearance of lesions of EMPD with subclinical extension.Nineteen patients with primary anogenital EMPD underwent mapping biopsies and excisional surgeries; biopsy samples were then taken at the periphery of well-demarcated lesions. Samples were transparentized and subjected to whole-mount immunostaining with anticytokeratin 7 antibody to label Paget cells. The histological border was evaluated in three dimensions by two-photon microscopy. The shape and location of the histological border were compared with those of the clinical border.In 21 samples taken at the lesion where subclinical extension was not shown by mapping biopsy, the shape and location of the histological border were almost identical to those of the clinical border. However, two samples exhibited small foci of Paget cells outside the clinical border, showing subclinically extended satellite lesions. In the two samples taken at the lesions where subclinical extension was shown by mapping biopsy, a continuous arrangement of Paget cells extending beyond the clinical border was identified. Subclinically extended Paget cells were detected solely outside hypopigmented patches with erythema.In EMPD, at least two patterns of subclinical extension exist: continuous and satellite lesions. Subclinical extension might exist preferentially outside hypopigmented patches with erythema.
Methylation of ESR1 and Tumour Suppressor Genes Together Constitute an Independent Outcome Predictor in Acute Myeloid Leukemia.
Authors: Corine J. Hess, Johannes Berkhof, Fedor Denkers, Gert J. Ossenkoppele, Gerrit Jan Schuurhuis, Quinten Waisfisz
Journal: Blood (2006)