tbuckley/cabot-search huggingface dataset:
Abstract CT126: Single arm study of neoadjuvant chemotherapy without taxane for BRCAness cases in triple-negative breast cancer
Authors: Takashi Ishikawa, Saeko Teraoka, Hiroshi Kaise, Kimito Yamada, Mari Hosonaga, Ai Ueda, Yoko Kawai, Miki Okazaki, Mari S. Oba, Eiichi Sato
Journal: Cancer Research (2016)

Abstract BACKGROUND: BRCA1 impaired cancers are sensitive to DNA damage. This is associated with the defective homologous recombination (HR) pathway in these tumors. In contrast, these tumors are resistant to mitotic poisons, because BRCA1 protein activates the mitotic spindle checkpoint and triggers apoptosis in microtubule damage. Both preclinical evidence and clinical evidence have shown that the single-agent taxane is not active for BRCA1 mutated breast cancers. It is reported that BRCA1 function may be impaired in approximately 60% of triple negative breast cancer (TNBC) without mutation. This is called ‘BRCAness’. Previous studies have demonstrated that BRCAness identified tumors with HR deficiency. Thus, taxane may not be necessary for all TNBC cases, although combined treatments of anthracycline and taxane are standard at present. STUDY PROTOCOL: We have launched a single arm study of neoadjuvant chemotherapy (NAC) for TNBC to confirm that taxane is unnecessary in BRCAness cases. For the study protocol, TNBC cases requiring NAC are enrolled. Four cycles of an anthracycline-based regimen (FEC 100 or dose-dense EC) are started and BRCAness is examined simultaneously in core-needle specimens. BRCAness is determined by Multiple Ligation-dependent Probe Amplification (MLPA) methods (FALCO Biosystems), which consist of 2 steps. These include copy number analysis in 34 loci specific to BRCA1 mutant and scoring with prediction analysis for microarray. If BRCAness is determined by MLPA, surgery is performed without proceeding to taxane. The primary endpoint is a pathological complete response (pCR) in surgical specimens. The expected pCR and threshold pCR are estimated at 55% and 40%, respectively, based on our previous randomized phase II trial comparing docetaxel plus cyclophosphamide with epirubicin plus cyclophosphamide followed by docetaxel for hormone receptor-negative breast cancer (Ishikawa T. ASCO 2013). With a one-sided significance of 5%, 70 BRCA cases are required. This study was approved in September 2015 and has been started. Interim analysis is planned when 30 cases are completed. Citation Format: Takashi Ishikawa, Saeko Teraoka, Hiroshi Kaise, Kimito Yamada, Mari Hosonaga, Ai Ueda, Yoko Kawai, Miki Okazaki, Mari S. Oba, Eiichi Sato. Single arm study of neoadjuvant chemotherapy without taxane for BRCAness cases in triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT126.
Abstract 355: HT flow cytometry platform enabling measurement of immune signaling in whole blood and T-cells for drug discovery
Authors: mark fereshteh, Litao Zhang, Xin Li, Sha Li, Yi Fan, Gary Schieven
Journal: Cancer Research (2016)

Abstract Oral agents targeting Janus-associated kinases (JAKs) are among the most promising new agents in clinical development. To better understand the relationship between JAK inhibition and clinical outcome, compounds targeting JAKs are required to be analyzed in peripheral whole blood. To date, this type of analysis has been low throughput and is associated with high cost. Here, we developed a robust 384-well flow based assay approach to screen small molecules for inhibition of JAK/STAT signaling in whole blood using high-throughput flow cytometry. The platform provides a highly sensitive analysis of signaling events in low volumes of blood facilitating a robust target engagement assay to measure inhibition of proximal signaling by selective JAK inhibitors. Further, automation technologies and processes optimization were established to overcome bottlenecks in sample integrity, handling and multiparametric data analysis without affecting assay performance. The result was dramatically increased sample throughput when compared to conventional manual flow cytometric approaches enabling the identification of novel selective JAK/STAT inhibitors enabling the investigation of IO and Immunology targets earlier in drug discovery. Citation Format: mark fereshteh, Litao Zhang, Xin Li, Sha Li, Yi Fan, Gary Schieven. HT flow cytometry platform enabling measurement of immune signaling in whole blood and T-cells for drug discovery. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 355.
Abstract 4586: FGFR2 amplification in serous ovarian cancer
Authors: Alexandra Tyulyandina, Ilya Tsimafeyeu, Irina Demidova, Marina Gikalo, Sergei Tjulandin
Journal: Cancer Research (2016)

Abstract Fibroblast growth factor receptor (FGFR) signaling pathway plays an important role in biology of cancer. Approximately 7% of ovarian cancer (OC) exhibits FGFR1 amplification. Recently the overexpression of FGFR2 was found in 95% of clear cell OC. Up to date there is no data about FGFR2 status in OC. 54 paraffin-embedded blocks from 18 patients with serous OC were analyzed by FISH to identify FGFR2 amplification. Scoring for amplification and polysomy level was adopted from previous studies for gastric cancer (Su X, et al. BJC 2014). Material from each patient had 3 samples: from primary tumor, from primary metastatic lesions, and from relapse. Intratumoral FGFR2 amplification heterogeneity was assessed in sections from all cases with FGFR2 amplification, and was defined as the presence of areas with different FISH scores within the same tumor in full sections. Amplification was observed in 3 patients (15.7%). Interestingly, in one case amplification was observed in primary ovarian tumor but not in the metastatic nor in relapse samples. In two other cases the FGFR2 amplification was detected in relapse samples and in primary metastatic samples but not in ovary. High-level polysomy (HLP) was observed in 10 patients (55.5%). In all of those patients HLP was revealed in the samples of relapse. In 3 patients HLP was found in all 3 samples, in 3 cases HLP was observed only after relapse, in 4 cases HLP in metastasis sample was the same as in relapse sample, but it wasn't observed in ovary samples. Eight of 13 FGFR2 amplified ovarian cancers or tumors with HLP (61.5%) displayed intratumoral heterogeneity within full sections. In 5 (27.8%) cases neither amplification nor high level polysomy was observed. In conclusion, this is the first study of FGFR2 FISH in serous ovarian adenocarcinoma, demonstrating a FGFR2 amplification and HLP in primary tumor, primary metastases and relapse. Furthermore, we found evidence for intratumoral heterogeneity of FGFR2 amplification and HLP in about 61.5% of ovarian cancers. This study was supported by grant from the “Oncoprogress Foundation”. FGFR2 amplification and high-level polysomy in patients with serous cancer (13 patients)N (%), patientsPrimary tumor (N samples)Primary metastasis (N samples)Relapse (N samples)Amplification3 (15.7%)122High level polysomy10 (55.5%)3410 Citation Format: Alexandra Tyulyandina, Ilya Tsimafeyeu, Irina Demidova, Marina Gikalo, Sergei Tjulandin. FGFR2 amplification in serous ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4586.
OC-095 A clinical overview of the presentation and management of orofacial granulomatosis in a combined oral medicine and gastroenterology clinic
Authors: H E Campbell, P Patel, C Nunes, M Escudier, T Elliott, T Poate, R J Cook, M C E Lomer, J Brostoff, S J Challacombe, J D Sanderson
Journal: Gut (2010)

<h3>Introduction</h3> Orofacial granulomatosis (OFG) is a rare chronic inflammatory disease of unknown aetiology sharing histological features with gut Crohn9s disease (CD). A notes review of 207 patients with OFG aimed to define the common presentation of this condition and establish differentiating features between those with and without concurrent diagnosis of CD. <h3>Methods</h3> Data were extracted for age of onset, gender, clinical features, blood parameters, concurrent CD and treatments used. Diagnosis of CD was established by standard criteria. <h3>Results</h3> Ninety-seven out of 207 patients (47%) were female. Median age of disease onset was 23 years (range 2–73 years). Referrals were mainly sourced from maxillo-facial surgeons (31%) and gastroenterologists (19%). The buccal mucosa (74%) and lower lip (68%) were the most common sites involved followed by gingivae (63.5%) and upper lip (61%). Forty-six (22%) had CD. Ulcers (46% vs 15%, p&lt;0.001) and mucosal scarring (20% vs 5%, p&lt;0.001) were more common in patients with CD than in those without as was a raised C reactive protein (73% vs 49%, p=0.016), abnormal full blood counts (46% vs 23%) and low haemoglobin (31% vs 11%). The sulcus (27% vs 13%, p=0.019) and fauces (4% vs 0%, p=0.008) were significantly more likely to be affected in those with CD. Of the patients with concurrent CD, half were diagnosed with this prior to onset of OFG symptoms. Conversely 42.5% had OFG symptoms prior to diagnosis of CD. The remaining patients (7.5%) presented with symptoms and were diagnosed with CD within the same year. The predominant treatment used (86%) was the cinnamon and benzoate free diet. Topical treatments including antifungal and steroidal creams, ointments, mouthwashes and intralesional steroid injections were used in 64% of cases. Azathioprine was used in 39% of patients and anti TNF α therapy in 7.5% of patients. Only 3% of patients required cheiloplasty. <h3>Conclusion</h3> OFG most commonly presents with buccal and lower lip involvement. Abnormalities in inflammatory markers, haematinic deficiencies and oral presentation of ulceration and scarring are all factors which can increase the likelihood of concurrent CD. Initial presentation of OFG is not necessarily predictive of further development of CD.
Abstract 1090: microRNA regulation of Nrf2 and the antioxidant response in breast cancer cells following redox therapy
Authors: Francesca Mascia, Kaytee L. Pokrzywinski, V. Ashutosh Rao.
Journal: Cancer Research (2016)

Abstract Mitoquinone (MitoQ), a redox-active mitochondrially targeted chemotherapy, activates autophagy through the production of reactive oxygen species (ROS) in breast cancer cells. Studies have also shown a concomitant activation of Nrf2 and the antioxidant response with MitoQ treatment. Nrf2 (nuclear factor (erythroid-derived 2)-like 2) is a transcription factor that regulates the antioxidant response element. Drugs that stimulate Nrf2 are ideal for the treatment of diseases induced by oxidative stress; however, over-activation of Nrf2 may promote tumor growth and diminish the effects of redox active chemotherapies. Therefore, understanding the relationship between autophagy and oxidative stress is crucial for determining the fate of cancer cells exposed to redox-active oncology agents. The aim of this study was to evaluate microRNA (miRNA) as a link between oxidative stress and autophagy through modulation of Nrf2 activity. microRNA are endogenous small (18-22 base pairs long) double stranded RNA that bind to the 3’ UTR of target mRNA. miRNA function through translational repression via mRNA recycling and degradation. To this aim we set out on finding miRNA that suppress the antioxidant response, modulated by Nrf2, in cancer cells after redox therapy with the goal of inducing a death response. After 24 hours of non-target pool or Nrf2 silencing, using small interfering RNAs, MDA-MB-231 cells were treated with DMSO or MitoQ for 18 hours. RNA was extracted and miRNAs were identified using Illumina RNA sequencing. DEseq revealed 97 miRNAs that were differentially expressed at α &amp;lt; 0.05. Biologically significant miRNAs were then distinguished by using a Log2 fold change cut off of -1.0 &amp;lt; and &amp;lt; 1.0, which identified 39 microRNAs. Since miRNA should be high when their target is low we were predominantly interested in the 15 miRNAs that were down-regulated (DMSO:MitoQ). 7 of the 15 down-regulated miRNAs were also down-regulated in the presence of Nrf2 silencing in both the DMSO and MitoQ treatments. We are currently investigating these 7 miRNAs in terms of the specific effect they have on the Nrf2 pathway during redox therapy. Citation Format: Francesca Mascia, Kaytee L. Pokrzywinski, V. Ashutosh Rao. microRNA regulation of Nrf2 and the antioxidant response in breast cancer cells following redox therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1090.
Care coordination for patients with chronic conditions did not reduce hospitalizations or Medicare costs
Authors: Tim Reynolds
Journal: Annals of Internal Medicine (2009)

Source Citation Peikes D, Chen A, Schore J, Brown R. Effects of care coordination on hospitalization, quality of care, and health care expenditures among Medicare beneficiaries: 15 randomized trials. JAMA. 2009;301:603−18. 19211468
Subclassification and outcome prediction of patients with muscle invasive urothelial carcinoma (MIUC) treated by radical cystectomy (RC) with a NanoString based molecular screening.
Authors: Sebastien Ly Rinaldetti, Thomas Worst, Annette Steidler, Cleo-Aron Weis, Arndt Hartmann, Christian Bolenz, Philipp Erben
Journal: Journal of Clinical Oncology (2016)

4525 Background: Transcriptome expression studies identified distinct bladder cancer subtypes of prognostic relevance and closely related with breast cancer molecular subclasses. Here we developed a molecular subtype-screening in a chemotherapy naive patient cohort with MIUC. Methods: FFPE samples of MIUC (pT2-T4, G2-3, exclusion of squamous carcinoma) were collected from a cohort of 47 patients (collection period from 1998-2012) treated exclusively with RC and bilateral lymphadenectomy. 80 genes were selected using two approaches. First, genes were selected from the prognostic gene signatures published previously (basal, luminal & p53-like). Second, we reanalyzed published microarray data with gene set enrichment analysis. Gene expression was measured with the NanoString nCounter technology after RNA extraction with a bead based system (Stratifyer). Results: Unsupervised hierarchical clustering separated the tumors into 3 clusters (Pearson coefficient > 0,75): basal, luminal and infiltrated. These subtypes present a distinct OS and DSS, over a follow-up period up to 12 years. The luminal subtype revealed an aggressive phenotype such as an OS of 24 months (p = 0,002) and a DSS of 38 months (p = 0,017). In contrast the infiltrated subtype showed best outcome (OS: 93 mo, DSS: 128 mo) whereas basal patients formed an intermediate risk group (OS: 87 mo, DSS: 108 mo). In silico validation of our gene panel with two recent microarray studies (GSE48276, GSE13507) confirmed the prognostic outcomes for MIUC. Our study confirms a highly subtype specific expression of drug targets. Genes like ERBB2 (HER2neu), ERBB3 and the FGFR gene family are exclusively expressed in the luminal subtype (p < 0,003) whereas EGFR is higher in the basal subtype (p = 0,031). Conclusions: This nCounter based molecular screening allows a risk stratification and survival prediction based on three main subtypes: basal, luminal and infiltrated. As the expression of drug targets is highly subtype specific, this molecular subclassification is needed in future clinical studies in order to underline its translational benefit by means of personalized therapy.
Human Mesenchymal Stem Cells Differentiate Promptly into Tissue-Specific Cell Types without Cell Fusion, Mitochondrial or Membrane Vesicular Transfer in Fetal Sheep.
Authors: Evan J. Colletti, Judith A. Airey, Esmail D. Zanjani, Christopher D. Porada, Graça Almeida-Porada
Journal: Blood (2007)
Cellular immunotherapy for refractory hematological malignancies.
Authors: John Leonard Reagan, Loren D. Fast, Kalyan Mantripragada, Martha Nevola, Kayla Rosati, Andrew Schumacher, Howard Safran, Matthew Isaac Quesenberry, Eric S. Winer, James N. Butera, Peter J. Quesenberry
Journal: Journal of Clinical Oncology (2015)

7039 Background: Allogeneic cellular infusion is a potent immune stimulus. We present data from our FDA approved IND Phase II clinical trial (BrUOG 273) where allogeneic haploidentical lymphocytes are infused without prior chemotherapy or radiation to create a rejection response that hypothetically breaks host tumor tolerance. Methods: Eligible patients have relapsed or refractory acute leukemia. HLA haplo donors undergo leukapheresis without G-CSF priming. 1-2x108CD3+ cells/kg were infused unprocessed immediately after collection. Peripheral blood collected 1-4, 8-24, 34-48, 72-96 and 168-192 hours post infusion were examined for effector cell populations, stimulatory/inhibitory signals, and cytokine release profiles. Wilcoxon rank sum tests were used for statistical analysis. Results: Five patients were infused haplo donor cells. Four developed hyperpyrexia post infusion that lasted 24-48 hours (median T 0-4 hours post infusion 98°F, median Tmax 8-192 hours post infusion 102.4°F, p = 0.009). Host CD8 T cells demonstrated decreased perforin expression post compared to pre-infusion (median pre 77.6%, median post 61%, p = 0.03) with no changes in granzyme A/B, LAMP1, or FasL expression. Rapid up-regulation of PD-1 on host CD8 T cells (median pre 5.6, median post 49.7, p = 0.005) was present. Non-statistically significant upregulation of PD-1 ligands occurred on leukemic blasts from 0-4 to 34-48 hours post infusion. Cytokine release profiles post infusion showed high IL-10 (median 86pg/mL) with low IFNg (median < 1pg/mL) and IL-6 (median 7.47pg/mL) levels. One of five patients demonstrated a decrease in marrow blast counts post therapy (43% pre to 21% 4 weeks post infusion). No dose limiting toxicities or durable chimerism was seen. Conclusions: Haplo cellular infusions are well tolerated and show biological activity in relapsed AML. One of five patients had a reduction in marrow blasts with haplo infusion alone. Host CD8 T cells were less activated post infusion compared to pre-infusion and increased inhibitory PD-1 expression post infusion. Cytokine release profiles were more anti-inflammatory than those previously described. Greater initial CD8 T cell activation +/- immune checkpoint inhibitory blockade may improve efficacy. Clinical trial information: NCT01685606.
Abstract 79: Andrographolide alters genes associated with DNA repair in prostate cancer
Authors: Ingrid Forestier-Román, María Sánchez-Vázquez, Krizia Rohena-Rivera, Carmen Cadilla, Magaly Martínez-Ferrer
Journal: Cancer Research (2016)

Abstract Prostate cancer is the most frequently diagnosed non-cutaneous cancer and the second cause of cancer-related deaths in American men. Andrographolide, a labdane diterpenoid that is a component of the medicinal plant Andrographis paniculata, has been reported to have a wide range of biological activities including anticarcinogenic properties. In previous studies, we found that Andrographolide inhibits cell growth, tumor growth and angiogenesis in prostate cancer. Therefore, the objective of this study is to determine the mechanism of action of Andrographolide in prostate cancer. In order to determine the mechanism of action, we did gene expression profile to compare genes differentially expressed in tumors treated with Andrographolide (10 mg/kg and 25 mg/kg) and their vehicle. Tumors were developed using a xenograft model in which the prostates of SCID mice were injected with 22RV1, and mice were treated bi-weekly with Andrographolide (10 mg/kg and 25 mg/kg). Tumor tissues were collected and snap frozen. Gene expression was analyzed using the Affymetrix GeneChip® Human Gene 2.0 array. Microarray studies showed a total of 674 genes differentially expressed in tumors treated with Andrographolide (10 mg/kg) when compared to their vehicle. In addition, 218 genes were differentially expressed in tumors treated with Andrographolide (25 mg/kg) when compared to their vehicle. Genes involved in cellular processes such as cell cycle, DNA damage response, MAPK signaling, TCA cycle, glycolysis and metabolism of amino acids were differentially expressed. Ingenuity Pathway Analysis (IPA) revealed networks associated to DNA replication, recombination and repair, and post-translational modification in tumors treated with Andrographolide (10 mg/kg). Moreover, IPA revealed networks associated to cell death and survival, cellular function and maintenance, and carbohydrate metabolism in tumors treated with Andrographolide (25 mg/kg). The microarray results were confirmed by quantitative real-time PCR. Our results demonstrated that Andrographolide altered the expression of genes associated with DNA repair which could be a possible mechanism of action of its anticarcinogenic effect. Citation Format: Ingrid Forestier-Román, María Sánchez-Vázquez, Krizia Rohena-Rivera, Carmen Cadilla, Magaly Martínez-Ferrer. Andrographolide alters genes associated with DNA repair in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 79.
Targeting the angio-proteostasis network: Combining the forces against cancer
Authors: Lindsey Devisscher, Margherita Vieri, Susan E. Logue, Jens Panse, Anja Geerts, Hans van Vlierberghe, Eric Chevet, Adrienne M. Gorman, Afshin Samali, Behzad Kharabi Masouleh
Journal: Pharmacology & Therapeutics (2016)