tbuckley/cabot-search huggingface dataset:
Bevacizumab (Bv) single-agent maintenance following Bv-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC): Results from an exploratory analysis of the AVAiL study
Authors: J. Mezger, J. von Pawel, M. Reck
Journal: Journal of Clinical Oncology (2009)

e19001 Background: The significant survival benefits observed with Bv plus chemotherapy in pivotal NSCLC trials were generated using treatment to progression. Given that little data on the use of single-agent Bv as maintenance therapy are currently available, we report here the results of an analysis focused on the maintenance phase of the AVAiL study. Methods: AVAiL, a randomized, international, placebo-controlled phase III trial, evaluated Bv plus cisplatin-gemcitabine (CG) in pts with previously untreated advanced, non-squamous NSCLC, with performance status 0/1. 1,043 pts (age 20–83) were randomized to C 80mg/m 2 and G 1,250mg/m 2 q3w for up to 6 cycles plus either Bv 7.5mg/kg q3w (Bv 7.5; n=345), Bv 15mg/kg q3w (Bv 15; n=351) or placebo (Pl; n=347). Bv/Pl was administered until disease progression. This retrospective analysis focused on progression-free survival (PFS) and overall survival (OS) of the 376 patients who received blinded Bv (n=174 and n=162 for Bv 7.5 and 15) or Pl monotherapy (n=41) after completing 6 cycles of CG + Bv or CG + Pl (as specified in the protocol; most patients received 6 cycles). PFS was measured from last day of last cycle of CG + Bv/Pl to disease progression or death. Results: In the overall population, Bv reduced the risk of progression or death by 25% vs Pl (PFS primary endpoint (HR=0.75 [0.64–0.87] and 0.85 [0.73–1] for Bv 7.5 and Bv 15, respectively). When analyzing the outcome of the post chemotherapy maintenance phase, the use of Bv as single agent yielded median PFS of 3.2 months (95%CI [3–5]) for Pl, 4.6 months (95%CI [4–6]) for Bv 7.5 and 4.6 months (95%CI [4–5]) for Bv 15.The OS results for this maintenance analysis are consistent with those from the overall population in which the PFS findings were not associated with an OS benefit. Conclusions: This post-hoc analysis, focused on the maintenance phase of AVAiL, suggests that Bv used as single-agent maintenance therapy appears to confer clinical benefit beyond the chemotherapy phase. This finding warrants further exploration in future studies. [Table: see text]
Phenotypic, Functional and Circadian Characterization of Peripheral Blood (PB) Multiple Myeloma (MM) Circulating Tumor Cells (CTCs)
Authors: Bruno Paiva, Teresa Paíno, Mercedes Garayoa, Laura San-Segundo, Montserrat Martin, Maria Luz Sanchez, Paloma Barcena, Luis Corchete, Enrique M Ocio, Maria Victoria Mateos, María-Belén Vidriales, Alberto Orfao, Jesus F. San Miguel
Journal: Blood (2012)
Abstract 2409: Ultrasensitive detection of genomic alterations in cell-free DNA by Droplet Digital PCR
Authors: Nga Wan Rachel Tam, Teiko Sumiyoshi, Rajesh Patel, Sundari Sarma, Astrid Kiermaier, Rajiv Raja
Journal: Cancer Research (2015)

Abstract As cancer cells die, they release small pieces of DNA into the bloodstream. These molecules of DNA are called circulating tumor DNA (ctDNA). ctDNA carry somatic aberrations that are found in the originating tumor tissue and can serve as excellent biomarkers. They can be extremely valuable as tools for disease monitoring, and samples for predictive and prognostic biomarkers. However, limited quality and quantity of formalin-fixed paraffin-embedded (FFPE) tissues and circulating cell-free DNA (cfDNA) samples available from patients pose a big challenge to performing DNA quantification, mutation profiling and copy number variation analysis. We explored the feasibility of using Droplet Digital PCR (ddPCR) technology to address this challenge. Using ddPCR, we studied the ability to perform high-sensitivity mutation analysis and accurate quantification of allele frequencies, and compared this approach to alternate methods such as next-generation sequencing (NGS). For mutation profiling, we examined a total of 22 mutation detection ddPCR assays across 7 oncogenes - KRAS, PIK3CA, EGFR, BRAF, NRAS, cKIT and AKT1. The assay sensitivity for the majority of mutation detection assays was found to be approximately 0.03%. We have identified/reconfirmed various mutations using matching FFPE/plasma samples from patients in various cancer types. Moreover, we have adapted the previously published HER2 CNV ddPCR assay to detect HER2 copy number variation in cfDNA. We will present data showing validation of this platform using commercially available DNA control, archival FFPE tissue and cfDNA samples and demonstrate improved sensitivity and specificity. The platform is being routinely used in our labs to analyze samples from multiple clinical trials. These efforts enable the development of a non-invasive method to overcome existing challenges to provide molecular understanding of patient's tumor evolution, and aid in the development of personalized therapies for cancer patients. Citation Format: Nga Wan Rachel Tam, Teiko Sumiyoshi, Rajesh Patel, Sundari Sarma, Astrid Kiermaier, Rajiv Raja. Ultrasensitive detection of genomic alterations in cell-free DNA by Droplet Digital PCR. [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 2409. doi:10.1158/1538-7445.AM2015-2409
Sphingosomal Vincristine in CHOP +/− Rituximab Is a Promising New Treatment for Patients with High Risk Untreated Aggressive Non-Hodgkin’s Lymphoma (NHL): Follow-Up Results of a Phase II Study Sphingosomal Vincristine in CHOP +/− Rituximab Is a Promising New Treatment for Patients with High Risk Untreated Aggressive Non-Hodgkin’s Lymphoma (NHL): Follow-Up Results of a Phase II Study.
Authors: Maria Alma Rodriguez, Andreas Sarris, Nam H. Dang, Luis Fayad, Andre Goy, Fredrick Hagemeister, Peter McLaughlin, Barbara Pro, Jorge Romaguera, Felipe Samaniego, Anas Younes, Fernando Cabanillas
Journal: Blood (2004)
Proteomic Analysis Identifies Differences in Multiple Myeloma (MM) Cells Sensitive and Resistant to AKT Inhibition.
Authors: Alissa Huston, Alexey Leontovich, Michael Timm, Yazan Alsayed, Ujjal Singha, Lanie Francis, Ganwei Lu, Judy Anderson, Suzanne Lentzsch, Irene Ghobrial
Journal: Blood (2005)
The JAK2 V617F Mutation Identifies Specific Subgroups of Myelodysplastic Syndrome (MDS).
Authors: M. Mansour Ceesay, Nicholas Lea, Wendy C. Ingram, Jose Cervera, Ulrich Germing, Pierre Fenaux, Bruno Cassinat, Jean-Jacques Kiladjian, Judith Varkonyi, Petar Antunovic, Nigel B. Westwood, Matthew J. Arno, Azim Mohamedali, Joop Gaken, Natalie Twine, Norbert Gattermann, Aristotoles Giagounidis, Zaida Garcia-Casado, Guillermo Sanz, Ghulam J. Mufti
Journal: Blood (2006)
Abstract LB-291: microRNA regulation of Nrf2: A link between autophagy and oxidative stress
Authors: Kaytee L. Pokrzywinski, V. Ashutosh Rao
Journal: Cancer Research (2015)

Abstract Understanding the relationship between autophagy and excessive oxidative stress is crucial for determining the fate of cancer cells exposed to redox-active chemotherapeutic agents. Previous studies have shown that Mitoquinone (MitoQ), a redox active, mitochondrialy targeted ubiquinone derivative, can induce autophagy through the generation of excess reactive oxygen species and stimulate the antioxidant response involving nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in breast cancer cells. Nrf2 is a transcription factor that is up-regulated during oxidative stress and activates the antioxidant response element, which in turn regulates antioxidant expression. The aim of this study was to evaluate microRNA (miRNA) as a link between oxidative stress and autophagy through modulation of Nrf2 activity. miRNA are endogenous 18-22 bp double stranded RNA that become active when bound to the 3′ UTR of target messenger RNA (mRNA). The primary goal was to suppress Nrf2 activity with miRNA so that oxidative stress, in the absence of antioxidants, can result in apoptosis rather than autophagy. miRNA expression was evaluated using Illumina RNA sequencing analyses in MDA-MB-231 human breast cancer cells after treatment with DMSO or MitoQ (5 μM), in the presence and absence of Nrf2 silencing RNA (siRNA). Preliminary results show that Nrf2 is the most active at or before 18hrs of treatment (tested up to 72hrs) accompanied by a significant increase in nuclear Nrf2 levels. We are currently evaluating the transcriptome to identify key miRNAs that were up-regulated during Nrf2 suppression and down-regulated during Nrf2 activation. Nrf2 activity was also assessed using a stably transfected GFP modified MDA-MB-231 cell line containing the 3′ UTR region of Nrf2. Prior to obtaining the transcriptome, preliminary Nrf2-miRNA tests were performed with miR-93 as this miRNA has been shown to regulate Nrf2 expression in other studies on human breast cancer cell lines. We are currently assessing the effect of miR-93 on Nrf2 regulation, autophagy and apoptosis to decipher how miR-93 and other microRNA regulate Nrf2 signaling following excessive oxidative stress. Citation Format: Kaytee L. Pokrzywinski, V. Ashutosh Rao. microRNA regulation of Nrf2: A link between autophagy and oxidative stress. [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 LB-291. doi:10.1158/1538-7445.AM2015-LB-291
598. Fusion of Mesenchymal Stem Cells Exclusively with “Degenerating” Cerebellar Neurons in Spinocerebellar Ataxia Type 1 Model Mice
Authors: Fathul Huda, Yiping Fan, Ayumu Konno, Yasunori Matsuzaki, Nobutaka Takahashi, Jerry Chan, Hirokazu Hirai
Journal: Molecular Therapy (2015)

Mesenchymal stem cells (MSCs) have the potential to migrate to damaged tissues where they participate in tissue repair. Previous studies suggest that intravenous or intracortical injections of MSCs results in the emergence of binucleated cerebellar Purkinje cells (PCs) containing a MSC-derived marker protein in mice suggestive of a fusion event. However, transdifferentiation of MSCs into PCs or transfer of a marker protein from a MSC to a PC cannot be completely ruled-out. Here we unequivocally showed a fusion of human fetal MSCs (hMSCs) with mouse PCs by combination of tetracycline-regulated system with Cre-dependent genetic inversion switch (flip-excision; FLEx). We performed intra-cerebellar injection of adeno-associated viral vectors expressing tetracycline transactivator (tTA) and Cre recombinase into either non-symptomatic (4 week-old) or clearly symptomatic (6 – 8 month-old) spinocerebellar ataxia type 1 (SCA1) mice. Two weeks after the treatment, the mice received injection of 50,000 geneticially-engineered hMSCs that expressed GFP only in the presence of Cre recombinase and tTA, which restricted GFP expression exclusively to cerebellar cells fused with hMSCs. We observed GFP-expressing PCs and interneurons in symptomatic, but not non-symptomatic, SCA1 mice as early as 2 weeks after the MSC injection. The frequency of GFP-expressing PCs did not increase when analysed at longer time points (≈23 weeks post hMSC grafting), suggesting that most hMSC fusion events occurred within 2 weeks of delivery. Using this model, we show conclusively that hMSC display a tendency to fuse with degenerating PC and interneurons, and not with normal neurons.
Final Results of a Phase I/II Trial of the Combination of Concurrent Lenalidomide, Thalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Myeloma
Authors: Jatin J. Shah, Robert Z. Orlowski, Sheeba K. Thomas, Raymond Alexanian, Michael Wang, Muzaffar H. Qazilbash, Uday R. Popat, Simrit Parmar, Nina Shah, Qaiser Bashir, Richard E. Champlin, Donna M. Weber
Journal: Blood (2012)
PTU-001 Transient response to botulinum toxin injection predicts the medium-term outcome after endoscopic sphincterotomy in type 2/3 sphincter of Oddi dysfunction
Authors: A S Austin, K Wheeler, M Larvin, R Hall, J Freeman
Journal: Gut (2010)

<b>In ILD, adherence to the training sessions in pulmonary rehabilitation predicts progression of exercise training loads; declining lung function is an independent predictor of failure to progress training loads</b>http://bit.ly/2Z4x9Nw
253. The Use of Osteoporotic BMSCs Engineered by Baculovirus-Mediated MicroRNAs Sponge to Heal Osteoporotic Bone Defect
Authors: Kuei-Chang Li, Chia-Lin Yeh, Yu-Han Chang, Yu-Chen Hu
Journal: Molecular Therapy (2015)

MicroRNAs (miRNAs) are important regulators of various biological processes, including osteoclastogenesis, osteoblast differentiation and bone formation. Recently, many studies revealed aberrant miRNAs expression in elderly osteoporotic patients. Although many pharmacological agents prevent osteoporotic fractures, the repair of bone defects following fracture draws much less attention. Therefore, we have attempted to utilize miRNAs for repairing osteoporotic bone defects. Here, we found that bone marrow-derived mesenchymal stem cells (BMSCs) harvested from rats with long-term estrogen deficiencies exhibited over-expression of certain miRNAs (e.g. miR-140 and miR-214). We hypothesized that suppressing the expression of miR-140 or miR-214 was able to promote the osteogenesis of osteoporotic BMSCs. To suppress the upregulation of miR-140 or miR-214, we constructed hybrid baculoviruses that exploited Cre-LoxP-mediated recombination for prolonged expression of the sponges of miR-140 or miR-214. Transduction of the osteoporotic BMSCs with the baculovirus persistently down-regulated the miR-140/miR-214 expression, enhanced the osteogenic differentiation of cells and mitigated osteoclast maturation via a paracrine fashion, yet expression of miR-214 sponge exhibited stronger effects. To augment the in vivo bone healing, we co-transduced the osteoporotic BMSCs with the hybrid baculovirus expressing miR-214 sponge and another baculovirus expressing BMP2. Allotransplantation of the BMP2/miR-214 sponges-expressing osteoporotic BMSCs into the critical-size defect (3 mm in diameter) at the femur metaphysis of ovariectomised rat potentiated the bone healing and remodeling, filling ~28% of bone volume/total volume (BV/TV) at 4 weeks in comparison to non-operated healthy group. The BMP2/miR-214 sponges-expressing osteoporotic BMSCs not only accelerated the healing, but also ameliorated the bone quality (density, trabecular number, trabecular thickness and trabecular space), as evaluated by micro computed tomography, histology and immunohistochemical staining. Altogether, this study paved a new avenue to treatment of osteoporotic bone defects using miRNA-modulated BMSCs.
A Phase I Study of Immunization of Indolent Non Hodgkin’s Lymphoma Patients with Autologous Monocyte-Derived Dendritic Cells Loaded with Heat Shocked and Killed Autologous Tumor Cells.
Authors: Massimo Di Nicola, Carmelo Carlo-Stella, Maddalena Marchesi, Gianluca Del Conte, Liliana Devizzi, Michele Magni, Paola Matteucci, Stefania Cresta, Roberta Mortarini, Andrea Anichini, Alessandro M. Gianni
Journal: Blood (2005)
Immunologic impact of the intestine in metabolic disease
Authors: Daniel A. Winer, Shawn Winer, Helen J. Dranse, Tony K.T. Lam
Journal: Journal of Clinical Investigation (2017)

Obesity and diabetes are associated with increased chronic low-grade inflammation and elevated plasma glucose levels. Although inflammation in the fat and liver are established features of obesity-associated insulin resistance, the intestine is emerging as a new site for immunologic changes that affect whole-body metabolism. Specifically, microbial and dietary factors incurred by diet-induced obesity influence underlying innate and adaptive responses of the intestinal immune system. These responses affect the maintenance of the intestinal barrier, systemic inflammation, and glucose metabolism. In this Review we propose that an understanding of the changes to the intestinal immune system, and how these changes influence systemic immunity and glucose metabolism in a whole-body integrative and a neuronal-dependent network, will unveil novel intestinal pathologic and therapeutic targets for diabetes and obesity.
Abstract 660: Polyisoprenylated cysteinyl amide inhibitors exhibit anti-tumor effects in human breast cancer cell lines
Authors: Olufisayo O. Salako, Rosemary A. Poku, Augustine T. Nkembo, Typhon Mazu, Hernan Flores-Rozas, Nazarius S. Lamango
Journal: Cancer Research (2015)

Abstract PURPOSE: Triple negative breast cancer (TNBC) is the most aggressive and fatal form of breast cancer. TNBC has no effective therapies since it is not driven by the estrogen (ER), progesterone (PR), and human epidermal growth factor type 2 (Her2/Neu) receptors for which there are targeted drugs. Human epidermal growth factor receptors (EGFR) are overexpressed in 92% of TNBC cases, however, anti-EGFR therapies are ineffective. Monomeric G-proteins that regulate cell proliferation, angiogenesis, migration and apoptosis operate downstream of EGFR and other signal transduction pathways. Polyisoprenylated methylated protein methyl esterase (PMPMEase) metabolizes monomeric G-proteins, allowing them to function properly. PMPMEase is overexpressed in many cancers and may serve as a biomarker and target for cancer therapy. We have synthesized polyisoprenylated cysteinyl amide inhibitors that may inhibit PMPMEase and/or disrupt polyisoprenylated protein function. We hypothesize that the PCAIs will promote anti-tumorigenic effects, inducing apoptosis, while inhibiting cell survival, proliferation, migration, and invasion. The purpose of this study was to test the effectiveness of PCAIs against the biological hallmarks of TNBC. METHODS: Four TNBC cell lines were treated with the PCAIs and analyzed for their effects on cell survival, viability, F-actin organization, cell migration and apoptosis. RESULTS: Treatment of TNBC cells with the PCAIs resulted in a concentration-dependent death of the TNBC cells with EC50 values ranging from 2.13 to 2.78 μM for NSL-BA-040 and NSL-BA-055 in media containing 5% FBS. AO/EB staining revealed early apoptosis at 1 μM. NSL-RD-036 inhibited MDA-MB-231 cell migration by 71% (163±10.7 cells in control versus 47±6.9 in treated (±SEM, N = 3). PCAIs induced complete disruption of F-actin filament organization at 2 μM in MDA-MB-468 cells. CONCLUSION: The PCAIs’ ability to induce apoptosis, and inhibit cell migration by disrupting F-actin filaments suggest that their potential therapeutic value could involve the inhibition of TNBC tumor growth, metastasis, and angiogenesis, which are all essential hallmarks for breast cancer progression. The PCAIs may ultimately fill the targeted therapy void in TNBC therapy. Citation Format: Olufisayo O. Salako, Rosemary A. Poku, Augustine T. Nkembo, Typhon Mazu, Hernan Flores-Rozas, Nazarius S. Lamango. Polyisoprenylated cysteinyl amide inhibitors exhibit anti-tumor effects in human breast cancer cell lines. [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 660. doi:10.1158/1538-7445.AM2015-660
126. Identification of Human Papillomavirus Entry Receptors with CRISPR-Cas9 Library
Authors: Xinping Fu, Lihua Tao, Aiwu Jin, Xiaoliu Zhang
Journal: Molecular Therapy (2016)

Human papillomaviruses (HPVs) are a family of small nonenveloped viruses that induce mostly benign papillomas. However, infection of several high-risk HPV types, most prominently HPV 16 and 18, can cause cervical cancer and other epithelial tumors. The cell biology of HPV entry is still a subject of scientific debate, and in particular, the cellular receptors for HPV infection have not been firmly determined. The present study was designed to use CRISPR-Cas9 gene knock-out library to identify cellular proteins that may be used by HPV for entry. HEK293 cells were initially transduced with CRISPR-Cas9 knockout screening libraries, and then selected with puromycin for two weeks. The cells were then transduced with HPV-16 pseudoviruses containing the GFP marker gene, and GFP-negative cells were subsequently selected by flow cytometry. This process was repeated multiple rounds to enrich the GFP− cell population, and the percentage of GFP+ cells went down from over 90% to less than 10% during this enrichment process. A combination of PCR and DNA sequencing was then used to determine the genes that had been knocked out from this cell population. Our data show that solute carrier family 35 (adenosine 3'-phospho 5'-phosphosulfate transporter) member B2 (SLC35B2), malectin (MLEC), xylosylprotein beta 1,4-galactosyltransferase and transmembrane protein 8C (TMEM8C) were the most frequently knocked out genes in these cells. We then validated the involvement of one of these genes, SLC35B2 in HPV entry, by either deleting genes from fresh HEK293 cells or by reintroducing the gene back to the cells that had it knocked out. Interestingly, SLC35B2 knockout was found to affect entry of some other viruses such as herpes simplex viruses. In conclusions, CRISPR-Cas9 knockout screening system is a useful tool for identifying cellular receptors for viruses such as HPV, in which the entry mechanism has not been fully elucidated.
Rituximab Mediated Depletion of B Cells Following Transplant of Human CD20 Transgenic Mouse Bone Marrow Results in Prolonged B Cell Depletion and Augmented Anti-Tumor Immune Response.
Authors: Yu D. Zhang, Hovav Nechushtan, Monica Jones, Andrew Chan, Seung-uon Shin, Dien Pham, Hyung-Mee Cho, Kyung-Hee Yi, Robert Levy, Joseph D. Rosenblatt
Journal: Blood (2005)