tbuckley/cabot-search huggingface dataset:
AB0927 Biological Drugs Use in Primary Immunodeficiencies
Authors: A. Robles-Marhuenda, T. Cobo-Ibáñez, J.J. Ríos-Blanco, F. Arnalich-Fernández
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Many patients with primary immunodeficiencies develop immune-mediated diseases that require biological treatment. For some time it has been denied the use of biological treatment to patients with immunodeficiencies, because of the theoretical risk of serious infections. <h3>Objectives</h3> To analyze our experience in the use of biological agents in patients with primary immunodeficiency. <h3>Methods</h3> Retrospective analysis of 8 patients over 18 years, diagnosed with primary imunodeficiency, by WHO classification, that have received biological treatment. Demographic data, type of immune-mediated disease, biological treatment used, response to treatment and rate of infection were record. <h3>Results</h3> We present 8 patients that have received biological drugs. The mean age was 23 years, all of whom were male,except one woman. The time evolution of the priamry immunodeficiency was on average 10.2 years. Five patients have a common variable immunodeficiency, two chronic granulomatous disease and one of them agammaglobulinemia-X. Patients with chronic granulomatous disease and agammaglobulinemia received anti-TNF, for the treatment of inflammatory bowel disease. While patients with common variable immunodeficiency received rituximab; two of them for immune-mediated thrombocytopenia, two for lymphoid interstitial pneumonitis and another by transverse myelitis. Agammaglobulinemia-X and one patient with chronic granulomatous disease precised the use of various anti-TNF (infliximab, adalimumab, certolizumab). All patients had disease improvement in which biological treatment was indicated. The rate of infection was lower along the use of biological drugs (median follow up 1.2 years) than along the treatment with other immunosuppressants. There was only one episode of serious infection that required hospitalization, a patient with agammaglobulinemia-X who presented a herpes zoster, while being trated with steroids and certolizumab for inflammatory bowel disease. The perceived quality of life was better when using biological agents than previously to it. <h3>Conclusions</h3> Our experience could open the prudent use of biological drugs for patients with primary immunodeficiencies, always under close monitoring and appropriate prescription. <h3>Disclosure of Interest</h3> None declared
Abstract B22: Loss of LncRNA XIST induces Epithelial to Mesenchymal Transition in Breast Cancer
Authors: Yin Liu, Fei Xing, Kerui Wu, Sambad Sharma, Kounosuke Watabe
Journal: Cancer Research (2016)

Abstract Brain is one of the major sites of metastasis of breast cancer, and approximately 20% of patients with aggressive breast cancer eventually develop the metastatic disease in the brain. Long non-coding RNAs (lncRNA) have recently drawn much attention due to their wide functional variations and potential roles in tumor progression. By performing lncRNA array analysis comparing non-metastatic primary tumors with brain metastatic tumors from breast cancer patients, we identified that lncRNA XIST expression was significantly down-regulated in brain metastatic tumors. The result of Taqman PCR validated the results in tumor samples and also indicated that XIST expression was down-regulated in brain metastatic cell lines compared to non-brain metastatic cell lines. Moreover, we found that the XIST expression was negatively correlated with breast cancer stage and brain metastasis-free survival. XIST is located on the q arm of the X chromosome (Xq13-2) and plays a critical role in the X inactivation, thus providing dosage equivalence between males and females. Importantly, XIST has been found to be down-regulated in several types of tumors including breast cancer. Loss of XIST facilitates escape of some X chromosome genes from inactivation. To further study the effect of XIST down-regulation on tumor cells, we knocked down XIST expression in MCF7 by siRNA. We found that the knockdown of XIST drastically altered the morphology of MCF7 cell from epithelial to mesenchymal type. Furthermore, several epithelial-mesenchymal transition (EMT)-related genes including ZEB2 and SNAIL were upregulated in the XIST knockdown cells. In addition, the results of qPCR, western blot and immunocytochemical analysis showed that the epithelial marker E-cad was significantly down-regulated, while mesenchymal markers N-cad and Vimentin were upregulated in MCF7-siXIST, SKBR-siXIST and ZR751-siXIST cells compared to the control cells. To further examine the effect of XIST knockdown in vivo, we transplanted MCF7-siXIST, SKBR3-siXIST and their control cells by intra-cardiac injection into nude mice. We found that knockdown of XIST significantly enhanced tumor metastasis, especially in the brain. Our results strongly suggest that lncRNA XIST plays a critical role in tumor progression and metastasis by inducing EMT. Citation Format: Yin Liu, Fei Xing, Kerui Wu, Sambad Sharma, Kounosuke Watabe. Loss of LncRNA XIST induces Epithelial to Mesenchymal Transition in Breast Cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B22.
The role of subcutaneous tissue stiffness on microneedle performance in a representative in vitro model of skin
Authors: K. Moronkeji, S. Todd, I. Dawidowska, S.D. Barrett, R. Akhtar
Journal: Journal of Controlled Release (2016)

There has been growing interest in the mechanical behaviour of skin due to the rapid development of microneedle devices for drug delivery applications into skin. However, most in vitro experimentation studies that are used to evaluate microneedle performance do not consider the biomechanical properties of skin or that of the subcutaneous layers. In this study, a representative experimental model of skin was developed which was comprised of subcutaneous and muscle mimics. Neonatal porcine skin from the abdominal and back regions was used, with gelatine gels of differing water content (67, 80, 88 and 96%) to represent the subcutaneous tissue, and a type of ballistic gelatine, Perma-Gel®, as a muscle mimic. Dynamic nanoindentation was used to characterize the mechanical properties of each of these layers. A custom-developed impact test rig was used to apply dense polymethylmethacrylate (PMMA) microneedles to the skin models in a controlled and repeatable way with quantification of the insertion force and velocity. Image analysis methods were used to measure penetration depth and area of the breach caused by microneedle penetration following staining and optical imaging. The nanoindentation tests demonstrated that the tissue mimics matched expected values for subcutaneous and muscle tissue, and that the compliance of the subcutaneous mimics increased linearly with water content. The abdominal skin was thinner and less stiff as compared to back skin. The maximum force decreased with gel water content in the abdominal skin but not in the back skin. Overall, larger and deeper perforations were found in the skin models with increasing water content. These data demonstrate the importance of subcutaneous tissue on microneedle performance and the need for representative skin models in microneedle technology development.
AB0405 Effects of Atorvastatin on Dynamics of Bone Mineral Density in Patients with Rheumatoid Arthritis
Authors: Y. Akhverdyan, B. Zavodovsky, J. Polyakova, L. Seewordova, M. Kuznetsova, A. Zborovsky
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> There are some data indicating that statins produce a pleiotropic effect and can increase bone mineral density. It is also known that some statins (pravastatin, simvastatin) have an anti-inflammatory effect. Simvastatin has been shown to be effective in the treatment of rheumatoid arthritis (RA) in humans. We failed to find any research data indicating that atorvastatin has anti-inflammatory effects. <h3>Objectives</h3> To study the effect of Atorvastatin on the dynamics of bone mineral density and inflammatory markers of osteoporosis (OP) in patients with RA. <h3>Methods</h3> We examined 170 RA patients aged 22 – 75 years (128 females (75.3%) and 42 males (24.7%)). Bone mineral density was measured with dual-energy X-ray absorptiometry (DEXA) (Lunar DPX-Pro, GE, USA). Additionally, we measured serum osteocalcin levels and urine CrossLaps with ELISA test. We divided the patients into two groups to study the effectiveness of Atorvastatin in the treatment of patients with RA/OP and osteopenia. Group 1 included 38 individuals who received Atorvastatin for 6 months at a dose of 20–40 micrograms per day. The experimental group included 29 patients with OP and osteopenia. They received calcium supplements at a dose of 1000 mg per day. <h3>Results</h3> We revealed that 84 (51.5%) out of 170 patients with RA had significantly lower Z- and T-scores values. We noted that 17 (20.2%) patients were diagnosed as having osteoporosis, while 67 (79.8%) had osteopenia. The most common manifestations of OP in RA patients included fractures, bone and back pain, as well as decreased muscle strength. We measured biochemical markers of bone turnover at baseline and after 6-month of the treatment. There was significant positive dynamic of clinical and laboratory parameters during a 6-month treatment with Atorvastatin in OP patients with RA. In this patients we observed BMD and muscle strength increasing, reducing of bone and back pain, decreasing of C-reactive protein. Urinary CrossLaps were significantly decreased. Atorvastatin was well tolerated. There were few of insignificant side effects which were reduced after the drug dose decreasing. Symptomatic improvement occurred within 2–3 months after starting of atorvastatin therapy. Second group patients who received calcium monotherapy showed signs of progressive OP: bone mineral density continued to decrease (mean -2.7±0.18%), while bone pain and biochemical markers of bone metabolism remained unchanged. <h3>Conclusions</h3> We concluded that Atorvastatin may be used in the treatment of RA patients and can help to stabilize bone mineral density and improve the OP symptoms. <h3>Disclosure of Interest</h3> None declared
The modification of natural products for medical use
Authors: Zongru Guo
Journal: Acta Pharmaceutica Sinica B (2016)

Drug innovation is characterized by painstaking molecular-level syntheses and modifications as the basic components of research and development. Similarly, natural products are chemically tailored and modified based upon their structural and biological properties. To some extent, the modification of natural products is quite different from de novo structure-based drug discovery. This review describes the general strategies and principles for the modification of natural products to drugs, as illustrated by several successful medicines that originated from natural products.
Activity of Bendamustine (TREANDA™) in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Cells with Alterations in DNA Damage Response Pathway.
Authors: Gaël Roué, Mónica López-Guerra, Pierre Milpied, Patricia Pérez-Galán, Neus Villamor, Elias Campo, Dolors Colomer
Journal: Blood (2006)
Multiplexed Digital Quantification of mRNA Abundance: a Highly Reproducible, PCR–independent Assessment of BAALC, ERG, and MN1 mRNA Levels in Acute Myeloid Leukemia (AML) Bone Marrow (BM) and Peripheral Blood (PB) Samples.
Authors: Jacqueline E. Payton, Guido Marcucci, Michael D. Radmacher, Kati Maharry, Christian Langer, Claudia D Baldus, Clara D. Bloomfield, Timothy J. Ley
Journal: Blood (2009)
An Improved Methodology to Overcome Key Issues in Human Fecal Metagenomic DNA Extraction
Authors: Jitendra Kumar, Manoj Kumar, Shashank Gupta, Vasim Ahmed, Manu Bhambi, Rajesh Pandey, Nar Singh Chauhan
Journal: Genomics Proteomics & Bioinformatics (2016)

Microbes are ubiquitously distributed in nature, and recent culture-independent studies have highlighted the significance of gut microbiota in human health and disease. Fecal DNA is the primary source for the majority of human gut microbiome studies. However, further improvement is needed to obtain fecal metagenomic DNA with sufficient amount and good quality but low host genomic DNA contamination. In the current study, we demonstrate a quick, robust, unbiased, and cost-effective method for the isolation of high molecular weight (>23kb) metagenomic DNA (260/280 ratio >1.8) with a good yield (55.8±3.8ng/mg of feces). We also confirm that there is very low human genomic DNA contamination (eubacterial: human genomic DNA marker genes=227.9:1) in the human feces. The newly-developed method robustly performs for fresh as well as stored fecal samples as demonstrated by 16S rRNA gene sequencing using 454 FLX+. Moreover, 16S rRNA gene analysis indicated that compared to other DNA extraction methods tested, the fecal metagenomic DNA isolated with current methodology retains species richness and does not show microbial diversity biases, which is further confirmed by qPCR with a known quantity of spike-in genomes. Overall, our data highlight a protocol with a balance between quality, amount, user-friendliness, and cost effectiveness for its suitability toward usage for culture-independent analysis of the human gut microbiome, which provides a robust solution to overcome key issues associated with fecal metagenomic DNA isolation in human gut microbiome studies.
Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management
Authors: Agnieszka Bierzynska, Hugh J. McCarthy, Katrina Soderquest, Ethan S. Sen, Elizabeth Colby, Wen Y. Ding, Marwa M. Nabhan, Larissa Kerecuk, Shivram Hegde, David Hughes, Stephen Marks, Sally Feather, Caroline Jones, Nicholas J.A. Webb, Milos Ognjanovic, Martin Christian, Rodney D. Gilbert, Manish D. Sinha, Graham M. Lord, Michael Simpson, Ania B. Koziell, Gavin I. Welsh, Moin A. Saleem
Journal: Kidney International (2017)
Plerixafor Plus Single-Dose Pegfilgrastim for Hematopoietic Stem and Progenitor Cell Mobilization: An Efficient and Safe Regimen In Good and Poor Mobilizer Patients
Authors: Kirsten Herbert, Lisa Demosthenous, Glen Wiesner, Emma Link, David Alan Westerman, Neil Came, John F Seymour, Miles Prince
Journal: Blood (2010)
Expression Cloning of Genes Enabling Erythropoietin -Independent Erythropoiesis in Vitro.
Authors: Tomoko Yokoo, Ryo Kurita, Atsushi Takahashi, Michiyo Okada, Hirotaka Kawano, Yoshie Miura, Takafumi Hiramoto, Hiroyuki Inoue, Youko Suehiro, Daisuke Sugiyama, Hua Lu, Akihiko Yoshimura, Norio Komatsu, Kenzaburo Tani
Journal: Blood (2009)
Disappearance of Minimal Residual DEK-CAN Fusion Transcript after Allogenic Hematopoietic Stem Cell Transplantation in a Child with t(6;9) Acute Myeloid Leukemia.
Authors: Hirohide Kawasaki, Yuichiro Imai, Yuichi Kuroyanagi, Yukihiro Noda, Takahide Nakano, Kazunari Kaneko
Journal: Blood (2006)
Increased Dose Rituximab Followed by Maintenance Rituximab As Initial Therapy for Indolent B Cell Lymphomas: A Phase II Trial,
Authors: Jeffrey A. Barnes, Kristen Stevenson, Ephraim P. Hochberg, Tak Takvorian, David C. Fisher, Ann LaCasce, Jennifer R. Brown, Anuj K. Mahindra, Donna Neuberg, Jeremy S. Abramson
Journal: Blood (2011)
Mycoplasma genitalium and Trichomonas vaginalis in France: a point prevalence study in people screened for sexually transmitted diseases
Authors: S. Pereyre, C. Laurier Nadalié, C. Bébéar, C. Arfeuille, A. Beby-Defaux, B. Berçot, S. Boisset, N. Bourgeois, M.-J. Carles, D. Decré, A.-L. Garand, S.-A. Gibaud, A. Grob, K. Jeannot, M. Kempf, F. Moreau, J. Petitjean-Lecherbonnier, M.-F. Prère, H. Salord, P. Verhoeven
Journal: Clinical Microbiology and Infection (2016)
Phase I, Randomized, Double-Blind, Placebo-Controlled, Single-Dose Escalation Study of the rFVIIa Variant (BAY 86–6150) In Hemophilia A or B with or without Inhibitors.
Authors: J.N. Mahlangu, M.J. Coetzee, M. Laffan, J. Windyga, T. T. Yee, J. Schroeder, Jesper Haaning, J.E. Siegel, G. Lemm
Journal: Blood (2010)
Characterization of Cytogenetic Abnormalities and Mutations in ASXL1, SRSF2, CBL and JAK2 Genes in Chronic Myelomonocytic Leukemia
Authors: Laura Palomo, Blanca Xicoy, Silvia Marce, Olga Garcia, Marta Cabezon, María José Jiménez, Isabel Granada, Javier Grau, Josep-Maria Ribera, Evarist Feliu, Fuensanta Millá, Lurdes Zamora
Journal: Blood (2012)
A Randomized, Double Blinded Study of Risedronate Versus Placebo for the Prevention of Bone Loss in Patients Receiving High Dose Corticosteroids for the Treatment of Acute Lymphocytic Leukemia and Lymphoblastic Lymphoma
Authors: Kyle Cash, Robert Gagel, J Lynn Palmer, Deborah A. Thomas, Gloria Mattiuzzi, Hagop M. Kantarjian, Susan O'Brien, Mimi Hu, Camilo Jimenez, Maria E Cabanillas
Journal: Blood (2011)
Melphalan + Prednisone Versus Melphalan + Prednisone + Thalidomide in Induction Therapy for Multiple Myeloma in Elderly Patients: Final Analysis of the Dutch Cooperative Group HOVON 49 Study
Authors: P. Wijermans, M. Schaafsma, Y. van Norden, R. Ammerlaan, S. Wittebol, H. Sinnige, Sonja Zweegman, M. van Marwijk Kooi, R. Van der Griend, H. Lokhorst, P. Sonneveld
Journal: Blood (2008)
Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells
Authors: Daniel W. Sherbenou, Blake T. Aftab, Yang Su, Christopher R. Behrens, Arun Wiita, Aaron C. Logan, Diego Acosta-Alvear, Byron C. Hann, Peter Walter, Marc A. Shuman, Xiaobo Wu, John P. Atkinson, Jeffrey L. Wolf, Thomas G. Martin, Bin Liu
Journal: Journal of Clinical Investigation (2016)

Multiple myeloma is incurable by standard approaches because of inevitable relapse and development of treatment resistance in all patients. In our prior work, we identified a panel of macropinocytosing human monoclonal antibodies against CD46, a negative regulator of the innate immune system, and constructed antibody-drug conjugates (ADCs). In this report, we show that an anti-CD46 ADC (CD46-ADC) potently inhibited proliferation in myeloma cell lines with little effect on normal cells. CD46-ADC also potently eliminated myeloma growth in orthometastatic xenograft models. In primary myeloma cells derived from bone marrow aspirates, CD46-ADC induced apoptosis and cell death, but did not affect the viability of nontumor mononuclear cells. It is of clinical interest that the CD46 gene resides on chromosome 1q, which undergoes genomic amplification in the majority of relapsed myeloma patients. We found that the cell surface expression level of CD46 was markedly higher in patient myeloma cells with 1q gain than in those with normal 1q copy number. Thus, genomic amplification of CD46 may serve as a surrogate for target amplification that could allow patient stratification for tailored CD46-targeted therapy. Overall, these findings indicate that CD46 is a promising target for antibody-based treatment of multiple myeloma, especially in patients with gain of chromosome 1q.
PTU-085 A NOTCH1-Driven Secretome Switch Modulates Immune Surveillance In Ras-Induced Senescence
Authors: M Hoare, Y Ito, T-W Kang, S Menon, R Salama, L Zender, M Narita
Journal: Gut (2016)

<h3>Introduction</h3> Oncogene-induced senescence (OIS) is an intrinsic tumour suppressor mechanism, but its impact on tumorigenesis is largely dependent on the nature of the senescence-associated secretory phenotype (SASP). Major components of the SASP include TGFβ1 and pro-inflammatory cytokines, such as IL1, IL6, and IL8, that have pleiotropic context-dependent effects. <h3>Methods</h3> We utilised the well validated ER:Ras<sup>G12V</sup> IMR90 HDF in vitro model which undergo Ras-induced senescence (RIS) with 4 OHT. Genetic manipulation was achieved through retroviral gene transfer; transcriptional profiling by mRNA-seq; validation through qPCR and immunoblotting. In vivo hepatocyte senescence was achieved through hydrodynamic tail-vein delivery of NRAS<sup>G12V</sup>-containing transposons. <h3>Results</h3> We have demonstrated that NOTCH1, a highly conserved receptor is up-regulated in RIS. In contrast to the up-regulation of NOTCH1, downstream signalling is dynamically regulated: the cleaved, active intracellular domain of NOTCH1 (N1ICD) and NOTCH-target genes were transiently up-regulated at an early phase of RIS, but down-regulated at full senescence. The dynamic expression patterns of N1ICD and TGF-β1 expression were nearly identical, and inversely correlated with the cytokines, IL1 and IL8. Inhibition of NOTCH1 signalling, through expression of a dominant-negative form of the NOTCH1 binding partner MAML1, led to a reduction in TGF-β1, but increased IL1 and IL8 expression during RIS. In addition, ectopic restoration of N1ICD in established RIS cells drove reciprocal secretome changes with reduced IL1 and IL8 and increased TGF-β1, suggesting NOTCH1 signalling plays a critical role in secretome switching. Utilising an NRAS-drive hepatocyte senescence model, NOTCH1 was upregulated during RIS in vivo. Previously it has been shown that the SASP in RIS is critical for the immune-mediated clearance of senescent hepatocytes. Consistent with the enhancement of the pro-inflammatory secretome, co-delivery of the NOTCH inhibitor dnMAML1 with RAS, accelerated the infiltration of CD3+ T-cells into the liver and promoted the clearance of senescent hepatocytes. Restoration of N1ICD in hepatocyte RIS led to senescence bypass and tumour formation. <h3>Conclusion</h3> The transition to RIS is correlated with a NOTCH1-mediated switch from a TGFβ-rich secretome to a proinflammatory secretome. Promotion of this proinflammatory secretome, through NOTCH inhibition enhances immune surveillance of senescent hepatocytes. This raises the possibility of therapeutically promoting the clearance of senescent cells in vivo. <h3>Disclosure of Interest</h3> None Declared
CD5+B Lymphocytes in the Bone Marrow of Immunic Hemocytopenia Patients and Its Clinical Significancy.
Authors: Zonghong Shao, Limin Xing, Rong Fu, Hong Liu, Jun Shi, Jie Bai, Meifeng Tu, Huaquan Wang, Zhenzhu Cui, Hairong Jia, Juan Sun, Chongli Yang
Journal: Blood (2005)
PI3Kδ inhibition elicits anti-leukemic effects through Bim-dependent apoptosis
Authors: M J Carter, K L Cox, S J Blakemore, A H Turaj, R J Oldham, L N Dahal, S Tannheimer, F Forconi, G Packham, M S Cragg
Journal: Leukemia (2016)

PI3Kδ plays pivotal roles in the maintenance, proliferation and survival of malignant B-lymphocytes. Although not curative, PI3Kδ inhibitors (PI3Kδi) demonstrate impressive clinical efficacy and, alongside other signaling inhibitors, are revolutionizing the treatment of hematological malignancies. However, only limited in vivo data are available regarding their mechanism of action. With the rising number of novel treatments, the challenge is to identify combinations that deliver curative regimes. A deeper understanding of the molecular mechanism is required to guide these selections. Currently, immunomodulation, inhibition of B-cell receptor signaling, chemokine/cytokine signaling and apoptosis represent potential therapeutic mechanisms for PI3Kδi. Here we characterize the molecular mechanisms responsible for PI3Kδi-induced apoptosis in an in vivo model of chronic lymphocytic leukemia (CLL). In vitro, PI3Kδi-induced substantive apoptosis and disrupted microenvironment-derived signaling in murine (Eμ-Tcl1) and human (CLL) leukemia cells. Furthermore, PI3Kδi imparted significant therapeutic responses in Eμ-Tcl1-bearing animals and enhanced anti-CD20 monoclonal antibody therapy. Responses correlated with upregulation of the pro-apoptotic BH3-only protein Bim. Accordingly, Bim−/− Eμ-Tcl1 Tg leukemias demonstrated resistance to PI3Kδi-induced apoptosis were refractory to PI3Kδi in vivo and failed to display combination efficacy with anti-CD20 monoclonal antibody therapy. Therefore, Bim-dependent apoptosis represents a key in vivo therapeutic mechanism for PI3Kδi, both alone and in combination therapy regimes.