tbuckley/cabot-search huggingface dataset:
Aurora – A Noninvasive, Wrist-worn Device for Ambulatory Hemodynamic Monitoring
Authors: Jeremiah (Miah) Wander, Dan Morris, Desney Tan
Journal: Circulation (2015)

Introduction: Continuous, minimally invasive monitoring of arterial health has significant potential for both improving our understanding of early progression of arteriosclerosis/atherosclerosis and enabling early treatment. Though devices exist that can report heart rate and heart rate variability in fully ambulatory settings, monitoring of pulse pressure wave morphology, including pulse wave velocity (PWV) and augmentation index (AIx) – two emerging indicators of arterial stiffness – is still currently limited to benchtop systems requiring an expert operator or cuff-based systems that are not well tolerated. Objective: To develop and validate a device capable of continuous monitoring of hemodynamic and electrophysiological signals, including computation of derived vascular stiffness indicators (peripheral PWV and AIx) comparable to current standards. Methods: We developed a wrist-worn device for continuous radial pulse wave capture and analysis (e.g., peripheral AIx computation) and pulse wave velocity measurement (measured from EKG landmarks to the radial pulse arrival time). The core sensors on the device are (1) a pressure sensor that rests over the radial artery, (2) a pair of dry EKG electrodes in lead-I configuration, and (3) a six-axis motion sensor. It includes a Bluetooth radio for data streaming, and sufficient on-board storage for 2 weeks of ambulatory studies. To validate the device against the current gold standard for radial tonometry, we recorded multiple 60-second sessions of tonometric data using both our device (2 sessions) and the standard Millar SPT-301 tonometer (3 sessions) in 28 subjects. We then compared AIx computed from these two devices. Results: Using our wrist-worn device we calculated AIx values that were highly consistent with those of the Millar tonometer (r = 0.927, mean difference ± SD of 0.026 ± 0.049). Conclusions: This platform enables continuous non-invasive hemodynamic monitoring. We intend to utilize it in future studies about how peripheral AIx and PWV behave over longer time periods, how they correlate to daily activities, including sleep, exercise, and food/medication intake, and – most importantly – whether they can serve as new, ambulatory indicators of cardiovascular risk.
Imatinib Mesylate for Patients (pts) with Hypereosinophilic Syndrome (HES) and Systemic Mastocytosis (SM): A Phase II Trial.
Authors: Elias Jabbour, Hagop Kantarjian, Srdan Verstovsek, Dan Jones, Susan O’Brien, Raja Luthra, Farhad Ravandi-Kashani, William Wierda, Francis Giles, Mary Beth Rios, Jorge Cortes
Journal: Blood (2004)
Lymphoscintigraphic SPECT/CT—Contralateral Axillary Sentinel Lymph Node Drainage in Breast Cancer
Authors: Ratna T. Koyyalamudi, Monica Anne Rossleigh
Journal: Clinical Nuclear Medicine (2016)

A 58-year-old woman with previous right breast carcinoma treated with lumpectomy, right axillary clearance, chemo-radiotherapy, and adjuvant hormonal therapy underwent a lymphoscintigraphy for a new right breast lesion. On planar images, an alternate route of lymphatic drainage was observed to the right internal mammary chain and the left axilla. A chest SPECT/CT was performed to confirm the location of the sentinel nodes. The patient underwent a right mastectomy and left axillary sentinel lymph node biopsy, which showed no evidence of lymphovascular invasion. Combining planar imaging and SPECT/CT techniques can accurately identify sentinel lymph nodes at their new unpredicted location.
141. Combinatorial Aptamer Transcripts (CATs) for HIV RT Suppression
Authors: Kyle J. Hill, Margaret J. Lange, Donald H. Burke
Journal: Molecular Therapy (2015)

The Human Immunodeficiency Virus (HIV) Reverse Transcriptase (RT) is a DNA polymerase encoded by the viral genome and it is preferentially targeted by current therapeutics due to its critical role in the viral life cycle. High affinity RNA aptamers that bind RT out-compete viral genome for access to the active site and thereby inhibit replication. Aptamer binding to RT during viral formation is believed to drive aptamer encapsidation into the budding virus, which leads to significantly reduced infectivity. We reasoned that co-transcribing multiple aptamer modules as combinatorial transcripts would increase avidity and packaging, resulting in greater net viral suppression. To test this hypothesis, we built a series of Combinatorial Aptamer Transcripts (CATs) carrying multiple, co-transcribed aptamer modules and compared their inhibitory capabilities as a function of valency. Specifically, aptamers from two different structural types (representing (6/5)AL and UCAA structural motifs) were combined into homodimeric and homotrimeric CATs. Two designs were explored for increasing valency; in the first we generated threads of homo-aptamer modules. In general, transcripts with more modules exhibited moderately increased RT inhibition in Primer Extension Assays and increased net binding affinity in Electrophoretic Mobility Shift Assays (EMSAs). The EMSAs do not show evidence of binding multiple RT per transcript, and preliminary cell-based assays do not indicate that this approach to multivalency improves net viral suppression. In contrast, an alternative design appears to be more promising, in which individual aptamer modules are incorporated into a stable3-Way Junction (3WJ) to increase modularity. The 3WJ structural core is expected both to isolate the individual aptamer structures from each other (and thereby reduce misfolding) and to allow sufficient separation to prevent steric hindrance in the binding of multiple RT. Other design features simplify the operational requirements of replacing individual modules with other aptamers or with libraries of aptamers. Initial data based on this design are encouraging. Combinatorial transcripts are expected to block evolutionary escape by forcing the virus to acquire multiple simultaneous mutations, especially for designs that include hetero-multimers. It is well established that combinations of small molecule drugs or of siRNA improves their targeting, delivery, and potency, while reducing their susceptibility to escape mutations. By demonstrating the benefits of multimerization we will inform downstream utilization of CATs as a therapeutic design in the treatment of HIV.
282. Circumventing Hematopoietic Toxicities and Reversing Sickle Phenotype by Lineage-Specific BCL11A Knock Down and γ-Globin Induction
Authors: Christian Brendel, Swaroopa Guda, Raffaele Renella, Daniel E. Bauer, Matthew C. Canver, Young-Jo Kim, Matthew M. Heeney, Denise Klatt, Jonathan Fogel, Michael D. Milsom, Stuart H. Orkin, Richard I. Gregory, David A. Williams
Journal: Molecular Therapy (2016)

The fetal hemoglobin repressor BCL11A represents a therapeutic target for β-hemoglobinopathies as reduced expression of BCL11A leads to simultaneous increased γ-globin and reduced β-globin expression. Reversing this hemoglobin switch is particularly relevant in sickle cell disease to reduce the βS concentration and increase expression of the protective fetal hemoglobin (HbF, α2γ2). Here we show that despite use of optimized shRNAs embedded into a miRNA (shRNAmiR) architecture to reduce non-specific cellular toxicities (Guda et al. MT, 2015), the knockdown of BCL11A profoundly and specifically impaired long-term engraftment of both human and mouse hematopoietic stem cells (HSCs). In competitive transplantation assays cells transduced with shRNAmiRs targeting the BCL11A mRNA were consistently underrepresented after hematopoietic reconstitution with gene modified HSCs. Although this effect was particularly pronounced in the B-cell compartment, it was also the case for all other assessed hematopoietic lineages. Mechanistically, while knock-down of BCL11A did not lead to a detectable phenotype in terms of apoptosis, growth or differentiation in human or mouse HSCs in vitro, a significant increase in S/G2-phase human HSCs after engraftment into NSG mice was found, a phenotype associated with stem cell exhaustion. To avoid this BCL11A-specific HSC toxicity, we suppressed BCL11A in erythroid cells in a lineage-specific fashion by using transcriptional regulatory elements derived from the β-globin locus. Utilizing this approach for the expression of the optimized shRNAmiRs led to stable long-term engraftment of mouse and human gene modified cells in congenic or NSG-mice, respectively. Transduced primary normal or sickle cell disease (SCD) human HSCs gave rise to erythroid cells with up to 90% reduction of BCL11A protein. These erythrocytes demonstrated 60-70% γ-chain expression and a corresponding increase in HbF at low vector copy numbers per cell (VCN<1.5). Similar results were obtained after in vitro differentiation of CD34+ cells harvested 16 weeks following engraftment in NSG mice. Transplantation of gene modified murine HSCs from BERK sickle cell mice led to a substantial improvement of sickle-associated hemolytic anemia and reticulocytosis, key phenotypes of SCD. In summary, we have shown an unexpected and severe toxicity of BCL11A knockdown in repopulating HSCs that has direct and important consequences for translation into human gene therapy trials. By utilizing erythroid lineage-specific and microRNA embedded expression of targeting shRNAs we demonstrate the capacity of lentivirus vectors to effect significant γ-globin induction leading to clinically relevant increases in HbF while obviating HSC toxicity.
Abstract 3773: Plk1-mediated stabilization of 53BP1 suppresses centrosome abnormal amplification
Authors: Hyungshin Yim, Sang-Uk Woo, Sol-Bi Shin, Raymond L. Erikson
Journal: Cancer Research (2015)

Abstract Mammalian Plk1 has been studied as an essential factor in regulating mitotic events through the phosphorylation of several Plk1-specific substrates. Here we show that in mitosis 53BP1 binds to the C-terminal polo-box domain of Plk1 and is a substrate for Plk1 in vitro. 53BP1 is hyper-phosphorylated and its level is up-regulated in cells expressing wild type Plk1 (Plk1-WT), but not in cells expressing a kinase-defective mutant (Plk1-KM). Depletion of Plk1 reduces the level of 53BP1 which is restored in cells treated with MG132. In cells expressing Plk1-KM but not in Plk1-WT cells, 53BP1 interacts with Mdm2 suggesting that 53BP1 turnover is regulated by Plk1-mediated phosphorylation. In mitosis, 53BP1 colocalizes with Plk1 to the centrosome and the spindle pole. Down-regulation of 53BP1 by shRNA induces multiple centrioles, multiple spindle poles, and mis-orientation of poles in HeLa cells. The data suggest that the phosphorylation of 53BP1 by Plk1 regulates its stability, and that this biochemical event plays a crucial role in modulating chromosomal amplification which ensures bipolarity in mitosis. Citation Format: Hyungshin Yim, Sang-Uk Woo, Sol-Bi Shin, Raymond L. Erikson. Plk1-mediated stabilization of 53BP1 suppresses centrosome abnormal amplification. [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 3773. doi:10.1158/1538-7445.AM2015-3773
Induction of Thymic Stromal Lymphopoietin in Mesenchymal Stem Cells by Interaction with Myeloma Cells
Authors: Shinji Nakajima, Hiroto Ohguchi, Yasushi Onishi, Mayumi Kamata, Tohru Fujiwara, Yoko Okitsu, Noriko Fukuhara, Kenichi Ishizawa, Hideo Harigae
Journal: Blood (2012)
Abstract 3410: Onodera's prognostic nutritional Index predicts survival in patients with unresectable advanced or recurrent colorectal cancer
Authors: Tetsuro Ikeya
Journal: Cancer Research (2015)

Abstract Background: Nutrition and immunity significantly affect the progression of cancer in cancer patients. Therefore, the evaluation of the nutritional and immune status would be useful as a prognostic factor and to determine the optimal treatment strategy for patients with unresectable metastatic colorectal cancer who are receiving chemotherapy. The aim of this retrospective study was to evaluate the prognostic significance of the nutritional and immune status in patients with unresectable metastatic colorectal cancer treated with chemotherapy. Methods: We retrospectively reviewed 80 patients with colorectal cancer. A total of 22 patients had metachronous unresectable cancer and 58 patients had synchronous unresectable cancer. All patients underwent combination chemotherapy with oxaliplatin or irinotecan plus 5-fluorouracil/leucovorin as first-line chemotherapy for unresectable metastatic colorectal cancer. We then examined the correlations between the Onodera's Prognostic Nutritional Index (OPNI) and the patients’ clinicopathological features. The OPNI was calculated as follows: 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count (per mm3). According to the receiver operating characteristic (ROC) curve analysis, the cut-off value for OPNI was 44.5. Results: Patients with a pretreatment OPNI of ≧44.5 demonstrated a longer OS than those with a pretreatment OPNI of &amp;lt;44.5. Moreover, we categorized these patients into four groups according to the combination of the pre- and post-treatment OPNI. The patients in the group with both OPNIs ≥ 44.5 exhibited a better prognosis compared to the other group (p = 0.001). Conclusion: The OPNI is considered to be a useful marker for predicting the long-term outcome in patients who receive chemotherapy for unresectable metastatic colorectal cancer. Citation Format: Tetsuro Ikeya. Onodera's prognostic nutritional Index predicts survival in patients with unresectable advanced or recurrent colorectal cancer. [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 3410. doi:10.1158/1538-7445.AM2015-3410
Crystal Structure Analysis Reveals That the Novel Type II Anti-CD20 Antibody GA101 Interacts with a Similar Epitope as Rituximab and Ocrelizumab but in a Fundamentally Different Way.
Authors: Gerhard J Niederfellner, Alfred Lammens, Manfred Schwaiger, Guy Georges, Kornelius Wiechmann, Andreas Franke, Wolfgang Schaefer, Stefan Jenewein, Jerry Slootstra, Ekkehard Moessner, Pablo Umana, Karl-Peter Hopfner, Christian Klein
Journal: Blood (2009)
CC-012 Case report: a case of a patient with diarrhoea and weight loss. Is this occult Crohn's disease or functional disease? Does it matter?
Authors: A M Verma, J A D Stewart
Journal: Gut (2010)

<h3>Introduction</h3> A 36-year-old patient was referred to general surgery with a change in bowel habit (constipation predominant), blood stained rectal discharge, right iliac fossa pain and weight loss. <h3>Methods</h3> Investigations were performed: CRP and platelet count were normal. Coeliac autoantibodies were negative. Sigmoidoscopy revealed faecally loaded rectum, no blood seen. CT colonoscopy was normal. The patient was referred to Gastroenterology. Over the course of the next year she was seen five times in outpatient clinic. She had now developed diarrhoea (with nocturnal symptoms). Sigmoidoscopy including biopsies was normal. Ultrasound of the abdomen was normal. Pelvic ultrasound (to rule out a gynaecological cause), revealed a thickened caecum with a normal terminal ileum. A MR scan was advised. MR scan showed a normal large and small faecally loaded bowel. Colonoscopy was arranged but was not tolerated due to pain and it was abandoned at the splenic flexure. Biopsies of the left colon were normal. <h3>Results</h3> The patient was seen again in Oct 08 with persistent diarrhoea, right iliac fossa pain and weight loss. These symptoms combined with the pelvic ultrasound showing thickening of the caecum suggested gut inflammation. A trial of mesalazine was commenced with a dramatic improvement of symptoms. Intolerance to mesalazine developed (headaches) and the patient commenced budesonide 9 mg per day for 2 weeks, to be followed by 6 mg for 2 weeks and 3 mg for 2 weeks. In May 09, the patient was reviewed and she stated that 6 mg of Budesonide daily controlled her symptoms but 3 mg did not. She was put back on 6 mg for the next 6 weeks and Azathioprine was commenced as long-term immunosuppression. The patient was intolerant to Azathioprine and has subsequently been maintained on long-term budesonide with good effect. <h3>Conclusion</h3> MR scanning has been shown extensively to be very effective in diagnosing Crohn9s disease including staging disease activity and complications (fistulating disease etc).1 High-resolution ultrasonography has also been shown to be a valuable tool for detecting small intestinal Crohn9s disease. It has similar diagnostic values as CT. In early disease the sensitivity substantially decreases. In known Crohn9s disease for following disease course, evaluating relapses and extraintestinal manifestations US is an excellent tool.2 This case highlights the dilemma of diagnosis vs management. The pragmatic approach taken here of treating this patient for Crohn9s disease without a clear diagnosis is controversial as the long-term use of immunosuppression is not without risk. However, the treatment has allowed the patient to be symptom free for the first time in 2–3 years and she is willing to take the risks of treatment.
Abstract 4911: Mutually exclusive FGFR2, HER2, and KRAS gene amplifications in gastric cancer revealed by multicolor FISH
Authors: Kakoli Das, Bavani Gunasegaran, Iain Beehuat Tan, Niantao Deng, Kiat Hon Lim, Patrick Tan
Journal: Cancer Research (2015)

Abstract Gastric cancer (GC) is a major cause of global cancer mortality. Previous genomic studies have reported that several RTK-RAS pathway components are amplified in GC, with individual tumours often amplifying one component and not others (“mutual exclusivity”). Here, we sought to validate these findings for three RTK/RAS components (FGFR2, HER2, KRAS) using fluorescence in situ hybridization (FISH) on a series of gastric tumours, cell lines and patient-derived xenografts. Applying dual-colour FISH on 137 gastric tumours (89 FFPE surgical resections and 48 diagnostic biopsies), we observed FGFR2 amplification in 7.3% and HER2 amplification in 2.2% of GCs. GCs exhibiting FGFR2 amplification were associated with high tumour grade (p = 0.034). In FISH positive tumours, striking differences in copy number levels between cancer cells in the same tumour were observed, suggesting intra-tumour heterogeneity. Using a multicolour FISH assay allowing simultaneous detection of FGFR2, HER2, and KRAS amplifications, we confirmed that these components exhibited a mutually exclusive pattern of gene amplification across patients. The FISH data was also strongly correlated with Q-PCR levels and at the protein level by immunohistochemistry. Our data confirms that RTK/RAS components are mutually exclusively amplified in GC, and demonstrates the feasibility of identifying multiple aneuploidies using a single FISH assay. Application of this assay to GC samples, particularly diagnostic biopsies, may facilitate enrollment of GC patients into clinical trials evaluating RTK/RAS directed therapies. However, the presence of intra-tumour heterogeneity may require multiple biopsy samples to be obtained per patient, before a definitive diagnosis can be attained. Citation Format: Kakoli Das, Bavani Gunasegaran, Iain Beehuat Tan, Niantao Deng, Kiat Hon Lim, Patrick Tan. Mutually exclusive FGFR2, HER2, and KRAS gene amplifications in gastric cancer revealed by multicolor FISH. [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 4911. doi:10.1158/1538-7445.AM2015-4911
Correlation Between Soluble Vascular Endothelial Growth Factor-a and Vascular Endothelial Growth Factor-Receptor 1 with Response to Chemotherapy in Childhood Acute Leukemia
Authors: Mitra Mehrazma, Khadije Arjomandi Rafsanjani, Behzad Torkamanipoor, Manoutchehr Keyhani
Journal: Blood (2008)
ROS1 rearrangement in lung adenocarcinoma: a retrospective cohort study
Authors: C. Bennati, R. Chiari, L. Marcomigni, V. Minotti, M. Giulio, C. Scafati, R. Matocci, G. Bellezza, S. Baglivo, D. Colabrese, L. Crinò
Journal: Annals of Oncology (2015)
Abstract 725: Restoration of miR-100 sensitizes luminal A breast cancer to paclitaxel treatment by targeting mTOR
Authors: Baotong Zhang, Ranran Zhao, Yuan He, Xing Fu, Jin-Tang Dong
Journal: Cancer Research (2015)

Abstract Based on molecular profiling, immunohistochemical detection of ERα, PR and Her2, and morphological evaluation, breast cancer is classified into five subtypes: Luminal A, Luminal B, Her2, Basal-like, and Normal-like. Each subtype has distinct prognosis and treatment response. The luminal A subtype nicely responds to endocrine therapy with a good prognosis, but is less responsive to chemotherapies including paclitaxel. According to a previous study, patients with luminal A breast cancer do not benefit from the addition of paclitaxel to their chemotherapies, but the underlying mechanisms are still not clear. We found that the expression of miRNA miR-100 is dramatically lower in luminal breast cancer cell lines compared to the basal-like subtype. In human breast cancer specimens, while miR-100 expression was downregulated when compared to the matched normal breast tissues, the downregulation in luminal A subtype tumors was more dramatic when compared to other subtypes. We therefore propose that lower levels of miR-100 expression could be responsible for decreased sensitivity of luminal A breast cancer to paclitaxel. To test this hypothesis, we expressed miR-100 in the MCF-7 luminal A breast cancer cell line, and found that expression of miR-100 sensitized MCF-7 cells to paclitaxel treatment by promoting paclitaxel-induced apoptosis and cell cycle arrest. We also suppressed miR-100 expression in the MDA-MB-231 basal-like cell line, and found that miR-100 downregulation desensitized MDA-MB-231 cells to paclitaxel. Tumorigenesis experiments in nude mice further support a role of miR-100 in luminal breast cancer's response to paclitaxel treatment. mTOR, an important player in the PI3K/mTOR signaling pathway, has been identified as a downstream target of miR-100, and combination of rapamycin, a mTOR inhibitor, with paclitaxel enhances the effect of chemotherapy in breast cancer. We found that miR-100 expression inhibited mTOR expression in MCF-7 cells, while suppression of miR-100 increased mTOR expression in MDA-MB-231 cells. These results suggest that miR-100 sensitizes luminal A breast cancer cells to paclitaxel via targeting mTOR. They also provide an explanation for the resistance of luminal A breast cancer to paclitaxel treatment. Citation Format: Baotong Zhang, Ranran Zhao, Yuan He, Xing Fu, Jin-Tang Dong. Restoration of miR-100 sensitizes luminal A breast cancer to paclitaxel treatment by targeting mTOR. [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 725. doi:10.1158/1538-7445.AM2015-725