tbuckley/cabot-search huggingface dataset:
A multivariate longitudinal algorithm for early detection of ovarian cancer using multiple biomarkers.
Authors: Z. Zhang, S. J. Skates, L. J. Sokoll, Z. Lu, C. H. Clarke, M. A. Hernandez, K. H. Lu, R. C. Bast
Journal: Journal of Clinical Oncology (2011)

5031 Background: Sequential measurements of CA125 have been used in a longitudinal algorithm to assess the risk of ovarian cancer. Rising CA125 followed by transvaginal sonography can achieve high specificity (99.6%) and positive predictive value (36%), but as 20% of ovarian cancers do not express CA125, sensitivity will not be optimal for preclinical disease. Multiple biomarkers may have greater sensitivity than CA125 alone. We developed and evaluated an algorithm that estimates risk of ovarian cancer using multiple biomarkers measured annually. Methods: Serum levels of CA125, CA15.3, CA72.4, CA19.9, and HE4 were evaluated in samples from the MDACC SPORE normal risk ovarian screening study (NROSS) and the GOG. The NROSS included 5 annual samples from 197 women for whom ovarian cancer was not detected and 9 cases (3 invasive ovarian cancer, 3 LMP ovarian cancer, 3 benign). The GOG contained preoperative sera from 95 Stage I ovarian cancer cases. 100 randomly selected controls together with the surgically evaluated cases in NROSS were used for model derivation. The remaining 97 from NROSS and the GOG cases were used for validation. The biomarkers were combined into a composite index using the UMSA learning algorithm. A simple longitudinal algorithm was then applied to assess the risk of cancer using both the composite index and CA125 at 98% specificity so that no more than 2% of women screened would be referred to ultrasound. Results: At a weighted average annual specificity of 98% on the first 5 time points of the longitudinal samples, the model’s sensitivity in detecting the GOG stage I cases was 81.1% (77/95). This compares favorably to a sensitivity of 73.7% (70/95) using CA125 alone at the same 5 year weighted annual specificity (p < 0.02). In longitudinal use of the composite index, the algorithm was able to detect all the ovarian cancer cases (3 invasive, 3 LMP) among the 9 surgically evaluated cases while maintaining a yearly average specificity of 98%. Conclusions: Multiple biomarkers can be combined in a longitudinal algorithm to improve detection of early stage ovarian cancer. Additional sample sets that include independent samples of longitudinally detected cancer cases will be needed to further validate the algorithm.
Neoadjuvant Therapy for Rectal Cancer Affects Lymph Node Yield and Status Without Clear Implications on Outcome: The Case for Eliminating a Metric and Using Preoperative Staging to Guide Therapy
Authors: Sherif R. Z. Abdel-Misih, Lai Wei, Al B. Benson, Steven Cohen, Lily Lai, John Skibber, Neal Wilkinson, Martin Weiser, Deborah Schrag, Tanios Bekaii-Saab
Journal: Journal of the National Comprehensive Cancer Network (2016)

Background: Nodal status has long been considered pivotal to oncologic care, staging, and management. This has resulted in the establishment of rudimentary metrics regarding adequate lymph node yield in colon and rectal cancers for accurate cancer staging. In the era of neoadjuvant treatment, the implications of lymph node yield and status on patient outcomes remains unclear. Patient and Methods: This study included 1,680 patients with locally advanced rectal cancer from the NCCN prospective oncology database stratified into 3 groups based on preoperative therapy received: no neoadjuvant therapy, neoadjuvant chemoradiation, and neoadjuvant chemotherapy. Clinicopathologic characteristics and survival were compared between the groups, with univariate and multivariate analyses undertaken. Results: The clinicopathologic characteristics demonstrated statistically significant differences and heterogeneity among the 3 groups. The neoadjuvant chemoradiation group demonstrated the statistically lowest median lymph node yield (n=15) compared with 17 and 18 for no-neoadjuvant and neoadjuvant chemotherapy, respectively (P<.0001). Neoadjuvant treatment did impact survival, with chemoradiation demonstrating increased median overall survival of 42.7 compared with 37.3 and 26.6 months for neoadjuvant chemotherapy and no-neoadjuvant therapy, respectively (P<.0001). Patients with a yield of fewer than 12 lymph nodes had improved median overall survival of 43.3 months compared with 36.6 months in patients with 12 or more lymph nodes (P=.009). Multivariate analysis demonstrated that neither node yield nor status were predictors for overall survival. Discussion: This analysis reiterates that nodal yield in rectal cancer is multifactorial, with neoadjuvant therapy being a significant factor. Node yield and status were not significant predictors of overall survival. A nodal metric may not be clinically relevant in the era of neoadjuvant therapy, and guidelines for perioperative therapy may need reconsideration.
Dysregulated CD4+CD25+ T- Regulatory Cells and TLRs in Myeloma.
Authors: Rao Prabhala, Paola Neri, Pierfrancesco Tassone, Masood A. Shammas, Jooeun Bae, Virginia M. Cumming, Charles K. Allam, John F. Daley, Frank Desarneud, Dharminder Chauhan, Elizabeth Blanchard, Kenneth Anderson, Nikhil C. Munshi
Journal: Blood (2004)
Inhalable oridonin-loaded poly(lactic- co -glycolic)acid large porous microparticles for in situ treatment of primary non-small cell lung cancer
Authors: Lifei Zhu, Miao Li, Xiaoyan Liu, Lina Du, Yiguang Jin
Journal: Acta Pharmaceutica Sinica B (2016)

Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. Traditional chemotherapy for this disease leads to serious side effects. Here we prepared an inhalable oridonin-loaded poly(lactic-
SF1126, a Novel PI3K Inhibitor Results in Downstream Inhibition of the PI3K Axis and Displays Sequence Specific Synergy When Combined with Bortezomib in Multiple Myeloma Cells
Authors: Ebenezer David, Xiaodong Peng, Benjamin G Barwick, Jonathan L Kaufman, Joseph R Garlich, Sagar Lonial
Journal: Blood (2008)
Sarcoidosis in the setting of combination ipilimumab and nivolumab immunotherapy: a case report &amp; review of the literature
Authors: Joshua E. Reuss, Paul R. Kunk, Anne M. Stowman, Alejandro A. Gru, Craig L. Slingluff, Elizabeth M. Gaughan
Journal: Journal for ImmunoTherapy of Cancer (2016)

We report a case of sarcoidosis in a patient with metastatic melanoma managed with combination ipilimumab/nivolumab. Sarcoid development has been linked with single agent immunotherapy but, to our knowledge, it has not been reported with combination ipilimumab/nivolumab treatment. This case raises unique management challenges for both the melanoma and the immunotherapy-related toxicity.A 46 year old Caucasian female with M1c-metastatic melanoma was managed with ipilimumab/nivolumab combination. Patient experienced response in baseline lesions but developed new clinical and radiographic findings. Biopsy of new lesions at two different sites both demonstrated tumefactive sarcoidosis. Staining of the biopsy tissue for PD-L1 expression demonstrated strong PD-L1 staining of the histiocytes and lymphocytes within the granulomas. Monotherapy nivolumab was continued without progression of sarcoid findings or clinical deterioration.Tissue biopsy for evaluation of new lesions on immunotherapy is an important step to help guide decision making, as non-melanoma lesions can mimic disease progression.
Allergen-Specific B Cell Quantity Is Similar in Allergic and Nonallergic Individuals, Whereas Allergen-Specific T Cells May Be Increased in Allergic Individuals
Authors: Faisal Khan, Aito Ueno-Yamanouchi, Bazir Serushago, Tom Bowen, Cathy Lu, Joanne Luider, Jan Storek
Journal: Blood (2008)
B Cell Receptors Of Chlamydophila Psittaci negative MALT Lymphomas Of The Ocular Adnexa Recognize Common Self-Antigens
Authors: Daxing Zhu, Xiaoqing Lu, Marcus Dühren-von Minden, Shruti Bhatt, Chen Lossos, Jennifer R. Chapman-Fredricks, Hendrik Veelken, Hassan Jumaa, Izidore S Lossos
Journal: Blood (2013)
ATM Mutant Lymphoid Tumour Cells Exhibit Impaired Activation of the Redox-Sensitive Nrf2-ARE Detoxification Pathway and Are Differentially Sensitive to Nrf2-Activating Compounds
Authors: Victoria J Weston, Angelo Agathanggelou, Paul AH Moss, Pamela R. Kearns, A. Malcolm R Taylor, Tatjana Stankovic
Journal: Blood (2010)
Thrombolytic Therapy for Reversal of Thrombosis In Paroxysmal Nocturnal Hemoglobinuria (PNH)
Authors: David J Araten, Rosario Notaro, Nancy A Kernan, Farid Boulad, Hugo Castro-Malaspina, Trudy N Small, Andromachi Scaradavou, Heather Magnan, Susan E Prockop, Sara Chaffee, Jason Gonsky, Raymond Thertulien, Roberto Tarquini, Lucio Luzzatto
Journal: Blood (2010)
ACRIN 6665/RTOG 0132 phase II trial of neoadjuvant imatinib mesylate (IM) for primary and recurrent operable malignant GIST: Imaging findings and correlation with genotype and GLUT4 expression
Authors: A. D. Van den Abbeele, C. Gatsonis, D. J. de Vries, Y. Melenevsky, A. Szot Barnes, J. T. Yap, A. K. Godwin, M. Blevins, B. Eisenberg, B. A. Siegel
Journal: Journal of Clinical Oncology (2009)

10552 Background: IM has improved the treatment of GIST patients (pts), but few achieve objective response despite significant clinical benefit. Imaging of tumor metabolism may provide earlier assessment of therapeutic response. In this study, FDG-PET metabolic response (MR) was compared with RECIST, GLUT4 expression, and KIT/PDGFRA mutation status. Methods: FDG-PET was done at baseline, 1–7 days, and 4 or 8 weeks (wk) after IM initiation. Best objective response was defined by RECIST. Immunohistochemical (IHC) tumor GLUT4 expression and mutation analyses were done at baseline and/or surgery. Background-subtracted SUVmax was measured in all lesions and summed; MR based on EORTC criteria was compared to RECIST, GLUT4 expression, and KIT/PDGFRA mutation status. Results: FDG-PET showed high tumor glycolytic activity at baseline (mean SUVmax = 14.2, range: 1.3–53.2), decreasing after 1 wk of IM (5.5, range: 0.5–47.7, p &lt; 0.001, n = 44), and again prior to surgery (3.0, range: 0.5–36.1, p &lt; 0.001, n = 40). FDG-PET response at wk 1 was 3 complete MR (CMR), 33 partial MR (PMR), 6 stable metabolic disease (SMD), and 2 progressive metabolic disease (PMD). Prior to surgery, FDG-PET response was 3 CMR, 33 PMR, 4 SMD, and no PMD. For 39 pts, RECIST best response was 2 PR, 36 SD, and 1 PD. GLUT4 expression decreased in 19 pts with PMR, and 3 with SMD. Among 12 pts with exon 11 mutation, 11 had PMR, 1 SMD; among 5 pts with wild-type genotype, 4 had PMR, and 1 SMD. Conclusions: After IM initiation, MR by FDG-PET was documented earlier (1–7 days), and was of much greater magnitude (36/40) than that documented by RECIST (2/39). IHC data suggest that: (1) GLUT4 plays a role in FDG uptake in GIST; (2) GLUT4 decreases in most pts with PMR; and, (3) the biologic action of IM interacts with glycolysis and GLUT4 expression. No difference in PMR was seen in pts with exon 11 vs. wild type mutations. [Table: see text]
The Microscope as a Tool for Disease Discovery—A Personal Voyage
Authors: Elaine S. Jaffe
Journal: Annual Review of Pathology Mechanisms of Disease (2016)

This review reflects the trajectory of my career in hematopathology, and my personal reflections on scientific advances in the field. During the course of more than 40 years, the approach to classification of hematological malignancies has evolved from descriptive approaches, based on either cytological or clinical features, to a modern approach, which incorporates cutting-edge technologies. My philosophy has focused on defining individual diseases, an approach that can best lead to an understanding of molecular pathogenesis. To quote Carolus Linnaeus ( 1 , p. 19), the father of taxonomy, “The first step in wisdom is to know the things themselves; this notion consists in having a true idea of the objects; objects are distinguished and known by classifying them methodically and giving them appropriate names. Therefore, classification and name-giving will be the foundation of our science.”
Abstract 5278: Mutation in protein tyrosine phosphatase receptor type K (PTPRK) enhances progression of colon cancer through WNT signaling
Authors: Masayuki Tojo, Kazuo Konishi, Keiko Shinjo, Fumiharu Ohka, Keisuke Katushima, Akira Hatanaka, Norihisa Ichimura, Hisako Nozawa, Tomoe Shimazaki, Hitoshi Yoshida, Yutaka Kondo
Journal: Cancer Research (2015)

Abstract Recent comprehensive genome analyses revealed the accumulation of genetic alterations in colorectal cancers (CRCs). However, it is still unknown which genetic alterations are closely associated with certain phenotype of CRCs, such as tumors with highly invasive character regardless of its small size. Here we examined the small invasive CRCs using high-throughput sequencing in order to clarify the common molecular features in those CRCs. Seven small invasive CRCs (types 0-IIa+IIc or 0-Is+IIc, less than 20mm in diameter and with submucosal massive invasion) were examined by exon sequencing. Seven thousands six variants (SNVs and indels) were detected. Among them, PTPRK was frequently mutated (3 cases, 43%; 1 nonsense and 2 missense mutations). We further examined public database (TCGA and COSMIC) and found that 50 of 617 (8.17%) CRCs contain PTPRK mutation. Those cases are frequent in proximal colon, extensively methylated (CIMP-H), microsatellite instability-high (MSI-H) and pathologically mucinous type. Consistent with clinical behavior, invasion assay in CRC cell lines revealed that CRCs with PTPRK domain D1 mutation showed high invasiveness via WNT signaling activity. These data indicate that PTPRK domain D1 mutation contributes to the invasiveness and progression of proximal CRCs, especially CIMP-H and MSI-H cases. Citation Format: Masayuki Tojo, Kazuo Konishi, Keiko Shinjo, Fumiharu Ohka, Keisuke Katushima, Akira Hatanaka, Norihisa Ichimura, Hisako Nozawa, Tomoe Shimazaki, Hitoshi Yoshida, Yutaka Kondo. Mutation in protein tyrosine phosphatase receptor type K (PTPRK) enhances progression of colon cancer through WNT signaling. [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 5278. doi:10.1158/1538-7445.AM2015-5278
Abstract 2313: Characterizing intratumoral cellular heterogeneity in human glioblastoma xenografts by 30+ parameter single-cell mass cytometry
Authors: Erin F. Simonds, Garry P. Nolan, William A. Weiss
Journal: Cancer Research (2015)

Abstract Introduction: Glioblastoma tumors contain dramatic intratumoral heterogeneity at the level of cellular phenotypes. High-parameter single-cell platforms such as mass cytometry offer an opportunity to simultaneously measure tumor subpopulations with unexpected combinations of differentiation markers, as well as stromal cells, vasculature, and infiltrating immune cells. Methods: A subcutaneous patient-derived xenograft from an adult with glioblastoma was enzymatically digested into a single-cell suspension. Half of the cells were treated with epidermal growth factor (EGF) at 20 ng/mL for 15 minutes. Both samples were then stained with a 32-marker antibody panel and measured by single-cell mass cytometry. The antibody panel included surface-expressed markers of stemness and differentiation, as well as intracellular markers to monitor cell cycle, apoptosis, and growth factor signaling. Unsupervised spectral clustering was used to segregate &amp;gt;200,000 tumor cells into 13 tumor cell subsets. Inducible signaling phenotypes were quantified in these subsets by comparing binding of phospho-specific antibodies in the stimulated sample, relative to the unstimulated control. Results: Many previously reported markers of cancer stem cells were detectable, but they did not agree on a single population of cells. Although the CD133+ fraction was rare (&amp;lt;5% of cells), it contained three distinct subpopulations of phenotypically distinct cells. The most informative markers for discriminating the tumor subsets were markers of stemness (i.e. CD133, CD44, Sox2) or integrin expression (i.e. CD49e, CD49f, CD51). The primitive cells (i.e. Sox2+) exhibited higher basal kinase activity across multiple pathways, including markers of cell division (i.e. Histone H3 pSer28). Short-term stimulation with EGF induced distinct responses in each of the different CD133+ subsets. Conclusions: Single-cell phenotyping by mass cytometry produced rich developmental and functional profiles of glioblastoma cell subsets. Subpopulations of primitive (CD133+) cells can exist in a single glioblastoma tumor and exhibit distinct signaling responses to external stimulation. Altogether, these results validate the use of this platform for investigation of the intratumoral cellular heterogeneity of solid neural tumors with this platform. Work is underway to identify correlations between intratumoral cellular phenotypes and upstream driver mutations in a larger cohort. Citation Format: Erin F. Simonds, Garry P. Nolan, William A. Weiss. Characterizing intratumoral cellular heterogeneity in human glioblastoma xenografts by 30+ parameter single-cell mass cytometry. [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 2313. doi:10.1158/1538-7445.AM2015-2313
Nanoparticles for multi-modality cancer diagnosis: Simple protocol for self-assembly of gold nanoclusters mediated by gadolinium ions
Authors: Wenxiu Hou, Fangfang Xia, Gabriel Alfranca, Hao Yan, Xiao Zhi, Yanlei Liu, Chen Peng, Chunlei Zhang, Jesus Martinez de la Fuente, Daxiang Cui
Journal: Biomaterials (2016)
Apicobasal polarity and Ras/Raf/MEK/ERK signalling in cancer
Authors: Juan Peng, Ama Gassama-Diagne
Journal: Gut (2016)

Many glandular epithelia such as the GI tract are composed of a sheet of cells polarised along their apicobasal axes with the apical membrane facing the lumen of the tube and the basolateral membrane binding to neighbouring cells and the basal extracellular matrix (ECM). Generation of these two membrane domains with distinct cellular macromolecular contents (including proteins and lipids) provides the basic building blocks that support tissue architecture and their various functions.1

The apicobasal polarisation of epithelial cells is a complex and multistage programme controlled by a network of proteins and lipids. It is initiated by cues from the ECM and cell–cell contacts that trigger changes to the cytoskeleton and hence the polarised organisation of endosomal trafficking that sort and deliver proteins and lipids to the apical and basolateral membrane domains. These events lead to the establishment of cell–cell junctional complexes comprising tight and adherens junctions2 (figure 1A). The establishment of polarity also requires the proper assembly and localisation of a set of evolutionarily conserved polarity proteins. These include the Par3/Par6/atypical protein kinase C (aPKC) and Crumbs/protein associated with Caenorhabditis elegans Lin-7 protein (PALS)/PALS1-associated TJ protein (PATJ) complexes that are mainly found apically. The Scribble/discs large (Dlg)/lethal giant larvae (Lgl) complex is located on the lateral surface of the cell2 (figure 1A). Another Par protein is liver kinase b1 (Lkb1, or Par4), which phosphorylates and activates a family of AMP-activated protein kinases to regulate cell growth, metabolism and polarity.1 Class I isoforms of phosphoinositide 3-kinases (PI3K)3 and their antagonising phosphatases phosphatase and tensin homologue4 (PTEN)) and SH2 domain containing inositol 5-phosphatase 25 (SHIP2) are crucial determinants of apicobasal polarity (figure 1A).



Figure 1 
Disruption of apicobasal polarity in cancer. (A) Major determinants of polarity in epithelial cells. (1) Normal simple glandular epitheliums …
Quantitative Assessment of Translocation Transcript Ratio Predicts for Relapse Free Survival Among Patients with Core Binding Factor Acute Myeloid Leukemia
Authors: Thuyvan Hoang, Wei Qiao, Jorge E. Cortes, Keyur Patel, Farhad Ravandi, Tapan M. Kadia, Mark Brandt, Raja Luthra, Hagop M. Kantarjian, Gautam Borthakur
Journal: Blood (2014)
561. Staphyloccocus aureus Cas9: An Alternative Cas9 for Genome Editing Applications
Authors: Ari E. Friedland, Alex Sousa, McKensie Collins, Morgan L. Maeder, Hari Jayaram, Grant G. Welstead, Sebastian Gloskowski, David Bumcrot
Journal: Molecular Therapy (2015)

The CRISPR/Cas9 system that is broadly used for genome editing in myriad model organisms and cell lines is derived from the bacterial species Streptoccocus pyogenes. Here we report the use and characterization of another Type II CRISPR endonuclease Cas9, from the bacterium Staphylococcus aureus. This Cas9, encoded by ≈3.2kb of DNA, is substantially smaller than the S. pyogenes Cas9 yet delivers comparable DNA cleavage rates as measured by NHEJ-induced inserts and deletions in HEK293T cells. The S. aureus Cas9 has a Protospacer Adjacent Motif (PAM) that is well defined and different from the S. pyogenes Cas9 PAM, thus extending the range of specific target sites for any locus of interest. We characterize single guide RNAs specific to the S. aureus Cas9 with a range in the length of targeting sequences, investigating differences in on-target DNA cleavage efficiency as well as off-target activity. Off target activity assays include detection of cleavage events at chromosomally-integrated target sequences and at endogenous loci genome-wide. Taken together, our results show that the S. aureus Cas9 is an effective tool for genome editing with properties similar to but distinct from the more widely used S. pyogenes Cas9.
584. Myoblast Fusion Mediates Morpholino Entry and Exon Skipping In Dystrophic Muscle
Authors: James S. Novak, Marie Nearing, Marshall W. Hogarth, Maria C. Vila, Jessica F. Boehler, Eric P. Hoffman, Kanneboyina Nagaraju, Sebahattin Cirak, Terence A. Partridge
Journal: Molecular Therapy (2016)

Duchenne muscular dystrophy (DMD) is a severe, progressive, X-linked myopathy involving cycles of muscle cell degeneration, regeneration, and inflammation. DMD results from mutations in the dystrophin gene that result in a consequent failure to translate dystrophin protein. Exon skipping is a promising therapeutic strategy employing antisense oligonucleotides (AO) to exclude exons that disrupt the open reading frame, so as to produce a truncated, partially functional dystrophin protein. Several different AOs, including the phosphorodiamidate morpholino (PMO) and the 2'O-methyl phosphorothioate (2'OMe), have been shown to induce dystrophin expression and are currently being investigated in clinical trials. However, drug uptake and efficacy is inconsistent and highly-variable between and within individual muscles. Our objective was to identify factors within dystrophic muscle responsible for the observed variability in myofiber penetration, exon skipping, and dystrophin expression following systemic AO administration. Specifically, we investigated the role of myofiber regeneration on exon skipping. By treating dystrophin-null mdx mice with a single high-dose of the PMO together with staggered pulses of bromodeoxyuridine (BrdU) we can precisely identify timeframes of myocyte proliferation and relate this to the efficiency of PMO delivery. Initially, we utilized a tagged-PMO to track its efficiency of entry into muscle fibers and determine how long after administration it persists. Intriguingly, we observed that the efficiency of entry of PMO into myofibers is strongly associated with the late stages of differentiation and fusion of satellite cells into regenerating dystrophic mdx myofibers. We also observed a specific co-localization of BrdU-positive myonuclei with dystrophin-positive myofibers when the pulse of BrdU immediately preceded PMO delivery, implying that satellite cell proliferation and fusion into regenerating myofibers play a crucial role in the effectiveness of PMO-mediated exon skipping. Our investigation of the mechanisms involved in PMO uptake and efficacy will provide valuable insights for optimizing protocols for this promising approach to therapy for DMD.