tbuckley/cabot-search huggingface dataset:
Pretreatment platelets count levels as a prognostic factor in triple-negative breast cancer in a Hispanic cohort.
Authors: Saul Campos Gomez, Marlid Cruz, Rodrigo Serrano Ortiz, Miguel Machado Reyes, Beatriz Soto Sanchez, Jesus Hernandez Alvarez, Jose Luis Barrera Franco, Paula Cabrera
Journal: Journal of Clinical Oncology (2014)

1115 Background: Platelet count has been reported to have predictive value in various cancer entities. Several studies suggest a negative impact of thrombocytosis for patient's survival in different types of cancer. In the case of breast cancer, evidence about involvement of platelets is still inconclusive. Therefore, the aim of our study was to assess the influence of pretreatment platelet count levels on survival and establish its prognostic relevance for breast cancer patients in a large cohort of triple negative breast cancer patients. Methods: We retrospectively studied patients diagnosed with primary triple negative breast cancer that had completed all phases of primary treatment from 2005 to 2012, finding 118 patients with platelet counts prior to therapy and clinical follow-up. Baseline platelet numbers were evaluated at diagnosis (before the start of any therapy for disease). Platelet levels were categorized into the following three groups: normal low (< 200 g/L), normal high (200-400 g/L) and thrombocytosis (> 400 g/L). Overall survival (OS) was assessed using the Kaplan-Meier method and were compared using the LogRank test. To evaluate the independent prognostic significance of NLR, multivariate Cox regression models were used. Results: Patients with lower platelets count (< 200 g/L) showed significantly lower median overall survival than those with normal high (200-300 g/L) and thrombocytosis (> 400 g/L) (33 months vs. 71 months, log Rank p=0.024). Pretreatment thrombocytosis was observed only in 9 patients (7.6%). Low platelets counts along with advanced stage were independently correlated with poor prognosis, with hazard ratio 1.2 (p 0.02), and 2.1 (p 0.001), respectively. Estimated media OS, for patients with low platelets count, normal high count and thrombocytosis were 56, 38 and 36 months respectively. Conclusions: In our retrospective study, normal low platelet counts at time of diagnosis were associated with poor prognosis in triple negative breast cancer. We hypothesize that platelets in normal high levels as scavenger of VEGF and therefore as a potent antiangiogenic cellular component of the tumor microvasculature in triple negative breast cancer can also be considered.
PK/PD modeling of biomarker (p-ERK) response and tumor growth to PD 0325901 in a human tumor xenograft mouse model
Authors: Jeffrey R. Koup, Jing Liu, Cho-Ming Loi, Curtis Howard, Keri Van Becelaere, Sally Przybranowski, Justin Walton, Judith Sebolt-Leopold, Ronald Merriman
Journal: Cancer Research (2004)

5409  PD0325901 is a potent, specific, and orally bioavailable inhibitor of MEK (MAP [mitogen-activated protein] Kinase/ERK Kinase). Inhibition of MEK blocks MEK-mediated phosphorylation of ERK1/2 (MAPK), resulting in inhibition of tumor growth. Experiments were conducted with PD 0325901 in SCID mice implanted with BxPC3, HT29, MiaPaCa2 and Colo205 tumor xenografts to evaluate PK/PD and efficacy relationships. Mice were treated with PD 0325901 for 14 days at doses selected to encompass ED50’s for each tumor type. A subset of mice were sacrificed following 5-days of treatment with PD 0325901 at 1, 4, 8, and 24 hours post-dose to determine plasma PD 0325901 concentrations and ERK1/2 phosphorylation (p-ERK) in tumor for PK/PD evaluation. Tumor mass was evaluated during and following drug administration until tumor mass had reached 750 mg in each mouse. The response of tumor concentration of p-ERK to plasma PD 0325901 concentration was modeled using an inhibitory sigmoid Emax, indirect response PK/PD model. Tumor Growth was modeled using an exponential growth model (including inhibitory Emax reduction of the growth rate constant by tumor mass, and drug concentration). In addition it was necessary to include an effect site compartment in the model to account for lags between changes in drug concentration and growth rate constant. Plasma PD 0325901 concentrations were adequately described by a one compartment linear pharmacokinetic model. Across all tumor types and pharmacodynamic responses evaluated, plasma concentrations of 100 ng/mL demonstrate significant (i.e. at or above IC50 values) activity. Inhibition of p-ERK was rapidly reversible as plasma PD 0325901 concentrations declined. Simulation of human p-ERK response, using predicted human PK parameters indicated that twice daily dosing may be required to maintain near maximal suppression of p-ERK throughout the dosing interval in patients. For three tumor types suppression of tumor growth lagged significantly behind changes in plasma PD 0325901 concentrations, but for the HT-29 tumor, suppression of tumor growth rate appears to be rapidly reversible. Thus, for optimal suppression of p-ERK and tumor growth in this more resistant tumor, twice daily dosing may enhance therapeutic effectiveness.
Re-emergence of yaws after single mass azithromycin treatment followed by targeted treatment: a longitudinal study
Authors: Oriol Mitjà, Charmie Godornes, Wendy Houinei, August Kapa, Raymond Paru, Haina Abel, Camila González-Beiras, Sibauk V Bieb, James Wangi, Alyssa E Barry, Sergi Sanz, Quique Bassat, Sheila A Lukehart
Journal: The Lancet (2018)
Treatment Characteristics and Deep Molecular Response in Chronic Phase - Chronic Myeloid Leukemia Patients Treated with Second-Line Nilotinib or Dasatinib: A Multi-Country Retrospective Chart Review Study
Authors: Jorge E. Cortes, Lynn Huynh, Estella Mendelson, Patricia Brandt, Darshan Dalal, Maral Dersarkissian, Diego Cortina, Sahil Narkhede, Mei Sheng Duh
Journal: Blood (2017)
Circular RNA circ-ITCH inhibits bladder cancer progression by sponging miR-17/miR-224 and regulating p21, PTEN expression
Authors: Chengdi Yang, Wenbo Yuan, Xiao Yang, Peng Li, Jingzi Wang, Jie Han, Jun Tao, Pengchao Li, Haiwei Yang, Qiang Lv, Wei Zhang
Journal: Molecular Cancer (2018)

Circ-ITCH is a circRNA generated from several exons of itchy E3 ubiquitin protein ligase (ITCH) and tumor suppressor served as a sponge for certain miRNAs targeting their parental transcripts of ITCH. However, the role of circ-ITCH in bladder cancer (BCa) was not reported. In the present study, we investigated the role of circ-ITCH in BCa. Quantitative real-time PCR was used to detect the expression of circ-ITCH and survival analysis was adopted to explore the association between circ-ITCH expression and the prognosis of BCa. BCa cells were stably transfected with lentivirus approach and cell proliferation, migration, invasion, cell cycle and cell apoptosis, as well as tumorigenesis in nude mice were performed to assess the effect of circ-ITCH in BCa. Biotin-coupled probe pull down assay, Biotin-coupled miRNA capture, Fluorescence in situ hybridization and Luciferase reporter assay were conducted to confirm the relationship between the circ-ITCH and the microRNA. In the present study, we found that circ-ITCH, is down-regulated in BCa tissues and cell lines. BCa patients with low circ-ITCH expression had shortened survival. Enforced- expression of circ-ITCH inhibited cells proliferation, migration, invasion and metastasis both in vitro and in vivo. Mechanistically, we demonstrated that circ-ITCH up-regulates the expression of miR-17 and miR-224 target gene p21 and PTEN through 'sponging' miR-17 and miR-224, which suppressed the aggressive biological behaviors of BCa. circ-ITCH acts as a tumor suppressor by a novel circ-ITCH/miR-17, miR-224/p21, PTEN axis, which may provide a potential biomarker and therapeutic target for the management of BCa.
Antigen Presentation by Extracellular Vesicles from Professional Antigen-Presenting Cells
Authors: Marthe F.S. Lindenbergh, Willem Stoorvogel
Journal: Annual Review of Immunology (2018)

The initiation and maintenance of adaptive immunity require multifaceted modes of communication between different types of immune cells, including direct intercellular contact, secreted soluble signaling molecules, and extracellular vesicles (EVs). EVs can be formed as microvesicles directly pinched off from the plasma membrane or as exosomes secreted by multivesicular endosomes. Membrane receptors guide EVs to specific target cells, allowing directional transfer of specific and complex signaling cues. EVs are released by most, if not all, immune cells. Depending on the type and status of their originating cell, EVs may facilitate the initiation, expansion, maintenance, or silencing of adaptive immune responses. This review focusses on EVs from professional antigen-presenting cells, their demonstrated and speculated roles, and their potential for cancer immunotherapy.
Endogenous IL-33 Contributes to Kidney Ischemia-Reperfusion Injury as an Alarmin
Authors: Maroua Ferhat, Aurélie Robin, Sébastien Giraud, Sandra Sena, Jean-Michel Goujon, Guy Touchard, Thierry Hauet, Jean-Philippe Girard, Jean-Marc Gombert, André Herbelin, Antoine Thierry
Journal: Journal of the American Society of Nephrology (2018)

Inflammation is a prominent feature of ischemia-reperfusion injury (IRI), which is characterized by leukocyte infiltration and renal tubular injury. However, signals that initiate these events remain poorly understood. We examined the role of the nuclear alarmin IL-33 in tissue injury and innate immune response triggered by experimental kidney ischemia-reperfusion. In wild-type mice, we found that IL-33 was constitutively expressed throughout the kidney in peritubular and periglomerular spaces, mainly by microvascular endothelial cells, from which it was released immediately during IRI. Compared with wild-type mice, mice lacking IL-33 (IL-33Gt/Gt) exhibited reductions in early tubular cell injury and subsequent renal infiltration of IFN-γ/IL-17A-producing neutrophils, with preservation of renal functions. This protection associated with decreased renal recruitment of myeloid dendritic cells, natural killer (NK) cells, and invariant natural killer T (iNKT) cells, the latter of which were reported as deleterious in IRI. Increases in the level of circulating IL-12, a key IL-33 cofactor, and the expression of ST2, an IL-33-specific receptor, on the surface of iNKT cells preceded the IL-33- and iNKT cell-dependent phase of neutrophil infiltration. Furthermore, IL-33 directly targeted iNKT cells in vitro, inducing IFN-γ and IL-17A production. We propose that endogenous IL-33 is released as an alarmin and contributes to kidney IRI by promoting iNKT cell recruitment and cytokine production, resulting in neutrophil infiltration and activation at the injury site. Our findings show a novel molecular mediator contributing to innate immune cell recruitment induced by renal ischemia-reperfusion and may provide therapeutic insights into AKI associated with renal transplantation.
Whole-Body Single-Cell Sequencing Reveals Transcriptional Domains in the Annelid Larval Body
Authors: Kaia Achim, Nils Eling, Hernando Martinez Vergara, Paola Yanina Bertucci, Jacob Musser, Pavel Vopalensky, Thibaut Brunet, Paul Collier, Vladimir Benes, John C Marioni, Detlev Arendt
Journal: Molecular Biology and Evolution (2018)

Animal bodies comprise diverse arrays of cells. To characterize cellular identities across an entire body, we have compared the transcriptomes of single cells randomly picked from dissociated whole larvae of the marine annelid Platynereis dumerilii. We identify five transcriptionally distinct groups of differentiated cells, each expressing a unique set of transcription factors and effector genes that implement cellular phenotypes. Spatial mapping of cells into a cellular expression atlas, and wholemount in situ hybridization of group-specific genes reveals spatially coherent transcriptional domains in the larval body, comprising, for example, apical sensory-neurosecretory cells versus neural/epidermal surface cells. These domains represent new, basic subdivisions of the annelid body based entirely on differential gene expression, and are composed of multiple, transcriptionally similar cell types. They do not represent clonal domains, as revealed by developmental lineage analysis. We propose that the transcriptional domains that subdivide the annelid larval body represent families of related cell types that have arisen by evolutionary diversification. Their possible evolutionary conservation makes them a promising tool for evo-devo research.
Pomalidomide Plus Low-Dose Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma and Renal Impairment: Results From a Phase II Trial
Authors: Meletios Dimopoulos, Katja Weisel, Niels W.C.J. van de Donk, Karthik Ramasamy, Barbara Gamberi, Matthew Streetly, Massimo Offidani, Frank Bridoux, Javier de la Rubia, Maria-Victoria Mateos, Antonio Ardizzoia, Elisabeth Kueenburg, Shona Collins, Antonia Di Micco, Barbara Rosettani, Yan Li, Pamela Bacon, Pieter Sonneveld
Journal: Journal of Clinical Oncology (2018)

Purpose Renal impairment (RI) limits treatment options in patients with relapsed/refractory multiple myeloma (RRMM). Here, we prospectively studied pomalidomide plus low-dose dexamethasone (LoDEX) in patients with RRMM and moderate or severe RI, including those receiving hemodialysis. Patients and Methods MM-013, a noncomparative, European phase II trial, enrolled three patient cohorts: moderate RI (cohort A; estimated glomerular filtration rate, 30 to < 45 mL/min/1.73 m2); severe RI (cohort B; estimated glomerular filtration rate, < 30 mL/min/1.73 m2); and severe RI that requires hemodialysis (cohort C). Patients received pomalidomide 4 mg/d on days 1 to 21 and LoDEX 20 or 40 mg once per week in 28-day cycles. The primary end point was overall response rate. Results Of 81 enrolled patients (33, 34, and 14 patients in cohorts A, B, and C, respectively), 13 were still receiving treatment at data cutoff (January 28, 2017). Overall response rates were 39.4%, 32.4%, and 14.3%, with a median duration of response of 14.7 months, 4.6 months, and not estimable, respectively. Of importance, 100%, 79.4%, and 78.6% of patients, respectively, achieved disease control. With a median follow-up of 8.6 months, median overall survival was 16.4 months, 11.8 months, and 5.2 months, respectively. Complete renal responses were observed only in cohort A (18.2%), and no patients in cohort C became hemodialysis independent. Grade 3 and 4 hematologic treatment-emergent adverse events and pomalidomide discontinuations as a result of treatment-emergent adverse events occurred more frequently in cohort C. Pomalidomide pharmacokinetics were comparable among the three renal cohorts. Conclusion Pomalidomide 4 mg/d plus LoDEX is efficacious in patients with RRMM with moderate or severe RI, including those who had more advanced disease and required hemodialysis. The safety profile was acceptable among the three groups, and no new safety signals were observed.
Immune evasion via PD-1/PD-L1 on NK cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL
Authors: Frank Vari, David Arpon, Colm Keane, Mark S. Hertzberg, Dipti Talaulikar, Sanjiv Jain, Qingyan Cui, Erica Han, Josh Tobin, Robert Bird, Donna Cross, Annette Hernandez, Clare Gould, Simone Birch, Maher K. Gandhi
Journal: Blood (2018)
Intra-Atrial Dyssynchrony During Sinus Rhythm Predicts Recurrence After the First Catheter Ablation for Atrial Fibrillation
Authors: Luisa Ciuffo, Susumu Tao, Esra Gucuk Ipek, Tarek Zghaib, Muhammad Balouch, Joao A.C. Lima, Saman Nazarian, David D. Spragg, Joseph E. Marine, Ronald D. Berger, Hugh Calkins, Hiroshi Ashikaga
Journal: JACC. Cardiovascular imaging (2018)
Palmitic Acid Hydroxystearic Acids Activate GPR40, Which Is Involved in Their Beneficial Effects on Glucose Homeostasis
Authors: Ismail Syed, Jennifer Lee, Pedro M. Moraes-Vieira, Cynthia J. Donaldson, Alexandra Sontheimer, Pratik Aryal, Kerry Wellenstein, Matthew J. Kolar, Andrew T. Nelson, Dionicio Siegel, Jacek Mokrosinski, I. Sadaf Farooqi, Juan Juan Zhao, Mark M. Yore, Odile D. Peroni, Alan Saghatelian, Barbara B. Kahn
Journal: Cell Metabolism (2018)
Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis
Authors: Lai Man Natalie Wu, Yaqi Deng, Jincheng Wang, Chuntao Zhao, Jiajia Wang, Rohit Rao, Lingli Xu, Wenhao Zhou, Kwangmin Choi, Tilat A. Rizvi, Marc Remke, Joshua B. Rubin, Randy L. Johnson, Thomas J. Carroll, Anat O. Stemmer-Rachamimov, Jianqiang Wu, Yi Zheng, Mei Xin, Nancy Ratner, Q. Richard Lu
Journal: Cancer Cell (2018)
Susceptibility of Neisseria gonorrhoeae to azithromycin and ceftriaxone in China: A retrospective study of national surveillance data from 2013 to 2016
Authors: Yue-Ping Yin, Yan Han, Xiu-Qin Dai, He-Ping Zheng, Shao-Chun Chen, Bang-Yong Zhu, Gang Yong, Na Zhong, Li-Hua Hu, Wen-Ling Cao, Zhong-Jie Zheng, Feng Wang, Qi Zhi, Xiao-Yu Zhu, Xiang-Sheng Chen
Journal: PLoS Medicine (2018)

Background Gonorrhea remains one of the most common sexually transmitted diseases worldwide. Successful treatment has been hampered by emerging resistance to each of the antibiotics recommended as first-line therapies. We retrospectively analyzed the susceptibility of gonorrhea to azithromycin and ceftriaxone using data from the China Gonococcal Resistance Surveillance Programme (China-GRSP) in order to provide evidence for updating the treatment recommendations in China. Methods and findings In this study, we included 3,849 isolates collected from patients with a confirmed positive Neisseria gonorrhoeae (N. gonorrhoeae) culture at clinic visits during the period of 1 January 2013 through 31 December 2016 in 7 provinces. Antimicrobial susceptibility testing of gonorrhea isolates using agar dilution was conducted to determine minimum inhibitory concentration (MIC). Resistance to azithromycin (RTA) was defined as MIC ≥ 1.0 mg/l, and decreased susceptibility to ceftriaxone (DSC) was defined as MIC ≥ 0.125 mg/l. The prevalence of isolates with RTA was 18.6% (710/3,827; 95% CI 17.4%–19.8%). The percentage of patients with DSC fluctuated between 9.7% and 12.2% over this period. The overall prevalence of isolates with both RTA and DSC was 2.3% (87/3,827; 95% CI 1.9%–2.8%) and it increased from 1.9% in 2013 to 3.3% in 2016 (chi-squared test for trend, P = 0.03). Study limitations include the retrospective study design and potential biases in the sample, which may overrepresent men with symptomatic infection, coastal residents, and people reporting as heterosexual. Conclusions To our knowledge, this is the first national study on susceptibility of N. gonorrhoeae to azithromycin and ceftriaxone in China. Our findings indicate high rates of RTA and DSC from 2013 to 2016. Although dual therapy with azithromycin and ceftriaxone has been recommended by WHO and many countries to treat gonorrhea, reevaluation of this therapy is needed prior to its introduction in China.
Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes
Authors: David A. Ostrov, Aimon Alkanani, Kristen A. McDaniel, Stephanie Case, Erin E. Baschal, Laura Pyle, Sam Ellis, Bernadette Pöllinger, Katherine J. Seidl, Viral N. Shah, Satish K. Garg, Mark A. Atkinson, Peter A. Gottlieb, Aaron W. Michels
Journal: Journal of Clinical Investigation (2018)

Major histocompatibility (MHC) class II molecules are strongly associated with many autoimmune disorders. In type 1 diabetes (T1D), the DQ8 molecule is common, confers significant disease risk, and is involved in disease pathogenesis. We hypothesized that blocking DQ8 antigen presentation would provide therapeutic benefit by preventing recognition of self-peptides by pathogenic T cells. We used the crystal structure of DQ8 to select drug-like small molecules predicted to bind structural pockets in the MHC antigen–binding cleft. A limited number of the predicted compounds inhibited DQ8 antigen presentation in vitro, with 1 compound preventing insulin autoantibody production and delaying diabetes onset in an animal model of spontaneous autoimmune diabetes. An existing drug with a similar structure, methyldopa, specifically blocked DQ8 in patients with recent-onset T1D and reduced inflammatory T cell responses to insulin, highlighting the relevance of blocking disease-specific MHC class II antigen presentation to treat autoimmunity.
Abstract 13295: Interaction Between Neural and Peripheral Effects of Intravenous Guanfacine in Determining Arterial Pressure and Sympathetic Nerve Activity
Authors: Toru Kawada, Shuji Shimizu, Masafumi Fukumitsu, Meihua Li, Can Zheng, Kazunori Uemura, Masaru Sugimachi
Journal: Circulation (2015)

Introduction: Guanfacine is a selective α 2A -adrenergic agonist and suppresses sympathetic nerve activity (SNA) by acting on the central nervous system. In the use of intravenous guanfacine in animal experiments, however, arterial pressure (AP) does not necessarily fall much even when SNA is markedly suppressed. Hypothesis: Intravenous guanfacine may act on peripheral α-adrenergic receptors to increase AP at a given SNA. Methods: To separately assess the neural and peripheral effects of intravenous guanfacine, an open-loop analysis of the carotid sinus baroreflex was performed in 7 anesthetized Wistar-Kyoto rats. Carotid sinus pressure was changed from 60 to 180 mmHg in a staircase manner while steady-state SNA and AP were measured. Effects of intravenous guanfacine (100 μg/kg, bolus) on the baroreflex response was examined. Results: As shown in the figure, the neural arc of the baroreflex approximated a sigmoid curve. Guanfacine reduced the response range of the neural arc from 89.8±2.2% to 32.9±10.9% (P&lt;0.01) and the minimum SNA from 11.6±1.9% to 2.4±1.2% (P&lt;0.01). The peripheral arc of the baroreflex approximated a straight line. Guanfacine increased the intercept from 67.6±7.1 to 92.8±8.5 mmHg (P&lt;0.01) without significantly affecting the slope of AP versus SNA. The operating point of the baroreflex was determined from the intersection between the neural and peripheral arcs on the baroreflex equilibrium diagram (denoted by a double circle). The operating-point SNA decreased from 47.5±6.0% to 13.6±3.9% (P&lt;0.01) whereas the operating-point AP was not decreased significantly (from 114.7±4.3 to 109.0±7.1 mmHg). Conclusions: The operating-point AP and SNA are determined through the interaction between the neural and peripheral effects of intravenous guanfacine. While the operating-point SNA was significantly decreased, the operating-point AP was relatively maintained via the peripheral effect.
Chromatin organisation and cancer prognosis: a pan-cancer study
Authors: Andreas Kleppe, Fritz Albregtsen, Ljiljana Vlatkovic, Manohar Pradhan, Birgitte Nielsen, Tarjei S Hveem, Hanne A Askautrud, Gunnar B Kristensen, Arild Nesbakken, Jone Trovik, Håkon Wæhre, Ian Tomlinson, Neil A Shepherd, Marco Novelli, David J Kerr, Håvard E Danielsen
Journal: The Lancet Oncology (2018)

Chromatin organisation affects gene expression and regional mutation frequencies and contributes to carcinogenesis. Aberrant organisation of DNA has been correlated with cancer prognosis in analyses of the chromatin component of tumour cell nuclei using image texture analysis. As yet, the methodology has not been sufficiently validated to permit its clinical application. We aimed to define and validate a novel prognostic biomarker for the automatic detection of heterogeneous chromatin organisation.
ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors)
Authors: K.L. Winthrop, X. Mariette, J.T. Silva, E. Benamu, L.H. Calabrese, A. Dumusc, J.S. Smolen, J.M. Aguado, M. Fernández-Ruiz
Journal: Clinical Microbiology and Infection (2018)