tbuckley/cabot-search huggingface dataset:
Abstract 12518: MicroRNA 139-5p Coordinates APLNR-CXCR4 Crosstalk During Vascular Maturation
Authors: Irinna Papangeli, Jongmin Kim, Inna Maier, Yujung Kang, Keiichiro Tanaka, Hyekyung Ju, Aram Lee, Yoko Kojima, Arndt Siekmann, Hyung Chun
Journal: Circulation (2015)

Rationale: Sprouting angiogenesis is governed by the concept of tip/stalk cells that guides our understanding of the transition from vascular sprouting to maturation and ultimately quiescence. The VEGF and Notch signaling pathways have been extensively described in regulating the discrimination between these two cell populations. However, several additional tip and stalk cell specific genes have been identified. To date, unresolved questions remain, and our understanding of the mechanisms by which these signaling processes are integrated is incomplete. Objective: We set out to investigate novel mechanisms by which signaling pathways involving two G protein coupled receptors (GPCRs), expressed in a mutually exclusive fashion in the tip/stalk cell populations, are intricately linked in vascular development. Methods/Results: Using a combination of in vivo and in vitro techniques, we demonstrate the critical role of crosstalk between APLNR and CXCR4 in vascular maturation. We show robust flow induced expression of the stalk cell specific APLNR, that leads to marked suppression of CXCR4 expression, a mechanism to achieve tip cell restricted expression of the latter. Retinas from Apln (ligand), Aplnr (receptor) and endothelial specific Aplnr deleted mice show retarded vascular expansion, reduced vascularized area and fewer vascular branch points. These phenotypes are in part due to increased expression of Cxcr4 in Apln-/- and Aplnr-/- retinal vessels as Cxcr4 inhibition through a selective inhibitor can ameliorate the Aplnr phenotype. The crosstalk between the two GPCRs was found to involve a key shear responsive microRNA, miR-139-5p, which is upregulated by APLN/APLNR signaling and directly targets CXCR4 in endothelial cells. In accordance, Apln-/- and Aplnr-/- retinal endothelial cells showed depleted levels of miR-139-5p. Lastly, we demonstrate that atorvastatin, an HMG-CoA reductase inhibitor shown to enhance APLNR signaling, can induce miR-139-5p expression and rescue the vascular phenotypes associated with APLN/APLNR deficiency. Conclusions: These findings provide key mechanistic insights into a critical microRNA based crosstalk between two GPCR signaling cascades, which regulates important steps in vascular maturation.
Overview of in vivo and ex vivo endpoints in murine food allergy models: Suitable for evaluation of the sensitizing capacity of novel proteins?
Authors: Laure Castan, Katrine L. Bøgh, Natalia Z. Maryniak, Michelle M. Epstein, Sahar Kazemi, Liam O'Mahony, Marie Bodinier, Joost J. Smit, Jolanda H. M. van Bilsen, Carine Blanchard, Robert Głogowski, Hana Kozáková, Martin Schwarzer, Mario Noti, Nicole de Wit, Grégory Bouchaud, Shanna Bastiaan‐Net
Journal: Allergy (2019)

Significant efforts are necessary to introduce new dietary protein sources to feed a growing world population while maintaining food supply chain sustainability. Such a sustainable protein transition includes the use of highly modified proteins from side streams or the introduction of new protein sources that may lead to increased clinically relevant allergic sensitization. With food allergy being a major health problem of increasing concern, understanding the potential allergenicity of new or modified proteins is crucial to ensure public health protection. The best predictive risk assessment methods currently relied on are in vivo models, making the choice of endpoint parameters a key element in evaluating the sensitizing capacity of novel proteins. Here, we provide a comprehensive overview of the most frequently used in vivo and ex vivo endpoints in murine food allergy models, addressing their strengths and limitations for assessing sensitization risks. For optimal laboratory-to-laboratory reproducibility and reliable use of predictive tests for protein risk assessment, it is important that researchers maintain and apply the same relevant parameters and procedures. Thus, there is an urgent need for a consensus on key food allergy parameters to be applied in future food allergy research in synergy between both knowledge institutes and clinicians.
2018 updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout
Authors: Pascal Richette, Michael Doherty, Eliseo Pascual, Victoria Barskova, Fabio Becce, Johann Castaneda, Malcolm Coyfish, Sylvie Guillo, Tim Jansen, Hein Janssens, Frédéric Lioté, Christian D Mallen, George Nuki, Fernando Perez-Ruiz, José Pimentao, Leonardo Punzi, Anthony Pywell, Alexander K So, Anne-Kathrin Tausche, Till Uhlig, Jakub Zavada, Weiya Zhang, Florence Tubach, Thomas Bardin
Journal: Annals of the Rheumatic Diseases (2019)

Although gout is the most common inflammatory arthritis, it is still frequently misdiagnosed. New data on imaging and clinical diagnosis have become available since the first EULAR recommendations for the diagnosis of gout in 2006. This prompted a systematic review and update of the 2006 recommendations. A systematic review of the literature concerning all aspects of gout diagnosis was performed. Recommendations were formulated using a Delphi consensus approach. Eight key recommendations were generated. A search for crystals in synovial fluid or tophus aspirates is recommended in every person with suspected gout, because demonstration of monosodium urate (MSU) crystals allows a definite diagnosis of gout. There was consensus that a number of suggestive clinical features support a clinical diagnosis of gout. These are monoarticular involvement of a foot or ankle joint (especially the first metatarsophalangeal joint); previous episodes of similar acute arthritis; rapid onset of severe pain and swelling; erythema; male gender and associated cardiovascular diseases and hyperuricaemia. When crystal identification is not possible, it is recommended that any atypical presentation should be investigated by imaging, in particular with ultrasound to seek features suggestive of MSU crystal deposition (double contour sign and tophi). There was consensus that a diagnosis of gout should not be based on the presence of hyperuricaemia alone. There was also a strong recommendation that all people with gout should be systematically assessed for presence of associated comorbidities and risk factors for cardiovascular disease, as well as for risk factors for chronic hyperuricaemia. Eight updated, evidence-based, expert consensus recommendations for the diagnosis of gout are proposed.
Retinoblastoma Inactivation Induces a Protumoral Microenvironment via Enhanced CCL2 Secretion
Authors: Fengkai Li, Shunsuke Kitajima, Susumu Kohno, Akiyo Yoshida, Shoichiro Tange, Soichiro Sasaki, Nobuhiro Okada, Yuuki Nishimoto, Hayato Muranaka, Naoko Nagatani, Misa Suzuki, Sayuri Masuda, Tran C. Thai, Takumi Nishiuchi, Tomoaki Tanaka, David A. Barbie, Naofumi Mukaida, Chiaki Takahashi
Journal: Cancer Research (2019)

Cancer cell-intrinsic properties caused by oncogenic mutations have been well characterized; however, how specific oncogenes and tumor suppressors impact the tumor microenvironment (TME) is not well understood. Here, we present a novel non-cell-autonomous function of the retinoblastoma (RB) tumor suppressor in controlling the TME. RB inactivation stimulated tumor growth and neoangiogenesis in a syngeneic and orthotropic murine soft-tissue sarcoma model, which was associated with recruitment of tumor-associated macrophages (TAM) and immunosuppressive cells such as Gr1+CD11b+ myeloid-derived suppressor cells (MDSC) or Foxp3+ regulatory T cells (Treg). Gene expression profiling and analysis of genetically engineered mouse models revealed that RB inactivation increased secretion of the chemoattractant CCL2. Furthermore, activation of the CCL2-CCR2 axis in the TME promoted tumor angiogenesis and recruitment of TAMs and MDSCs into the TME in several tumor types including sarcoma and breast cancer. Loss of RB increased fatty acid oxidation (FAO) by activating AMP-activated protein kinase that led to inactivation of acetyl-CoA carboxylase, which suppresses FAO. This promoted mitochondrial superoxide production and JNK activation, which enhanced CCL2 expression. These findings indicate that the CCL2-CCR2 axis could be an effective therapeutic target in RB-deficient tumors. SIGNIFICANCE: These findings demonstrate the cell-nonautonomous role of the tumor suppressor retinoblastoma in the tumor microenvironment, linking retinoblastoma loss to immunosuppression.
PB1949 CHRONIC MYELOID LEUKEMIA PATIENTS WITH BOTH HIGH TH1 AND HIGH CD8+ T‐CELL LEVELS SHOW THE BETTER REMISSION, AND THE GOOD THERAPEUTIC RESPONSE ACCOMPANIES WITH THE HIGHER TH1 LEVEL
Authors: J. Dai, X. Yang, Q. Wei, M. Zou, Y. Wang, H. Li, X. Huang, X. Wang
Journal: HemaSphere (2019)

Background: The immune mornitoring on chronic myeloid leulemia (CML) patients may provide valuable guidence for the therapeutic strategies and prognosis prediction of this hematological malignancy. Aims: To investigate the correlation of Th1 and CD8+T‐based immunological characteristics of CML patients with the clinical efficacy. Methods: To analyze the Th1 proportion (Th1/CD4+T) and the CD8+T proportion (CD8+T/Lymphocyte) in the peripheral blood of all the CML patients diagnosed in our center. And the remission status at the same timepoint of the blood test are evaluated. The data is further statistically analyzed in different groups. Results: 70% of the patients in newly‐diagnosed group (n = 10), 15.38% of the patients in complete cytogenetic response(CCyR) group (n = 13) and 15.15% of the patients in molecular response 4.5(MR4.5) group (n = 67) respectively show a Th1 level below the lower limit of normal, therefore, the low‐Th1 percentage of the newly‐diagnosed group is significantly higher than that of the CCyR group and that of the MR4.5group ( P = 0.01; P = 0.00). On the other hand, the average of the actual Th1 value in the newly‐diagnosed group is also significantly lower than that in the CCyR group and that in the MR4.5 group ( P = 0.01; P = 0.00). As we have observed in clinic work that those patients with both high‐Th1 and high‐CD8+T levels (both higher than the upper limit of normal) mostly obtain better remission situations, furthermore, we analyze the relevant groups of CML patients statistically in this study. The results show: The MR4.5 rate in the high‐Th1 and high‐CD8+T group (n = 15) is significantly higher than that in the high‐Th1 and not‐high‐CD8+T group (n = 17) ( P = 0.03), while the un‐remission rate in these two groups doesn’t show a statistically significant difference ( P = 0.74). On the other hand, the MR4.5 rate in the high‐Th1 and high‐CD8+T group is also significantly higher than that in the low‐Th1 and high‐CD8+T group (here “low‐Th1” represents that the Th1 level is below the lower limit of normal; n = 10) ( P = 0.00), while the un‐remission rate in the high‐Th1 and high‐CD8+T group is significantly lower than that in the low‐Th1 and high‐CD8+T group ( P = 0.00). Summary/Conclusion: The good therapeutic efficacy of CML patients after treatment shows a significantly higher Th1 level compared with the level at diagnosis. And those patients with a Th1 level and a CD8+T level both higher than the upper limit of normal show the higher remission rate and the deeper remission level.
Pertuzumab in combination with trastuzumab and chemotherapy for Chinese patients with HER2‐positive metastatic gastric or gastroesophageal junction cancer: a subpopulation analysis of the JACOB trial
Authors: Tianshu Liu, Yanru Qin, Jin Li, Ruihua Xu, Jianming Xu, Shujun Yang, Shukui Qin, Yuxian Bai, Changping Wu, Yixiang Mao, Haiyan Wu, Yilin Ge, Lin Shen
Journal: Cancer Communications (2019)

Abstract Background The JACOB trial (NCT01774786) was a double‐blinded, placebo‐controlled, randomized, multicenter, international, phase III trial evaluating the efficacy and safety of adding pertuzumab to trastuzumab and chemotherapy in first‐line treatment of human epidermal growth factor receptor 2 (HER2)‐positive metastatic gastric cancer/gastroesophageal junction cancer (GEJC). The aim of this analysis was to investigate efficacy and safety outcomes in the Chinese subpopulation from the JACOB trial. Methods This post hoc subpopulation analysis included all patients recruited in mainland China ( n = 163; 20.9%) between June 2013 and January 2016. The patients were randomly assigned in a 1:1 ratio to receive pertuzumab plus trastuzumab and chemotherapy (pertuzumab group; n = 82) or placebo plus trastuzumab and chemotherapy (control group; n = 81). Intravenous pertuzumab (840 mg) and trastuzumab (8 mg/kg loading and 6 mg/kg maintenance doses) were given every 3 weeks until disease progression or unacceptable toxicity. Chemotherapy was given as per standard regimens/doses of capecitabine or 5‐fluorouracil plus cisplatin. The primary endpoint was overall survival (OS); secondary efficacy endpoints included progression‐free survival (PFS), and overall objective response rate (ORR). Results The median OS was 18.7 months in the pertuzumab group and 16.1 months in the control group (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.49 to 1.14). The median PFS was 10.5 and 8.6 months in the pertuzumab and control groups, respectively (HR 0.85; 95% CI 0.60 to 1.21), and the median ORRs were 68.9% and 55.7%, respectively. The treatment effect in this Chinese subpopulation showed consistency with that in the global ITT population with numerically lower HR for OS and PFS compared with the control group. The safety profiles of the pertuzumab and control groups in this Chinese subpopulation analysis were generally comparable. The most common grade 3–5 adverse events were neutropenia, anemia, and leukopenia. However, due to the nature of being a post hoc subgroup analysis, the results presented here are descriptive only and need to be interpreted with caution. Conclusions OS and PFS were numerically improved by adding pertuzumab to trastuzumab and chemotherapy as first‐line treatment in Chinese HER2‐positive gastric cancer/GEJC patients, and this regimen demonstrated an acceptable safety profile. Trial registration ClinicalTrials.gov . NCT01774786. Registered on 24 January 2013, https://clinicaltrials.gov/ct2/show/NCT01774786
A Novel Predictor of Response to Gemtuzumab Ozogamicin Therapy in AML Provides Strategies for Sensitization of Leukemia Stem Cells in Individual Patients
Authors: Stanley W.K. Ng, Schoof E Erwin, Amanda Mitchell, Mark D. Minden, Lars Bullinger, Hartmut Döhner, Hervé Dombret, Claude Preudhomme, Meyling Cheok, John E. Dick, Jean C.Y. Wang
Journal: Blood (2018)
Thrombopoietin Receptor Agonist Use, Efficacy and Toxicity in Children with Immune Thrombocytopenia: Data from an Italian Multicenter Survey
Authors: Paola Giordano, Giuseppe Lassandro, Marco Spinelli, Momcilo Jancovic, Paola Saracco, Giovanna Russo, Ilaria Fotzi, Saverio Ladogana, Fiorina Giona, Alessandra Tolva, Simone Cesaro, Maria Gabelli, Margherita Nardi, Lucia Dora Notarangelo, Ilaria Fontanili, Antonio Ruggiero, Assunta Tornesello, Valentina Palladino, Giovanni Carlo Del Vecchio
Journal: Blood (2018)
PB2162 INCIDENCE &amp; SEVERITY OF BORTEZOMIB‐INDUCED PERIPHERAL NEUROPATHY WITH THE USE OF GENERIC BORTEZOMIB IN MONOCLONAL GAMMOPATHIES: A PROSPECTIVE STUDY FROM INDIA
Authors: U. K. Nath, S. Vaniyath, R. Chetia, D. Chattopadhyay
Journal: HemaSphere (2019)

Background: The proteasome inhibitor Bortezomib is one of the most effective frontline drugs in the therapeutic armamentarium against monoclonal gammopathies. However, drug‐induced peripheral neuropathy is the major dose‐limiting toxicity and adversely affects quality of life. Generic preparations of bortezomib are mainstay of therapy in resource‐poor countries due to significantly higher cost of original brand of bortezomib. Aims: The present study aims to analyze the incidence &amp; severity of bortezomib‐induced peripheral neuropathy (BIPN) in patients of monoclonal gammopathies receiving generic bortezomib in a resource‐poor setting. Methods This non‐randomized, prospective study enrolled total 73 bortezomib‐naïve patients of monoclonal gammopathies between July 2016 &amp; February 2019. Both newly diagnosed &amp; relapsed patients of symptomatic multiple myeloma (MM), Waldenstrom macroglobulinemia (WM) &amp; primary amyloidosis, who had no baseline evidence of peripheral neuropathy were included. Patients having disease‐related neuropathy &amp; patients who had earlier received thalidomide or other neurotoxic drugs were excluded. All study patients received one of the generic bortezomib brands available in India. Bortezomib was initially administered at 1.3 mg/m 2 dose, by subcutaneous injection, on days 1,8,15,22 of each 28 days’ cycle. Patients were clinically evaluated for BIPN before each cycle, &amp; at onset of BIPN symptoms. Bortezomib dose was modified according to grade of BIPN (Table 1). Bortezomib was discontinued in grade 3‐4 neuropathy, &amp; restarted after BIPN symptoms improved to &lt; grade 3. Results: Median patient age was 58 years (32‐76 years). Majority (62/73 patients, 85%) had MM, eight patients had WM &amp; three patients had Primary Amyloidosis. Twenty‐seven patients in the study (37%) developed BIPN during treatment. Severity of BIPN in study is shown in Table 2. BIPN symptoms were reversible in 90% patients after discontinuation of bortezomib. Median follow up was 7 months (2‐18 months). image Summary/Conclusion: In our study, approximately one‐third of patients with monoclonal gammopathies treated with subcutaneously administered generic bortezomib developed bortezomib‐induced peripheral neuropathy. The incidence of severe (grade 3‐4) BIPN was about 12%, leading to temporary/permanent discontinuation of bortezomib and also interfering with quality of life. image
Neural Competitive Queuing of Ordinal Structure Underlies Skilled Sequential Action
Authors: Katja Kornysheva, Daniel Bush, Sofie S. Meyer, Anna Sadnicka, Gareth Barnes, Neil Burgess
Journal: Neuron (2019)

Fluent retrieval and execution of movement sequences is essential for daily activities, but the neural mechanisms underlying sequence planning remain elusive. Here participants learned finger press sequences with different orders and timings and reproduced them in a magneto-encephalography (MEG) scanner. We classified the MEG patterns for each press in the sequence and examined pattern dynamics during preparation and production. Our results demonstrate the "competitive queuing" (CQ) of upcoming action representations, extending previous computational and non-human primate recording studies to non-invasive measures in humans. In addition, we show that CQ reflects an ordinal template that generalizes across specific motor actions at each position. Finally, we demonstrate that CQ predicts participants' production accuracy and originates from parahippocampal and cerebellar sources. These results suggest that the brain learns and controls multiple sequences by flexibly combining representations of specific actions and interval timing with high-level, parallel representations of sequence position.
PS1080 LYMPHOMA ASSOCIATED HEMOPHAGOCYTIC SYNDROME: A SINGLE‐CENTER EXPERIENCE
Authors: J.A. Rojas Martínez, C. Prats‐Martín, L. Pérez Ortega, R. Morales Camacho, T. Knight Asorey, O. Pérez‐López, T. Caballero‐Velázquez, F. De la Cruz‐Vicente, M.T. Vargas de los Monteros, R. Bernal Ruiz, J.A. Pérez‐Simón
Journal: HemaSphere (2019)

Background: Aproximately 1% of the patients with haematological malignancies will develope an hemophagocytic syndrome. Some types of lymphoma are associated with higher risks of developing hemophagocytic syndrome. It is described a high rate of lymphoma associated hemophagocytic syndrome (LAHS) related‐mortality. Only few studies have addressed LAHS. Aims: To describe the clinical and epidemiological features and the prognosis of LAHS in a tertiary hospital from January 2008 to December 2018. Methods: We performed a ambispective observational study of the cases of hemophagocytic lymphohistiocytosis (HLH) diagnosed by bone marrow aspirate. The diagnosis was made according to the diagnostic criteria of the International Histiocyte Society (IHS‐2004). Lymphoma classification followed the World Health Organization (WHO) 2017 system. Epidemiological and clinical features of the patients diagnosed of LAHS were analysed. Statistics performed with SPSS 17.0. image Results: 48 patients were diagnosed with HLH in our center in this period. 16 cases (37%) were associated to lymphoma. The median age for patients diagnosed with LAHS was 63 (range: 13–80). The most common histological type was diffuse large B cell lymphoma, which occurred in 7 of 16 patients (44 %). Peripheral T cell lymphoma and Hodgkin lymphoma occurred both in 3 of 16 patients. 7 patients (44%) had other known risk factor for LAHS: viral infection, autoimmune disease and immunosuppression. The clinical and analytical features are summarized in Table 1. The histopathological analysis of the bone marrow did not identify hemophagocytosis in any cases. Most of the patients diagnosed with LAHS (9 of 14) were treated with the first‐line chemotherapy regimen for lymphoma. 3 patients were treated following the HLH‐2004 protocol. 2 patients died before receiving any treatment. The median overall survival time was 88 days (range: 0 days‐6 years). The three months mortality rate was 50%. 4 patients are still alive with 2, 3, 35 and 71 months after the diagnosis of LAHS (Fig 1). image Summary/Conclusion: The most common associated lymphoma was diffuse large B cell lymphoma. 44% of the patients had other known risk factor for LAHS. The bone marrow aspirate is superior to the histopathological examination for the diagnosis of LAHS. The three months mortality rate was 50%. Further researches are needed to gain better understanding about this entity.
Construct of MoSe2/Bi2Se3 nanoheterostructure: Multimodal CT/PT imaging-guided PTT/PDT/chemotherapy for cancer treating
Authors: Ying Wang, Jingxiang Zhao, Zhe Chen, Feng Zhang, Qian Wang, Wei Guo, Kai Wang, Huiming Lin, Fengyu Qu
Journal: Biomaterials (2019)
Quality and Safety in Healthcare, Part LIV
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2019)

Abstract Physician burnout can be a contributing factor to depression, substance abuse, problems with relationships, and thoughts of suicide. Burnout of physicians also results in decreased quality, safety, and outcomes for patients and more financial costs for health-care institutions. It is not enough for health-care systems to focus on helping the individual; these organizations also need to understand that they are the main cause of physician burnout and take appropriate action to reform their processes.