tbuckley/cabot-search huggingface dataset:
Immunotherapy of triple-negative breast cancer with cathepsin D-targeting antibodies
Authors: Yahya Ashraf, Hanane Mansouri, Valérie Laurent-Matha, Lindsay B. Alcaraz, Pascal Roger, Séverine Guiu, Danielle Derocq, Gautier Robin, Henri-Alexandre Michaud, Helène Delpech, Marta Jarlier, Martine Pugnière, Bruno Robert, Anthony Puel, Lucie Martin, Flavie Landomiel, Thomas Bourquard, Oussama Achour, Ingrid Fruitier-Arnaudin, Alexandre Pichard, Emmanuel Deshayes, Andrei Turtoi, Anne Poupon, Joëlle Simony-Lafontaine, Florence Boissière-Michot, Nelly Pirot, Florence Bernex, William Jacot, Stanislas du Manoir, Charles Theillet, Jean-Pierre Pouget, Isabelle Navarro-Teulon, Nathalie Bonnefoy, André Pèlegrin, Thierry Chardès, Pierre Martineau, Emmanuelle Liaudet-Coopman
Journal: Journal for ImmunoTherapy of Cancer (2019)

Triple-negative breast cancer (TNBC) treatment is currently restricted to chemotherapy. Hence, tumor-specific molecular targets and/or alternative therapeutic strategies for TNBC are urgently needed. Immunotherapy is emerging as an exciting treatment option for TNBC patients. The aspartic protease cathepsin D (cath-D), a marker of poor prognosis in breast cancer (BC), is overproduced and hypersecreted by human BC cells. This study explores whether cath-D is a tumor cell-associated extracellular biomarker and a potent target for antibody-based therapy in TNBC.Cath-D prognostic value and localization was evaluated by transcriptomics, proteomics and immunohistochemistry in TNBC. First-in-class anti-cath-D human scFv fragments binding to both human and mouse cath-D were generated using phage display and cloned in the human IgG1 λ format (F1 and E2). Anti-cath-D antibody biodistribution, antitumor efficacy and in vivo underlying mechanisms were investigated in TNBC MDA-MB-231 tumor xenografts in nude mice. Antitumor effect was further assessed in TNBC patient-derived xenografts (PDXs).High CTSD mRNA levels correlated with shorter recurrence-free survival in TNBC, and extracellular cath-D was detected in the tumor microenvironment, but not in matched normal breast stroma. Anti-cath-D F1 and E2 antibodies accumulated in TNBC MDA-MB-231 tumor xenografts, inhibited tumor growth and improved mice survival without apparent toxicity. The Fc function of F1, the best antibody candidate, was essential for maximal tumor inhibition in the MDA-MB-231 model. Mechanistically, F1 antitumor response was triggered through natural killer cell activation via IL-15 upregulation, associated with granzyme B and perforin production, and the release of antitumor IFNγ cytokine. The F1 antibody also prevented the tumor recruitment of immunosuppressive tumor-associated macrophages M2 and myeloid-derived suppressor cells, a specific effect associated with a less immunosuppressive tumor microenvironment highlighted by TGFβ decrease. Finally, the antibody F1 inhibited tumor growth of two TNBC PDXs, isolated from patients resistant or not to neo-adjuvant chemotherapy.Cath-D is a tumor-specific extracellular target in TNBC suitable for antibody-based therapy. Immunomodulatory antibody-based strategy against cath-D is a promising immunotherapy to treat patients with TNBC.
A Two-Part Study of Givinostat in Patients with Polycythemia Vera: The Maximum Tolerated Dose Selection and the Proof of Concept Final Results
Authors: Alessandro Rambaldi, Alessandra Iurlo, Alessandro M. Vannucchi, Richard Noble, Nikolas von Bubnoff, Attilio Guarini, Andrzej Hellmann, Bruno Martino, Antonio Pezzutto, Giuseppe Carli, Marianna De Muro, Paolo Di Bartolomeo, Mary Frances Frances McMullin, Nathalie Cambier, Jean-Pierre Marolleau, Ruben A Mesa, Raoul Tibes, Paolo Bettica, Sara Manzoni, Silvia Di Tollo
Journal: Blood (2017)
A novel machine-learning-based infection screening system via 2013–2017 seasonal influenza patients' vital signs as training datasets
Authors: Sumiyakhand Dagdanpurev, Shigeto Abe, Guanghao Sun, Hidekazu Nishimura, Lodoiravsal Choimaa, Yukiya Hakozaki, Takemi Matsui
Journal: Journal of Infection (2019)
Single-domain antibody fusion proteins can target and shuttle functional proteins into macrophage mannose receptor expressing macrophages
Authors: Yannick De Vlaeminck, Quentin Lecocq, Philippe Giron, Carlo Heirman, Xenia Geeraerts, Evangelia Bolli, Kiavash Movahedi, Sam Massa, Steve Schoonooghe, Kris Thielemans, Cleo Goyvaerts, Jo A. Van Ginderachter, Karine Breckpot
Journal: Journal of Controlled Release (2019)
Locum is suspended for 12 months for pretending to clerk patient after stent procedure
Authors: Clare Dyer
Journal: BMJ (2019)

A doctor has been suspended from the UK medical register for 12 months after a tribunal found that he failed to attend a patient who was waiting to see him after a stenting procedure, then dishonestly wrote in her medical notes as if he had examined her.

Attila Czipp, who had previously practised in cardiology in his native Hungary, was working as a locum senior house officer in acute medicine at the Royal Cornwall Hospital when a 72 year old patient who had just undergone coronary artery stenting after a heart attack arrived in the coronary care unit.

Around midnight, Czipp was assigned the routine task of “clerking” the patient, an admission …
Therapeutic potential of connective tissue growth factor (CTGF) in triple-negative breast cancer
Authors: H. Kim, S. Son
Journal: Annals of Oncology (2019)

Background: Matricellular proteins are a subset of extracellular matrix (ECM) proteins which are dynamically expressed and serve many regulatory roles. Among matricellular proteins, the CCN family, a group of secreted proteins are known to regulate cell adhesion, migration, proliferation, differentiation, apoptosis, survival, senescence, and gene expression. Connective tissue growth factor (CTGF), also known as CCN2, is a member of the CCN family. CTGF is known to have many roles in biological processes such as cell proliferation, migration, adhesion, and angiogenesis. Methods: To investigate the function of CTGF in triple-negative breast cancer cells (TNBC), we silenced CTGF in TNBC cell lines using short hairpin RNA. Knockdown of CTGF was verified by western blot, qPCR, and immunostaining. The effect of CTGF knockdown on TNBCs was examined by cell proliferation assay, adhesion assay, migration assays, metabolism assays, and cell cycle analysis. Results: Knockdown of CTGF decreased cell proliferation, adhesion, migration, glucose uptake, ATP production and lactate production. Since CTGF is a secreted protein, we gave recombinant human CTGF (rhCTGF) to the cells and found that rhCTGF induced activation of the Src/FAK/MAPK pathway and led to expression of proteins related to cell cycle progression. Also, when CTGF-specific antibodies were given to the cells, they expressed cytotoxicity by neutralizing the extracellular CTGF and decreasing CTGF-mediated signalling. Conclusions: We suggest that the secreted CTGF mediates tumor cell progression via modulation of cell proliferation, adhesion, migration and metabolism and could possess a potential for being a therapeutic target. Legal entity responsible for the study: Hanyang University. Funding: National Research Foundation of Korea. Disclosure: All authors have declared no conflicts of interest.
RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43
Authors: Jacob R. Mann, Amanda M. Gleixner, Jocelyn C. Mauna, Edward Gomes, Michael R. DeChellis-Marks, Patrick G. Needham, Katie E. Copley, Bryan Hurtle, Bede Portz, Noah J. Pyles, Lin Guo, Christopher B. Calder, Zachary P. Wills, Udai B. Pandey, Julia K. Kofler, Jeffrey L. Brodsky, Amantha Thathiah, James Shorter, Christopher J. Donnelly
Journal: Neuron (2019)
SP0020 How to Optimize Doppler Settings for Slow Flow
Authors: L. Terslev
Journal: Annals of the Rheumatic Diseases (2014)

<h3></h3> Doppler ultrasound allows the visualization of perfusion in the inflamed synovium and therefore allows the diagnosis and quantification of inflammatory activity in a joint, tendon or enthesis. The issue when choosing Doppler modality in a rheumatological setting is the sensitivity for slow flow. This may be colour of power Doppler depending on the machine. Always choose the Doppler modality that provides the most flow information. The preset on the ultrasound machines are not per se set optimally for slow flow. The most important parameters to adjust are frequency, gain, PRF and thereby the filters, focus and colour priority. <i>Doppler frequency</i> behaves as the grey-scale frequency. High Doppler frequency gives better resolution on the expense of penetration. <i>Gain</i> determines the sensitivity of the system to slow flow and is adjusted by increasing the gain until noise pixels are present in the image and then gradually lowering the gain until only very few noise pixels are seen in the image. By lowering the gain further noise and motion artefacts may be prevented but also loss of slow flow information. The <i>PRF i</i>s the pulse repetition frequency and determines the sensitivity to slow flow. The PRF must be kept as low as possible (around 500 Hz) because linked with the PRF adjustments are the filters. The higher the PRF the higher the filters are and high filters will eliminate slow flow. <i>Focus</i> in Doppler is like focus in grey-scale. It must be palce in the region of interest to get optimal resolution. <i>Colour priority</i> may not be adjusted easily in all machine but is a function that determines what is the most important in the image: the colours or the greys. Also adjust to a 100% to ensure maximal flow information. Adjusting the many parameters of the Doppler should not be done at every examination. Fortunately, there is little difference from patient to patient and from joint to joint with respect to Doppler settings. An exception is the hip joint because of its deep location. Once the sensitivity of the Doppler has been maximised, the settings may be saved as a set-up, which the machine reverts to at every new exam. It is possible to have many different set-ups, which can be named to our liking such as knee, obese knee, wrist etc. Using the same settings from patient to patient and from visit to visit is important if we wish to gauge the treatment response longitudinally or compare patients. Therefore it is also important that the same make and model of ultrasound machine are used from visit to visit. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.6259
Romidepsin-CHOEP Plus Intensification with up-Front Stem-Cell Transplantation in Peripheral T-Cell Lymphoma: Final Results of Phase Ib PTCL13 Study of the Fondazione Italiana Linfomi
Authors: Annalisa Chiappella, Cristiana Carniti, Andrea Evangelista, Maria Giuseppina Cabras, Alessandro Re, Manuela Zanni, Vittorio Stefoni, Armando Santoro, Angela Giovanna Congiu, Anna Dodero, Stefano A. Pileri, Giovannino Ciccone, Paolo Corradini
Journal: Blood (2018)
Preoperative Breast Magnetic Resonance Imaging in Women With Local Ductal Carcinoma in Situ to Optimize Surgical Outcomes: Results From the Randomized Phase III Trial IRCIS
Authors: Corinne Balleyguier, Ariane Dunant, Luc Ceugnart, Marguerite Kandel, Marie-Pierre Chauvet, Pascal Chérel, Chafika Mazouni, Philippe Henrot, Philippe Rauch, Jocelyne Chopier, Sonia Zilberman, Isabelle Doutriaux-Dumoulin, Isabelle Jaffre, Aurélie Jalaguier, Gilles Houvenaeghel, Nicole Guérin, Françoise Callonnec, Claire Chapellier, Ines Raoust, Marie-Christine Mathieu, Françoise Rimareix, Julia Bonastre, Jean-Rémi Garbay
Journal: Journal of Clinical Oncology (2019)

We evaluated the addition of breast magnetic resonance imaging (MRI) to standard radiologic evaluation on the re-intervention rate in women with ductal carcinoma in situ (DCIS) undergoing breast-conserving surgery.Women with biopsy-proven DCIS corresponding to a unifocal microcalcification cluster or a mass less than 30 mm were randomly assigned to undergo MRI or standard evaluation. The primary end point was the re-intervention rate for positive or close margins (< 2 mm) in the 6 months after randomization ( ClinicalTrials.gov identifier: NCT01112254).A total of 360 patients from 10 hospitals in France were included in the study. Of the 352 analyzable patients, 178 were randomly assigned to the MRI arm, and 174 were assigned to the control arm. In the intent-to-treat analysis, 82 of 345 patients with the assessable end point were reoperated for positive or close margins within 6 months, resulting in a re-intervention rate of 20% (35 of 173) in the MRI arm and 27% (47 of 172) in the control arm. The absolute difference of 7% (95% CI, -2% to 16%) corresponded to a relative reduction of 26% (stratified odds ratio, 0.68; 95% CI, 0.41 to 1.1; P = .13). When considering only the per-protocol population with an assessable end point, the difference was 9% (stratified odds ratio, 0.59; 95% CI, 0.35 to 1.0; P = .05). Total mastectomy rates were 18% (31 of 176) in the MRI arm and 17% (30 of 173) in the control arm (stratified P = .93). For 100 lesions seen on MRI, nonmass-like enhancement was more predominant (82%) than mass enhancement (20%). Nevertheless, no specific morphologic and kinetic parameters for DCIS were identified.The study did not show sufficient surgical improvement with the use of preoperative MRI to be clinically relevant in DCIS staging. However, this could be reconsidered with the improvement of new MRI sequences and new modalities in magnetic resonance techniques.
Reply
Authors: Eriks Smagris, Soumik BasuRay, Jesper Gromada, Jonathan C. Cohen, Helen H. Hobbs
Journal: Hepatology (2015)

Potential conflict of interest: Dr. Hobbs is employed by Pfizer. Dr. Gromada is employed by and owns stock and intellectual property rights with Regeneron. We discussed the possibility that PNPLA3‐148M, which may sequester CGI‐58, or another protein involved in triglyceride (TG) mobilization, thus resulting in hepatic steatosis. The finding that CGI‐58 levels were increased in the lipid droplets of the mutant mice (Fig. 6) supported this hypothesis. To test whether accumulation of CGI‐58 on the droplet was causally related to the increase in hepatic TG content, we evaluated mice expressing a PNPLA3‐148M transgene, another model of PNPLA3‐associated hepatic steatosis. These animals developed steatosis in the absence of any increase in CGI‐58 content on lipid droplets. Thus, accumulation of CGI‐58 is not a prerequisite for development of hepatic steatosis in association with expression of mutant PNPLA3. As we stated in the Discussion: "we speculated that PNPLA3‐148M promotes hepatic steatosis by sequestering CGI‐58, thereby limiting hydrolysis of lipid droplet TG by ATGL. The marginal increase in CGI‐58 accumulation on lipid droplets of PNPLA3‐148M transgenic mice despite a 2‐fold increase in liver fat content and massive accumulation of the mutant PNPLA3 protein (Fig. 7) argues against this hypothesis."
LEKTI domains D6, D7 and D8+9 serve as substrates for transglutaminase 1: implications for targeted therapy of Netherton syndrome
Authors: H. Wiegmann, F. Valentin, T. Tarinski, E. Liebau, K. Loser, H. Traupe, V. Oji
Journal: British Journal of Dermatology (2019)

Transglutaminase (TG)1 plays a key role in the formation of the cornified envelope and thus in the maintenance of the epidermal barrier. Patients with Netherton syndrome (LEKTI deficiency) have increased activity of both TG1 and serin proteases. To determine whether there is a functional biochemical link between TG1 and LEKTI and whether LEKTI domains could possibly serve as substrates for TG1. We analysed the protein sequence of LEKTI for possible TG1 recognition sites using bioinformatics. Synthetic peptides and recombinant LEKTI domains D6, D7 and D8+9 were examined in vitro and in situ for possible substrate specificity. The recombinant LEKTI domains were studied for inhibitory activity in a kallikrein (KLK)5 activity test. We identified possible TG1 consensus sequences in LEKTI domains D6, D7 and D8+9, pointing to a novel biological link between these two proteins. Indeed, synthesized short peptides from these consensus sequences were incorporated into the TG1 activity zone of the epidermis. In vitro the entire recombinant domains of LEKTI showed substrate specificity for TG1, which was again confirmed in situ. The inhibitory activity of the recombinant LEKTI domains was confirmed by a KLK5 inhibition test. The strongest inhibition was observed for domains D8+9. There are specific domains of LEKTI that are recognized and processed by TG1. LEKTI domains D6, D7 and D8+9 contribute to the formation and protection of the cornified envelope. These results impact the development of protein replacement therapy approaches for Netherton syndrome. What's already known about this topic? LEKTI and transglutaminase (TG)1 are key proteins involved in the terminal differentiation of the epidermis. Lack of LEKTI causes Netherton syndrome; TG1 deficiency causes lamellar ichthyosis. The serine protease inhibitor LEKTI is processed into different functional units. Among different target proteases, kallikrein (KLK)5 appears to be a key player in disease pathology. It has been demonstrated that LEKTI domain 6 inhibits KLK5 and KLK7; LEKTI domains 8–11 also inhibit KLK14. What does this study add? The single LEKTI domains 6, 7 and the functional unit of domains 8 and 9 contain recognition motifs for TG1. We show that these domains and unit are crosslinked into the epidermis by TG1. Functional analyses of the recombinant LEKTI domains revealed that LEKTI D8+9 has the strongest inhibitory effect on KLK5. What is the translational message? The novel functional link between LEKTI and TG1 should be taken into account when considering the development of a targeted topical protein therapy for Netherton syndrome. The unit of domains D8+9 may be sufficient for this purpose.
P026 Control of Α2,6-sialylation in B-cells, and consequences of reduced B-cell sialylation in patients with rheumatoid arthritis
Authors: L Johnston, L Ouboussad, A Aslam, MH Buch
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Student for a master or a PhD. <h3>Introduction</h3> Sialic acids are a family of 9-carbon sugars, added to the termini of glycoprotein chains, which are present on the surface of many cells, and secreted proteins.<sup>1</sup> Sialic acids on glycan chains of the Fc fragment of IgG molecules can affect how IgG binds Fc receptors.<sup>2</sup> In RA and other autoimmune conditions, disease specific auto-antibodies display decreased Fc sialylation compared with normal IgG.<sup>3</sup> It has also been shown that plasmablasts from patients with RA display reduced cell surface sialylation compared to healthy control cells.<sup>4</sup> Factors which determine B-cell surface sialylation, including regulation of ST6Gal1and NEU1 which add and cleave sialic acid from glycoprotein chains respectively, and consequences of altered sialylation have not been well described. <h3>Objectives</h3> The aim of this study was to investigate factors which influence α2,6-sialylation in B-cells from the peripheral blood of healthy controls and patients with RA, and to investigate regulation of expression of ST6Gal1 and NEU1 in B-cells. <h3>Methods</h3> B-cells isolated from the peripheral blood of healthy volunteers were cultured for 48 hours in the presence of TLR ligands, anti-IgM, CD40L, cytokines (TNF, IL-4, IL-6, IL-17) before α2,6-sialylation of the B-cell surface, and mRNA expression of genes related to α2,6-sialylation were measured by SNA lectin flow cytometry, and qPCR respectively. PBMCs were also isolated from peripheral blood and T and B-cells activated using CD3/28 beads and anti-IgM/CD40L respectively, before measuring B-cell sialylation and expression of ST6Gal1 and NEU1 mRNA. <h3>Results</h3> Surface α2,6 sialylation was found to be increased in B-cells stimulated with TLR ligands or anti-IgM/CD40L. This was accompanied by a decrease in expression of both ST6Gal1 and NEU1 mRNA over 48 hours. Surface sialylation was also increased by activated T-cells in co-culture experiments, however sialylation was reduced in B-cell cultures in the presence of TNF. <h3>Conclusions</h3> α2,6-sialic acid is upregulated on the surface of healthy control B-cells in response to activation <i>in vitro</i>, and may be downregulated by TNF. Further experiments will determine if the environment in which naïve/memory B-cells are activated determines plasmablast/plasma cell sialylation, and if B-cells from patients with RA undergo the same changes in response to stimuli. <h3>References</h3> Traving C, Schauer R. <i>Cell Mol Life Sci</i> 1998;54:1330–1349. Sondermann P, <i>et al. PNAS</i> 2013;110:9868–9872. Dekkers G, <i>et al. Front Immunol</i> 2018;9:553. Pfeifle R, <i>et al. Nat Immunol</i> 2017;18(1):104–113. <h3>Disclosure of Interest</h3> None declared.
Lifesaving Stenting of Pulmonary Arteries Critically Narrowed by Mediastinal Lymphoma
Authors: Ewa Trejnowska, Roland Fiszer, Paul Armatowicz, Magda Tarczyńska-Słomian, Agnieszka Wiklińska, Paulina Kurdyś, Krystian Ślusarz, Karol Kocaj, Piotr Knapik
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Video 2. Implantation of two stents on a balloon catheter in the right pulmonary artery.The long sheath curvature was impossible to cross with a long stent because of the size of the tumor.As a result, it was decided to implant 2 shorter stents.Video 3. Pulmonary angiography in the anterior-posterior view.Dilatation of the right pulmonary artery after implantation of two stents with good perfusion of the right lung.The left pulmonary artery remains narrowed after several unsuccessful attempts at balloon dilatation.
Evaluating Treatment Effect of Transcatheter Interatrial Shunt Device Using Heart Failure Event Rates—Reply
Authors: Sanjiv J. Shah, Ted Feldman, Joseph Massaro
Journal: JAMA Cardiology (2019)

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KZF-L162R Mutation Affects Splenic Mature B Cell Development and Alters Expression of Aiolos Target Genes
Authors: Gregory Lazarian, Shanye Yin, Alba Font-tello, Elisa Ten Hacken, Tomasz Sevastianik, Daniel Tom, Fara Faye Regis, Amy Gill, Mei Zheng, Katia Georgopoulos, Donna S Neuberg, Lili Wang, Ruben D. Carrasco, Catherine J. Wu
Journal: Blood (2018)