tbuckley/cabot-search huggingface dataset:
Safety and efficacy of epigallocatechin gallate in multiple system atrophy (PROMESA): a randomised, double-blind, placebo-controlled trial
Authors: Johannes Levin, Sylvia Maaß, Madeleine Schuberth, Armin Giese, Wolfgang H Oertel, Werner Poewe, Claudia Trenkwalder, Gregor K Wenning, Ulrich Mansmann, Martin Südmeyer, Karla Eggert, Brit Mollenhauer, Axel Lipp, Matthias Löhle, Joseph Classen, Alexander Münchau, Jan Kassubek, Florin Gandor, Daniela Berg, Silvia Egert-Schwender, Cornelia Eberhardt, Friedemann Paul, Kai Bötzel, Birgit Ertl-Wagner, Hans-Jürgen Huppertz, Ingrid Ricard, Günter U Höglinger, Elisabeth André, Christiane Blankenstein, Monica Canelo, Marco Düring, Jens Ebentheuer, Christopher Fricke, Alexander Gerbes, Stefan Groiss, Doreen Gruber, Christian Hartmann, Thomas Kirchner, Daniel Kroneberg, Martin Kunz, Stefan Lorenzl, Alexia Moldovan, Anna Noda, Heidi Pape, Gesine Respondek, Eva Schäffer, Martina Schneider, Alfons Schnitzler, Walter Schulz-Schaeffer, Johannes Schwarz, Cornelia Skowronek, Alexander Storch, Vera Tadic, Dávid Vadász, Benno Zimmermann
Journal: The Lancet Neurology (2019)
NHS is more “vicious” to whistleblowers than any other organisation, author tells <i>The BMJ</i>
Authors: Abi Rimmer
Journal: BMJ (2019)

Whistleblowing can lead to positive change but the way that the NHS deals with people who speak out is vicious, the author Margaret Heffernan has said.

The author and businesswoman has written about whistleblowing and why companies don’t respond well to it in her book Wilful Blindness: Why We Ignore the Obvious at our Peril .

Speaking on The …
Abstract 978: Tim-4+ tissue-resident macrophages impair antitumor T-cell immunity
Authors: Andrew Chow, Sara Schad, Sai K. Sharma, Sadna Budhu, Aditi Gupta, Corrin Pimentel, Hong Zhong, Jason S. Lewis, John T. Poirier, Jedd D. Wolchok, Charles M. Rudin, Taha Merghoub
Journal: Cancer Research (2019)

Abstract Over 600,000 Americans and 8 million worldwide die of cancer each year. The success of immune checkpoint blockade with anti-PD-1 therapy has been a remarkable clinical advance. However, most patients do not respond to anti-PD-1 monotherapy and the majority of those who initially do respond eventually succumb to the disease. There is currently an unmet need to identify therapeutic strategies to overcome resistance and further enhance the efficacy of anti-PD-1 therapy. Tim-4 is a phosphatidylserine (PS) receptor that has been reported to be expressed on myeloid cells. Prior work has demonstrated that Tim-4 deficiency or blockade in mice is associated with features of autoimmunity and enhanced anti-tumor immunity. Using flow cytometry, immunohistochemistry, and in vivo biodistribution, we determined that Tim-4 is expressed predominantly on tissue-resident macrophages, such as Kupffer cells, peritoneal macrophages, pleural macrophages, and lymph node macrophages, but not tumor-associated macrophages, in mice and humans. We provide evidence that Tim-4+ macrophages produce high levels of the cytokines TNF-α and TGF-β, which have been linked to T cell dysfunction, and also the TGF-β activating integrin αv (CD51). Antibody blockade of Tim-4 enhances the anti-tumor activity of anti-PD-1 therapy after subcutaneous tumor inoculation of B16 melanoma, CT26 colon carcinoma, and MC38 colon carcinoma. Finally, combined blockade of Tim-4 and PD-1 resulted in substantially more curative responses in a MC38 model of peritoneal carcinomatosis, compared to anti-PD-1 monotherapy. This was associated with enhanced CD8+ T cell infiltration into the peritoneal cavity, increased CD8+ T cell/Foxp3+ regulatory T cell ratio, and reduced expression of the exhaustion marker PD-1. Thus, we show that Tim-4+ tissue-resident macrophages impair anti-tumor T cell immunity and antibody blockade of Tim-4 is a strategy that should be considered for clinical studies in cancers resistant to anti-PD-1 monotherapy. Citation Format: Andrew Chow, Sara Schad, Sai K. Sharma, Sadna Budhu, Aditi Gupta, Corrin Pimentel, Hong Zhong, Jason S. Lewis, John T. Poirier, Jedd D. Wolchok, Charles M. Rudin, Taha Merghoub. Tim-4+ tissue-resident macrophages impair antitumor T-cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 978.
Abstract 19603: Disruption of βPDGF Receptor-Dependent PI3k and Plcγ Signaling Protects from Hypoxia-Induced Pulmonary Hypertension
Authors: Henrik Ten Freyhaus, Wiebke Janssen, Maike Leuchs, Mario Zierden, Eva Berghausen, Marius Vantler, Evren Caglayan, Ralph T Schermuly, Michelle D Tallquist, Stephan Rosenkranz
Journal: Circulation (2012)

Background: Vascular remodeling is critical during the pathogenesis of pulmonary hypertension (PH). Growth factors, such as platelet-derived growth factor (PDGF), appear to be involved in these processes. With pharmacological inhibitors, we demonstrated previously that phosphatidyl inositol-3 kinase (PI3K) and phospholipase Cγ (PLCγ) are the critical mediators of βPDGF receptor (βPDGFR)-dependent proliferation and migration in pulmonary arterial smooth muscle cells (PASMC). Whereas expression data and data with the tyrosine kinase inhibitor imatinib suggest a role for PDGF in PH, data from genetic models is lacking. Methods and results: We utilized βPDGFR F3/F3 (“F3”) mice that were generated by introducing point mutations of the PI3K and PLCγ binding sites into the βPDGFR locus by gene targeting. We isolated PASMC from F3 and wild-type (WT) mice. Co-immunoprecipitation experiments after PDGF treatment showed that PI3K and PLCγ did not bind to the activated F3 receptor, whereas overall phosphorylation and binding of RasGap and SHP-2 were unaffected. In line with these observations, PDGF-mediated phosphorylation of Akt and Erk 1/2 was inhibited in F3-PASMC compared to WT. To address, if cellular responses were altered, we analyzed βPDGFR-dependent proliferation (as BrdU incorporation) and migration (modified Boyden chamber). These experiments revealed that these responses were essentially completely blocked in F3-PASMC compared to WT. To analyze the development and severity of PH in vivo, we exposed F3 and WT mice to hypoxia for 3 weeks. Following this treatment, right ventricular systolic pressure (RVSP) was measured by right heart catheterization, and right ventricular (RV) hypertrophy was assessed as RV weight/left ventricular + septal weight (RV/LV+S). These analyses revealed that RVSP and RV/LV+S were significantly reduced in F3 compared to WT mice. Conclusions: These data show that disruption of βPDGFR-dependent PI3K and PLCγ signaling blocks PDGF-dependent proliferation and migration of PASMC in vitro and protects from the development of hypoxia-induced PH in vivo. Consequently, these data support a critical role of PDGF during the pathogenesis of PH.
Abstract 1765: In vivo modeling of <i>RIT1</i> function in development and lung cancer
Authors: Maria McSharry
Journal: Cancer Research (2019)

Abstract Ras-like in most tissues 1 (RIT1) encodes a ubiquitously expressed RAS-family small GTPase. Recently, somatic RIT1 mutations were identified in lung adenocarcinoma and myeloid malignancies, and germline RIT1 mutations were found in. RIT1 is also implicated hematopoietic malignancies and in Noonan syndrome, a “Rasopathy” affecting craniofacial development and associated with congenital heart disease. Of a variety of RIT1 mutations discovered, the most recurrent mutation observed was M90I. In this study, murine models were used to determine whether expression of RIT1M90I mutation is sufficient for tumor initiation or developmental phenotypes observed in Noonan patients. Mice were genetically engineered at the Rosa26 locus to harbor RIT1M90I under the control of a lox-Cre system (LSL-RIT1M90I). The Cre recombinase protein was introduced via intratracheal delivery of adenovirus to the lungs. At one-year post treatment, 7 of the 10 LSL-RIT1M90I mice examined exhibited the expected genetic recombination. Tumors were observed in 3 of these mice, one of which was wild-type for p53. No visible tumors were seen in mice lacking the RIT1M90I gene or in cases where recombination was not observed, regardless of p53 status. Mouse embryonic fibroblasts (MEFs) were infected by adenovirus to recapitulate the in vivo studies and evaluate transformation. In vitro experiments conducted in RIT1M90I MEFs demonstrated faithful recombination of the transgene upon treatment with Cre. Protein analysis of these same cells reflected higher levels of RIT1 protein in transgenic cells treated with Cre, while in all other conditions, RIT1 was undetectable. Preliminary data from an immortalization assay suggested enhanced proliferation of MEFs expressing the RIT1M90I gene compared to wild-type counterparts. Cre recombinase was expressed body-wide in tamoxifen (4OHT) inducible mice (UBC-Cre-ERT2) LSL-RIT1M90I animals crossed to the inducible UBC-Cre-ERT2 system exhibited faithful recombination of the transgene upon treatment with 4OHT. To determine the consequences of constitutive expression of RIT1M90I, RIT1M90I sires were crossed to dams harboring constitutively active Cre recombinase or to a constitutively active Cre SRY-box promoter (Sox2-Cre). Of the 100 pups observed, none contained both RIT1M90I and Cre recombinase (p &amp;lt; 0.0001), indicating embryonic lethality induced by RIT1 activation. These data demonstrate the powerful effect of RIT1 activation on murine embryonic development and will enable future efforts on the characterization of the mechanism of RIT1-induced Noonan Syndrome and lung cancer. Citation Format: Maria McSharry. In vivo modeling of RIT1 function in development and lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1765.
Rituximab with Dose-Adjusted EPOCH (R-DA-EPOCH) As First-Line Treatment in Patients with Double-Hit Lymphoma: Preliminary Results in 35 Consecutive Patients from Two Institutions
Authors: Alessandra Tucci, Anna Guidetti, Anna Dodero, Francesca Schieppati, Alessandro Re, Nicola Bianchetti, Chiara Bottelli, Angela Passi, Maria Miscio, Simona Fisogni, Piera Balzarini, Fabio Facchetti, Paolo Corradini, Giuseppe Rossi
Journal: Blood (2017)
Abstract 1542: Bispecific T cell engager-induced toxicity in an immunocompetent solid tumor model
Authors: Claire Godbersen-Palmer, Tiffany Coupet, Zakaria Grada, Charles Sentman
Journal: Cancer Research (2019)

Abstract Chimeric antigen receptor (CAR) T cells and bispecific T cell engagers have demonstrated clinical efficacy, however are often accompanied by severe toxicity including cytokine release syndrome (CRS), neurotoxicity or macrophage activation syndrome (MAS). Mechanistic understanding of the development of these toxicities and testing of therapeutic interventions is limited by a lack of suitable immunocompetent pre-clinical models. We have developed both human and murine versions of a bispecific molecule with specific activity against target expressing tumor cells in vitro and in vivo. These bispecific proteins are constructed from the extracellular portion of either mouse or human NKG2D receptor and target cells expressing the cognate ligands by redirecting T cells through their CD3 binding arm. Using the murine bispecific protein, mNKG2DxCD3, we have developed an immunocompetent mouse tumor model which exhibits treatment induced toxicity and recapitulates key features similar to those observed in human CRS. Toxicity was observed between the 2nd and 4th bispecific protein injections but was not observed following subsequent injections. Monitoring of toxicity kinetics showed transient symptoms peaking 3-4 hours following bispecific protein injection with complete resolution after 8 hours. Weight loss and elevated plasma cytokines including IFNγ, IL6, TNFα, IL2 and IL10 were also associated with toxicity. Pathology analysis showed a reduction in white pulp in the mouse spleens, however, other organs evaluated (brain, kidney, lung and heart) were normal. Using mouse genetic knockout models, we were able to show that T cells, IFNγ and Perforin were required for development of this toxicity. Additionally, In vivo depletion of either CD4+ or CD8+ T cells was sufficient to prevent the onset of toxicity. These findings highlight the importance of T cell activation and function and shed light on the mechanistic underpinnings of bispecific T cell engager protein induced toxicity. Citation Format: Claire Godbersen-Palmer, Tiffany Coupet, Zakaria Grada, Charles Sentman. Bispecific T cell engager-induced toxicity in an immunocompetent solid tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1542.
Abstract 1162: CD24 regulates cancer stem cell like traits in bladder cancer
Authors: Akira Oki, Mohammad Obaidul Hoque
Journal: Cancer Research (2019)

Abstract Tumors are hierarchically organized by a rare population of cancer stem cells (CSCs) that contributes to cancer initiation, progression, and treatment failure. A better understanding of the molecular mechanisms underlying urothelial CSC regulation and the identification of key molecules associated with CSC generation and maintenance are pivotal for the molecular-targeting therapy. CD24 is overexpressed and acts as a lynchpin of tumorigenesis and metastatic progression in urothelial carcinoma of the bladder (UCB). However, its contribution to cancer stem-like traits of CD24 have not been determined. The functional relevance of CD24 was evaluated using in vitro and in vivo approaches. The knockdown of CD24 attenuated cancer stemness properties including sphere formation, self-renewal, invasion, chemo-resistance, and tumor initiation. The high-CD24-expressing cells, isolated from patient-derived UCB xenograft tumors, exhibited their enhanced stemness properties. Biologically, CD24 was associated with the expression of several key CSC-related molecules, including CD133, ABCG2, and YAP1. In human UCB samples, CD24 was overexpressed not only in primary tumors, but also in urine from UCB subjects. Conclusion: CD24 plays a crucial role in maintaining the urothelial cancer stem-like traits. Note: This abstract was not presented at the meeting. Citation Format: Akira Oki, Mohammad Obaidul Hoque. CD24 regulates cancer stem cell like traits in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1162.
Abstract 565: A novel T-cell costimulatory Humabody® VH therapeutic for PSMA-positive tumors
Authors: James W. Legg, Brian McGuinness, Sophie Archer, Phil Bland-Ward, Verena Brucklacher, Jenny Craigen, Carolyn Edwards, Emma Hames, Jay Majithiya, pavel Pisa, Bhindu Revi, Nikki Royale, Angelica Sette, Yumin Teng, Lorraine Thompson, Wembin Wang, Chris Wilson, Chris Wyre, Chris Rossant
Journal: Cancer Research (2019)

Abstract Agonistic monoclonal antibodies targeting CD137/4-1BB have shown much preclinical promise but their clinical development has been slowed due to a poor therapeutic index, in particular liver toxicity. CB307 is a novel half-life extended bispecific Humabody VH targeting CD137 (4-1BB) and prostate specific membrane antigen (PSMA). The design of CB307 enables agonism of CD137 selectively in the presence of PSMA positive tumour cells and in this way enable tumour selective T cell activation whilst minimising systemic activation. The molecular weight of CB307 is less than 50 kDa (around a third of the size of a standard IgG) and it does not contain an Fc domain, thereby avoiding interaction with Fc receptors. Half life extension is achieved through the inclusion of a VH domain with specificity for human serum albumin (HSA). The identification of CB307 using the Crescendo Mouse™ which develops fully human VH domains in a background devoid of light chains will be described along with characterisation of the key properties of the molecule in in vitro and in vivo models. In dual target binding assays CB307 shows potent co-binding to both PSMA and CD137 targets and mediates CD137 signalling in an NFKB cell reporter assay in the presence of PSMA positive cells but not PSMA negative cells. Co-incubation of primary human T-cells from healthy individuals or cancer patients together with PSMA positive tumour cells and CD3 stimulation induces T-cell activation and cytokine release. In an in vivo model using NSG mice engrafted with human PBMCs the growth of PSMA positive DU145 prostate tumour cells is inhibited by a surrogate bispecific. Together these data support progression of CB307 into clinical development. Citation Format: James W. Legg, Brian McGuinness, Sophie Archer, Phil Bland-Ward, Verena Brucklacher, Jenny Craigen, Carolyn Edwards, Emma Hames, Jay Majithiya, pavel Pisa, Bhindu Revi, Nikki Royale, Angelica Sette, Yumin Teng, Lorraine Thompson, Wembin Wang, Chris Wilson, Chris Wyre, Chris Rossant. A novel T-cell costimulatory Humabody® VH therapeutic for PSMA-positive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 565.
Evolving neoantigen profiles in colorectal cancers with DNA repair defects
Authors: Giuseppe Rospo, Annalisa Lorenzato, Nabil Amirouchene-Angelozzi, Alessandro Magrì, Carlotta Cancelliere, Giorgio Corti, Carola Negrino, Vito Amodio, Monica Montone, Alice Bartolini, Ludovic Barault, Luca Novara, Claudio Isella, Enzo Medico, Andrea Bertotti, Livio Trusolino, Giovanni Germano, Federica Di Nicolantonio, Alberto Bardelli
Journal: Genome Medicine (2019)

Neoantigens that arise as a consequence of tumor-specific mutations can be recognized by T lymphocytes leading to effective immune surveillance. In colorectal cancer (CRC) and other tumor types, a high number of neoantigens is associated with patient response to immune therapies. The molecular processes governing the generation of neoantigens and their turnover in cancer cells are poorly understood. We exploited CRC as a model system to understand how alterations in DNA repair pathways modulate neoantigen profiles over time. We performed whole exome sequencing (WES) and RNA sequencing (RNAseq) in CRC cell lines, in vitro and in vivo, and in CRC patient-derived xenografts (PDXs) to track longitudinally genomic profiles, clonal evolution, mutational signatures, and predicted neoantigens. The majority of CRC models showed remarkably stable mutational and neoantigen profiles; however, those carrying defects in DNA repair genes continuously diversified. Rapidly evolving and evolutionary stable CRCs displayed characteristic genomic signatures and transcriptional profiles. Downregulation of molecules implicated in antigen presentation occurred selectively in highly mutated and rapidly evolving CRC. These results indicate that CRCs carrying alterations in DNA repair pathways display dynamic neoantigen patterns that fluctuate over time. We define CRC subsets characterized by slow and fast evolvability and link this phenotype to downregulation of antigen-presenting cellular mechanisms. Longitudinal monitoring of the neoantigen landscape could be relevant in the context of precision medicine.
Abstract 5772: The Impact of Aortic Plaque Morphology on Survival Rate and the Incidence of Subsequent Embolic Event: Very Long-Term Follow-Up Data
Authors: Chisato Izumi, Shuichi Takahashi, Sumiyo Hashiwada, Koji Hanazawa, Jiro Sakamoto, Kazuyasu Yoshitani, Makoto Miyake, Kazuaki Kaitani, Toshiaki Izumi, Hiromitsu Gen, Yoshihisa Nakagawa
Journal: Circulation (2008)

Atheromatous plaques of the aorta have been regarded as a potential source of emboli, but there are few reports about the frequency and prognosis of patients with thoracic aortic plaques and about the relationship between plaque morphology and prognosis, especially long-term follow-up data. The purpose of this study is to clarify the impact of aortic atheromatous plaque morphology on survival rate and the incidence of subsequent embolic event. We retrospectively investigated 1570 consecutive patients who underwent transesophageal echocardiography between 1991 and 2003. The presence of severe plaque (&gt;5mm in thickness) in the thoracic aorta were examined. Survival rate and subsequent embolic event rate were compared between patients with severe plaque and 109 control patients. The control patients were selected from the patients who showed no or mild plaque and as they were matched for age, gender, and risk factors of atherosclerosis with the patients with severe aortic plaque. The relationship between aortic plaque morphology and prognosis was also estimated, according to the presence of ulceration, calcification, hypoechoic plaques, and mobile plaques. Mean follow-up period was 8.7 years. Among 1570 patients, severe aortic plaque was detected in 92 patients (5.9%). These 92 patients showed significantly low survival rate and high subsequent embolic event rate compared with control patients (8-year survival rate, 50% vs 87%, 8-year embolic event free rate, 57% vs 90%). The relative risk of death was significantly increased for ulceration (2.4, 95% CI;1.1–5.2) and the relative risk of embolic events was significantly increased for mobile plaques (2.2, 95% CI;1.1–5.1). In conclusion, aortic plaque &gt; 5mm in thickness was a predictor of a low survival rate and a high embolic event rate. Among patients with aortic plaque &gt;5mm in thickness, ulceration was a predictor of a low survival rate and mobile plaque was a predictor of a high embolic event rate.
Abstract LB-065: A high quality neoantigen fitness model cooperates with T lymphocyte infiltrates to identify glioblastoma patients with the longest survival
Authors: Jing Zhang, Francesca P. Caruso, Jason K. Sa, Sune Justesen, Do-Hyun Nam, Peter Sims, Michele Ceccarelli, Anna Lasorella, Antonio Iavarone
Journal: Cancer Research (2019)

Abstract Malignant glioma (glioblastoma, GBM) is a lethal cancer resistant to multimodality therapeutic approaches. A high burden of tumor-specific mutant peptides (neoantigens) correlates with a more favorable prognosis and response to immunotherapies in selected solid tumors but the role of neoantigens and how they impact clinical outcome in most tumors including GBM remains unclear. Here, we exploited the similarity between tumor neoantigens and infectious disease-derived immune epitopes and applied a neoantigen fitness model for the identification of high quality neoantigens in human GBM. The neoantigen quality fitness model stratified GBM patients with more favorable clinical outcome and, together with tumor infiltration of CD8 T lymphocytes, identified a subgroup of GBM patients with the longest survival, thus exhibiting optimal performance. Conversely, neither tumor neoantigen burden from a quantity model nor the isolated enrichment of CD8 T lymphocytes could predict better survival of GBM patients. The GBM subgroup that emerged from the neoantigen quality model displays distinct genomic and transcriptomic features that should guide patient stratification for immunotherapy and maximal benefit of GBM patients. Citation Format: Jing Zhang, Francesca P. Caruso, Jason K. Sa, Sune Justesen, Do-Hyun Nam, Peter Sims, Michele Ceccarelli, Anna Lasorella, Antonio Iavarone. A high quality neoantigen fitness model cooperates with T lymphocyte infiltrates to identify glioblastoma patients with the longest survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-065.