tbuckley/cabot-search huggingface dataset:
FRI0238 AUTOLOGOUS FAT GRAFTING IN THE TREATMENT OF FACIAL SCLERODERMA: A SINGLE - CENTRE EXPERIENCE
Authors: P. Faggioli, L. Castelnovo, A. Tamburello, M. Falaschi, E. Saporiti, A. M. Lurati, A. Laria, A. Mazzone
Journal: Annals of the Rheumatic Diseases (2020)

Background: Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by progressive cutaneous and internal organ fibrosis. Orofacial manifestations are disabling and treatment options are limited. Fat Tissue Grafting (FTG) can be used for treating facial manifestations of the fibrosis. Objectives: In this study, we aimed to assess the safety and efficacy of FGT of our cohort of patients with SSc. Methods: We enrolled 20 SSc (18 W, 2 M) patients, from 2016 to 2019, suffering from facial sclerosis and restricted mouth opening capacity. FTG was carried out in accord with modified Colemans’ procedure (1): fat tissue was taken from periumbilical or trochanteric areas and was injected in 8 different points around the mouth. No side effects or adverse reactions have been documented. Evaluations included mouth opening capacity by measuring interincisal distance, oral functionality (MHISS scale) and patient global satisfaction (by Global Health scale). Results: A 11 mm (8 - 18mm range) median increase of interincisal distance was reported at month 6 and in 80% of patients at month 12, too (p&lt;0.03). A significant improvement in MHISS scale was also observed (p&lt;003). The patient satisfaction questionnaire showed 95% positive results and 80% of the patient replied affirmatively to the question about the repetition of FTG but only 2 patients required new FTG after 12 months. Conclusion: Our results showed that FTG improved mouth opening capacity and that aesthetic and functional results were satisfying to about 90% of the patients; long-term effects of this type of treatment are currently unknown. However, our and litterature data at 12 months follow-up seems to confirm the benefits in long term, despite the filling effect is over. This study – that’s one of the largest case series described right now (2) - supports the possible therapeutic role of autologous FTG in improving facial scleroderma both in aesthetic and in functional aspects. References: [1]Coleman SR. Structural fat grafting: more than a permanent filler. Plast Reconstr Surg. 2006; 118: 108S-20S [2]Fat Grafting for the Treatment of Scleroderma.Strong AL, Rubin JP, Kozlow JH, Cederna PS. Plast Reconstr Surg. 2019 Dec;144(6):1498-1507. doi: 10.1097/PRS.0000000000006291. Disclosure of Interests: None declared
Beware of wolves in sheep's clothing: immune cell plasticity and instability in health and disease
Authors: Alessia Alunno, Onelia Bistoni, Roberto Gerli
Journal: Annals of the Rheumatic Diseases (2020)

We read with great interest the article by Watad et al that characterised for the first time T lymphocytes in normal human enthesis.1 The authors demonstrated that entheseal resident CD4+ and CD8+ T cells show increased expression of immunomodulatory genes, including interleukin (IL)-10 and transforming growth factor-β compared with the circulating counterpart and that on stimulation they acquire the capability to produce tumour necrosis factor (TNF)-α and IL-17. Of note, normal entheseal T cells do not express FoxP3 as peripheral blood regulatory T cells (Treg), but its expression can be induced in specific conditions (eg, in the presence of phosphodiesterase type 4 inhibitor).

The plasticity and instability of immune cells in response to the stimuli of the local microenvironment are a highly interesting field of research under investigation in rheumatic and musculoskeletal diseases (RMDs).2 The article by Watad et al provides important insights that will help to better understand pathogenic mechanisms underlying the spectrum of spondyloarthritis (SpA). However, in light of data from experimental models and patients with RMDs, including SpA, some aspects should …
Inflammatory IFIT3 renders chemotherapy resistance by regulating post-translational modification of VDAC2 in pancreatic cancer
Authors: Zhefang Wang, Jie Qin, Jiangang Zhao, Jiahui Li, Dai Li, Marie Popp, Felix Popp, Hakan Alakus, Bo Kong, Qiongzhu Dong, Peter J Nelson, Yue Zhao, Christiane J Bruns
Journal: Theranostics (2020)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide and effective therapy remains a challenge. IFIT3 is an interferon-stimulated gene with antiviral and pro-inflammatory functions. Our previous work has shown that high expression of IFIT3 is correlated with poor survival in PDAC patients who receive chemotherapy suggesting a link between IFIT3 and chemotherapy resistance in PDAC. However, the exact role and molecular mechanism of IFIT3 in chemotherapy resistance in PDAC has been unclear. Methods: A group of transcriptome datasets were downloaded and analyzed for the characterization of IFIT3 in PDAC. Highly metastatic PDAC cell line L3.6pl and patient-derived primary cell TBO368 were used and IFIT3 knockdown and the corresponding knockin cells were established for in vitro studies. Chemotherapy-induced apoptosis, ROS production, confocal immunofluorescence, subcellular fractionation, chromatin-immunoprecipitation, co-immunoprecipitation and mass spectrometry analysis were determined to further explore the biological role of IFIT3 in chemotherapy resistance of PDAC. Results: Based on PDAC transcriptome data, we show that IFIT3 expression is associated with the squamous molecular subtype of PDAC and an increase in inflammatory response and apoptosis pathways. We further identify a crucial role for IFIT3 in the regulation of mitochondria-associated apoptosis during chemotherapy. Knockdown of IFIT3 attenuates the chemotherapy resistance of PDAC cells to gemcitabine, paclitaxel, and FOLFIRINOX regimen treatments, independent of individual chemotherapy regimens. While IFIT3 overexpression was found to promote drug resistance. Co-immunoprecipitation identified a direct interaction between IFIT3 and the mitochondrial channel protein VDAC2, an important regulator of mitochondria-associated apoptosis. It was subsequently found that IFIT3 regulates the post-translational modification-O-GlcNAcylation of VDAC2 by stabilizing the interaction of VDAC2 with O-GlcNAc transferase. Increased O-GlcNAcylation of VDAC2 protected PDAC cells from chemotherapy induced apoptosis. Conclusions: These results effectively demonstrate a central mechanism by which IFIT3 expression can affect chemotherapy resistance in PDAC. Targeting IFIT3/VDAC2 may represent a novel strategy to sensitize aggressive forms of pancreatic cancer to conventional chemotherapy regimens.
Letter by Abbas Regarding Articles, “Balloon-Expandable Versus Self-Expanding Transcatheter Aortic Valve Replacement: A Propensity-Matched Comparison From the FRANCE-TAVI Registry” and “Impact of Sapien 3 Balloon-Expandable Versus Evolut R Self-Expandable Transcatheter Aortic Valve Implantation in Patients With Aortic Stenosis: Data From a Nationwide Analysis”
Authors: Amr E. Abbas
Journal: Circulation (2020)
Effectiveness of different treatments in obesity hypoventilation syndrome
Authors: V.R. Ramírez Molina, J.F. Masa Jiménez, F.J. Gómez de Terreros Caro, J. Corral Peñafiel
Journal: Pulmonology (2020)

Obesity hypoventilation syndrome (OHS) is an undesirable consequence of obesity, defined as daytime hypoventilation, sleep disorder breathing and obesity; during the past few years the prevalence of extreme obesity has markedly increased worldwide consequently increasing the prevalence of OHS. Patients with OHS have a lower quality of life and a higher risk of unfavourable cardiometabolic consequences. Early diagnosis and effective treatment can lead to significant improvement in patient outcomes; therefore, such data has noticeably raised interest in the management and treatment of this sleep disorder. This paper will discuss the findings on the main current treatment modalities OHS will be discussed.
Covid-19: The communication needs of D/deaf healthcare workers and patients are being forgotten
Authors: Helen Grote, Fizz Izagaren
Journal: BMJ (2020)

Covid-19: The communication needs of D/deaf healthcare workers and patients are being forgottenWe need to ensure that in our response to covid-19, the rights of those with hearing loss are not forgotten, say Helen Grote and Fizz Izagaren Helen Grote, 1 Fizz Izagaren 2We are two deaf doctors who rely on lipreading in our daily work.The debates about personal protective equipment (PPE) during this coronavirus outbreak have revolved around adequate supplies 1 and whether the fit testing and face masks supplied by hospital trusts give enough protection. 2 The communication needs of those who rely on lipreading have been completely overlooked.
Response by Vincent et al to Letter Regarding Article, “Balloon-Expandable Versus Self-Expanding Transcatheter Aortic Valve Replacement: A Propensity-Matched Comparison From the FRANCE-TAVI Registry”
Authors: Flavien Vincent, Julien Ternacle, Cédric Delhaye, Vincent Auffret, Nicolas Debry, Thibaut Manigold, Alessandro Cosenza, Nicolas Amabile, Thibault Lhermusier, Sina Porouchani, Geraud Souteyrand, Benoit Lattuca, Eric Van Belle
Journal: Circulation (2020)
Bacterial extracellular vesicle-coated multi-antigenic nanovaccines protect against drug-resistant <i>Staphylococcus aureus</i> infection by modulating antigen processing and presentation pathways
Authors: Gang Chen, Yanan Bai, Zhenzhen Li, Fei Wang, Xuelian Fan, Xin Zhou
Journal: Theranostics (2020)

Background: Vaccination provides an alternative to antibiotics in addressing drug-resistant Staphylococcus aureus (S. aureus) infection.However, vaccine potency is often limited by a lack of antigenic breadth and a demand on the generation of antibody responses alone.Methods: In this study, bacterial extracellular vesicles (EVs) coating indocyanine green (ICG)-loaded magnetic mesoporous silica nanoparticles (MSN) were constructed as multi-antigenic vaccines (EV/ICG/MSN) with the ability to modulate antigen presentation pathways in dendritic cells (DCs) to induce cellular immune responses.Results: Exposing the EV/ICG/MSNs to a laser could promote DC maturation and enhance the proteasome-dependent antigen presentation pathway by facilitating endolysosomal escape, improving proteasome activity, and elevating MHC-I expression.Immunization by EV/ICG/MSNs with laser irradiation in vivo triggered improved CD8 + T cell responses while maintaining CD4 + T cell responses and humoral immunity.In addition, in vivo tracking data revealed that the vaccine could be efficiently transported from the injection site into lymph nodes.Skin infection experiments showed that the vaccine not only prevented and treated superficial infection but also decreased bacterial invasiveness, thus strongly suggesting that EV/ICG/MSNs were effective in preventing complications resulting from the introduction of S. aureus infections. Conclusion:This multi-antigenic nanovaccine-based modulation of antigen presentation pathways provides an effective strategy against drug-resistant S. aureus infection.
Semaphorin 3B–associated membranous nephropathy is a distinct type of disease predominantly present in pediatric patients
Authors: Sanjeev Sethi, Hanna Debiec, Benjamin Madden, Marina Vivarelli, M. Cristine Charlesworth, Aishwarya Ravindran, LouAnn Gross, Tim Ulinski, David Buob, Cheryl L. Tran, Francesco Emma, Francesca Diomedi-Camassei, Fernando C. Fervenza, Pierre Ronco
Journal: Kidney International (2020)

Membranous nephropathy results from subepithelial antigen-antibody complex deposition along the glomerular basement membrane. Although PLA2R, THSD7A, and NELL-1 account for a majority (about 80%) of the target antigens, the target antigen in the remaining cases is not known. Using laser microdissection of PLA2R-negative glomeruli of patients with membranous nephropathy followed by mass spectrometry we identified a unique protein, Semaphorin 3B, in three cases. Mass spectrometry failed to detect Semaphorin-3B in 23 PLA2R-associated cases of membranous nephropathy and 88 controls. Semaphorin 3B in all three cases was localized to granular deposits along the glomerular basement membrane by immunohistochemistry. Next, an additional eight cases of Semaphorin 3B-associated membranous nephropathy were identified in three validation cohorts by immunofluorescence microscopy. In four of 11 cases, kidney biopsy also showed tubular basement membrane deposits of IgG on frozen sections. Confocal microscopy showed that both IgG and Semaphorin 3B co-localized to the glomerular basement membrane. Western blot analysis of five available sera showed reactivity to reduced Semaphorin 3B in four of four patients with active disease and no reactivity in one patient in clinical remission; there was also no reactivity in control sera. Eight of the 11 cases of Semaphorin 3B-associated membranous nephropathy were pediatric cases. Furthermore, in five cases, the disease started at or below the age of two. Thus, Semaphorin 3B-associated membranous nephropathy appears to be a distinct type of disease; more likely to be present in pediatric patients.
Edward Ernest Cockayne
Authors: Isabel Cockayne, Sarah Cockayne
Journal: BMJ (2020)

Edward Ernest Cockayne (“Ted”) was born in Broken Cross near Macclesfield, a mill town in Cheshire, as the only child of Ernest and Sarah Cockayne on 29 February 1940. Sarah hailed from Ireland, and Edward never forgot his Irish roots. Both parents were nurses at the local psychiatric hospital and he was fond of relating the fact that he wore clogs to walk to school in his early years. He grew up to love sport and the outdoors, particularly rugby, walking, gardening, fishing and working on a local farm. He began his lifelong love of learning at King’s School, Macclesfield, and was inspired to become a doctor on reading A J Cronin’s The Citadel .

He studied medicine at Guy’s Hospital (1958-63) and met his future wife, Elizabeth, who was a nurse at Guy’s; they were married in June 1964. After completing initial jobs in London, he became attracted to general practice and moved to a rural practice in Woolpit, Suffolk, where he was …
Abstract 34: Improve decision making in clinical trials through machine learning and EHR
Authors: LiMing Shen, Tao Sheng, Xaiodong Luo
Journal: Clinical Cancer Research (2020)

Abstract One of the key contributors to the failure of oncology trials is patient selection bias. A bias that results in a lower observed efficacy in phase II may lead to a premature decision to abort a trial, whereas a bias in the positive direction may result in an expensive failure in phase III. We propose an approach in which RWE is used to model a proxy endpoint that is available in RWE but is also related to the endpoint in clinical trial, on patient profile; the model is then used on clinical trial patients to predict their proxy endpoints, which in turn is used to quantitatively assess selection bias and infer the effect of bias on the observed efficacy of the trial. We used an ongoing metastatic breast cancer trial to demonstrate this approach. Medication, demography, vital signs, and time of death of the target patient population were extracted from Optum Humetica. These data were then used to train a ML survival model to predict OS based on patient profiles in a virtual trial. For this oncology trial, we chose OS as a proxy endpoint as it has a well-established strong correlation with the observed efficacy in terms of PFS and time on drug duration. OS is an endpoint. The term proxy is used here in the sense that it is not the endpoint used in the earlier-phase trial. The model is then used to predict risk profiles for patients in the actual trial, and the difference between risk profile of the trial patients and that of the RWE target population provides a quantitative assessment of selection bias of the trial population. The effectiveness of this approach depends on the predictive power of the model. A nonpredictive model obviously cannot detect bias even when it is present. To quantitatively assess the predictive power of the model, we subsampled the RWE population to simulate a trial population with different risk profiles and use the model to determine a threshold in risk difference beyond which the model can detect a significant difference. In this context, we also compared Cox PH, decision tree, and a neural network model with respect to their predictive power in term of concordance score. We then compared the risk profile of the clinical trial patients with that of the target patient population. As RWE data become more abundant and data interoperability and quality improve, the prediction model will become more accurate and bias detection will become more sensitive. We believe this approach will lead to an effective framework whereby RWE data can be used to improve the success rate of oncology clinical trials. Citation Format: LiMing Shen, Tao Sheng, Xaiodong Luo. Improve decision making in clinical trials through machine learning and EHR [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 34.
Targeting MEF2D-fusion Oncogenic Transcriptional Circuitries in B-cell Precursor Acute Lymphoblastic Leukemia
Authors: Shinobu Tsuzuki, Takahiko Yasuda, Shinya Kojima, Masahito Kawazu, Koshi Akahane, Takeshi Inukai, Masue Imaizumi, Takanobu Morishita, Koichi Miyamura, Toshihide Ueno, Sivasundaram Karnan, Akinobu Ota, Toshinori Hyodo, Hiroyuki Konishi, Masashi Sanada, Hirokazu Nagai, Keizo Horibe, Akihiro Tomita, Kyogo Suzuki, Hideki Muramatsu, Yoshiyuki Takahashi, Yasushi Miyazaki, Itaru Matsumura, Hitoshi Kiyoi, Yoshitaka Hosokawa, Hiroyuki Mano, Fumihiko Hayakawa
Journal: Blood Cancer Discovery (2020)

The cellular context that integrates gene expression, signaling, and metabolism dictates the oncogenic behavior and shapes the treatment responses in distinct cancer types. Although chimeric fusion proteins involving transcription factors (TF) are hallmarks of many types of acute lymphoblastic leukemia (ALL), therapeutically targeting the fusion proteins is a challenge. In this work, we characterize the core regulatory circuitry (CRC; interconnected autoregulatory loops of TFs) of B-ALL involving MEF2D-fusions and identify MEF2D-fusion and SREBF1 TFs as crucial CRC components. By gene silencing and pharmacologic perturbation, we reveal that the CRC integrates the pre-B-cell receptor (BCR) and lipid metabolism to maintain itself and govern malignant phenotypes. Small-molecule inhibitors of pre-BCR signaling and lipid biosynthesis disrupt the CRC and silence the MEF2D fusion in cell culture and show therapeutic efficacy in xenografted mice. Therefore, pharmacologic disruption of CRC presents a potential therapeutic strategy to target fusion protein-driven leukemia.Cancer type-specific gene expression is governed by transcription factors involved in a highly interconnected autoregulatory loop called CRC. Here, we characterized fusion protein-driven CRC and identified its pharmacologic vulnerabilities, opening therapeutic avenues to indirectly target fusion-driven leukemia by disrupting its CRC.See related commentary by Sadras and Müschen, p. 18. This article is highlighted in the In This Issue feature, p. 5.
AB0397 LUPUS FATIGUE PROBLEMS IN THE RUSSIAN COHORT OF PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS (RENAISSANCE).
Authors: E. Aseeva, S. Solovyev, G. Koilubaeva, N. Nikishina, E. Nasonov, A. Lila
Journal: Annals of the Rheumatic Diseases (2020)

Background: Objectives: To determine the dependency of fatigue from SLE activity, irreversible organ damage and HRQoL in SLE patients of the Renaissance cohort. Methods: 328 Russian SLE patients were enrolled in the study (M/F 30/298) who fulfilled SLICC 2012 criteria. The SLEDAI 2K activity, SLICC damage index, Facit Fatigue scale, and health related quality of life (HRQol) using the LupusQol questionnaire were evaluated. Results: Based on the Facit Fatigue scale scores fatigue was verified in 148 (45%) out of 328 patients with SLE. Following lupus fatigue status patients were divided into two groups - 148 and 168 patients respectively. The groups were perfectly matched in terms of age, duration of the disease, duration of GCs therapy, and damage scores (Table 1) Characteristics mean (SD) Patients with lupus fatigue (n=148) Patients without lupus fatigue (n=168) P (Mann-Whitney) Age in years 35,31±12,03 33,68±10,68 0,13 Disease durationin in years 9,57±9,47 10,1±9,17 0,6 Duration of glucocorticoid therapy in month 72,81±7158 79,43±75,98 0,6 SLICC DaI, score 1,55±1,37 1,69±1,23 0,44 C3 Mu\ml 0,88±0,33 0,87±0,31 0,75 C4 Mu\ml 0,15±0,12 0,16±0,14 0,36 ANF, hep2 641± 453 550± 402 0,4 Fatigue scores by the Facit fatigue scale 25,16±6,58 42,43±4,56 0,000 The SLEDAI 2K activity scores were significantly higher in the group with lupus fatigue - 9.6±6.0 vs 6.7±4.2 ( p =0.01) as compared to values in the group without fatigue, as well as the level of antibodies to DNA ( p =0.02), 110.2±34.2 and 82.3±20.5, respectively. There was a significant decrease in HRQoL in patients with lupus fatigue based on scores in all eight scales of the questionnaire ( p =0.00), Figure 1. Comparative assessment of HRQoL using the LupusQol questionnaire in 328 SLE patients with and without fatigue. Conclusion: Almost half (45%) SLE patients in the Russian cohort experience fatigue. It is associated with disease activity on the SLEDAI 2k scale and high levels of antibodies to DNA. All patients experiencing lupus fatigue have significantly worse HRQoL based on scores in all eight scales of the questionnaire LupusQol. Disclosure of Interests: None declared
Liposomal Nanotherapy for Treatment of Atherosclerosis
Authors: Anastasia Darwitan, Yee Shan Wong, Luong T. H. Nguyen, Bertrand Czarny, Anita Vincent, Anu Maashaa Nedumaran, Yang Fei Tan, Aristo Muktabar, Jin Kai Tang, Kee Woei Ng, Subbu Venkatraman
Journal: Advanced Healthcare Materials (2020)

Abstract Atherosclerosis is a chronic disease that can lead to life‐threatening events such as myocardial infarction and stroke, is characterized by the build‐up of lipids and immune cells within the arterial wall. It is understood that inflammation is a hallmark of atherosclerosis and can be a target for therapy. In support of this concept, an injectable nanoliposomal formulation encapsulating fluocinolone acetonide (FA), a corticosteroid, is developed that allows for drug delivery to atherosclerotic plaques while reducing the systemic exposure to off‐target tissues. In this study, FA is successfully incorporated into liposomal nanocarriers of around 100 nm in size with loading efficiency of 90% and the formulation exhibits sustained release up to 25 d. The anti‐inflammatory effect and cholesterol efflux capability of FA‐liposomes are demonstrated in vitro. In vivo studies carried out with an apolipoprotein E‐knockout (Apoe −/− ) mouse model of atherosclerosis show accumulation of liposomes in atherosclerotic plaques, colocalization with plaque macrophages and anti‐atherogenic effect over 3 weeks of treatment. This FA‐liposomal‐based nanocarrier represents a novel potent nanotherapeutic option for atherosclerosis.
Letter to the editor: Wide indication for SARS-CoV-2-testing allowed identification of international risk areas during the early phase of the COVID-19 pandemic in Germany
Authors: Ute Rexroth, Osamah Hamouda, Johanna Hanefeld, Bettina Ruehe, Lothar H Wieler, Lars Schaade
Journal: Eurosurveillance (2020)

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