tbuckley/cabot-search huggingface dataset:
Incerta-thalamic Circuit Controls Nocifensive Behavior via Cannabinoid Type 1 Receptors
Authors: Hao Wang, Ping Dong, Chao He, Xiao-Yang Feng, Yue Huang, Wei-Wei Yang, Hua-Jing Gao, Xiao-Fan Shen, Shan Lin, Shu-Xia Cao, Hong Lian, Jiadong Chen, Min Yan, Xiao-Ming Li
Journal: Neuron (2020)
Response to: ‘Severe COVID-19 associated pneumonia in 3 patients with systemic sclerosis treated with rituximab’ by Avouac<i>et al</i>
Authors: Philippe Guilpain, Clément Le Bihan, Vincent Foulongne, Patrice Taourel, Nathalie Pansu, Alexandre Thibault Jacques Maria, Boris Jung, Romaric Larcher, Kada Klouche, Vincent Le Moing
Journal: Annals of the Rheumatic Diseases (2020)

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
SAT0265 RISK FACTORS FOR INFECTIOUS COMPLICATIONS FOLLOWING RITUXIMAB TREATMENT – MULTICENTER POLISH EXPERIENCE
Authors: A. Masiak, M. Ziętkiewicz, K. Wójcik, K. Wawrzycka-Adamczyk, M. Madej, J. Kur-Zalewska, M. Wisłowska, H. Storoniak, M. Komorniczak, I. Brzosko, M. Brzosko, A. Dębska-Ślizień, J. Musiał, Z. Zdrojewski
Journal: Annals of the Rheumatic Diseases (2020)

Background: Rituximab (RTX) is a B cell depleting monoclonal antibody with proven efficacy in the treatment of ANCA-associated vasculitis (AAV). The infectious complications occur in 15-25%. Objectives: We aimed to assess the frequency and risk factors of infections in patients with AAV receiving RTX among Polish patients. Methods: 7 tertiary referral centers experienced in the treatment of vasculitis completed a questionnaire regarding AAV patients treated with RTX. Results: Among 49 patients included in the analysis (47 with GPA, 2 with MPA; 36/73% men; mean age at diagnosis 42,45±14,9 yrs., mean age on RTX initiation 46,14±14,72 yrs.,) at least one infection occurred in 20 patients (40.82%) after mean time of 16,65±16,01 weeks since the administration of RTX. Patients were followed for a mean time of 26,88±21,94 months. There were no differences in the incidence of infectious complications by gender, age, BMI, smoking status, severity of the disease, activity of the disease (BVAS), time from diagnosis to RTX initiation, carriage of staphylococcus aureus in the upper respiratory tract, total dose of CYC before RTX treatment. We didn’t observe severe hypogammaglobulinemia or neutropenia after RTX treatment. 40% of the observed infections occurred during the first month, 35% between second and sixth month of follow-up, while 25% were observed between 6 and 12 months after the RTX initiation. Of the 20 patients who developed infection, 12 (24.5%) had further infections. Antibiotic prophylaxis with trimethoprim–sulfamethoxazole was administered in 40 out of 49 (81.63%). Upper respiratory tract infection was the most common infectious complication (n=11), followed by lower respiratory tract (n=4), soft tissues (n=4) and urinary tract infections (n=4), lacrimal gland abscess (n=2) and abdomen (n=1). In cases with a positive microbial result Staphylococcus aureus (n=4), Klebsiella pneumoniae (n=2), Pseudomonas aeruginosa (n=1), Candida (n=1) and others (n=6) were identified. No fatalities were recorded and only 3 patients had severe infection with the necessity of prolonged treatment. Conclusion: Despite the high number of infections in our group treated with RTX, most of them were not severe. Upper respiratory tract was the most common site of infection. Disclosure of Interests: None declared
AB0463 ETIOLOGY OF PALPABLE PURPURA; A SINGLE CENTER EXPERIENCE
Authors: G. Kaynar, O. C. İçaçan, S. Çelik, M. Yalçin Mutlu, C. Bes
Journal: Annals of the Rheumatic Diseases (2020)

Background: Purpura are lesions that occur after bleeding on the skin, mucous or serosal surfaces. Purpura can be classified into 2 subgroups; which are linked to thrombocytopenia and non-trombocytopenic purpura. While thrombocytopenic purpura often occurs due to a hematological disease; in non-trombocytopenic purpura etiological causes are very variable, and systemic vasculitis has an important place among them. Objectives: The demographic features of the patients applying with purpura and the underlying causes and diseases were aimed to be revealed. Methods: 44 consecutive patients (22 women, 22 men) who were admitted to the hospital in the last 6 months, due to purpura were evaluated. Average age of patients was 49.6 ± 19.6 years. Patients were questioned about a recent infection, drug use, concomitant or underlying diseases. The serological tests and other laboratory tests for etiology were performed and biopsy was taken from the skin lesions which are appropriate. Results: While 4 (9%) patients had widespread purpura on the trunk-upper-lower extremities, in 22 (50%) patients purpuric lesions were limited only to the lower limb. The period between the onset of the first symptom and the admission to the hospital was longer than 4 weeks in 35 (79.5%) patients, and shorter than 1 week in 9 (20.5%) patients. 24 (54%) patients had an anamnesis of infection 2-3 weeks before purpura, and 20 (45%) patients had an anamnesis of drug use. The most common accompanying symptom was abdominal pain and was present in 15 (34%) patients. Biopsy was performed from the skin lesion in 37 patients. Histopathological examination of all was compatible with leukocytoclastic vasculitis. In indirect immunofluorescence staining, 17 were found to be IgA positive. 2 (4.5%) patients were diagnosed PR3-ANCA positive granulomatosis with polyangiitis. 1 patient had Hepatitis B virus infection was detected in 1 patient (2.2%), HIV infection was detected in 1 patient (2.2%) and malignancy was detected in 1 patient (2.2%). Conclusion: In our study, the most common reason was found as IgA vasculitis in patients presenting with palpable purpura. Although vasculitic involvement was limited to the skin in most patients, organ-threatening systemic vasculitis was detected in a few patients. Patients applying with Purpura should be questioned for infection and drug use, should be examined for underlying diseases including systemic vasculitis, and closely monitored for organ involvement. Disclosure of Interests: None declared
The long and winding road of cardiomyocyte maturation
Authors: Giovanni Maroli, Thomas Braun
Journal: Cardiovascular Research (2020)

Knowledge about the molecular mechanisms regulating cardiomyocyte (CM) proliferation and differentiation has increased exponentially in recent years. Such insights together with the availability of more efficient protocols for generation of CMs from induced pluripotent stem cells (iPSCs) have raised expectations for new therapeutic strategies to treat congenital and non-congenital heart diseases. However, the poor regenerative potential of the postnatal heart and the incomplete maturation of iPSC-derived CMs represent important bottlenecks for such therapies in future years. CMs undergo dramatic changes at the doorstep between prenatal and postnatal life, including terminal cell cycle withdrawal, change in metabolism, and further specialization of the cellular machinery required for high-performance contraction. Here, we review recent insights into pre- and early postnatal developmental processes that regulate CM maturation, laying specific focus on genetic and metabolic pathways that control transition of CMs from the embryonic and perinatal to the fully mature adult CM state. We recapitulate the intrinsic features of CM maturation and highlight the importance of external factors, such as energy substrate availability and endocrine regulation in shaping postnatal CM development. We also address recent approaches to enhance maturation of iPSC-derived CMs in vitro, and summarize new discoveries that might provide useful tools for translational research on repair of the injured human heart.
Safety, immunogenicity, and clinical efficacy of durvalumab in combination with folate receptor alpha vaccine TPIV200 in patients with advanced ovarian cancer: a phase II trial
Authors: Dmitriy Zamarin, Sven Walderich, Aliya Holland, Qin Zhou, Alexia E Iasonos, Jean M Torrisi, Taha Merghoub, Lewis F Chesebrough, Autumn S Mcdonnell, Jacqueline M Gallagher, Yanyun Li, Travis J Hollmann, Rachel N Grisham, Courtney L Erskine, Mathew S Block, Keith L Knutson, Roisin E O’Cearbhaill, Carol Aghajanian, Jason A Konner
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immune checkpoint inhibitors (ICIs) to date have demonstrated limited activity in advanced ovarian cancer (OC). Folate receptor alpha (FRα) is overexpressed in the majority of OCs and presents an attractive target for a combination immunotherapy to potentially overcome resistance to ICI in OCs. The current study sought to examine clinical and immunologic responses to TPIV200, a multiepitope FRα vaccine administered with programmed death ligand 1 (PD-L1) inhibitor durvalumab in patients with advanced platinum-resistant OC. Methods Following Simon two-stage phase II trial design, 27 patients were enrolled. Treatment was administered in 28-day cycles (intradermal TPIV200 and granulocyte-macrophage colony-stimulating factor (GM-CSF) for 6 cycles and intravenous durvalumab for 12 cycles). Primary endpoints included overall response rate and progression-free survival at 24 weeks. Translational parameters focused on tumor microenvironment, PD-L1 and FRα expression, and peripheral vaccine-specific immune responses. Results Treatment was well tolerated, with related grade 3 toxicity rate of 18.5%. Increased T cell responses to the majority of peptides were observed in all patients at 6 weeks (p&lt;0.0001). There was one unconfirmed partial response (3.7%) and nine patients had stable disease (33.3%). Clinical benefit was not associated with baseline FRα or PD-L1 expression. One patient with prolonged clinical benefit demonstrated loss of FRα expression and upregulation of PD-L1 in a progressing lesion. Despite the low overall response rate, the median overall survival was 21 months (13.5–∞), with evidence of benefit from postimmunotherapy regimens. Conclusions Combination of TPIV200 and durvalumab was safe and elicited robust FRα-specific T cell responses in all patients. Unexpectedly durable survival in this heavily pretreated population highlights the need to investigate the impact of FRα vaccination on the OC biology post-treatment.
Abstract A17: Polyploid giant cancer cells lead to evolution of drug resistance in high-grade ovarian cancer
Authors: Na Niu, Xiaoran Li, Jun Yao, Anil Sood, Jinsong Liu
Journal: Cancer Research (2020)

Abstract Whole genomic duplications (WGD) have been reported in 37% to 56% of high-grade cancers. WGD leads to formation of polyploid giant cancer cells (PGCCs) with salient and atypical nuclear morphology noted by light microscopy. However, PGCCs are generally considered nonviable due to their inability to execute mitosis. We have recently reported that PGCCs are capable of generating mitosis-competent progeny cells via primitive amitotic division including budding, splitting, and burst. We have further demonstrated that PGCCs are part of the process of somatic reprogramming named the giant cell life cycle composed of four distinct but overlapping phases including initiation, self-renewal, termination, and stability. The giant cell life cycle resets the somatic cell from the mitotic cycle to stress-induced endoreplication cell cycle via WGD to form PGCCs. The PGCCs activate endogenous embryonic factors for the reprogramming, which leads to the birth of drug-resistant cells by clonal selection from newly generated heterogeneous cancer stem cells. However, the underlying genetic and epigenetic mechanisms during WGD remain unclear. By mapping DNA methylation and whole-genome sequencing, monitoring the telomere dynamics, and tracking the cellular and nuclear morphology using microscopic time-lapse imaging observations during the time course of giant cell life cycle, we hereby provide new evidence that the daughters cells derived from PGCCs have massive alterations at the whole-genome and epigenome levels. The reprogrammed resistant daughter cells are achieved, at least in part, by genomic instability via shortened telomeres. Targeting PGCCs and promoting their differentiation during the course of giant cell life cycle may represent a novel approach to intercept drug resistance. Citation Format: Na Niu, Xiaoran Li, Jun Yao, Anil Sood, Jinsong Liu. Polyploid giant cancer cells lead to evolution of drug resistance in high-grade ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A17.
Abstract 11186: SGLT1 Exhibits Ischemic Tolerance and Contributes to Cardioprotection During Ischemia-Reperfusion Injury in Diet-Induced Obese Mice
Authors: Akira Yoshii, Tomohisa Nagoshi, Yusuke Kashiwagi, Haruka Kimura, Yoshiro Tanaka, Keiichi Ito, Takuya Yoshino, Toshikazu D Tanaka, Michihiro Yoshimura
Journal: Circulation (2018)

Although recent large clinical trials showed that SGLT2 inhibitors reduced cardiovascular events in diabetic patients, the regulation of cardiac SGLTs (SGLT1 is the dominant isoform), as compared t...
m6A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development
Authors: Yimeng Gao, Radovan Vasic, Yuanbin Song, Rhea Teng, Chengyang Liu, Rana Gbyli, Giulia Biancon, Raman Nelakanti, Kirsten Lobben, Eriko Kudo, Wei Liu, Anastasia Ardasheva, Xiaoying Fu, Xiaman Wang, Poorval Joshi, Veronica Lee, Burak Dura, Gabriella Viero, Akiko Iwasaki, Rong Fan, Andrew Xiao, Richard A. Flavell, Hua-Bing Li, Toma Tebaldi, Stephanie Halene
Journal: Immunity (2020)
Micro-RNA Clusters Integrate Evolutionary Constraints on Expression and Target Affinities: The miR-6/5/4/286/3/309 Cluster in Drosophila
Authors: Qu Zhe, Wing Chung Yiu, Ho Yin Yip, Wenyan Nong, Clare W C Yu, Ivy H T Lee, Annette Y P Wong, Nicola W Y Wong, Fiona K M Cheung, Ting Fung Chan, Kwok Fai Lau, Silin Zhong, Ka Hou Chu, Stephen S Tobe, David E K Ferrier, William G Bendena, Jerome H L Hui
Journal: Molecular Biology and Evolution (2020)

Abstract A striking feature of micro-RNAs is that they are often clustered in the genomes of animals. The functional and evolutionary consequences of this clustering remain obscure. Here, we investigated a micro-RNA cluster miR-6/5/4/286/3/309 that is conserved across drosophilid lineages. Small RNA sequencing revealed expression of this micro-RNA cluster in Drosophila melanogaster leg discs, and conditional overexpression of the whole cluster resulted in leg appendage shortening. Transgenic overexpression lines expressing different combinations of micro-RNA cluster members were also constructed. Expression of individual micro-RNAs from the cluster resulted in a normal wild-type phenotype, but either the expression of several ancient micro-RNAs together (miR-5/4/286/3/309) or more recently evolved clustered micro-RNAs (miR-6-1/2/3) can recapitulate the phenotypes generated by the whole-cluster overexpression. Screening of transgenic fly lines revealed downregulation of leg-patterning gene cassettes in generation of the leg-shortening phenotype. Furthermore, cell transfection with different combinations of micro-RNA cluster members revealed a suite of downstream genes targeted by all cluster members, as well as complements of targets that are unique for distinct micro-RNAs. Considered together, the micro-RNA targets and the evolutionary ages of each micro-RNA in the cluster demonstrate the importance of micro-RNA clustering, where new members can reinforce and modify the selection forces on both the cluster regulation and the gene regulatory network of existing micro-RNAs. Key words: micro-RNA, cluster, evolution.
Analysis of a SARS-CoV-2-Infected Individual Reveals Development of Potent Neutralizing Antibodies with Limited Somatic Mutation
Authors: Emilie Seydoux, Leah J. Homad, Anna J. MacCamy, K. Rachael Parks, Nicholas K. Hurlburt, Madeleine F. Jennewein, Nicholas R. Akins, Andrew B. Stuart, Yu-Hsin Wan, Junli Feng, Rachael E. Whaley, Suruchi Singh, Michael Boeckh, Kristen W. Cohen, M. Juliana McElrath, Janet A. Englund, Helen Y. Chu, Marie Pancera, Andrew T. McGuire, Leonidas Stamatatos
Journal: Immunity (2020)
Abstract 15018: Chronic E-cigarette Users Exhibit Abnormal Myocardial Blood Flow With Stress
Authors: Mohamad Rashid, Katherine Davoren, Norma B Moy, Fida Nafeh, Robert Elashoff, Chulkyu Kim, Andy Kim, Elizabeth Kim, Michael D Nelson, Susan Cheng, Florian Rader
Journal: Circulation (2019)

Background: Electronic (e-) cigarettes are marketed as a safer alternative to conventional tobacco cigarettes. Although e-cigarettes contain a lower level of nicotine, the delivery method involves ...
Genetic screens reveal CCDC115 as a modulator of erythroid iron and heme trafficking
Authors: Amin Sobh, Alex Loguinov, Jie Zhou, Supak Jenkitkasemwong, Rola Zeidan, Nader El Ahmadie, Abderrahmane Tagmount, Mitchell Knutson, Paula G. Fraenkel, Christopher D. Vulpe
Journal: American Journal of Hematology (2020)

Abstract Transferrin‐bound iron (TBI), the physiological circulating iron form, is acquired by cells through the transferrin receptor (TfR1) by endocytosis. In erythroid cells, most of the acquired iron is incorporated into heme in the mitochondria. Cellular trafficking of heme is indispensable for erythropoiesis and many other essential biological processes. Comprehensive elucidation of molecular pathways governing and regulating cellular iron acquisition and heme trafficking is required to better understand physiological and pathological processes affecting erythropoiesis. Here, we report the first genome‐wide clustered regularly interspaced short palindromic repeats (CRISPR) screens in human erythroid cells to identify determinants of iron and heme uptake, as well as heme‐mediated erythroid differentiation. We identified several candidate modulators of TBI acquisition including TfR1, indicating that our approach effectively revealed players mechanistically relevant to the process. Interestingly, components of the endocytic pathway were also revealed as potential determinants of transferrin acquisition. We deciphered a role for the vacuolar‐type H+ − ATPase (V‐ ATPase) assembly factor coiled‐coil domain containing 115 (CCDC115) in TBI uptake and validated this role in CCDC115 deficient K562 cells. Our screen in hemin‐treated cells revealed perturbations leading to cellular adaptation to heme, including those corresponding to trafficking mechanisms and transcription factors potentiating erythroid differentiation. Pathway analysis indicated that endocytosis and vesicle acidification are key processes for heme trafficking in erythroid precursors. Furthermore, we provided evidence that CCDC115, which we identified as required for TBI uptake, is also involved in cellular heme distribution. This work demonstrates a previously unappreciated common intersection in trafficking of transferrin iron and heme in the endocytic pathway of erythroid cells.
Multicenter Phase I Trial of a DNA Vaccine Encoding the Androgen Receptor Ligand-binding Domain (pTVG-AR, MVI-118) in Patients with Metastatic Prostate Cancer
Authors: Christos E. Kyriakopoulos, Jens C. Eickhoff, Anna C. Ferrari, Michael T. Schweizer, Ellen Wargowski, Brian M. Olson, Douglas G. McNeel
Journal: Clinical Cancer Research (2020)

Preclinical studies demonstrated that a DNA vaccine (pTVG-AR, MVI-118) encoding the androgen receptor ligand-binding domain (AR LBD) augmented antigen-specific CD8+ T cells, delayed prostate cancer progression and emergence of castration-resistant disease, and prolonged survival of tumor-bearing mice. This vaccine was evaluated in a multicenter phase I trial.Patients with metastatic castration-sensitive prostate cancer (mCSPC) who had recently begun androgen deprivation therapy were randomly assigned to receive pTVG-AR on one of two treatment schedules over one year, and with or without GM-CSF as a vaccine adjuvant. Patients were followed for 18 months. Primary objectives were safety and immune response. Secondary objectives included median time to PSA progression, and 18-month PSA-PFS (PPFS).Forty patients were enrolled at three centers. Twenty-seven patients completed treatment and 18 months of follow-up. Eleven patients (28%) had a PSA progression event before the 18-month time point. No grade 3 or 4 adverse events were observed. Of 30 patients with samples available for immune analysis, 14 (47%) developed Th1-type immunity to the AR LBD, as determined by IFNγ and/or granzyme B ELISPOT. Persistent IFNγ immune responses were observed irrespective of GM-CSF adjuvant. Patients who developed T-cell immunity had a significantly prolonged PPFS compared with patients without immunity (HR = 0.01; 95% CI, 0.0-0.21; P = 0.003).pTVG-AR was safe and immunologically active in patients with mCSPC. Association between immunity and PPFS suggests that treatment may delay the time to castration resistance, consistent with preclinical findings, and will be prospectively evaluated in future trials.See related commentary by Shenderov and Antonarakis, p. 5056.
Expanding the spectrum of European Respiratory Society official scientific documents: short documents complement clinical practice guidelines, statements and technical standards
Authors: Nicolas Roche, Thomy Tonia, Marc Miravitlles, Valérie Vaccaro, Céline Genton, Tobias Welte, Thierry Troosters, Guy Brusselle, Chris Brightling
Journal: European Respiratory Journal (2020)

In this issue of the European Respiratory Journal ( ERJ ), the European Respiratory Society (ERS) releases its first “short guideline” document, dealing with inhaled corticosteroid (ICS) withdrawal in COPD [1]. This guideline belongs to a new type of “short guidance” documents developed and published by the ERS; the main goal and characteristic is the shortened timeframe between project initiation and final output, thanks to a more restricted focus. Most importantly, these documents are not short versions of original guidelines and statements: they result from an original process. The European Respiratory Society now issues short official scientific documents <https://bit.ly/3brN9jO>
“B” aware: Memory lane access is restricted!
Authors: Ruth Kennedy, Ulf Klein
Journal: The Journal of Experimental Medicine (2020)

Understanding the molecular mechanisms that govern the differentiation of high-affinity germinal center (GC) B cells into memory B cells versus plasma cells is a major quest of adaptive immunity. In this issue, Toboso-Navasa et al. (https://doi.org/10.1084/jem.20191933) provide evidence that the MYC-MIZ1 transcriptional repressor complex restricts the differentiation of GC B cells into MBCs.