tbuckley/cabot-search huggingface dataset:
Highly elevated polygenic risk scores are better predictors of myocardial infarction risk early in life than later
Authors: Monica Isgut, Jimeng Sun, Arshed A. Quyyumi, Greg Gibson
Journal: Genome Medicine (2021)

Abstract Background Several polygenic risk scores (PRS) have been developed for cardiovascular risk prediction, but the additive value of including PRS together with conventional risk factors for risk prediction is questionable. This study assesses the clinical utility of including four PRS generated from 194, 46K, 1.5M, and 6M SNPs, along with conventional risk factors, to predict risk of ischemic heart disease (IHD), myocardial infarction (MI), and first MI event on or before age 50 (early MI). Methods A cross-validated logistic regression (LR) algorithm was trained either on ~ 440K European ancestry individuals from the UK Biobank (UKB), or the full UKB population, including as features different combinations of conventional established-at-birth risk factors (ancestry, sex) and risk factors that are non-fixed over an individual’s lifespan (age, BMI, hypertension, hyperlipidemia, diabetes, smoking, family history), with and without also including PRS. The algorithm was trained separately with IHD, MI, and early MI as prediction labels. Results When LR was trained using risk factors established-at-birth, adding the four PRS significantly improved the area under the curve (AUC) for IHD (0.62 to 0.67) and MI (0.67 to 0.73), as well as for early MI (0.70 to 0.79). When LR was trained using all risk factors, adding the four PRS only resulted in a significantly higher disease prevalence in the 98th and 99th percentiles of both the IHD and MI scores. Conclusions PRS improve cardiovascular risk stratification early in life when knowledge of later-life risk factors is unavailable. However, by middle age, when many risk factors are known, the improvement attributed to PRS is marginal for the general population.
Next‐Generation Vaccines: Nanoparticle‐Mediated DNA and mRNA Delivery
Authors: William Ho, Mingzhu Gao, Fengqiao Li, Zhongyu Li, Xue‐Qing Zhang, Xiaoyang Xu
Journal: Advanced Healthcare Materials (2021)

Abstract Nucleic acid vaccines are a method of immunization aiming to elicit immune responses akin to live attenuated vaccines. In this method, DNA or messenger RNA (mRNA) sequences are delivered to the body to generate proteins, which mimic disease antigens to stimulate the immune response. Advantages of nucleic acid vaccines include stimulation of both cell‐mediated and humoral immunity, ease of design, rapid adaptability to changing pathogen strains, and customizable multiantigen vaccines. To combat the SARS‐CoV‐2 pandemic, and many other diseases, nucleic acid vaccines appear to be a promising method. However, aid is needed in delivering the fragile DNA/mRNA payload. Many delivery strategies have been developed to elicit effective immune stimulation, yet no nucleic acid vaccine has been FDA‐approved for human use. Nanoparticles (NPs) are one of the top candidates to mediate successful DNA/mRNA vaccine delivery due to their unique properties, including unlimited possibilities for formulations, protective capacity, simultaneous loading, and delivery potential of multiple DNA/mRNA vaccines. This review will summarize the many varieties of novel NP formulations for DNA and mRNA vaccine delivery as well as give the reader a brief synopsis of NP vaccine clinical trials. Finally, the future perspectives and challenges for NP‐mediated nucleic acid vaccines will be explored.
Association of Obstructive Sleep Apnea With the Risk of Male Infertility in Taiwan
Authors: Yi-Han Jhuang, Chi-Hsiang Chung, I-Duo Wang, Chung-Kan Peng, En Meng, Wu-Chien Chien, Ping-Ying Chang
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Obstructive sleep apnea (OSA) has been proposed as a risk factor in infertility. However, to date, the association between OSA and male infertility has not been examined in a population-based study. <h3>Objective</h3> To investigate the risk factor of OSA in male infertility and the outcome of OSA treatment for the risk of male infertility. <h3>Design, Setting, and Participants</h3> This case-control population-based study collected data from the Longitudinal Health Insurance Database, a subset of the National Health Insurance Research Database in Taiwan. Male patients with a diagnosis of infertility and at least 3 outpatient visits or 1 hospitalization between January 1, 2000, and December 31, 2013, were included and matched by age, sex, and date of infertility diagnosis with individuals without an infertility diagnosis. Data analysis was performed from October 22, 2018, to April 22, 2019. <h3>Exposures</h3> Patients with male infertility and randomly selected patients without male infertility were matched using a 1:4 propensity score matching ratio. <h3>Main Outcomes and Measures</h3> A primary outcome was the risk factor of OSA (diagnosed through polysomnography). A secondary outcome was the association of the risk of male infertility with OSA exposure time interval (short term, middle term, and long term) and OSA management (ie, none, continuous positive airway pressure, uvulopalatopharyngoplasty, or both). <h3>Results</h3> A total of 4607 male patients with infertility (mean [SD] age, 34.18 [5.44] years) and 18 428 control patients (mean [SD] age, 34.28 [5.81] years) were included. In the multivariate conditional logistic regression analysis, OSA was an independent risk factor associated with infertility (adjusted odds ratio [OR], 1.24; 95% CI, 1.10-1.64;<i>P</i> = .003). The absolute risk was 0.204 (95% CI, 0.092-0.391). For patients with OSA in the group without treatment, the adjusted OR was 1.80 (95% CI, 1.56-2.07;<i>P</i> &lt; .001) for infertility compared with patients without OSA. <h3>Conclusions and Relevance</h3> Results of this study support the hypothesis that OSA increases the risk of infertility in male patients, and the risk is associated with the OSA exposure time. Furthermore, no OSA management or treatment is associated with a higher infertility risk.
A Vaccination with Boosted Cross Presentation by ER‐Targeted Antigen Delivery for Anti‐Tumor Immunotherapy
Authors: Yingying Shi, Chunqi Zhu, Yu Liu, Yichao Lu, Xiang Li, Bing Qin, Zhenyu Luo, Lihua Luo, Mengshi Jiang, Junlei Zhang, Guannan Guan, Cheng Zheng, Jian You
Journal: Advanced Healthcare Materials (2021)

Abstract Vaccination is a widely‐accepted resort against the invasion or proliferation of bacteria, parasites, viruses, and even cancer, which accounts heavily on an active involvement of CD8 + T cells. As one of the pivotal strategies taken by dendritic cells (DCs) to promote the responsiveness of CD8 + T cells to exogenous antigens, cross presentation culminates in an elevated overall host defense against cancer or infection. However, the precise mechanisms regulating such a process remains elusive, and current attempts to fuel cross presentation usually fail to exert efficiency. Here, model antigen OVA‐loaded, endoplasmic reticulum (ER)‐targeting cationic liposome (OVA@lipoT) is developed and characterized with a booster effect on the activation and maturation of DCs. Moreover, OVA@lipoT pulsed DCs exhibit overwhelming superiority in triggering cytotoxic T lymphocyte response both in vivo and in vitro. Data reveal that lipoT alters the intracellular trafficking and presenting pathway of antigen, which promotes cross presentation and bears close relationship to the ER‐associated degradation (ERAD). These results may drop a hint about the interconnectivity between cross presentation and ER‐targeted antigen delivery, provide extra information to the understanding of ERAD‐mediated cross priming, and even shed new light on the design and optimization of vaccines against currently intractable cancers or virus‐infection.
THU0094 Experimental mycoplasma fermentans infection in rheumatoid synovial fibroblasts induces m161ag expression
Authors: S Kitajima, M Kawano, H Mutoh, I Koni, H Mabuchi, M Matsumoto, T Seya
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Mycoplasma fermentans (Mf) is one of the most likely of the several infectious agents which may be involved in the pathogenesis of rheumatoid arthritis (RA). Mf has been shown to induce arthritis experimentally in rabbits, and several reports have succeeded in detecting it in synovial fluids in RA patients. M161Ag is a 43-kDa surface lipoprotein of Mf, which induces cytokine production in monocytes and activates the host complement system. <h3>Objectives</h3> The aim of this study was to investigate whether M161Ag can be induced on rheumatoid synovial fibroblasts by an Mf infected cell line <i>in vitro</i>. <h3>Methods</h3> Rheumatoid synovial cells were isolated from synovial tissue specimens obtained at operation. Production of Mf infected rheumatoid synovial cells was performed using a coculture system of synovial cells and P39 (+) cells, which were Mf containing human leukaemia cell lines, for three days. PCR with mycoplasma specific primers were done to detect Mf DNA in synovial cells. M161Ag expression was evaluated by an immunohistochemical method with MK5 and MK53 monoclonal anti M161Ag antibodies, and mRNA production was also evaluated by the RT-PCR method. <h3>Results</h3> Freshly isolated rheumatoid synovial cells were negative for Mf DNA using PCR with mycoplasma specific primers. DNA of Mf ribosomal RNA was detected in the synovial fibroblasts after coculture of synovial cells and P39 (+) cells by PCR with mycoplasma specific primers. Moreover, the expression of M161Ag was detected only on Mf infected synovial cells using the immunohistochemichal method with MK5 or MK53 monoclonal antibodies. <h3>Conclusion</h3> Experimental <i>in vitro</i> Mf infection in rheumatoid synovial fibroblasts was demonstrated to induce the expression of M161Ag. The significance of this finding requires clarification in further studies. <h3>References</h3> Matsumoto M, <i>et al</i>. A novel protein that participates in nonself discrimination of malignant cells by homologous complement. Nat Med. 1997;3:1266 Matsumoto M, et al. Structural and functional properties of complement-activating protein M161Ag, a Mycoplasma fermentans gene product that induces cytokine production by human monocytes. J Biol Chem. 1998;273:12407
Tisagenlecleucel infusion in patients with relapsed/refractory ALL and concurrent serious infection
Authors: Erin M Hall, Dwight E Yin, Rakesh K Goyal, Atif A Ahmed, Grace S Mitchell, Shawn D St. Peter, Terrie G Flatt, Ibrahim A Ahmed, Weijie Li, Richard J Hendrickson, Keith J August, G Doug Myers
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated durable efficacy and a manageable safety profile in pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) in the ELIANA pivotal trial and real-world experience. Experience from investigator-led studies prior to ELIANA suggests that infections and inflammatory conditions may exacerbate the severity of cytokine release syndrome (CRS) associated with CAR-T cell therapy, leading to extreme caution and strong restrictions for on-study and commercial infusion of tisagenlecleucel in patients with active infection. CRS intervention with interleukin (IL)-6 blockade and/or steroid therapy was introduced late in the course during clinical trials due to concern for potential negative effect on efficacy and persistence. However, earlier CRS intervention is now viewed more favorably. Earlier intervention and consistency in management between providers may promote broader use of tisagenlecleucel, including potential curative therapy in patients who require remission and recovery of hematopoiesis for management of severe infection. Main body Patient 1 was diagnosed with B-ALL at 23 years old. Fourteen days before tisagenlecleucel infusion, the patient developed fever and neutropenia and was diagnosed with invasive Mucorales infection and BK virus hemorrhagic cystitis. Aggressive measures were instituted to control infection and to manage prolonged cytopenias during CAR-T cell manufacturing. Adverse events, including CRS, were manageable despite elevated inflammatory markers and active infection. The patient attained remission and recovered hematopoiesis, and infections resolved. The patient remains in remission ≥1 year postinfusion. Patient 2 was diagnosed with pre–B-ALL at preschool age. She developed severe septic shock 3 days postinitiation of lymphodepleting chemotherapy. After receiving tisagenlecleucel, she experienced CRS with cardiac dysfunction and extensive lymphadenopathy leading to renovascular compromise. The patient attained remission and was discharged in good condition to her country of origin. She remained in remission but expired on day 208 postinfusion due to cardiac arrest of unclear etiology. Conclusions Infusion was feasible, and toxicity related to tisagenlecleucel was manageable despite active infections and concurrent inflammation, allowing attainment of remission in otherwise refractory pediatric/young adult ALL. This may lead to consideration of tisagenlecleucel as a potential curative therapy in patients with managed active infections.
THU0021 IDENTIFICATION OF MUSCLE ASSOCIATED KEY GENES TO SUPPORT AXIAL SPONDYLOARTHRITIS DIAGNOSIS BY TRANSCRIPTOMIC APPROACH, THE MYOSPA STUDY
Authors: A. Mashayekhi Sardoo, D. Sobral, L. Domingues, S. Rodrigues-Manica, R. Pinheiro Torres, A. Neto, P. Alves, J. Costa, A. R. Grosso, J. Branco, F. Pimentel Dos Santos
Journal: Annals of the Rheumatic Diseases (2020)

Background: Early diagnosis of axial Spondyloarthritis (axSpA) represents a major clinical challenge nowadays. Increasing evidence has determined that early diagnosis, prompt treatment initiation and early achievement of remission are the best predictors of long-term clinical, functional and radiographic outcomes. New tools to support the diagnosis are needed. Objectives: This study aims to identify differentially expressed genes that may improve the current clinical diagnosis approach for early axSpA. Methods: A cross-sectional study was conducted on 50 participants, 25 patients with axSpA (according to ASAS criteria) and 25 Healthy Controls, matched by gender, age and levels of physical activity. Peripheral blood samples were collected and RNA-Seq technology was performed. Normalization of raw data, and identification of differentially expressed genes was obtained using edgeR and limma-voom R packages. Gene Set Enrichment Analysis (GSEA) and Functional Enrichment analysis using Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations were also performed. A number of Differently Expressed Genes were highlighted. Results: 311 genes were identified as being significantly differentially expressed between patients and controls. In details, 129 downregulated (7 genes have fold change more than 1) and 182 upregulated genes (3 genes have fold change more than 1) are highlighted. These genes are mostly involved in Myogenesis, Innate Immune Signalling and JAK/STAT pathways. Several genes with functions of skeletal muscle development and muscle contraction were identified. Conclusion: The evidence disclosed that regulation of muscle development and contraction may be also engaged in physiopathology mechanisms of axSpA. These new cues open new perspectives for diagnosis and therapeutic approaches in axSpA. Acknowledgments: To all patients and healthy people who participate in MyoSpA study Disclosure of Interests: Atlas Mashayekhi Sardoo: None declared, Daniel Sobral: None declared, Lucia Domingues: None declared, Santiago Rodrigues-Manica Speakers bureau: Jansse, MSD, Novartis, Rita Pinheiro Torres: None declared, Agna Neto: None declared, Patricia Alves: None declared, Julia Costa: None declared, Ana Rita Grosso: None declared, Jaime Branco Speakers bureau: Vitoria, Fernando Pimentel dos Santos Speakers bureau: Novartis, Pfizer, Biogen, Vitoria,
AB1128 ULTRASOUND SYNOVITIS AND SQUEEZE TEST: IS THERE A RELATIONSHIP?
Authors: K. Ben Abdelghani, K. Saadaoui, A. Fazaa, S. Miladi, K. Ouenniche, L. Souabni, S. Kassab, S. Chkili, L. Zakraoui, A. Laatar
Journal: Annals of the Rheumatic Diseases (2020)

Background: The squeeze test or the Gaenslen’s test is an easy and rapid method to identify arthritis in metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints. It’s characterized by tenderness upon lateral compression of MCP or MTP joints. This is a useful clinical exam for the early diagnosis of Rheumatoid Arthritis (RA). Objectives: The aim of our study is to assess the real value of that test and its association with synovitis. Methods: A prospective study including RA patients (2010 ACR/EULAR criteria) was conducted at the Rheumatology Department of Mongi Slim Hospital Tunis. US examination was performed by an experimented rheumatologist blinded to clinical data using a machine type Esaote MyLAb 60 with a linear probe of 6-18 MHz. MCP joints were assessed in dorsal longitudinal view, in mode B and Power Doppler. Synovitis was defined and Flexor digitorum Tenosynovitis was defined according to OMERACT. A p&lt;0.05 was considered statistically significant. Results: Forty-three cases of RA were included. The mean age was 58.92 years [27 - 81]. The sex ratio was 0.16. Among our patients, 46.5% of cases were receiving methotrexate with a mean dose of 15,875 mg / week [7.5 - 22.5]. Corticosteroids were used in 55.8% of our patients with a mean dose of 8.65 mg / day [2.5 - 30]. Moreover, 23.25% of the patients were on biologics. The mean value of morning stiffness was 37 min [0 - 150], the mean value of the global assessment of the disease by the patient was 5/10 [1 - 8]. The Gaenslen’s test was positive bilaterally in 25,6% of cases, in the right hand and in the left one in respectively 39.5% and 27.9% of the patients. Tenosynovitis of the flexors were found clinically in 11.6% case. The mean CRP was 29.7 mg / L [0.2 - 275] and the mean ESR was 65 mm [3 - 120]. The mean value of DAS28 and DAS28 CRP were respectively 5.20 ± 1.43 [2.69 – 9.00] and 4.33 ± 1.43 [1.35 – 8.32]. Overall, 430 joints and 430 flexor tendons were assessed by Ultrasound. Ninety-one synovitis were detected with a mean of 2.56 synovitis in MCP per patient [0 - 10]. Flexor tenosynovitis was found in 53.5% of patients. A statistically significant correlation was found between the squeeze test and presence of ultrasound synovitis of the MCP whatever the site of the synovitis; on the right side (r = 0.507; p &lt; 10 -3 ), or the left one (r = 0.607; p &lt; 10 -3 ) but no correlation between the clinically detected tenosynovitis and the ultrasound tenosynovitis (p = 0.364). We found a significant correlation between the Gleason test and ultrasound tenosynovitis on both side with r = 0.368 and p = 0.015 on the right hand and r = 0.441 and p = 0.003 on the left one. Conclusion: The squeeze test seems to be a very useful and practical clinical examination to easily detect synovitis and aid in the early diagnosis of RA Disclosure of Interests: None declared
Mutational Signature Analysis Reveals Widespread Contribution of Pyrrolizidine Alkaloid Exposure to Human Liver Cancer
Authors: Yisheng He, Mai Shi, Xu Wu, Jiang Ma, Kevin Tak‐Pan Ng, Qingsu Xia, Lin Zhu, Peter Pi‐Cheng Fu, Kwan Man, Stephen Kwok‐Wing Tsui, Ge Lin
Journal: Hepatology (2021)

Background and Aims Mutational signature analyses are an effective tool in identifying cancer etiology. Humans are frequently exposed to pyrrolizidine alkaloids (PAs), the most common carcinogenic phytotoxins widely distributed in herbal remedies and foods. However, due to the lack of human epidemiological data, PAs are classified as group II hepatocarcinogens by the World Health Organization. This study identified a PA mutational signature as the biomarker to investigate the association of PA exposure with human liver cancer. Approach and Results Pyrrole‐protein adducts (PPAs), the PA exposure biomarker, were measured and found in 32% of surgically resected specimens from 34 patients with liver cancer in Hong Kong. Next, we delineated the mode of mutagenic and tumorigenic actions of retrorsine, a representative PA, in mice and human hepatocytes (HepaRG). Retrorsine induced DNA adduction, DNA damage, and activation of tumorigenic hepatic progenitor cells, which initiated hepatocarcinogenesis. PA mutational signature, as the unique molecular fingerprint of PA‐induced mutation, was derived from exome mutations in retrorsine‐exposed mice and HepaRG cells. Notably, PA mutational signature was validated in genomes of patients with PPA‐positive liver cancer but not patients with PPA‐negative liver cancer, confirming the specificity of this biomarker in revealing PA‐associated liver cancers. Furthermore, we examined the established PA mutational signature in 1,513 liver cancer genomes and found that PA‐associated liver cancers were potentially prevalent in Asia (Mainland China [48%], Hong Kong [44%], Japan [22%], South Korea [6%], Southeast Asia [25%]) but minor in Western countries (North America [3%] and Europe [5%]). Conclusions This study provides a clinical indication of PA‐associated liver cancer. We discovered an unexpectedly extensive implication of PA exposure in patients with liver cancer, laying the scientific basis for precautionary approaches and prevention of PA‐associated human liver cancers.