tbuckley/cabot-search huggingface dataset:
A large-scale genome and transcriptome sequencing analysis reveals the mutation landscapes induced by high-activity adenine base editors in plants
Authors: Shaofang Li, Lang Liu, Wenxian Sun, Xueping Zhou, Huanbin Zhou
Journal: Genome biology (2022)

The high-activity adenine base editors (ABEs), engineered with the recently-developed tRNA adenosine deaminases (TadA8e and TadA9), show robust base editing activity but raise concerns about off-target effects.In this study, we perform a comprehensive evaluation of ABE8e- and ABE9-induced DNA and RNA mutations in Oryza sativa. Whole-genome sequencing analysis of plants transformed with four ABEs, including SpCas9n-TadA8e, SpCas9n-TadA9, SpCas9n-NG-TadA8e, and SpCas9n-NG-TadA9, reveal that ABEs harboring TadA9 lead to a higher number of off-target A-to-G (A>G) single-nucleotide variants (SNVs), and that those harboring CRISPR/SpCas9n-NG lead to a higher total number of off-target SNVs in the rice genome. An analysis of the T-DNAs carrying the ABEs indicates that the on-target mutations could be introduced before and/or after T-DNA integration into plant genomes, with more off-target A>G SNVs forming after the ABEs had integrated into the genome. Furthermore, we detect off-target A>G RNA mutations in plants with high expression of ABEs but not in plants with low expression of ABEs. The off-target A>G RNA mutations tend to cluster, while off-target A>G DNA mutations rarely clustered.Our findings that Cas proteins, TadA variants, temporal expression of ABEs, and expression levels of ABEs contribute to ABE specificity in rice provide insight into the specificity of ABEs and suggest alternative ways to increase ABE specificity besides engineering TadA variants.
Abstract P084: Sex Differences In Testosterone On Interleukin-6 At Baseline And In Response To Mental Stress
Authors: Samaah Sullivan, An Young, Mariana Garcia, Zakaria Almuwaqqat, Kasra Moazzami, Brad Pearce, Allison Hankus, Emily G Driggers, Lisa Elon, Oleksiy Levantsevych, Mhmtjamil Alkhalaf, Mohamad N Jajeh, Amit J Shah, Tene T Lewis, J Douglas Bremner, Arshed A Quyyumi, Viola Vaccarino
Journal: Circulation (2022)

Introduction: Young and middle-aged women with ischemic heart disease are a high-risk group for morbidity and mortality particularly after a myocardial infarction (MI). This group exhibits higher concentrations of the inflammatory cytokine interleukin-6 (IL-6) at baseline and in response to mental stress compared to men. The reasons for these differences are unknown; however, sex hormones may play a role. While testosterone has been shown to have anti-inflammatory effects among men; the role of testosterone on inflammatory cytokines among women has been understudied, and no research has examined the influence of testosterone on IL-6 response to stress. Hypothesis: Among young and middle-aged patients with a recent MI, higher concentrations of testosterone have anti-inflammatory effects among men at baseline and in response to mental stress; but are associated with greater inflammation among women. Methods: We studied 269 patients 61 years old or younger who were hospitalized for a MI in the previous 8 months. We measured plasma IL-6 (pg/mL) before and 90 minutes after mental stress (speech task). Inflammatory response was defined as the difference between IL-6 levels 90-minutes post mental stress and resting values. Serum free testosterone (pg/mL) was measured before mental stress. Differences across sex and time were examined with mixed models for repeated measures after natural log-transformation of IL-6. Results: The mean age was 51 years (range: 26-61); 48% were women and 64% African American. Mean values of free testosterone among men and women were 12.6 pg/mL (range: 0.9-29.0) and 1.8 pg/mL (range: 0.3-15.6), respectively. After adjusting for demographic factors (age, race, income), lifestyle and medical history (BMI, hypertension, diabetes, depression) and medication use, the association of testosterone with the IL-6 response to stress differed by sex (p for testosterone-by-sex-by-time interaction = 0.06). Among men, higher levels of testosterone were associated with lower concentrations of IL-6 at rest (β = -0.04; p = &lt;.0001), but was attenuated after stress (β = -0.001; p = 0.93). This change in slopes across time or inflammatory response for men was significant (p = &lt;.0001). In contrast, among women, higher levels of testosterone tended to be associated with higher IL-6 at rest (β = 0.04; p = 0.07) and after stress (β = 0.04; p = 0.14), indicating no change between time points or inflammatory response to stress (p=0.75). Conclusions: Among young and middle-aged survivors of a recent MI, higher concentrations of free testosterone are associated with lower inflammation among men, but with an opposite trend of higher inflammation among women.
Toll-Interacting Protein and Altered Lung Microbiota in Idiopathic Pulmonary Fibrosis
Authors: Jay H. Lipinski, John R. Erb-Downward, Gary B. Huffnagle, Kevin R. Flaherty, Fernando J. Martinez, Bethany B. Moore, Robert P. Dickson, Imre Noth, David N. O’Dwyer
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Toll-Interacting Protein and Altered Lung Microbiota in Idiopathic Pulmonary Fibrosis." American Journal of Respiratory and Critical Care Medicine, 206(2), pp. 224–227
Impact of <i>TP53</i> Genomic Alterations in Large B-Cell Lymphoma Treated With CD19-Chimeric Antigen Receptor T-Cell Therapy
Authors: Roni Shouval, Ana Alarcon Tomas, Joshua A. Fein, Jessica R. Flynn, Ettai Markovits, Shimrit Mayer, Aishat Olaide Afuye, Anna Alperovich, Theodora Anagnostou, Michal J. Besser, Connie Lee Batlevi, Parastoo B. Dahi, Sean M. Devlin, Warren B. Fingrut, Sergio A. Giralt, Richard J. Lin, Gal Markel, Gilles Salles, Craig S. Sauter, Michael Scordo, Gunjan L. Shah, Nishi Shah, Ruth Scherz-Shouval, Marcel van den Brink, Miguel-Angel Perales, Maria Lia Palomba
Journal: Journal of Clinical Oncology (2021)

Tumor-intrinsic features may render large B-cell lymphoma (LBCL) insensitive to CD19-directed chimeric antigen receptor T cells (CAR-T). We hypothesized that TP53 genomic alterations are detrimental to response outcomes in LBCL treated with CD19-CAR-T.Patients with LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing was performed on pre-CAR-T tumor samples in a subset of patients. Response and survival rates by histologic, cytogenetic, and molecular features were assessed. Within a cohort of newly diagnosed LBCL with genomic and transcriptomic profiling, we studied interactions between cellular pathways and TP53 status.We included 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T (axicabtagene ciloleucel [50%], tisagenlecleucel [32%], and lisocabtagene maraleucel [18%]). Outcomes echoed pivotal trials: complete response (CR) rate 54%, median overall survival (OS) 21.1 months (95% CI, 14.8 to not reached), and progression-free survival 6 months (3.4 to 9.7). Histologic and cytogenetic LBCL features were not predictive of CR. In a subset of 82 patients with next-generation sequencing profiling, CR and OS rates were comparable with the unsequenced cohort. TP53 alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariable and multivariable regression models; the 1-year OS in TP53-altered LBCL was 44% (95% CI, 29 to 67) versus 76% (65 to 89) in wild-type (P = .012). Transcriptomic profiling from a separate cohort of patients with newly diagnosed lymphoma (n = 562) demonstrated that TP53 alterations are associated with dysregulation of pathways related to CAR-T-cell cytotoxicity, including interferon and death receptor signaling pathway and reduced CD8 T-cell tumor infiltration.TP53 is a potent tumor-intrinsic biomarker that can inform risk stratification and clinical trial design in patients with LBCL treated with CD19-CAR-T. The role of TP53 should be further validated in independent cohorts.
Detection of Chyle Leakage Site With Lymphoscintigraphy SPECT/CT in a Patient With Chylothorax Secondary to T-Cell Lymphoblastic Leukemia
Authors: Selin Kesim, Salih Ozguven, Kevser Oksuzoglu, Tanju Yusuf Erdil
Journal: Clinical Nuclear Medicine (2021)

We present a pediatric case with T-cell lymphoblastic leukemia and persistent chylothorax who was referred to lymphoscintigraphy to identify the site of leakage. Planar lymphoscintigraphy with SPECT/CT revealed hot spots at the left jugulovenous angle and the confluens of the vena brachiocephalica to vena cava, which were compatible with the sites of leakage. Hybrid imaging with SPECT/CT technique have great impact on accurate detection of the defects in the lymphatic system in patients with chylothorax.
Investigation of an international outbreak of multidrug-resistant monophasic Salmonella Typhimurium associated with chocolate products, EU/EEA and United Kingdom, February to April 2022
Authors: Lesley Larkin, Maria Pardos de la Gandara, Ann Hoban, Caisey Pulford, Nathalie Jourdan-Da Silva, Henriette de Valk, Lynda Browning, Gerhard Falkenhorst, Sandra Simon, Raskit Lachmann, Rikard Dryselius, Nadja Karamehmedovic, Stefan Börjesson, Dieter van Cauteren, Valeska Laisnez, Wesley Mattheus, Roan Pijnacker, Maaike van den Beld, Joël Mossong, Catherine Ragimbeau, Anne Vergison, Lin Thorstensen Brandal, Heidi Lange, Patricia Garvey, Charlotte Salgaard Nielsen, Silvia Herrera León, Carmen Varela, Marie Chattaway, François-Xavier Weill, Derek Brown, Paul McKeown
Journal: Eurosurveillance (2022)

An extensive multi-country outbreak of multidrug-resistant monophasic Salmonella Typhimurium infection in 10 countries with 150 reported cases, predominantly affecting young children, has been linked to chocolate products produced by a large multinational company. Extensive withdrawals and recalls of multiple product lines have been undertaken. With Easter approaching, widespread product distribution and the vulnerability of the affected population, early and effective real-time sharing of microbiological and epidemiological information has been of critical importance in effectively managing this serious food-borne incident.
Predicting RNA splicing from DNA sequence using Pangolin
Authors: Tony Zeng, Yang I Li
Journal: Genome biology (2022)

Abstract Recent progress in deep learning has greatly improved the prediction of RNA splicing from DNA sequence. Here, we present Pangolin, a deep learning model to predict splice site strength in multiple tissues. Pangolin outperforms state-of-the-art methods for predicting RNA splicing on a variety of prediction tasks. Pangolin improves prediction of the impact of genetic variants on RNA splicing, including common, rare, and lineage-specific genetic variation. In addition, Pangolin identifies loss-of-function mutations with high accuracy and recall, particularly for mutations that are not missense or nonsense, demonstrating remarkable potential for identifying pathogenic variants.
Small molecules facilitate single factor-mediated sweat gland cell reprogramming
Authors: Shuai-Fei Ji, Lai-Xian Zhou, Zhi-Feng Sun, Jiang-Bing Xiang, Shao-Yuan Cui, Yan Li, Hua-Ting Chen, Yi-Qiong Liu, Huan-Huan Gao, Xiao-Bing Fu, Xiao-Yan Sun
Journal: Military Medical Research (2022)

Abstract Background Large skin defects severely disrupt the overall skin structure and can irreversibly damage sweat glands (SG), thus impairing the skin’s physiological function. This study aims to develop a stepwise reprogramming strategy to convert fibroblasts into SG lineages, which may provide a promising method to obtain desirable cell types for the functional repair and regeneration of damaged skin. Methods The expression of the SG markers cytokeratin 5 (CK5), cytokeratin 10 (CK10), cytokeratin 18 (CK18), carcino-embryonic antigen (CEA), aquaporin 5 (AQP5) and α-smooth muscle actin (α-SMA) was assessed with quantitative PCR (qPCR), immunofluorescence and flow cytometry. Calcium activity analysis was conducted to test the function of induced SG-like cells (iSGCs). Mouse xenograft models were also used to evaluate the in vivo regeneration of iSGCs. BALB/c nude mice were randomly divided into a normal group, SGM treatment group and iSGC transplantation group. Immunocytochemical analyses and starch-iodine sweat tests were used to confirm the in vivo regeneration of iSGCs. Results EDA overexpression drove HDF conversion into iSGCs in SG culture medium (SGM). qPCR indicated significantly increased mRNA levels of the SG markers CK5, CK18 and CEA in iSGCs, and flow cytometry data demonstrated (4.18 ± 0.04)% of iSGCs were CK5 positive and (4.36 ± 0.25)% of iSGCs were CK18 positive. The addition of chemical cocktails greatly accelerated the SG fate program. qPCR results revealed significantly increased mRNA expression of CK5, CK18 and CEA in iSGCs, as well as activation of the duct marker CK10 and luminal functional marker AQP5. Flow cytometry indicated, after the treatment of chemical cocktails, (23.05 ± 2.49)% of iSGCs expressed CK5 + and (55.79 ± 3.18)% of iSGCs expressed CK18 + , respectively. Calcium activity analysis indicated that the reactivity of iSGCs to acetylcholine was close to that of primary SG cells [(60.79 ± 7.71)% vs. (70.59 ± 0.34)%, ns]. In vivo transplantation experiments showed approximately (5.2 ± 1.1)% of the mice were sweat test positive, and the histological analysis results indicated that regenerated SG structures were present in iSGCs-treated mice. Conclusion We developed a SG reprogramming strategy to generate functional iSGCs from HDFs by using the single factor EDA in combination with SGM and small molecules. The generation of iSGCs has important implications for future in situ skin regeneration with SG restoration.
SARS-CoV-2 Omicron triggers cross-reactive neutralization and Fc effector functions in previously vaccinated, but not unvaccinated, individuals
Authors: Simone I. Richardson, Vimbai Sharon Madzorera, Holly Spencer, Nelia P. Manamela, Mieke A. van der Mescht, Bronwen E. Lambson, Brent Oosthuysen, Frances Ayres, Zanele Makhado, Thandeka Moyo-Gwete, Nonkululeko Mzindle, Thopisang Motlou, Amy Strydom, Adriano Mendes, Houriiyah Tegally, Zelda de Beer, Talita Roma de Villiers, Annie Bodenstein, Gretha van den Berg, Marietjie Venter, Tulio de Oliviera, Veronica Ueckermann, Theresa M. Rossouw, Michael T. Boswell, Penny L. Moore
Journal: Cell Host & Microbe (2022)

The SARS-CoV-2 Omicron variant escapes neutralizing antibodies elicited by vaccines or infection. However, whether Omicron triggers cross-reactive humoral responses to other variants of concern (VOCs) remains unknown. We used plasma from 20 unvaccinated and 7 vaccinated individuals infected by Omicron BA.1 to test binding, Fc effector function, and neutralization against VOCs. In unvaccinated individuals, Fc effector function and binding antibodies targeted Omicron and other VOCs at comparable levels. However, Omicron BA.1-triggered neutralization was not extensively cross-reactive for VOCs (14- to 31-fold titer reduction), and we observed 4-fold decreased titers against Omicron BA.2. In contrast, vaccination followed by breakthrough Omicron infection associated with improved cross-neutralization of VOCs with titers exceeding 1:2,100. This has important implications for the vulnerability of unvaccinated Omicron-infected individuals to reinfection by circulating and emerging VOCs. Although Omicron-based immunogens might be adequate boosters, they are unlikely to be superior to existing vaccines for priming in SARS-CoV-2-naive individuals.
110P Updated efficacy and safety of entrectinib in patients (pts) with NTRK fusion-positive (NTRK-fp) NSCLC
Authors: B.C. Cho, C-H. Chiu, E. Massarelli, S.P. Chawla, G.L. Buchschacher, K. Goto, S-W. Kim, T.R. Overbeck, H.H.F. Loong, C.E. Chee, P. Garrido, S. Heinzmann, B. Pitcher, T. John
Journal: Annals of Oncology (2022)
Reply to “Reporting pediatric brain tumors according to their behavior code can result in biased survival estimates—A European perspective to Girardi et al”
Authors: Fabio Girardi, Michel P Coleman, Claudia Allemani
Journal: Neuro-Oncology (2022)

We welcome the remarks of Hoogendijk et al on our study, which revealed wide international variation in the distribution of histology and behavior among children and adults diagnosed with a brain tumor. More than 90% of brain tumors diagnosed in children in Europe are histologically verified,1 and benign tumors are usually included in survival estimates because they can also kill. Hoogendijk et al simulate the impact of varying the proportion of malignant and nonmalignant brain tumors on incidence and survival among 2705 children and adolescents diagnosed in the Netherlands during 2000-2017. The impact of misclassification of behavior on survival for malignant tumors appeared remarkable. Accurate comparison of population-based survival for brain tumors raises complex problems. Global differences in access to care may result in under-diagnosis or under-registration; even in countries with optimal healthcare systems, nonmalignant brain tumors, by far the most common type in children, may still not be reported by law. Even if all brain tumors are diagnosed, the pathological diagnosis may be inaccurate, or cancer registration incomplete. The clinical behavior of brain tumors is also very variable, so categorization by behavior alone may be simplistic.
The establishment of CDK9/RNA PolII/H3K4me3/DNA methylation feedback promotes HOTAIR expression by RNA elongation enhancement in cancer
Authors: Chi Hin Wong, Chi Han Li, Joanna Hung Man Tong, Duo Zheng, Qifang He, Zhiyuan Luo, Ut Kei Lou, Jiatong Wang, Ka-Fai To, Yangchao Chen
Journal: Molecular Therapy (2022)

Long non-coding RNA HOX Transcript Antisense RNA (HOTAIR) is overexpressed in multiple cancers with diverse genetic profiles. Importantly, since HOTAIR heavily contributes to cancer progression by promoting tumor growth and metastasis, HOTAIR becomes a potential target for cancer therapy. However, the underlying mechanism leading to HOTAIR deregulation is largely unexplored. Here, we performed a pan-cancer analysis using more than 4,200 samples and found that intragenic exon CpG island (Ex-CGI) was hypermethylated and was positively correlated to HOTAIR expression. Also, we revealed that Ex-CGI methylation promotes HOTAIR expression through enhancing the transcription elongation process. Furthermore, we linked up the aberrant intragenic tri-methylation on H3 at lysine 4 (H3K4me3) and Ex-CGI DNA methylation in promoting transcription elongation of HOTAIR. Targeting the oncogenic CDK7-CDK9-H3K4me3 axis downregulated HOTAIR expression and inhibited cell growth in many cancers. To our knowledge, this is the first time that a positive feedback loop that involved CDK9-mediated phosphorylation of RNA Polymerase II Serine 2 (RNA PolII Ser2), H3K4me3, and intragenic DNA methylation, which induced robust transcriptional elongation and heavily contributed to the upregulation of oncogenic lncRNA in cancer has been demonstrated. Targeting the oncogenic CDK7-CDK9-H3K4me3 axis could be a novel therapy in many cancers through inhibiting the HOTAIR expression.
Mitochondria-targeted supramolecular coordination container encapsulated with exogenous itaconate for synergistic therapy of joint inflammation
Authors: Xuzhuo Chen, Chang Li, Xiankun Cao, Xinlin Jia, Xinwei Chen, Zhenqiang Wang, Weifeng Xu, Fengrong Dai, Shanyong Zhang
Journal: Theranostics (2022)

Rationale: Inflammatory macrophages and osteoclasts (OCs) play critical roles in joint inflammation, which feature the excessive production of reactive oxygen species (ROS), resulting in synovial inflammation and bone erosion.Scavenging ROS, especially by modulating mitochondrial metabolic activity, could be a desirable strategy for the management of inflammatory joints.This study aimed to develop a mitochondria-targeted supramolecular drug delivery system with exogenous and endogenous ROS-scavenging activities for the treatment of joint inflammation.Methods: In this study, we utilized a zinc-based metal-organic supercontainer (MOSC) as a proton sponge and electron reservoir with outstanding proton binding capacity, extracellular ROS-scavenging ability, and biocompatibility to establish an efficient supramolecular nanocarrier for endo/lysosomal escape and mitochondrial targeting.4-Octyl itaconate (4-OI), an itaconate derivative, served as the loaded guest for the construction of a synergistic therapeutic system for inflammatory macrophages and OCs.Results: After the effective encapsulation of 4-OI, 4-OI@Zn-NH-pyr not only exhibited potent ROS-scavenging capacity, but also reduced ROS production by mediating mitochondrial respiration in inflammatory macrophages.Regarding its anti-inflammatory efficacy, 4-OI@Zn-NH-pyr ameliorated the inflammatory reaction by activating nuclear factor erythroid 2-related factor 2 (Nrf2), thus increasing the production of antioxidants, apart from the inhibition of NF-κB pathways.Additionally, receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and function was remarkably suppressed by 4-OI@Zn-NH-pyr.Consistent with in vitro observations, 4-OI@Zn-NH-pyr efficiently inhibited synovial inflammation and subchondral bone destruction in an acute arthritis model.Conclusion: By using MOSCs that are highly reactive to ROS as drug-loaded matrices for the first time, this study provides an avenue for the management of severe joint inflammation by designing synergistic supramolecular drug-delivery systems with subcellular targeting and ROS-scavenging capacity.
Prognosis of Patients with Chronic Obstructive Pulmonary Disease Not Eligible for Major Clinical Trials
Authors: Yunus Çolak, Børge G. Nordestgaard, Peter Lange, Jørgen Vestbo, Shoaib Afzal
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Randomized controlled trials only include a subset of patients with chronic obstructive pulmonary disease (COPD) fulfilling strict inclusion criteria. Thus, most patients with COPD in a real-world setting do not have the necessary evidence to support treatment effectiveness. Objectives: To test the hypotheses that most individuals with COPD in the general population are not represented in major clinical trials despite clinically significant disease with exacerbations and early death. Methods: In 105,630 adults from a Danish contemporary population-based cohort, we defined COPD as age 40 or more years, chronic respiratory symptoms, history of smoking exposure, and airflow limitation with FEV1/FVC < 0.70. Outcomes included acute exacerbations and all-cause mortality. Symptomatic smokers without COPD were used as a reference group. Measurements and Main Results: Of all, 7,516 (7%) and 16,079 (15%) were symptomatic smokers with and without COPD. Only 44% of those with COPD were eligible for major clinical trials when applying FEV1 < 80% predicted, smoking history of 10 or more pack-years, and no comorbid asthma as common inclusion criteria. During the median 8.9 years of follow-up, we observed 2,130 acute exacerbations and 3,973 deaths in symptomatic smokers. Compared with symptomatic smokers without COPD, multivariable-adjusted hazard ratios for exacerbations were 7.45 (95% confidence interval, 5.41-10.3) and 29.0 (21.1-39.8) in those with COPD, respectively, excluded and eligible for clinical trials. Corresponding hazard ratios for all-cause mortality were 1.21 (1.11-1.31) and 1.67 (1.54-1.81), respectively. Conclusions: More than half of individuals with COPD in the general population are excluded from major clinical trials; however, these individuals have a clinically significant disease with exacerbations and early death compared with symptomatic smokers without COPD.
Senescent immune cells release grancalcin to promote skeletal aging
Authors: Chang-Jun Li, Ye Xiao, Yu-Chen Sun, Wen-Zhen He, Ling Liu, Mei Huang, Chen He, Min Huang, Kai-Xuan Chen, Jing Hou, Xu Feng, Tian Su, Qi Guo, Yan Huang, Hui Peng, Mi Yang, Guang-Hui Liu, Xiang-Hang Luo
Journal: Cell Metabolism (2022)