tbuckley/cabot-search huggingface dataset:
Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma
Authors: Jonathan Wong, Emily Gruber, Belinda Maher, Mark Waltham, Zahra Sabouri-Thompson, Ian Jong, Quinton Luong, Sidney Levy, Beena Kumar, Daniella Brasacchio, Wendy Jia, Joan So, Hugh Skinner, Alexander Lewis, Simon J Hogg, Stephin Vervoort, Carmen DiCorleto, Micheleine Uhe, Jeanette Gamgee, Stephen Opat, Gareth P Gregory, Galina Polekhina, John Reynolds, Eliza A Hawkes, Gajan Kailainathan, Robin Gasiorowski, Lev M Kats, Jake Shortt
Journal: Leukemia (2022)

Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1-5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOAG17V mutations associated with improved PFS (median 5.47 vs. 1.35 months; Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile; decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.
Epigenetic Modification of the von Willebrand Factor Promoter Drives Platelet Aggregation on the Pulmonary Endothelium in Chronic Thromboembolic Pulmonary Hypertension
Authors: Xue D. Manz, Robert Szulcek, Xiaoke Pan, Petr Symersky, Chris Dickhoff, Jisca Majolée, Veerle Kremer, Elisabetta Michielon, Ekaterina S. Jordanova, Teodora Radonic, Irene V. Bijnsdorp, Sander R. Piersma, Thang V. Pham, Connie R. Jimenez, Anton Vonk Noordegraaf, Frances S. de Man, Reinier A. Boon, Jan Voorberg, Peter L. Hordijk, Jurjan Aman, Harm Jan Bogaard
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: von Willebrand factor (vWF) mediates platelet adhesion during thrombosis. While chronic thromboembolic pulmonary hypertension (CTEPH) is associated with increased plasma levels of vWF, the role of this protein in CTEPH has remained enigmatic. Objectives: To identify the role of vWF in CTEPH. Methods: CTEPH-specific patient plasma and pulmonary endarterectomy material from patients with CTEPH were used to study the relationship between inflammation, vWF expression, and pulmonary thrombosis. Cell culture findings were validated in human tissue, and proteomics and chromatin immunoprecipitation were used to investigate the underlying mechanism of CTEPH. Measurements and Main Results: vWF is increased in plasma and the pulmonary endothelium of CTEPH patients. In vitro, the increase in vWF gene expression and the higher release of vWF protein upon endothelial activation resulted in elevated platelet adhesion to CTEPH endothelium. Proteomic analysis revealed that nuclear factor (NF)-κB2 was significantly increased in CTEPH. We demonstrate reduced histone tri-methylation and increased histone acetylation of the vWF promoter in CTEPH endothelium, facilitating binding of NF-κB2 to the vWF promoter and driving vWF transcription. Genetic interference of NFκB2 normalized the high vWF RNA expression levels and reversed the prothrombotic phenotype observed in CTEPH-pulmonary artery endothelial cells. Conclusions: Epigenetic regulation of the vWF promoter contributes to the creation of a local environment that favors in situ thrombosis in the pulmonary arteries. It reveals a direct molecular link between inflammatory pathways and platelet adhesion in the pulmonary vascular wall, emphasizing a possible role of in situ thrombosis in the development or progression of CTEPH.
The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function
Authors: Mathias Wenes, Alison Jaccard, Tania Wyss, Noelia Maldonado-Pérez, Shao Thing Teoh, Anouk Lepez, Fabrice Renaud, Fabien Franco, Patrice Waridel, Céline Yacoub Maroun, Benjamin Tschumi, Nina Dumauthioz, Lianjun Zhang, Alena Donda, Francisco Martín, Denis Migliorini, Sophia Y. Lunt, Ping-Chih Ho, Pedro Romero
Journal: Cell Metabolism (2022)

Glycolysis, including both lactate fermentation and pyruvate oxidation, orchestrates CD8+ T cell differentiation. However, how mitochondrial pyruvate metabolism and uptake controlled by the mitochondrial pyruvate carrier (MPC) impact T cell function and fate remains elusive. We found that genetic deletion of MPC drives CD8+ T cell differentiation toward a memory phenotype. Metabolic flexibility induced by MPC inhibition facilitated acetyl-coenzyme-A production by glutamine and fatty acid oxidation that results in enhanced histone acetylation and chromatin accessibility on pro-memory genes. However, in the tumor microenvironment, MPC is essential for sustaining lactate oxidation to support CD8+ T cell antitumor function. We further revealed that chimeric antigen receptor (CAR) T cell manufacturing with an MPC inhibitor imprinted a memory phenotype and demonstrated that infusing MPC inhibitor-conditioned CAR T cells resulted in superior and long-lasting antitumor activity. Altogether, we uncover that mitochondrial pyruvate uptake instructs metabolic flexibility for guiding T cell differentiation and antitumor responses.
Subcortical Neuronal Correlates of Sleep in Neurodegenerative Diseases
Authors: Jun Y. Oh, Christine M. Walsh, Kamalini Ranasinghe, Mihovil Mladinov, Felipe L. Pereira, Cathrine Petersen, Neus Falgàs, Leslie Yack, Tia Lamore, Rakin Nasar, Caroline Lew, Song Li, Thomas Metzler, Quentin Coppola, Natalie Pandher, Michael Le, Hilary W. Heuer, Helmut Heinsen, Salvatore Spina, William W. Seeley, Joel Kramer, Gil D. Rabinovici, Adam L. Boxer, Bruce L. Miller, Keith Vossel, Thomas C. Neylan, Lea T. Grinberg
Journal: JAMA Neurology (2022)

Sleep disturbance is common among patients with neurodegenerative diseases. Examining the subcortical neuronal correlates of sleep disturbances is important to understanding the early-stage sleep neurodegenerative phenomena.
The Challenge of Genetic Variants of Uncertain Clinical Significance
Authors: Wylie Burke, Erik Parens, Wendy K. Chung, Sara M. Berger, Paul S. Appelbaum
Journal: Annals of Internal Medicine (2022)

Genomic tests expand diagnostic and screening opportunities but also identify genetic variants of uncertain clinical significance (VUSs). Only a minority of VUSs are likely to prove pathogenic when later reassessed, but resolution of the uncertainty is rarely timely. That uncertainty adds complexity to clinical decision making and can result in harms and costs to patients and the health care system, including the time-consuming analysis required to interpret a VUS and the potential for unnecessary treatment and adverse psychological effects. Current efforts to improve variant interpretation will help reduce the scope of the problem, but the high prevalence of rare and novel variants in the human genome points to VUSs as an ongoing challenge. Additional strategies can help mitigate the potential harms of VUSs, including testing protocols that limit identification or reporting of VUSs, subclassification of VUSs according to the likelihood of pathogenicity, routine family-based evaluation of variants, and enhanced counseling efforts. All involve tradeoffs, and the appropriate balance of measures is likely to vary for different test uses and clinical settings. Cross-specialty deliberation and public input could contribute to systematic and broadly supported policies for managing VUSs.
Analysis of memory B cells identifies conserved neutralizing epitopes on the N-terminal domain of variant SARS-Cov-2 spike proteins
Authors: Zijun Wang, Frauke Muecksch, Alice Cho, Christian Gaebler, Hans-Heinrich Hoffmann, Victor Ramos, Shuai Zong, Melissa Cipolla, Briana Johnson, Fabian Schmidt, Justin DaSilva, Eva Bednarski, Tarek Ben Tanfous, Raphael Raspe, Kaihui Yao, Yu E. Lee, Teresia Chen, Martina Turroja, Katrina G. Milard, Juan Dizon, Anna Kaczynska, Anna Gazumyan, Thiago Y. Oliveira, Charles M. Rice, Marina Caskey, Paul D. Bieniasz, Theodora Hatziioannou, Christopher O. Barnes, Michel C. Nussenzweig
Journal: Immunity (2022)

SARS-CoV-2 infection or vaccination produces neutralizing antibody responses that contribute to better clinical outcomes. The receptor-binding domain (RBD) and the N-terminal domain (NTD) of the spike trimer (S) constitute the two major neutralizing targets for antibodies. Here, we use NTD-specific probes to capture anti-NTD memory B cells in a longitudinal cohort of infected individuals, some of whom were vaccinated. We found 6 complementation groups of neutralizing antibodies. 58% targeted epitopes outside the NTD supersite, 58% neutralized either Gamma or Omicron, and 14% were broad neutralizers that also neutralized Omicron. Structural characterization revealed that broadly active antibodies targeted three epitopes outside the NTD supersite including a class that recognized both the NTD and SD2 domain. Rapid recruitment of memory B cells producing these antibodies into the plasma cell compartment upon re-infection likely contributes to the relatively benign course of subsequent infections with SARS-CoV-2 variants, including Omicron.
Steroid-induced fibroblast growth factors drive an epithelial-mesenchymal inflammatory axis in severe asthma
Authors: Riccardo Guidi, Daqi Xu, David F. Choy, Thirumalai R. Ramalingam, Wyne P. Lee, Zora Modrusan, Yuxin Liang, Scot Marsters, Avi Ashkenazi, Alison Huynh, Jessica Mills, Sean Flanagan, Shannon Hambro, Victor Nunez, Laurie Leong, Ashley Cook, Tiffany Hao Tran, Cary D. Austin, Yi Cao, Christine Clarke, Reynold A. Panettieri, Cynthia Koziol-White, William F. Jester, Fen Wang, Mark S. Wilson
Journal: Science Translational Medicine (2022)

Asthma and inflammatory airway diseases restrict airflow in the lung, compromising gas exchange and lung function. Inhaled corticosteroids (ICSs) can reduce inflammation, control symptoms, and improve lung function; however, a growing number of patients with severe asthma do not benefit from ICS. Using bronchial airway epithelial brushings from patients with severe asthma or primary human cells, we delineated a corticosteroid-driven fibroblast growth factor (FGF)–dependent inflammatory axis, with FGF-responsive fibroblasts promoting downstream granulocyte colony-stimulating factor (G-CSF) production, hyaluronan secretion, and neutrophilic inflammation. Allergen challenge studies in mice demonstrate that the ICS, fluticasone propionate, inhibited type 2–driven eosinophilia but induced a concomitant increase in FGFs, G-CSF, hyaluronan, and neutrophil infiltration. We developed a model of steroid-induced neutrophilic inflammation mediated, in part, by induction of an FGF-dependent epithelial-mesenchymal axis, which may explain why some individuals do not benefit from ICS. In further proof-of-concept experiments, we found that combination therapy with pan-FGF receptor inhibitors and corticosteroids prevented both eosinophilic and steroid-induced neutrophilic inflammation. Together, these results establish FGFs as therapeutic targets for severe asthma patients who do not benefit from ICS.
MFN2 Prevents Neointimal Hyperplasia in Vein Grafts via Destabilizing PFK1
Authors: Yuanjun Tang, Yiting Jia, Linwei Fan, Han Liu, Yuan Zhou, Miao Wang, Yuefeng Liu, Juanjuan Zhu, Wei Pang, Jing Zhou
Journal: Circulation Research (2022)

Mechanical forces play crucial roles in neointimal hyperplasia after vein grafting; yet, our understanding of their influences on vascular smooth muscle cell (VSMC) activation remains rudimentary.A cuff mouse model was used to study vein graft hyperplasia. Fifteen percent to 1 Hz uniaxial cyclic stretch (arterial strain), 5% to 1 Hz uniaxial cyclic stretch or a static condition (venous strain) were applied to the cultured VSMCs. Metabolomics analysis, cell proliferation and migration assays, immunoblotting, co-immunoprecipitation, mutagenesis, pull-down and surface plasmon resonance assays were employed to elucidate the potential molecular mechanisms.RNA-sequencing in vein grafts and the controls identified changes in metabolic pathways and downregulation of mitochondrial protein MFN2 (mitofusin 2) in the vein grafts. Exposure of VSMCs to 15% stretch resulted in MFN2 downregulation, mitochondrial fragmentation, metabolic shift from mitochondrial oxidative phosphorylation to glycolysis, and cell proliferation and migration, as compared with that to a static condition or 5% stretch. Metabolomics analysis indicated an increased generation of fructose 1,6-bisphosphate, an intermediate in the glycolytic pathway converted by PFK1 (phosphofructokinase 1) from fructose-6-phosphate, in cells exposed to 15% stretch. Mechanistic study revealed that MFN2 physically interacts through its C-terminus with PFK1. MFN2 knockdown or exposure of cells to 15% stretch promoted stabilization of PFK1, likely through interfering the association between PFK1 and the E3 ubiquitin ligase TRIM21 (E3 ubiquitin ligase tripartite motif [TRIM]-containing protein 21), thus, decreasing the ubiquitin-protease-dependent PFK1 degradation. In addition, study of mechanotransduction utilizing pharmaceutical inhibition indicated that the MFN2 downregulation by 15% stretch was dependent on inactivation of the SP1 (specificity protein 1) and activation of the JNK (c-Jun N-terminal kinase) and ROCK (Rho-associated protein kinase). Adenovirus-mediated MFN2 overexpression or pharmaceutical inhibition of PFK1 suppressed the 15% stretch-induced VSMC proliferation and migration and alleviated neointimal hyperplasia in vein grafts.MFN2 is a mechanoresponsive protein that interacts with PFK1 to mediate PFK1 degradation and therefore suppresses glycolysis in VSMCs.
Remotely boosting hyaluronidase activity to normalize the hypoxic immunosuppressive tumor microenvironment for photothermal immunotherapy
Authors: Yiqiong Liu, Dailin Xu, Ying Liu, Xiao Zheng, Jie Zang, Wanli Ye, Yuge Zhao, Ruiqing He, Shuangrong Ruan, Tingting Zhang, Haiqing Dong, Yan Li, Yongyong Li
Journal: Biomaterials (2022)
Genomic and epidemiological report of the recombinant XJ lineage SARS-CoV-2 variant, detected in northern Finland, January 2022
Authors: Erika Lindh, Teemu Smura, Soile Blomqvist, Kirsi Liitsola, Hanna Vauhkonen, Laura Savolainen, Jaana Ikonen, Jukka Ronkainen, Jyri Taskila, Tea Taskila, Pertti Sakaranaho, Carita Savolainen-Kopra, Olli Vapalahti, Niina Ikonen
Journal: Eurosurveillance (2022)

Recombinant sequences of the SARS-CoV-2 Omicron variant were detected in surveillance samples collected in north-western Finland in January 2022. We detected 191 samples with an identical genome arrangement in weeks 3 to 11, indicating sustained community transmission. The recombinant lineage has a 5'-end of BA.1, a recombination breakpoint between orf1a and orf1b (nucleotide position 13,296-15,240) and a 3'-end of BA.2 including the S gene. We describe the available genomic and epidemiological data about this currently circulating recombinant XJ lineage.
Microglia and Neurodevelopmental Disorders
Authors: John R. Lukens, Ukpong B. Eyo
Journal: Annual Review of Neuroscience (2022)

Mounting evidence indicates that microglia, which are the resident immune cells of the brain, play critical roles in a diverse array of neurodevelopmental processes required for proper brain maturation and function. This evidence has ultimately led to growing speculation that microglial dysfunction may play a role in neurodevelopmental disorder (NDD) pathoetiology. In this review, we first provide an overview of how microglia mechanistically contribute to the sculpting of the developing brain and neuronal circuits. To provide an example of how disruption of microglial biology impacts NDD development, we also highlight emerging evidence that has linked microglial dysregulation to autism spectrum disorder pathogenesis. In recent years, there has been increasing interest in how the gut microbiome shapes microglial biology. In the last section of this review, we put a spotlight on this burgeoning area of microglial research and discuss how microbiota-dependent modulation of microglial biology is currently thought to influence NDD progression.
Advancements in cell membrane camouflaged nanoparticles: A bioinspired platform for cancer therapy
Authors: Namdev Dhas, Mónica C. García, Ritu Kudarha, Abhijeet Pandey, Ajinkya Nitin Nikam, Divya Gopalan, Gasper Fernandes, Soji Soman, Sanjay Kulkarni, Raviraja N. Seetharam, Ruchi Tiwari, Sarika Wairkar, Chandrakantsing Pardeshi, Srinivas Mutalik
Journal: Journal of Controlled Release (2022)
Association of Familial Hypercholesterolemia and Statin Use With Risk of Dementia in Norway
Authors: Liv J. Mundal, Jannicke Igland, Karianne Svendsen, Kirsten B. Holven, Trond P. Leren, Kjetil Retterstøl
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Hypercholesterolemia, which is a cardiovascular risk factor, may also be associated with dementia risk. The benefit of statin treatment on dementia risk is controversial. <h3>Objective</h3> To determine whether individuals with familial hypercholesterolemia (FH), who have been exposed to lifelong hypercholesterolemia, have an excess risk of dementia and whether statin use is associated with dementia risk. <h3>Design, Setting, and Participants</h3> This was a prospective cohort study performed from 2008 to 2018 in Norway. Statistical analysis was performed from January 2021 to February 2022. This study included individuals with genetically verified FH and age-matched and sex-matched controls obtained from the general Norwegian population. <h3>Exposures</h3> Dementia was defined according to<i>International Statistical Classification of Diseases and Related Health Problems, Tenth Revision</i>codes F00-03 and G30. <h3>Main Outcomes and Measures</h3> Incident cases of total dementia, vascular dementia, Alzheimer disease–dementia in Alzheimer disease, and data on lipid-lowering medication were obtained from the Norwegian Patient Registry, Cause of Death Registry, and the Norwegian Prescription Database. Hazard ratios (HRs) for risk of dementia for individuals with FH vs matched controls were calculated using Cox regression. The cumulative sum of defined daily doses (DDDs) of statins prescribed during study follow-up was calculated for individuals with FH and was analyzed as a time-varying covariate with 3 levels: 1 to 4999 DDDs, 5000 to 10 000 DDDs, and more than 10 000 DDDs. <h3>Results</h3> Among the 3520 individuals with FH (1863 women [52.9%]; mean [SD] age at the start of follow-up, 51.8 [11.5] years) and the 69 713 controls (36 958 women [53.0%]; mean [SD] age at the start of follow-up, 51.7 [11.5] years), 62 patients with FH (39 women [62.9%]) and 1294 controls (801 women [61.9%]) had developed dementia over the course of 10 years of follow-up. Most dementia cases occurred among individuals aged 70 years and older (39 patients with FH [62.9%] and 870 patients [67.2%] in the control group). We found no excess risk of dementia in patients with FH vs matched controls (HR for total dementia, 0.9; 95% CI, 0.7-1.2). There was no association between cumulative DDDs of statins and total dementia in patients with FH with HRs of 1.2 (95% CI, 0.4-3.8) for cumulative DDDs of 5000 to 10 000 and 1.9 (95% CI, 0.7-5.0) for cumulative DDDs greater than 10 000. <h3>Conclusions and Relevance</h3> These findings suggest that individuals with FH have no excess risk of dementia compared with age-matched and sex-matched controls and that there is no association between use of statins and risk of dementia in patients with FH.
Allogeneic double-negative CAR-T cells inhibit tumor growth without off-tumor toxicities
Authors: Daniel Vasic, Jong Bok Lee, Yuki Leung, Ismat Khatri, Yoosu Na, Daniel Abate-Daga, Li Zhang
Journal: Science Immunology (2022)

The development of autologous chimeric antigen receptor T (CAR-T) cell therapies has revolutionized cancer treatment. Nevertheless, the delivery of CAR-T cell therapy faces challenges, including high costs, lengthy production times, and manufacturing failures. To overcome this, attempts have been made to develop allogeneic CAR-T cells using donor-derived conventional CD4+ or CD8+ T cells (Tconvs), but severe graft-versus-host disease (GvHD) and host immune rejection have made this challenging. CD3+CD4-CD8- double-negative T cells (DNTs) are a rare subset of mature T cells shown to fulfill the requirements of an off-the-shelf cellular therapy, including scalability, cryopreservability, donor-independent anticancer function, resistance to rejection, and no observed off-tumor toxicity including GvHD. To overcome the challenges faced with CAR-Tconvs, we evaluated the feasibility, safety, and efficacy of using healthy donor-derived allogeneic DNTs as a CAR-T cell therapy platform. We successfully transduced DNTs with a second-generation anti-CD19-CAR (CAR19) without hampering their endogenous characteristics or off-the-shelf properties. CAR19-DNTs induced antigen-specific cytotoxicity against B cell acute lymphoblastic leukemia (B-ALL). In addition, CAR19-DNTs showed effective infiltration and tumor control against lung cancer genetically modified to express CD19 in xenograft models. CAR19-DNT efficacy was comparable with that of CAR19-Tconvs. However, unlike CAR19-Tconvs, CAR19-DNTs did not cause alloreactivity or xenogeneic GvHD-related mortality in xenograft models. These studies demonstrate the potential of using allogeneic DNTs as a platform for CAR technology to provide a safe, effective, and patient-accessible CAR-T cell treatment option.
Publisher Correction: Cerebral amyloid angiopathy is associated with glymphatic transport reduction and time-delayed solute drainage along the neck arteries
Authors: Xinan Chen, Xiaodan Liu, Sunil Koundal, Rena Elkin, Xiaoyue Zhu, Brittany Monte, Feng Xu, Feng Dai, Maysam Pedram, Hedok Lee, Jonathan Kipnis, Allen Tannenbaum, William E. Van Nostrand, Helene Benveniste
Journal: Nature Aging (2022)
Breaking the Skin Color Barriers for Asthma Medications — It’s Not Black, Brown, or White
Authors: Tyra Bryant-Stephens
Journal: New England Journal of Medicine (2022)

Although asthma disproportionately affects Black and Latinx patients, they are underrepresented in studies of therapy, which makes it difficult to determine whether the results may be applied to them. Since race is not a biologic but a social construct, health disparities among persons with asthma are not a result of the color of the patient’s skin but rather the result of the structural and systemic racist practices that render these patients at risk for poor outcomes and that must be addressed when studying these populations. In this issue of the Journal, Israel and colleagues1 report the results of the Person . . .
18F-FDG PET/CT Uptake in Acute Pontine Infarct Mimicking Intracranial Metastasis
Authors: Banu SathyaMurthi, Sivakumar Muthu, James Howard, Rakesh Sajjan
Journal: Clinical Nuclear Medicine (2022)

Infarcts are generally nonviable and are not avid on an 18 F-FDG PET/CT. Here, we discuss a 53-year-old man who presented with chest pain and raised d -dimer. CT pulmonary angiogram was performed to exclude pulmonary embolism, which identified incidental lung nodules. 18 F-FDG PET/CT was performed for the assessment of lung nodules, which showed incidental focal FDG uptake in the pons. This was concluded as an acute infarct on subsequent MR scan. This highlights the importance of not interpreting all focal FDG uptakes as malignant. In rare circumstances, false-positive benign causes should be considered, such as in this rare case of an acute pontine infarct.