tbuckley/cabot-search huggingface dataset:
PDGFA-associated protein 1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification
Authors: Verónica Delgado-Benito, Maria Berruezo-Llacuna, Robert Altwasser, Wiebke Winkler, Devakumar Sundaravinayagam, Sandhya Balasubramanian, Marieta Caganova, Robin Graf, Ali Rahjouei, Marie-Thérèse Henke, Madlen Driesner, Lisa Keller, Alessandro Prigione, Martin Janz, Altuna Akalin, Michela Di Virgilio
Journal: The Journal of Experimental Medicine (2020)

The establishment of protective humoral immunity is dependent on the ability of mature B cells to undergo antibody gene diversification while adjusting to the physiological stressors induced by activation with the antigen. Mature B cells diversify their antibody genes by class switch recombination (CSR) and somatic hypermutation (SHM), which are both dependent on efficient induction of activation-induced cytidine deaminase (AID). Here, we identified PDGFA-associated protein 1 (Pdap1) as an essential regulator of cellular homeostasis in mature B cells. Pdap1 deficiency leads to sustained expression of the integrated stress response (ISR) effector activating transcription factor 4 (Atf4) and induction of the ISR transcriptional program, increased cell death, and defective AID expression. As a consequence, loss of Pdap1 reduces germinal center B cell formation and impairs CSR and SHM. Thus, Pdap1 protects mature B cells against chronic ISR activation and ensures efficient antibody diversification by promoting their survival and optimal function.
Randomized Double-Blind Clinical Trial Comparing Ultra Rapid Lispro With Lispro in a Basal-Bolus Regimen in Patients With Type 2 Diabetes: PRONTO-T2D
Authors: Thomas Blevins, Qianyi Zhang, Juan P. Frias, Hideaki Jinnouchi, Annette M. Chang
Journal: Diabetes Care (2020)

OBJECTIVE To evaluate the efficacy and safety of ultra rapid lispro (URLi) versus lispro in patients with type 2 diabetes on a basal-bolus insulin regimen. RESEARCH DESIGN AND METHODS This was a phase 3, treat-to-target, double-blind 26-week study. After an 8-week lead-in to optimize basal insulin glargine or degludec in combination with prandial lispro treatment, patients were randomized to blinded URLi (n = 336) or lispro (n = 337) injected 0–2 min prior to meals. Patients could continue metformin and/or a sodium–glucose cotransporter 2 inhibitor. The primary end point was change in HbA1c from baseline to 26 weeks (noninferiority margin 0.4%), with multiplicity-adjusted objectives for postprandial glucose (PPG) excursions during a standardized meal test. RESULTS HbA1c improved for both URLi and lispro, and noninferiority was confirmed: estimated treatment difference (ETD) 0.06% (95% CI −0.05; 0.16). Mean change in HbA1c was −0.38% for URLi and −0.43% for lispro, with an end-of-treatment HbA1c of 6.92% and 6.86%, respectively. URLi was superior to lispro in controlling 1- and 2-h PPG excursions: 1-h ETD, −0.66 mmol/L (95% CI −1.01, −0.30); 2-h ETD, −0.96 mmol/L (−1.41, −0.52). Significantly lower PPG excursions were evident from 0.5 to 4.0 h postmeal with URLi treatment. There were no significant treatment differences in rates of severe or documented hypoglycemia (&amp;lt;3.0 mmol/L). Incidence of overall treatment-emergent adverse events was similar between treatments. CONCLUSIONS URLi compared with lispro in a basal-bolus regimen was confirmed to be noninferior for HbA1c and superior to lispro for PPG control in patients with type 2 diabetes.
B protected: from vertical HCV transmission?
Authors: Katharina Zoldan, Maike Hofmann
Journal: Gut (2020)

HCV infection is a global health burden with about 71 million chronically infected people worldwide, putting them at risk of progressive liver disease, including liver cirrhosis and hepatocellular carcinoma. HCV is transmitted via parenteral routes. The most frequent transmission nowadays is by contaminated instruments used for injections. Only few HCV infections occur through vertical mother-to-child transmission (MTCT). Still, the major cause of paediatric hepatitis is vertical transmission of HCV affecting roughly 3.5 million children and adolescents worldwide. The risk of MTCT in viraemic pregnant women is about 5%.1 This vertical transmission rate is rather low compared with other chronic viral infections, for example, HIV and HBV infection. The mechanisms underlying the low vertical transmission of HCV are still elusive and include possible successful immune protection and/or an effective barrier function by the placenta.

In this issue, Lutckii et al 2 investigate vertical HCV exposure from an immunological perspective. The study was conducted in a unique cohort of children who were unexposed, HCV-exposed but uninfected or HCV-infected compared with healthy newborns and HCV-infected adults. Here, the comparison of HCV-exposed but uninfected children to unexposed children was of special interest in order to address the question of immune alterations on vertical HCV exposure. HIV coinfection was an exclusion criterion in this study to further pinpoint HCV-specific effects. The analyses were focused on B cells, innate immune cells (myeloid cells and natural killer (NK) cells) and soluble factors (eg, …
The molecular biology and immune control of chronic Toxoplasma gondii infection
Authors: Xiao-Yu Zhao, Sarah E. Ewald
Journal: Journal of Clinical Investigation (2020)

Toxoplasma gondii is an incredibly successful parasite owing in part to its ability to persist within cells for the life of the host. Remarkably, at least 350 host species of T. gondii have been described to date, and it is estimated that 30% of the global human population is chronically infected. The importance of T. gondii in human health was made clear with the first reports of congenital toxoplasmosis in the 1940s. However, the AIDS crisis in the 1980s revealed the prevalence of chronic infection, as patients presented with reactivated chronic toxoplasmosis, underscoring the importance of an intact immune system for parasite control. In the last 40 years, there has been tremendous progress toward understanding the biology of T. gondii infection using rodent models, human cell experimental systems, and clinical data. However, there are still major holes in our understanding of T. gondii biology, including the genes controlling parasite development, the mechanisms of cell-intrinsic immunity to T. gondii in the brain and muscle, and the long-term effects of infection on host homeostasis. The need to better understand the biology of chronic infection is underscored by the recent rise in ocular disease associated with emerging haplotypes of T. gondii and our lack of effective treatments to sterilize chronic infection. This Review discusses the cell types and molecular mediators, both host and parasite, that facilitate persistent T. gondii infection. We highlight the consequences of chronic infection for tissue-specific pathology and identify open questions in this area of host-Toxoplasma interactions.
Anti–PD-1 Therapy–Associated Type 1 Diabetes in a Pediatric Patient With Relapsed Classical Hodgkin Lymphoma
Authors: Raynald A. Samoa, Hayley S. Lee, Sung H. Kil, Bart O. Roep
Journal: Diabetes Care (2020)

Immune checkpoint inhibitors (ICIs) perturb T-cell regulatory pathways to enhance antitumor immunity. However, an increase reporting of ICI-associated diabetes is observed in adults. To our knowledge, no cases have been reported in the pediatric population.We describe a pediatric case of ICI-associated type 1 diabetes in a 12-year-old Hispanic boy with Hodgkin lymphoma. The patient had a history of autologous hematopoietic stem cell transplantation and was treated with pembrolizumab after disease progression.The patient was admitted for diabetic ketoacidosis after five cycles of pembrolizumab. The patient was discharged with daily insulin injections and has continued on exogenous insulin ever since.The expanded ICI use may lead to more cases in pediatric patients as has been observed in adults. Considering the acute manifestation of diabetes and the added burden of lifelong insulin therapy, in particular for pediatric patients and their families, monitoring and education of ICI-associated diabetes in children is needed.
Genetically-programmed, mesenchymal stromal cell-laden &amp; mechanically strong 3D bioprinted scaffolds for bone repair
Authors: Hosam Al-Deen M. Abu Awwad, Lalitha Thiagarajan, Janos M. Kanczler, Mahetab H. Amer, Gordon Bruce, Stuart Lanham, Robin M.H. Rumney, Richard O.C. Oreffo, James E. Dixon
Journal: Journal of Controlled Release (2020)

Additive manufacturing processes used to create regenerative bone tissue engineered implants are not biocompatible, thereby restricting direct use with stem cells and usually require cell seeding post-fabrication. Combined delivery of stem cells with the controlled release of osteogenic factors, within a mechanically-strong biomaterial combined during manufacturing would replace injectable defect fillers (cements) and allow personalized implants to be rapidly prototyped by 3D bioprinting. Through the use of direct genetic programming via the sustained release of an exogenously delivered transcription factor RUNX2 (delivered as recombinant GET-RUNX2 protein) encapsulated in PLGA microparticles (MPs), we demonstrate that human mesenchymal stromal (stem) cells (hMSCs) can be directly fabricated into a thermo-sintered 3D bioprintable material and achieve effective osteogenic differentiation. Importantly we observed osteogenic programming of gene expression by released GET-RUNX2 (8.2-, 3.3- and 3.9-fold increases in OSX, RUNX2 and OPN expression, respectively) and calcification (von Kossa staining) in our scaffolds. The developed biodegradable PLGA/PEG paste formulation augments high-density bone development in a defect model (~2.4-fold increase in high density bone volume) and can be used to rapidly prototype clinically-sized hMSC-laden implants within minutes using mild, cytocompatible extrusion bioprinting. The ability to create mechanically strong 'cancellous bone-like' printable implants for tissue repair that contain stem cells and controlled-release of programming factors is innovative, and will facilitate the development of novel localized delivery approaches to direct cellular behaviour for many regenerative medicine applications including those for personalized bone repair.
Differential IRF8 Transcription Factor Requirement Defines Two Pathways of Dendritic Cell Development in Humans
Authors: Urszula Cytlak, Anastasia Resteu, Sarah Pagan, Kile Green, Paul Milne, Sheetal Maisuria, David McDonald, Gillian Hulme, Andrew Filby, Benjamin Carpenter, Rachel Queen, Sophie Hambleton, Rosie Hague, Hana Lango Allen, James E.D. Thaventhiran, Gina Doody, Matthew Collin, Venetia Bigley
Journal: Immunity (2020)

The formation of mammalian dendritic cells (DCs) is controlled by multiple hematopoietic transcription factors, including IRF8. Loss of IRF8 exerts a differential effect on DC subsets, including plasmacytoid DCs (pDCs) and the classical DC lineages cDC1 and cDC2. In humans, cDC2-related subsets have been described including AXL+SIGLEC6+ pre-DC, DC2 and DC3. The origin of this heterogeneity is unknown. Using high-dimensional analysis, in vitro differentiation, and an allelic series of human IRF8 deficiency, we demonstrated that cDC2 (CD1c+DC) heterogeneity originates from two distinct pathways of development. The lymphoid-primed IRF8hi pathway, marked by CD123 and BTLA, carried pDC, cDC1, and DC2 trajectories, while the common myeloid IRF8lo pathway, expressing SIRPA, formed DC3s and monocytes. We traced distinct trajectories through the granulocyte-macrophage progenitor (GMP) compartment showing that AXL+SIGLEC6+ pre-DCs mapped exclusively to the DC2 pathway. In keeping with their lower requirement for IRF8, DC3s expand to replace DC2s in human partial IRF8 deficiency.
Convergent Evolution in Breadth of Two VH6-1-Encoded Influenza Antibody Clonotypes from a Single Donor
Authors: Nicholas C. Wu, Sarah F. Andrews, Julie E. Raab, Sarah O’Connell, Chaim A. Schramm, Xintao Ding, Michael J. Chambers, Kwanyee Leung, Lingshu Wang, Yi Zhang, John R. Mascola, Daniel C. Douek, Julie E. Ledgerwood, Adrian B. McDermott, Ian A. Wilson
Journal: Cell Host & Microbe (2020)

Understanding how broadly neutralizing antibodies (bnAbs) to influenza hemagglutinin (HA) naturally develop in humans is critical to the design of universal influenza vaccines. Several classes of bnAbs directed to the conserved HA stem were found in multiple individuals, including one encoded by heavy-chain variable domain VH6-1. We describe two genetically similar VH6-1 bnAb clonotypes from the same individual that exhibit different developmental paths toward broad neutralization activity. One clonotype evolved from a germline precursor recognizing influenza group 1 subtypes to gain breadth to group 2 subtypes. The other clonotype recognized group 2 subtypes and developed binding to group 1 subtypes through somatic hypermutation. Crystal structures reveal that the specificity differences are primarily mediated by complementarity-determining region H3 (CDR H3). Thus, while VH6-1 provides a framework for development of HA stem-directed bnAbs, sequence differences in CDR H3 junctional regions during VDJ recombination can alter reactivity and evolutionary pathways toward increased breadth.
Perspectives on Urinary Tract Infection and Race
Authors: Kathy N. Shaw, Richard G. Bachur, Marc H. Gorelick
Journal: JAMA Pediatrics (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Early Relapse Risk in Patients with Newly Diagnosed Multiple Myeloma Characterized by Next-generation Sequencing
Authors: Mattia D'Agostino, Gian Maria Zaccaria, Bachisio Ziccheddu, Even H. Rustad, Elisa Genuardi, Andrea Capra, Stefania Oliva, Daniel Auclair, Jennifer Yesil, Paola Colucci, Jonathan J. Keats, Manuela Gambella, Sara Bringhen, Alessandra Larocca, Mario Boccadoro, Niccolò Bolli, Francesco Maura, Francesca Gay
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Duration of first remission is important for the survival of patients with multiple myeloma. Experimental Design: From the CoMMpass study (NCT01454297), 926 patients with newly diagnosed multiple myeloma, characterized by next-generation sequencing, were analyzed to evaluate those who experienced early progressive disease (PD; time to progression, TTP ≤18 months). Results: After a median follow-up of 39 months, early PD was detected in 191/926 (20.6%) patients, 228/926 (24.6%) patients had late PD (TTP &amp;gt;18 months), while 507/926 (54.8%) did not have PD at the current follow-up. Compared with patients with late PD, patients with early PD had a lower at least very good partial response rate (47% vs. 82%, P &amp;lt; 0.001) and more frequently acquired double refractoriness to immunomodulatory drugs (IMiD) and proteasome inhibitors (PI; 21% vs. 8%, P &amp;lt; 0.001). Patients with early PD were at higher risk of death compared with patients with late PD and no PD (HR, 3.65; 95% CI, 2.7–4.93; P &amp;lt; 0.001), showing a dismal median overall survival (32.8 months). In a multivariate logistic regression model, independent factors increasing the early PD risk were TP53 mutation (OR, 3.78, P &amp;lt; 0.001), high lactate dehydrogenase levels (OR, 3.15, P = 0.006), λ-chain translocation (OR, 2.25, P = 0.033), and IGLL5 mutation (OR, 2.15, P = 0.007). Carfilzomib-based induction (OR, 0.15, P = 0.014), autologous stem-cell transplantation (OR, 0.27, P &amp;lt; 0.001), and continuous therapy with PIs and IMiDs (OR, 0.34, P = 0.024) mitigated the risk of early PD. Conclusions: Early PD identifies a high-risk multiple myeloma population. Further research is needed to better identify baseline features predicting early PD and the optimal treatment approaches for patients at risk.
Prevention of shoulder problems trial (UK-PROSPER): Exercise to prevent shoulder problems in patients undergoing breast cancer treatment
Authors: Julie Bruce, Bruno Mazuquin, Pankaj Mistry, Esther Williamson, Ranjit Lall, Raghavan Vidya, Emma Withers, Sophie Rees, Alastair Canaway, Stavros Petrou, Sarah E Lamb, Alastair M Thompson
Journal: Cancer Research (2020)
Early Predictors of Arteriovenous Fistula Maturation: Preoperative Arterial Diameter Alone Is Not Enough
Authors: Pasquale Zamboli, Massimo Punzi, Umberto Marcello Bracale, Antonio Pisani
Journal: Journal of the American Society of Nephrology (2020)

Given the lack of high-quality evidence, the use to date of preoperative ultrasound for vascular access planning has not improved the maturation rates of the arteriovenous fistula (AVF). Recently in JASN , Farrington et al. [1][1] in their retrospective analysis involving 300 catheter-dependent
Key diagnostic markers for autoimmune lymphoproliferative syndrome with molecular genetic diagnosis
Authors: Emese Molnár, Nesrine Radwan, Gábor Kovács, Hajnalka Andrikovics, Frances Henriquez, Anton Zarafov, Matthew Hayman, Daniela Linzner, Adrian J. Thrasher, Matthew Buckland, Siobhan O. Burns, Kimberly C. Gilmour
Journal: Blood (2020)
Single-Cell Transcriptomic Analysis Identifies a Unique Pulmonary Lymphangioleiomyomatosis Cell
Authors: Minzhe Guo, Jane J. Yu, Anne Karina Perl, Kathryn A. Wikenheiser-Brokamp, Matt Riccetti, Erik Y. Zhang, Parvathi Sudha, Mike Adam, Andrew Potter, Elizabeth J. Kopras, Krinio Giannikou, S. Steven Potter, Sue Sherman, Stephen R. Hammes, David J. Kwiatkowski, Jeffrey A. Whitsett, Francis X. McCormack, Yan Xu
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Lymphangioleiomyomatosis (LAM) is a metastatic neoplasm of reproductive-age women associated with mutations in tuberous sclerosis complex genes. LAM causes cystic remodeling of the lung and progressive respiratory failure. The sources and cellular characteristics of LAM cells underlying disease pathogenesis remain elusive.Objectives: Identification and characterization of LAM cells in human lung and uterus using a single-cell approach.Methods: Single-cell and single-nuclei RNA sequencing on LAM (n = 4) and control (n = 7) lungs, immunofluorescence confocal microscopy, ELISA, and aptamer proteomics were used to identify and validate LAMCORE cells and secreted biomarkers, predict cellular origins, and define molecular and cellular networks in LAM.Measurements and Main Results: A unique cell type termed LAMCORE was identified, which was distinct from, but closely related to, lung mesenchymal cells. LAMCORE cells expressing signature genes included known LAM markers such as PMEL, FIGF, CTSK, and MLANA and novel biomarkers validated by aptamer screening, ELISA, and immunofluorescence microscopy. LAM cells in lung and uterus are morphologically indistinguishable and share similar gene expression profiles and biallelic TSC2 mutations, supporting a potential uterine origin for the LAMCORE cell. Effects of LAM on resident pulmonary cell types indicated recruitment and activation of lymphatic endothelial cells.Conclusions: A unique population of LAMCORE cells was identified in lung and uterus of patients with LAM, sharing close transcriptomic identity. LAM cell selective markers, secreted biomarkers, and the predicted cellular molecular features provide new insights into the signaling and transcriptional programs that may serve as diagnostic markers and therapeutic targets to influence the pathogenesis of LAM.
Government must apologise to those affected by Primodos, valproate, and mesh, says review
Authors: Elisabeth Mahase
Journal: BMJ (2020)

The UK government must immediately issue an apology “on behalf of the healthcare system” to people affected by three medical interventions—Primodos, sodium valproate, and pelvic mesh—and ensure they are listened to, supported, and compensated, a long awaited safety review has concluded.1

“The system, and those that oversee it, need to acknowledge what has gone so badly wrong,” said the report of the review, chaired by the life peer Julia Cumberlege. It came after years—decades in the case of sodium valproate and Primodos—of campaigning by patients and affected families.

The independent review was commissioned in 2018 by then health secretary for England, Jeremy Hunt, to assess use of the three medical interventions across the NHS.2 The report has found that in all three instances patients’ concerns were often dismissed and that as a result they had to fight to be heard. There were many occasions where regulatory bodies could have acted sooner and where poor communication with doctors and between doctors prevented patients knowing about the risks of the interventions.

Concerns were also raised regarding conflicts of interest, “both potential and real, in the provision of care or treatment, particularly where …
Insulin Given With DPP4 Inhibitors Might Protect Blood Vessels in Patients With Diabetes
Authors: Tracy Hampton
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Three Cases of Diffuse, Intense Stomach Uptake on DOTATATE PET
Authors: Martin S. Auerbach, Joseph R. Pisegna, Stephen Kim, Run Yu
Journal: Clinical Nuclear Medicine (2020)

Abstract Incidental tracer uptake on DOTATATE PET is increasingly encountered in clinical practice. We describe 3 patients with suspected or known neuroendocrine tumor who were found to have diffuse and intense stomach uptake on DOTATATE PET. All patients underwent esophagogastroduodenoscopy and/or endoscopic ultrasound; the cause of the stomach uptake was attributed to proton-pump inhibitor use, chronic gastritis, and gastrinoma, respectively. These 3 cases highlight that diffuse and intense stomach DOTATATE uptake can be a benign finding probably attributed to proton-pump inhibitor use, chronic gastritis, or gastrinoma.