tbuckley/cabot-search huggingface dataset:
Integrative metabolomics and transcriptomics identifies itaconate as an adjunct therapy to treat ocular bacterial infection
Authors: Sukhvinder Singh, Pawan Kumar Singh, Alokkumar Jha, Poonam Naik, Joveeta Joseph, Shailendra Giri, Ashok Kumar
Journal: Cell Reports Medicine (2021)

The eye is highly susceptible to inflammation-mediated tissue damage evoked during bacterial infection. However, mechanisms regulating inflammation to protect the eye remain elusive. Here, we used integrated metabolomics and transcriptomics to show that the immunomodulatory metabolite itaconate and immune-responsive gene 1 (Irg1) are induced in bacterial (Staphylococcus aureus)-infected mouse eyes, bone-marrow-derived macrophages (BMDMs), and Müller glia. Itaconate levels are also elevated in the vitreous of patients with bacterial endophthalmitis. Irg1 deficiency in mice led to increased ocular pathology. Conversely, intraocular administration of itaconate protects both Irg1−/− and wild-type mice from bacterial endophthalmitis by reducing inflammation, bacterial burden, and preserving retinal architecture and visual function. Notably, itaconate exerts synergistic effects with antibiotics. The protective, anti-inflammatory effects of itaconate are mediated via activation of NRF2/HO-1 signaling and inhibition of NLRP3 inflammasome. Collectively, our study demonstrates the Irg1/itaconate axis is a regulator of intraocular inflammation and provides evidence for using itaconate, along with antibiotics, to treat bacterial infections.
The effectiveness of contact investigation among contacts of tuberculosis patients: a systematic review and meta-analysis
Authors: Kavindhran Velen, Rashmi Vijay Shingde, Jennifer Ho, Greg James Fox
Journal: European Respiratory Journal (2021)

Background We aimed to evaluate the effectiveness of contact investigation in comparison with passive case detection alone, and estimate the yield of co-prevalent and incident tuberculosis (TB) and latent TB infection (LTBI) among contacts of patients with TB. Methods A systematic search was undertaken of studies published between 1 January 2011 and 1 October 2019 in the English language. The proportion of contacts diagnosed with co-prevalent TB, incident TB and/or LTBI was estimated. Evaluation of the effectiveness of contact investigation included randomised trials, while the yield of contact investigation (co-prevalent/incident TB and LTBI) was assessed in nonrandomised studies. Results Data were extracted from 244 studies, of which 187 studies measured the proportion of contacts diagnosed with TB disease and 135 studies measured LTBI prevalence. Individual randomised trials demonstrated that contact investigation increased TB case notification (relative risk 2.5, 95% CI 2.0–3.2) and TB case detection (OR 1.34, 95% CI 0.43–4.24) and decreased mortality (relative risk 0.6, 95% CI 0.4–0.8) and population TB prevalence (risk ratio 0.82, 95% CI 0.64–1.04). The overall pooled prevalence of TB was 3.6% (95% CI 3.3–4.0%; I 2 =98.9%, 181 studies). The pooled prevalence of microbiologically confirmed TB was 3.2% (95% CI 2.6–3.7%; I 2 =99.5%, 106 studies). The pooled incidence of TB was highest in the first year after exposure to index patients (2.0%, 95% CI 1.1–3.3%; I 2 =96.2%, 14 studies) and substantially lower 5 years after exposure to index patients (0.5%, 95% CI 0.3–0.9%; one study). The pooled prevalence of LTBI among contacts was 42.4% (95% CI 38.5–46.4%; I 2 =99.8%, 135 studies). Conclusions This systematic review and meta-analysis found that contact investigation was effective in high-burden settings. The higher pooled prevalence estimates of microbiologically confirmed TB compared with previous reviews suggests newer rapid molecular diagnostics contribute to increased case detection.
Survival prediction and treatment optimization of multiple myeloma patients using machine-learning models based on clinical and gene expression data
Authors: Adrián Mosquera Orgueira, Marta Sonia González Pérez, José Ángel Díaz Arias, Beatriz Antelo Rodríguez, Natalia Alonso Vence, Ángeles Bendaña López, Aitor Abuín Blanco, Laura Bao Pérez, Andrés Peleteiro Raíndo, Miguel Cid López, Manuel Mateo Pérez Encinas, José Luis Bello López, Maria Victoria Mateos Manteca
Journal: Leukemia (2021)
Abstract 17087: Mesenchymal Stem Cell-Derived Extracellular Vesicle Therapy Delivered in a Hydrogel Preserves Hemodynamic Function Following Myocardial Infarction
Authors: Mark R Helmers, Jakub Jarmula, Samuel Kim, Alexis Schiazza, Peter Altshuler, Jason A Burdick, Pavan Atluri
Journal: Circulation (2020)

Introduction: Mesenchymal Stem Cell (MSC)-derived Extracellular Vesicles (EVs) are an emerging regenerative therapy for treatment of ischemic cardiomyopathy. In this study, we determine the efficacy of MSC-EV therapy in a shear-thinning hydrogel (STG) delivered via intramyocardial injection to the border zone of rat hearts following myocardial infarction (MI). Hypothesis: MSC EV-loaded STGs will preserve hemodynamic function and minimize ventricular scar formation in a rat model of acute MI. Methods: EVs were isolated from MSCs by PEG precipitation, and the EV proteome was characterized by MaxQuant 1.5.1.2 and Metacore analysis software. Varying concentrations of EVs were administered to rats following induction of acute MI by ligation of the left anterior descending artery. EVs were delivered in either sterile phosphate buffered saline (PBS) or STG for sustained EV release. Chronic injury was assessed at 4 weeks post-MI through transthoracic echocardiography, intraventricular pressure-volume loop displacement, and histology. Results: MSC EV proteomic analysis highlighted upregulation of VEGF angiogenic cascades and ILK-mediated proliferative pathways. The mean left ventricle ejection fraction (LVEF) for each treatment group at four weeks is displayed in Table 1. A 20 ug dose of MSC EVs in STG improved LVEF by 19.12% (p&lt;0.05) compared to PBS, with a 90 ug dose of MSC EVs in STG increasing LVEF by 23.56% (p&lt;0.01) (Fig. 1). Conclusions: Intramyocardial injection of MSC EVs in STG post-MI showed concentration dependent improvements in hemodynamics. These findings show that high doses of MSC EV in STG may have potential as a therapy for ischemic cardiomyopathy. Proteomic analysis revealed that angiogenesis, recruitment of cardiac progenitor cells, and immune modulation may be mechanistic drivers of MSC-EV therapy.
Abstract 075: Differences In Body Composition At Baseline And In Response To Exercise Training By Metabolic Health And Weight Status
Authors: Alexis Jones, Jacob L Barber, James S Skinner, Claude Bouchard, Mark A Sarzynski
Journal: Circulation (2021)

Background: Body composition is known to differ across metabolic health and weight phenotypes. Regular exercise improves body composition, yet little is known about differences in exercise response across metabolic health and weight phenotypes. Methods: Normal weight (n=376) and overweight/obese (OWOB) adults (n=456) from the HERITAGE Family Study (56% female, 38% Black) completed a 20-week endurance training program. Four groups based on baseline BMI and metabolic risk were created: metabolically healthy normal weight, MHNW; metabolically unhealthy normal weight, MUNW; metabolically healthy OWOB, MHO; and metabolically unhealthy OWOB, MUO. Unhealthy was defined as having ≥2 metabolic syndrome components. General linear models tested for differences in baseline and change in measures of body composition (fat mass [FM], fat-free mass [FFM], % body fat [%BF], visceral fat) after adjusting for age, sex, and ethnicity (and baseline value in change models). Results: Table 1 shows adjusted mean baseline and change in body composition values by group. Baseline body composition tended to track with weight status, with NW adults having lower FM, %BF, and visceral fat compared to obese adults (p&lt;0.05), regardless of metabolic health. However, the MHO group had lower baseline values of these traits compared to MUO (p&lt;0.05). Body composition measures significantly improved with exercise training in all groups, however, the magnitude of change differed between groups. For example, both NW groups had larger decreases in %BF compared to the obese groups, with MUNW showing the largest decrease. Conversely, MHNW showed the largest decrease in visceral fat, which was greater than both obese groups, but change in visceral fat was similar between MHO and MUNW. Conclusions: Normal weight adults tended to have better body composition profiles at baseline and larger improvements with exercise compared to obese adults, regardless of metabolic health. Within weight groups, body composition improved regardless of metabolic health status.
Abstract 14689: SDPR/Cavin-2 Regulates Adipocyte Differentiation With Suppression of PPARγ and C/EBPα Expressions in 3T3L1 Cells
Authors: Yusuke Higuchi, Takehiro Ogata, Akira Sakamoto, Naohiko Nakanishi, Yumika Tsuji, Shinya Tomita, Satoaki Matoba
Journal: Circulation (2019)

Introduction: Congenital generalized lipodystrophy is an autosomal recessive disorder characterized by deficiency of adipose tissue which is evident at birth and is accompanied by a severe resistan...
GPs should be able to delist patients who racially abuse staff, say leaders
Authors: Gareth Iacobucci
Journal: BMJ (2021)

Health ministers should commit to a “zero tolerance” approach to any patients’ complaints against general practices that arise from staff challenging racism, GP leaders have urged.

A motion passed by the UK annual conference of local medical committees on 12 May also urged health ministers across the four nations to “publicly and repeatedly” deliver the message that no patient is entitled to refuse care because of a clinician’s ethnicity and to identify and publicise daily examples of racism to which NHS colleagues are subjected.

The motion was passed after the conference heard a series of distressing …
Risk of the Watch-and-Wait Concept in Surgical Treatment of Intraductal Papillary Mucinous Neoplasm
Authors: Christine Tjaden, Marta Sandini, André L. Mihaljevic, Jörg Kaiser, Ekaterina Khristenko, Philipp Mayer, Ulf Hinz, Matthias M. Gaida, Christoph Berchtold, Markus K. Diener, Martin Schneider, Arianeb Mehrabi, Beat P. Müller-Stich, Oliver Strobel, Thilo Hackert, Markus W. Büchler
Journal: JAMA Surgery (2021)

The natural history of intraductal papillary mucinous neoplasms (IPMNs) remains uncertain. The inconsistencies among published guidelines preclude accurate decision-making. The outcomes and potential risks of a conservative watch-and-wait approach vs a surgical approach must be compared.To provide an overview of the surgical management of IPMNs, focusing on the time of resection.This cohort study was conducted in a single referral center; all patients with pathologically proven IPMN who received a pancreatic resection at the institution between October 2001 and December 2019 were analyzed. Preoperatively obtained images and the medical history were scrutinized for signs of progression and/or malignant features. The timeliness of resection was stratified into too early (adenoma and low-grade dysplasia), timely (intermediate-grade dysplasia and in situ carcinoma), and too late (invasive cancer). The perioperative characteristics and outcomes were compared between these groups.Timeliness of resection according to the final pathological findings.The risk of malignant transformation at the final pathology.Of 1439 patients, 438 (30.4%) were assigned to the too early group, 504 (35.1%) to the timely group, and 497 (34.5%) to the too late group. Radiological criteria for malignant conditions were detected in 53 of 382 patients (13.9%), 149 of 432 patients (34.5%), and 341 of 385 patients (88.6%) in the too early, timely, and too late groups, respectively (P < .001). Patients in the too early group underwent more parenchyma-sparing resections (too early group, 123 of 438 [28.1%]; timely group, 40 of 504 [7.9%]; too late group, 5 of 497 [1.0%]; P < .001), while morbidity (too early group, 112 of 438 [25.6%]; timely group, 117 of 504 [23.2%]; too late group, 158 of 497 [31.8%]; P = .002) and mortality (too early group, 4 patients [0.9%]; timely, 4 [0.8%]; too late, 13 [2.6%]; P = .03) were highest in the too late group. Of the 497 patients in the too late group, 124 (24.9%) had a previous history of watch-and-wait care.Until the biology and progression patterns of IPMN are clarified and accurate guidelines established, a watch-and-wait policy should be applied with caution, especially in IPMN bearing a main-duct component. One-third of IPMNs reach the cancer stage before resection. At specialized referral centers, the risks of surgical morbidity and mortality are justifiable.
Vemurafenib plus Rituximab in Refractory or Relapsed Hairy-Cell Leukemia
Authors: Enrico Tiacci, Luca De Carolis, Edoardo Simonetti, Monia Capponi, Achille Ambrosetti, Eugenio Lucia, Agostino Antolino, Alessandro Pulsoni, Samantha Ferrari, Pier L. Zinzani, Stefano Ascani, Vincenzo M. Perriello, Luigi Rigacci, Gianluca Gaidano, Roberta Della Seta, Natalia Frattarelli, Paolo Falcucci, Robin Foà, Giuseppe Visani, Francesco Zaja, Brunangelo Falini
Journal: New England Journal of Medicine (2021)

Hairy-cell leukemia (HCL) is a CD20+ indolent B-cell cancer in which a BRAF V600E kinase-activating mutation plays a pathogenetic role. In clinical trials involving patients with refractory or relapsed HCL, the targeting of BRAF V600E with the oral BRAF inhibitor vemurafenib led to a response in 91% of the patients; 35% of the patients had a complete response. However, the median relapse-free survival was only 9 months after treatment was stopped.In a phase 2, single-center, academic trial involving patients with refractory or relapsed HCL, we assessed the safety and efficacy of vemurafenib (960 mg, administered twice daily for 8 weeks) plus concurrent and sequential rituximab (375 mg per square meter of body-surface area, administered for 8 doses over a period of 18 weeks). The primary end point was a complete response at the end of planned treatment.Among the 30 enrolled patients with HCL, the median number of previous therapies was 3. A complete response was observed in 26 patients (87%) in the intention-to-treat population. All the patients who had HCL that had been refractory to chemotherapy (10 patients) or rituximab (5) and all those who had previously been treated with BRAF inhibitors (7) had a complete response. Thrombocytopenia resolved after a median of 2 weeks, and neutropenia after a median of 4 weeks. Of the 26 patients with a complete response, 17 (65%) were cleared of minimal residual disease (MRD). Progression-free survival among all 30 patients was 78% at a median follow-up of 37 months; relapse-free survival among the 26 patients with a response was 85% at a median follow-up of 34 months. In post hoc analyses, MRD negativity and no previous BRAF inhibitor treatment correlated with longer relapse-free survival. Toxic effects, mostly of grade 1 or 2, were those that had previously been noted for these agents.In this small study, a short, chemotherapy-free, nonmyelotoxic regimen of vemurafenib plus rituximab was associated with a durable complete response in most patients with refractory or relapsed HCL. (Funded by the European Research Council and others; HCL-PG03 EudraCT number, 2014-003046-27.).
Pioglitazone, a peroxisome proriferator-activated receptor-γ agonist, preserved contractile function in Dahl salt-sensitive hypertensive rats
Authors: Kawai M, Kawashima S, Fukushima K, Ueyama T, Satomi(Kobayashi) S, Toh R, Sugimura K, Yokoyama M
Journal: Circulation (2004)
A Novel, Suction-Based Transdermal DNA Vaccine Delivery Platform Induces Immunogenicity to SARS-CoV-2 in Rats
Authors: E. O. Lallow, N. C. Jhumur, I. Ahmed, S. B. Kudchodkar, C. C. Roberts, M. Jeong, J. Melnik, S. Park, J. W. Shan, J. D. Zahn, D. I. Shreiber, J. Singer, Y. Park, J. N. Maslow, H. Lin
Journal: Molecular Therapy (2021)
Extracellular vesicles as a drug delivery system: A systematic review of preclinical studies
Authors: Pol Escudé Martinez de Castilla, Lingjun Tong, Chenyuan Huang, Alexandros Marios Sofias, Giorgia Pastorin, Xiaoyuan Chen, Gert Storm, Raymond M. Schiffelers, Jiong-Wei Wang
Journal: Advanced Drug Delivery Reviews (2021)
Neuraminidase and SIGLEC15 modulate the host defense against pulmonary aspergillosis
Authors: Intan M.W. Dewi, Cristina Cunha, Martin Jaeger, Mark S. Gresnigt, Marina E. Gkountzinopoulou, Fadel M. Garishah, Cláudio Duarte-Oliveira, Cláudia F. Campos, Lore Vanderbeke, Agustin Resendiz Sharpe, Roger J. Brüggemann, Paul E. Verweij, Katrien Lagrou, Greetje Vande Velde, Quirijn de Mast, Leo A.B. Joosten, Mihai G. Netea, Andre J.A.M. van der Ven, Joost Wauters, Agostinho Carvalho, Frank L. van de Veerdonk
Journal: Cell Reports Medicine (2021)

Influenza-associated pulmonary aspergillosis (IAPA) has been reported increasingly since the advent of use of neuraminidase (NA) inhibitors following the 2009 influenza pandemic. We hypothesize that blocking host NA modulates the immune response against Aspergillus fumigatus. We demonstrate that NA influences the host response against A. fumigatus in vitro and that oseltamivir increases the susceptibility of mice to pulmonary aspergillosis. Oseltamivir impairs the mouse splenocyte and human peripheral blood mononuclear cell (PBMC) killing capacity of A. fumigatus, and adding NA restores this defect in PBMCs. Furthermore, the sialic acid-binding receptor SIGLEC15 is upregulated in PBMCs stimulated with A. fumigatus. Silencing of SIGLEC15 decrease PBMC killing of A. fumigatus. We provide evidence that host NA activity and sialic acid recognition are important for anti-Aspergillus defense. NA inhibitors might predispose individuals with severe influenza to invasive aspergillosis. These data shed light on the pathogenesis of invasive fungal infections and may identify potential therapeutic targets.
Plarr's Lives of the Fellows of the Royal College of Surgeons of England.
Journal: JAMA (1930)

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Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies
Authors: Sæmundur Rögnvaldsson, Thorvardur Jon Love, Sigrun Thorsteinsdottir, Elín Ruth Reed, Jón Þórir Óskarsson, Íris Pétursdóttir, Guðrún Ásta Sigurðardóttir, Brynjar Viðarsson, Páll Torfi Önundarson, Bjarni A. Agnarsson, Margrét Sigurðardóttir, Ingunn Þorsteinsdóttir, Ísleifur Ólafsson, Ásdís Rósa Þórðardóttir, Elías Eyþórsson, Ásbjörn Jónsson, Andri S. Björnsson, Gunnar Þór Gunnarsson, Runólfur Pálsson, Ólafur Skúli Indriðason, Gauti Kjartan Gíslason, Andri Ólafsson, Guðlaug Katrín Hákonardóttir, Manje Brinkhuis, Sara Lovísa Halldórsdóttir, Tinna Laufey Ásgeirsdóttir, Hlíf Steingrímsdóttir, Ragnar Danielsen, Inga Dröfn Wessman, Petros Kampanis, Malin Hultcrantz, Brian G. M. Durie, Stephen Harding, Ola Landgren, Sigurður Yngvi Kristinsson
Journal: Blood Cancer Journal (2021)

Abstract Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Population-based screening for MGUS could identify candidates for early treatment in MM. Here we describe the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM), the first population-based screening study for MGUS including a randomized trial of follow-up strategies. Icelandic residents born before 1976 were offered participation. Blood samples are collected alongside blood sampling in the Icelandic healthcare system. Participants with MGUS are randomized to three study arms. Arm 1 is not contacted, arm 2 follows current guidelines, and arm 3 follows a more intensive strategy. Participants who progress are offered early treatment. Samples are collected longitudinally from arms 2 and 3 for the study biobank. All participants repeatedly answer questionnaires on various exposures and outcomes including quality of life and psychiatric health. National registries on health are cross-linked to all participants. Of the 148,704 individuals in the target population, 80 759 (54.3%) provided informed consent for participation. With a very high participation rate, the data from the iStopMM study will answer important questions on MGUS, including potentials harms and benefits of screening. The study can lead to a paradigm shift in MM therapy towards screening and early therapy.
Rationally designed protein cross-linked hydrogel for bone regeneration via synergistic release of magnesium and zinc ions
Authors: Xin Chen, Baoyu Tan, Shang Wang, Rongze Tang, Zhiteng Bao, Gaoyang Chen, Shuai Chen, Wanze Tang, Zhenmin Wang, Canling Long, William W. Lu, Dazhi Yang, Liming Bian, Songlin Peng
Journal: Biomaterials (2021)

The development of recombinant protein cross-linked injectable hydrogels with good mechanical strength and effective drug loading capacity for bone regeneration is extremely attractive and rarely reported. Here, we report the fabrication of a smart hydrogel delivery system by incorporating a rationally designed T4 lysozyme mutant (T4M) to mediate the localized delivery and synergistic release of Mg2+ and Zn2+ for bone repair. Apart from its intrinsic antibacterial properties, T4M bears abundant free amine groups on its surface to function as effective covalent crosslinkers to strengthen the hydrogel network as well as exhibits specific binding affinity to multivalent cations such as Zn2+. Moreover, the integrin receptor-binding Arg-Gly-Asp (RGD) sequence was introduced onto the C-terminus of T4 lysozyme to improve its cellular affinity and further facilitate rapid tissue regeneration. The final composite hydrogel displays excellent injectability, improved mechanical properties, antibacterial activity, and unique bioactivities. The effective loading of Mg2+/Zn2+ in the hydrogels could mediate the sequential and sustained release of Mg2+ and Zn2+, thereby resulting in synergistic enhancement on bone regeneration through modulation of the MAPK signaling pathway. We believe that the strategy proposed in this paper opens up a new route for developing protein cross-linked smart delivery systems for tissue regeneration.
Mitotic and Apoptotic Figures on a Peripheral-Blood Smear
Authors: Robert D.H. Markewitz, Justina Dargvainiene
Journal: New England Journal of Medicine (2021)

A 31-year-old man with refractory acute myeloid leukemia presented with worsening pain due to known spinal involvement of the leukemia. The white-cell count was 91,100 per cubic millimeter, and a peripheral-blood smear showed multiple mitotic and apoptotic figures.