tbuckley/cabot-search huggingface dataset:
The Path to Progress Preclinical Studies of Age-Related Neurodegenerative Diseases: A Perspective on Rodent and hiPSC-Derived Models
Authors: Gabriella MacDougall, Logan Y. Brown, Boris Kantor, Ornit Chiba-Falek
Journal: Molecular Therapy (2021)

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent age-related neurodegenerative diseases, and currently no effective clinical treatments exist for either, despite decades of clinical trials. The failure to translate preclinical findings into effective treatments is indicative of a problem in the current evaluation pipeline for potential therapeutics. At present, there are no useful animal models for AD and PD research that reflect the entire biology of the diseases, specifically, the more common non-Mendelian forms. Whereas the field continues to seek suitable rodent models for investigating potential therapeutics for these diseases, rodent models have still been used primarily for preclinical studies. Here, we advocate for a paradigm shift toward the application of human-induced pluripotent stem cell (hiPSC)-derived systems for PD and AD modeling and the development of improved human-based models in a dish for drug discovery and preclinical assessment of therapeutic targets.
HiDeF: identifying persistent structures in multiscale ‘omics data
Authors: Fan Zheng, She Zhang, Christopher Churas, Dexter Pratt, Ivet Bahar, Trey Ideker
Journal: Genome biology (2021)

In any 'omics study, the scale of analysis can dramatically affect the outcome. For instance, when clustering single-cell transcriptomes, is the analysis tuned to discover broad or specific cell types? Likewise, protein communities revealed from protein networks can vary widely in sizes depending on the method. Here, we use the concept of persistent homology, drawn from mathematical topology, to identify robust structures in data at all scales simultaneously. Application to mouse single-cell transcriptomes significantly expands the catalog of identified cell types, while analysis of SARS-COV-2 protein interactions suggests hijacking of WNT. The method, HiDeF, is available via Python and Cytoscape.
FDG PET/CT and MRI Features of Pathologically Proven Schwannomas
Authors: Benjamin J. Dewey, Benjamin M. Howe, Robert J. Spinner, Geoffrey B. Johnson, Mark A. Nathan, Doris E. Wenger, Stephen M. Broski
Journal: Clinical Nuclear Medicine (2021)

The aim of this study was to examine the MRI and FDG PET/CT imaging features of pathologically proven schwannomas.This institutional review board-approved retrospective study examined biopsy-proven schwannomas that underwent FDG PET/CT and/or MRI at our institution between January 1, 2002, and April 1, 2018. PET/CT features analyzed included SUVmax, metabolic ratios, volumetric metabolic measures, presence of calcification, and pattern of FDG activity. MRI features included T1/T2 signal, enhancement pattern, margins, perilesional edema, presence of muscular denervation, and size.Ninety-five biopsy-proven schwannomas were identified (40 with both PET and MRI, 35 with PET only, and 20 with MRI only), 46 females and 49 males, average age of 57.7 ± 15.3 years. The average largest dimension was 4.6 ± 2.7 cm, the average SUVmax was 5.4 ± 2.7, and lesion SUVmax/liver SUVmean was 2.2 ± 1.2. Eleven (15%) of 75 lesions had SUVmax greater than 8.1, 26/75 (35%) had SUVmax greater than 6.1, and 14/75 (19%) had lesion SUVmax/liver SUVmean greater than 3.0. On MRI, 29/53 (55%) demonstrated internal nonenhancing areas. Twenty-eight (70%) of 40 lesions with both MRI and PET demonstrated at least 1 imaging feature concerning for malignant peripheral nerve sheath tumor (irregular margins, internal nonenhancement, perilesional edema, heterogeneous FDG uptake, or SUVmax >8.1). Lesions with heterogeneous FDG activity had higher SUVmax (6.5 ± 0.5 vs 4.7 ± 0.4, P = 0.0031) and more frequent internal nonenhancement on MRI (P = 0.0218).Schwannomas may be large, be intensely FDG avid, and demonstrate significant heterogeneity, features typically associated with malignant peripheral nerve sheath tumors. A significant proportion exhibit FDG activity above cutoff levels previously thought useful in differentiating malignant from benign peripheral nerve sheath tumors.
Correspondence on ‘EULAR/ACR classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups’
Authors: Irfan Mohammad, Phani Kumar Devarasetti, Liza Rajasekhar
Journal: Annals of the Rheumatic Diseases (2021)

The publication of the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) 2017 classification criteria for adult and juvenile idiopathic inflammatory myopathy is a landmark with 186 citations as of date.1 Patients with dermatomyositis (DM) and polymyositis (PM) differ with respect to clinical features, autoantibody profile and treatment response and have been subgrouped for a long time now.2

We studied 26 consecutive adult patients over 1 year seen in a tertiary teaching hospital in south India, satisfying either the 2017 criteria or 1975 Bohan-Peter criteria for idiopathic inflammatory myositis (IIM). Patients were subclassified using the 2017 criteria subclassification tree. Those with typical skin rash (heliotrope, Gottron papule or Gottrons sign) were classified as DM (n=14) and the rest as PM (n=12). There were no patients satisfying the criteria for IBM. Overlap myositis was excluded. …
The CXCL12gamma chemokine immobilized by heparan sulfate on stromal niche cells controls adhesion and mediates drug resistance in multiple myeloma
Authors: Zemin Ren, Hildo Lantermans, Annemieke Kuil, Willem Kraan, Fernando Arenzana-Seisdedos, Marie José Kersten, Marcel Spaargaren, Steven T. Pals
Journal: Journal of Hematology & Oncology (2021)

The survival and proliferation of multiple myeloma (MM) cells in the bone marrow (BM) critically depend on interaction with stromal cells expressing the chemokine CXCL12. CXCL12 regulates the homing to the BM niche by mediating the transendothelial migration and adhesion/retention of the MM cells. The gamma isoform of CXCL12 (CXCL12γ) has been reported to be highly expressed in mouse BM and to show enhanced biological activity compared to the 'common' CXCL12α isoform, mediated by its unique extended C-terminal domain, which binds heparan sulfate proteoglycans (HSPGs) with an extraordinary high affinity. Here, we investigated the expression of CXCL12γ in human BM and studied its functional role in the interaction of MM cells with BM stromal cells (BMSCs). We assessed CXCL12γ mRNA and protein expression by human BMSCs using qPCR, flow cytometry, and immunohistochemistry. CRISPR-Cas9 was employed to delete CXCL12γ and the heparan sulfate (HS) co-polymerase EXT1 in BMSCs. To study the functional roles of BMSC-derived CXCL12γ and HSPGs in the interaction of MM cells with BMSCs cells, MM cell lines and primary MM cells were co-cultured with BMSCs. We observed that CXCL12γ is expressed in situ by reticular stromal cells in both normal and MM BM, as well as by primary BMSC isolates and BMSC lines. Importantly, upon secretion, CXCL12γ, unlike the CXCL12α isoform, was retained on the surface of BMSCs. This membrane retention of CXCL12γ is HSPG mediated, since it was completely annulated by CRISPR-Cas9-mediated deletion of the HS co-polymerase EXT1. CXCL12γ expressed by BMSCs and membrane-retained by HSPGs supported robust adhesion of MM cells to the BMSCs. Specific genetic deletion of either CXCL12γ or EXT1 significantly attenuated the ability of BMSCs to support MM cell adhesion and, in addition, impaired their capacity to protect MM cells from bortezomib-induced cell death. We show that CXCL12γ is expressed by human BMSCs and upon secretion is retained on their cell surface by HSPGs. The membrane-bound CXCL12γ controls adhesion of MM cells to the stromal niche and mediates drug resistance. These findings designate CXCL12γ and associated HSPGs as partners in mediating MM-niche interaction and as potential therapeutic targets in MM.
An integrated in silico immuno-genetic analytical platform provides insights into COVID-19 serological and vaccine targets
Authors: Daniel Ward, Matthew Higgins, Jody E. Phelan, Martin L. Hibberd, Susana Campino, Taane G. Clark
Journal: Genome Medicine (2021)

Abstract During COVID-19, diagnostic serological tools and vaccines have been developed. To inform control activities in a post-vaccine surveillance setting, we have developed an online “immuno-analytics” resource that combines epitope, sequence, protein and SARS-CoV-2 mutation analysis. SARS-CoV-2 spike and nucleocapsid proteins are both vaccine and serological diagnostic targets. Using the tool, the nucleocapsid protein appears to be a sub-optimal target for use in serological platforms. Spike D614G (and nsp12 L314P) mutations were most frequent (&gt; 86%), whilst spike A222V/L18F have recently increased. Also, Orf3a proteins may be a suitable target for serology. The tool can accessed from: http://genomics.lshtm.ac.uk/immuno (online); https://github.com/dan-ward-bio/COVID-immunoanalytics (source code).
Abstract 24011: Inducible Depletion of Calpain-2 Attenuates Obesity-accelerated Abdominal Aortic Aneurysms in mice
Authors: Aida Javidan, Weihua Jiang, Jessica J. Moorleghen, Venkateswaran Subramanian
Journal: Circulation (2017)

Background and Objective: Recent clinical studies demonstrated that abdominal adiposity is associated with increased risk of abdominal aortic aneurysm (AAA) development. Calpains are non-lysosomal calcium dependent cysteine proteases that are highly expressed in human and experimental AAAs. Using a pharmacological inhibitor and genetically deficient mice, we identified that calpain-2 (a major ubiquitous isoform) plays a critical role in Angiotensin II (AngII)-induced AAA formation in mice. In addition, calpain inhibition strongly suppressed adipose tissue inflammation in obese mice. The purpose of this study was to determine the functional contribution of calpain-2 in obesity-accelerated AAA. Methods and Results: Calpain-2 floxed mice that were hemizygous for β-actin Cre-ERT2 were produced by breeding male Cre-ERT2 to female calpain-2 floxed mice. At 8 weeks of age, male non-Cre littermates (Cre-) and Calp-2 x Cre-ERT2 (Cre+) mice were injected with tamoxifen (25 mg/kg, i.p.) daily for 5 consecutive days. After 2 weeks, Western blot analyses showed a complete depletion of calpain-2 protein in the aorta and periaortic adipose tissue from Cre+ mice compared to non-Cre littermates. Mice were fed a high fat diet (60% Kcal) for 20 weeks. After 16 weeks of diet feeding, mice were infused with AngII (1,000 ng/kg/min) by osmotic minipumps for 4 weeks. Depletion of calpain-2 had no effect on high fat diet-induced body weight gain, fat mass, glucose and insulin tolerance. Interestingly, calpain-2 depletion significantly attenuated AngII-induced expansion of ex-vivo maximal diameter of abdominal aortas in obese mice (Cre-: 1.4 ± 0.14; Cre+: 0.9 ± 0.04 mm; P&lt;0.001). In addition, calpain-2 depletion significantly reduced the incidence of AngII-induced AAAs in mice (Cre-: 75%, Cre+: 7%; P&lt; 0.001). Conclusion: These findings suggest that calpain-2 plays a critical role in AngII-induced AAA development in diet-induced obese mice.
Trust is ordered to pay £7500 to man who was not “best fit” for role with young women
Authors: Clare Dyer
Journal: BMJ (2021)

An employment tribunal has ordered an NHS trust to pay £7580 (€8524; $10 348) for sex and age discrimination after it rejected a middle aged man for a job working mainly with women in their early 30s.

Guy’s and St Thomas’ NHS Foundation Trust decided that Neil McClements would not be the “best fit” for the role as a project manager on the Digital Health London Accelerator, even though he scored highest at interview.

The job he applied for in June 2018 would have required him to work with and support the programme director Jenny Thomas, and to work closely with and report to Charlotte Lee, a doctor and regional lead for the accelerator …
NU01.01 Real World Data on Maintenance Therapy Utilization and Overall Survival Among Advanced Non-Small Cell Lung Cancer Patients Treated with Pemetrexed in combination with Pembrolizumab and Platinum Chemotherapy in the US
Authors: K. Bayo, H. Aggarwal, Y. Han, C. Muehlenbein, Y.E. Zhu, J.S. Kim
Journal: Journal of Thoracic Oncology (2021)
Assessment of Neonatal Abstinence Syndrome Surveillance — Pennsylvania, 2019
Authors: Kathleen H. Krause, Joann F. Gruber, Elizabeth C. Ailes, Kayla N. Anderson, Victoria L. Fields, Kimberlea Hauser, Callie L. Howells, Allison Longenberger, Nancy McClung, Lisa P. Oakley, Jennita Reefhuis, Margaret A. Honein, Sharon M. Watkins
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

As described in the Neonatal Abstinence Syndrome: 2018 Report released by the Pennsylvania Bureau of Epidemiology, the Pennsylvania NAS surveillance system was established through an emergency declaration that made NAS a reportable condition throughout the state.The Pennsylvania NAS surveillance case definition required health care providers at birthing facilities and pediatric hospitals to report infants born on or after January 10, 2018, to residents of Pennsylvania who received a diagnosis of NAS (based on prenatal exposure to opiate drugs anytime during pregnancy and the presence of at least one symptom of withdrawal) during the neonatal period (birth through 28 days of life).Reports were submitted through a web-based system.
Image gallery: first take a good picture, then tell a good story
Authors: N. Rajan
Journal: British Journal of Dermatology (2021)

Clinical images leave impressions, central to the way we learn and practise dermatology.They shape our clinical diagnoses, and impact on our management decisions.Nobel laureate Daniel Kahneman wrote eloquently about how human decision making is informed by the priming of prior experience, forming what is termed the 'available heuristic', or 'knee jerk' type response. 1In this vein, we, in our role as dermatologists, are primed by visual experiencein our clinics, textbooks and journals.
Monocytes in sarcoidosis are potent TNF producers and predict disease outcome
Authors: Rico Lepzien, Sang Liu, Paulo Czarnewski, Mu Nie, Björn Österberg, Faezzah Baharom, Jamshid Pourazar, Gregory Rankin, Anders Eklund, Matteo Bottai, Susanna Kullberg, Anders Blomberg, Johan Grunewald, Anna Smed-Sörensen
Journal: European Respiratory Journal (2021)

Background Pulmonary sarcoidosis is an inflammatory disease characterised by granuloma formation and heterogeneous clinical outcome. Tumour necrosis factor (TNF) is a pro-inflammatory cytokine contributing to granuloma formation and high levels of TNF have been shown to associate with progressive disease. Mononuclear phagocytes (MNPs) are potent producers of TNF and highly responsive to inflammation. In sarcoidosis, alveolar macrophages have been well studied. However, MNPs also include monocytes/monocyte-derived cells and dendritic cells, which are poorly studied in sarcoidosis, despite their central role in inflammation. Objective To determine the role of pulmonary monocyte-derived cells and dendritic cells during sarcoidosis. Methods We performed in-depth phenotypic, functional and transcriptomic analysis of MNP subsets from blood and bronchoalveolar lavage (BAL) fluid from 108 sarcoidosis patients and 30 healthy controls. We followed the clinical development of patients and assessed how the repertoire and function of MNP subsets at diagnosis correlated with 2-year disease outcome. Results Monocytes/monocyte-derived cells were increased in blood and BAL of sarcoidosis patients compared to healthy controls. Interestingly, high frequencies of blood intermediate monocytes at time of diagnosis associated with chronic disease development. RNA sequencing analysis showed highly inflammatory MNPs in BAL of sarcoidosis patients. Furthermore, frequencies of BAL monocytes/monocyte-derived cells producing TNF without exogenous stimulation at time of diagnosis increased in patients that were followed longitudinally. In contrast to alveolar macrophages, the frequency of TNF-producing BAL monocytes/monocyte-derived cells at time of diagnosis was highest in sarcoidosis patients that developed progressive disease. Conclusion Our data show that pulmonary monocytes/monocyte-derived cells are highly inflammatory and can be used as a predictor of disease outcome in sarcoidosis patients.
Backslide or forward progress? Virtual care at U.S. healthcare systems beyond the COVID-19 pandemic
Authors: Spencer D. Dorn
Journal: npj Digital Medicine (2021)

The COVID-19 pandemic forced most U.S. healthcare systems to quickly pivot to virtual care. However, since peaking in late April, care has largely shifted back to in-person. Health systems are now challenged to further develop and integrate useful, usable, and sustainable virtual care tools into their broader care model in ways that benefit their organizations and the communities they serve.
Targeting Leukemia-Initiating Cells in Acute Lymphoblastic Leukemia
Authors: Francesco Tamiro, Andrew P. Weng, Vincenzo Giambra
Journal: Cancer Research (2021)

The concept that different leukemias are developmentally distinct and, like in normal hematopoiesis, generated by restricted populations of cells named leukemia-initiating cells (LIC), is becoming more established. These cancer stem-like cells have been assumed to have unique properties, including the capability of self-renewing and giving rise to "differentiated" or non-LICs that make up the whole tumor. Cell populations enriched with LIC activity have been characterized in different hematopoietic malignancies, including human acute lymphoblastic leukemia (ALL). Related studies have also demonstrated that LICs are functionally distinct from bulk cells and modulated by distinct molecular signaling pathways and epigenetic mechanisms. Here we review several biological and clinical aspects related to LICs in ALL, including (i) immunophenotypic characterization of LIC-enriched subsets in human and mouse models of ALL, (ii) emerging therapeutics against regulatory signaling pathways involved in LIC progression and maintenance in T- and B-cell leukemias, (iii) novel epigenetic and age-related mechanisms of LIC propagation, and (iv) ongoing efforts in immunotherapy to eradicate LIC-enriched cell subsets in relapsed and refractory ALL cases. Current conventional treatments do not efficiently eliminate LICs. Therefore, innovative therapeutics that exclusively target LICs hold great promise for developing an effective cure for ALL.
Embryo implantation in the laboratory: an update on current techniques
Authors: Samuel Ojosnegros, Anna Seriola, Amélie L Godeau, Anna Veiga
Journal: Human Reproduction Update (2020)

Abstract BACKGROUND The embryo implantation process is crucial for the correct establishment and progress of pregnancy. During implantation, the blastocyst trophectoderm cells attach to the epithelium of the endometrium, triggering intense cell-to-cell crosstalk that leads to trophoblast outgrowth, invasion of the endometrial tissue, and formation of the placenta. However, this process, which is vital for embryo and foetal development in utero, is still elusive to experimentation because of its inaccessibility. Experimental implantation is cumbersome and impractical in adult animal models and is inconceivable in humans. OBJECTIVE AND RATIONALE A number of custom experimental solutions have been proposed to recreate different stages of the implantation process in vitro, by combining a human embryo (or a human embryo surrogate) and endometrial cells (or a surrogate for the endometrial tissue). In vitro models allow rapid high-throughput interrogation of embryos and cells, and efficient screening of molecules, such as cytokines, drugs, or transcription factors, that control embryo implantation and the receptivity of the endometrium. However, the broad selection of available in vitro systems makes it complicated to decide which system best fits the needs of a specific experiment or scientific question. To orient the reader, this review will explore the experimental options proposed in the literature, and classify them into amenable categories based on the embryo/cell pairs employed. The goal is to give an overview of the tools available to study the complex process of human embryo implantation, and explain the differences between them, including the advantages and disadvantages of each system. SEARCH METHODS We performed a comprehensive review of the literature to come up with different categories that mimic the different stages of embryo implantation in vitro, ranging from initial blastocyst apposition to later stages of trophoblast invasion or gastrulation. We will also review recent breakthrough advances on stem cells and organoids, assembling embryo-like structures and endometrial tissues. OUTCOMES We highlight the most relevant systems and describe the most significant experiments. We focus on in vitro systems that have contributed to the study of human reproduction by discovering molecules that control implantation, including hormones, signalling molecules, transcription factors and cytokines. WIDER IMPLICATIONS The momentum of this field is growing thanks to the use of stem cells to build embryo-like structures and endometrial tissues, and the use of bioengineering to extend the life of embryos in culture. We propose to merge bioengineering methods derived from the fields of stem cells and reproduction to develop new systems covering a wider window of the implantation process.
Helen Salisbury: Respectful disagreement
Authors: Helen Salisbury
Journal: BMJ (2021)

All GPs will have experienced that uncomfortable feeling when they've referred a patient for an expert opinion but the response doesn't seem quite right.You wonder if important details were missing from the referral letter, or if maybe the patient became miraculously, but temporarily, better in Outpatients.Whatever the cause, it leaves you with a dilemma: do you follow the specialist's advice because this is their area of expertise (and, frankly, it's disrespectful to do otherwise), or do you contact them again for further discussion, to check