tbuckley/cabot-search huggingface dataset:
Regulation of E2F1 phosphorylation, subcellular distribution and stability in keratinocytes.
Authors: Lina Dagnino, Iordanka Ivanova
Journal: Cancer Research (2008)

101  E2F transcription factors play key roles in epidermal keratinocyte growth, differentiation and transformation. We have shown that E2F1 protein stability and subcellular localization are regulated by a Ca2+-regulated signaling cascade that triggers activation of protein kinase C δ and η, as well as p38β mitogen-activated protein kinase (MAPK). This pathway activates CRM1-mediated E2F1 nuclear export and degradation ( Oncogene 26: 1147, 2007). We further investigated the mechanism of p38β MAPK regulation of E2F1, and have determined that E2F1 forms a complex with p38β MAPK primarily in differentiated keratinocytes. In vitro kinase assays revealed that E2F1 is phosphorylated by p38β MAPK on Ser403 and Thr433. We next determined the role of E2F1 phosphorylation by assessing alterations in subcellular localization and protein stability in phosphorylation E2F1 mutants expressed in keratinocytes. Whereas wild type E2F1 exhibits a predominantly cytoplasmic distribution in differentiated keratinocytes, E2F1(S403A), E2F1(T433A) and E2F1(S403A;T433A) are retained in the nucleus. These mutants are also more stable in differentiating keratinocytes, relative to wild type E2F1. Phosphorylation of Ser403 and Thr433 may also be crucial for normal differentiation, as evidenced by the failure of differentiating keratinocytes exogenously expressing E2F1(S403A), E2F1(T433A) and E2F1(S403A;T433A) to express involucrin, a marker of differentiation in the epidermis.  In conclusion, we have identified a previously unrecognized mode of E2F1 regulation involving phosphorylation of Ser403 and Thr433 by p38β MAPK during epidermal maturation. Mutation of these residues results in E2F1 nuclear retention and increased protein stability, which appears to interfere with proper keratinocyte differentiation.
Musashi 2 influences chronic lymphocytic leukemia cell survival and growth making it a potential therapeutic target
Authors: Florencia Palacios, Xiao-Jie Yan, Gerardo Ferrer, Shih-Shih Chen, Stefano Vergani, Xuejing Yang, Jeffrey Gardner, Jaqueline C. Barrientos, Philip Rock, Richard Burack, Jonathan E. Kolitz, Steven L. Allen, Michael G. Kharas, Omar Abdel-Wahab, Kanti R. Rai, Nicholas Chiorazzi
Journal: Leukemia (2021)

Abstract Progression of chronic lymphocytic leukemia (CLL) results from the expansion of a small fraction of proliferating leukemic B cells. When comparing the global gene expression of recently divided CLL cells with that of previously divided cells, we found higher levels of genes involved in regulating gene expression. One of these was the oncogene Musashi 2 (MSI2), an RNA-binding protein that induces or represses translation. While there is an established role for MSI2 in normal and malignant stem cells, much less is known about its expression and role in CLL. Here we report for the first time ex vivo and in vitro experiments that MSI2 protein levels are higher in dividing and recently divided leukemic cells and that downregulating MSI2 expression or blocking its function eliminates primary human and murine CLL and mature myeloid cells. Notably, mature T cells and hematopoietic stem and progenitor cells are not affected. We also confirm that higher MSI2 levels correlate with poor outcome markers, shorter time-to-first-treatment, and overall survival. Thus, our data highlight an important role for MSI2 in CLL-cell survival and proliferation and associate MSI2 with poor prognosis in CLL patients. Collectively, these findings pinpoint MSI2 as a potentially valuable therapeutic target in CLL.
Effect of PEEP and Proning on Ventilation and Perfusion in COVID-19 ARDS.
Authors: François Perier, Samuel Tuffet, Tommaso Maraffi, Glasiele Alcala, Marcus Victor, Anne-Fleur Haudebourg, Nicolas De Prost, Marcelo Amato, Guillaume Carteaux, Armand Mekontso Dessap
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
A farewell to normative null hypothesis testing in base rate research
Authors: Jonathan J. Koehler
Journal: Behavioral and Brain Sciences (1997)

I agree with Gibbs that the message of the base rate literature reads differently depending on which null hypothesis is used to frame the issue. But I argue that the normative null hypothesis, H 0 : “People use base rates in a Bayesian manner,” is no longer appropriate. I also challenge Adler 's distinction between unused and ignored base rates, and criticize Goodie 's reluctance to shift research attention to the field. Macchi 's arguments about textual ambiguities in traditional base rate problems suggest that empirical testing is needed to tease apart the effects of problem clarification and problem framing. Macdonald 's, Fletcher 's and Snow 's skepticism about the value of Bayesian methods in real world judgment tasks is treated as a challenge for the next generation of empirical base rate studies.
FRI0178 Followup of platelet activation in a patient with antiphospholipid syndrome upon tirofiban treatment
Authors: A Perniok, A Messis, C Specker, M Siebler, M Schneider
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Patients with primary or secondary antiphospholipid syndrome (APS) often suffer from stroke leading to high degree of disability. Though it is well known that phospholipid antibodies induce a procoagulatory scenario, antibody status does not well characterise patients at risk. Using transcranial Doppler ultrasound of intracerebral arteries we could detect microembolic signals correlating well with phospholipid antibody titer as well as with history of stroke. In these patients we could also demonstrate elevated levels of platelet activation markers (p-selectin) as well as increased platelet leukocyte aggregation. Tirofiban is a potent, highly selective and reversible inhibitor of platelet gpIIb/IIIa receptor which binds fibrinogen on platelet surface. <h3>Objectives</h3> We treated a patient with primary APS and refractory transitory ischaemic attacks with tirofiban and detected microembolic signals as well as platelet activation markers and platelet-leukocyte aggregations (PLA). <h3>Methods</h3> In fresh venous citrate-anticoagulated whole blood expression of gp Ib (CD41), gp IIb/IIIa (CD42b), fibrinogen binding and p-selectin (CD62p) was analysed using a flowcytometric double staining method. In parallel we detected PLA by determining percentage of platelet marker/leukocyte marker (CD42b/CD45) double posi-tive leukocytes. <h3>Results</h3> Upon Tirofiban treatment we found a reduction of platelet activation markers (p-selectin, fibrinogen binding, CD63). Under steady state conditions with tirofiban expression of platelet activation markers and platelet leukocyte interaction normalised completely compared to normal healthy donors. The morning after each infusion there was a rebound phenomenon, which could also be observed in platelet activation markers and PLA. This rebound phenomenon could be reproduced upon sequential administration of tirofiban in parallel with rate of microembolic events. <h3>Conclusion</h3> In a patient with primary APS therapeutic intervention with tirofiban, a reversible inhibitor of platelet gpIIb/IIIa receptor, induced a clinical improvement of transitory ischaemic attacks. In parallel with clinical improvement there was a modulation of microembolic signals as well as platelet activation markers and PLA. Flowcytometric measurement of platelet activation can be a useful tool in monitoring platelet hyperreactivity in APS upon therapeutic intervention.
Changes in the epidemiology and management of bacterial infections in cirrhosis
Authors: Salvatore Piano, Marta Tonon, Paolo Angeli
Journal: Clinical and Molecular Hepatology (2021)

Patients with cirrhosis are susceptible to develop infections because of immune dysfunction, changes in microbiome and increase in bacterial translocation from the gut to systemic circulation. Bacterial infections can worse the clinical course of the disease, triggering the development of complications such as acute kidney injury, hepatic encephalopathy, organ failures and acute on chronic liver failure. In recent years, the spread of multi drug resistant bacteria made more challenging the management of infections in patients with cirrhosis. Hence, the mortality rate associated to sepsis is increasing in these patients. Therefore, the optimization of the management of infections has a high priority in cirrhosis. Herein we reviewed the recent changes in the epidemiology and the management of bacterial infections in patients with liver cirrhosis.
Effects of Vitamin C Supplementation on Glycemic Control and Cardiovascular Risk Factors in People With Type 2 Diabetes: A GRADE-Assessed Systematic Review and Meta-analysis of Randomized Controlled Trials
Authors: Shaun A. Mason, Michelle A. Keske, Glenn D. Wadley
Journal: Diabetes Care (2021)

BACKGROUND Evidence suggests that vitamin C supplementation could be a potential therapy in type 2 diabetes. However, its effectiveness and evidence quality require further evaluation. PURPOSE To investigate the efficacy of oral vitamin C supplementation in improving glycemic control, cardiovascular risk factors, and oxidative stress in people with type 2 diabetes. DATA SOURCES Databases (PubMed, Embase, Scopus, Cochrane Library) and clinical trial registries were searched for randomized controlled trials up to 8 September 2020. STUDY SELECTION Trials in adults with type 2 diabetes were included. Trials were excluded if supplements were not exclusive to vitamin C and if &amp;lt;2 weeks in duration. DATA EXTRACTION Primary outcomes were HbA1c, glucose, cholesterol, triglycerides, and blood pressure (BP). Data were extracted for changes in outcomes between vitamin C and control groups. Evidence certainty was assessed using Grading of Recommendations, Assessment, Development, and Evaluation methods. DATA SYNTHESIS Twenty-eight studies (N = 1,574 participants) were included in the review. Outcomes that changed to a statistically and clinically significant extent with vitamin C were systolic BP (mean difference −6.27 [95% CI −9.60, −2.96] mmHg; P = 0.0002), with moderate evidence certainty, and HbA1c (−0.54% [−0.90, −0.17]; P = 0.004) and diastolic BP (−3.77 [−6.13, −1.42] mmHg; P = 0.002) with very low evidence certainty. LIMITATIONS Studies were predominantly short term (&amp;lt;6 months) with a small number of participants (n &amp;lt; 100). CONCLUSIONS While evidence from short-term studies suggests that vitamin C supplementation may improve glycemic control and BP in people with type 2 diabetes, vitamin C supplementation cannot currently be recommended as a therapy until larger, long-term, and high-quality trials confirm these findings.
Risk of Hematologic Malignant Neoplasms From Abdominopelvic Computed Tomographic Radiation in Patients Who Underwent Appendectomy
Authors: Kyung Hee Lee, Seungjae Lee, Ji Hoon Park, Sung Soo Lee, Hae Young Kim, Won Jin Lee, Eun Shil Cha, Kwang Pyo Kim, Woojoo Lee, Ji Yun Lee, Kyoung Ho Lee
Journal: JAMA Surgery (2021)

Whether computed tomography (CT) radiation is truly carcinogenic remains controversial. Large epidemiological studies that purportedly showed an association between CT radiation and carcinogenesis were limited by confounding by indication and reverse causation, because the reasons for CT examination were unknown.To measure the risk of hematologic malignant neoplasms associated with perioperative abdominopelvic CT radiation among patients who underwent appendectomy for acute appendicitis.This nationwide population-based cohort study used the National Health Insurance Service claims database in South Korea to assess 825 820 patients who underwent appendectomy for appendicitis from January 1, 2005, to December 31, 2015, and had no underlying risk factors for cancer. Patients were divided into CT-exposed (n = 306 727) or CT-unexposed (n = 519 093) groups. The study was terminated on December 31, 2017, and data were analyzed from October 30, 2018, to September 27, 2020.Perioperative abdominopelvic CT examination from 7 days before to 7 days after appendectomy.The primary outcome was the incidence rate ratio (IRR) of hematologic malignant neoplasms for both groups. The secondary outcomes were IRR of abdominopelvic organ cancers and IRR of all cancers. The lag period was 2 years for the primary outcome and 5 years for secondary outcomes. The IRRs were calculated using Poisson regression models with adjustment for age and sex.Among the study population of 825 820 patients (52.9% male; median age, 28 [interquartile range, 15-41] years), hematologic malignant neoplasms developed in 323 patients in the CT-exposed group during 1 486 518 person-years and 500 patients in the CT-unexposed group during 3 422 059 person-years. For all hematologic malignant neoplasms, the IRR for the CT-exposed vs CT-unexposed group was 1.26 (95% CI, 1.09-1.45; P = .002). In terms of individual categories of hematologic malignant neoplasms, the CT-exposed group had an elevated risk only for leukemia (IRR, 1.40 [98.75% CI, 1.04-1.87, adjusted by Bonferroni correction]; P = .005). There was no between-group difference in incidence rate of abdominopelvic organ cancers (IRR, 1.07 [95% CI, 1.00-1.15]; P = .06) and that of all cancers (IRR, 1.04 [95% CI, 0.99-1.09]; P = .14).This study controlled for reverse causation bias by defining the reasons for CT scan, and findings suggest that abdominopelvic CT radiation is associated with a higher incidence of hematologic malignant neoplasms. Efforts should be continued for judicious use of CT examinations.
The cortical origin and initial spread of medial temporal tauopathy in Alzheimer’s disease assessed with positron emission tomography
Authors: Justin S. Sanchez, J. Alex Becker, Heidi I. L. Jacobs, Bernard J. Hanseeuw, Shu Jiang, Aaron P. Schultz, Michael J. Properzi, Samantha R. Katz, Alexa Beiser, Claudia L. Satizabal, Adrienne O’Donnell, Charles DeCarli, Ron Killiany, Georges El Fakhri, Marc D. Normandin, Teresa Gómez-Isla, Yakeel T. Quiroz, Dorene M. Rentz, Reisa A. Sperling, Sudha Seshadri, Jean Augustinack, Julie C. Price, Keith A. Johnson
Journal: Science Translational Medicine (2021)

Advances in molecular positron emission tomography (PET) have enabled anatomic tracking of brain pathology in longitudinal studies of normal aging and dementia, including assessment of the central model of Alzheimer's disease (AD) pathogenesis, according to which TAU pathology begins focally but expands catastrophically under the influence of amyloid-β (Aβ) pathology to mediate neurodegeneration and cognitive decline. Initial TAU deposition occurs many years before Aβ in a specific area of the medial temporal lobe. Building on recent work that enabled focus of molecular PET measurements on specific TAU-vulnerable convolutional temporal lobe anatomy, we applied an automated anatomic sampling method to quantify TAU PET signal in 443 adult participants from several observational studies of aging and AD, spanning a wide range of ages, Aβ burdens, and degrees of clinical impairment. We detected initial cortical emergence of tauopathy near the rhinal sulcus in clinically normal people and, in a subset with longitudinal 2-year follow-up data (n = 104), tracked Aβ-associated spread of TAU from this site first to nearby neocortex of the temporal lobe and then to extratemporal regions. Greater rate of TAU spread was associated with baseline measures of both global Aβ burden and medial temporal lobe TAU. These findings are consistent with clinicopathological correlation studies of Alzheimer's tauopathy and enable precise tracking of AD-related TAU progression for natural history studies and prevention therapeutic trials.
Infection and transmission of SARS-CoV-2 in London care homes reporting no cases or outbreaks of COVID-19: Prospective observational cohort study, England 2020
Authors: Anna Jeffery-Smith, Kate Dun-Campbell, Roshni Janarthanan, Jonathan Fok, Emma Crawley-Boevey, Amoolya Vusirikala, Elena Fernandez Ruiz De Olano, Marina Sanchez Perez, Suzanne Tang, Thomas AJ Rowland, Edward Wynne-Evans, Anita Bell, Bharat Patel, Zahin Amin-Chowdhury, Felicity Aiano, Karthik Paranthaman, Thomas Ma, Maria Saavedra-Campos, Joanna Ellis, Angie Lackenby, Heather Whitaker, Richard Myers, Katja Höschler, Kevin Brown, Mary E Ramsay, Nandini Shetty, J. Yimmy Chow, Shamez Ladhani, Maria Zambon
Journal: The Lancet Regional Health - Europe (2021)
Normal and defective pathways in biogenesis and maintenance of the insulin storage pool
Authors: Ming Liu, Yumeng Huang, Xiaoxi Xu, Xin Li, Maroof Alam, Anoop Arunagiri, Leena Haataja, Li Ding, Shusen Wang, Pamela Itkin-Ansari, Randal J. Kaufman, Billy Tsai, Ling Qi, Peter Arvan
Journal: Journal of Clinical Investigation (2021)

Both basal and glucose-stimulated insulin release occur primarily by insulin secretory granule exocytosis from pancreatic β cells, and both are needed to maintain normoglycemia. Loss of insulin-secreting β cells, accompanied by abnormal glucose tolerance, may involve simple exhaustion of insulin reserves (which, by immunostaining, appears as a loss of β cell identity), or β cell dedifferentiation, or β cell death. While various sensing and signaling defects can result in diminished insulin secretion, somewhat less attention has been paid to diabetes risk caused by insufficiency in the biosynthetic generation and maintenance of the total insulin granule storage pool. This Review offers an overview of insulin biosynthesis, beginning with the preproinsulin mRNA (translation and translocation into the ER), proinsulin folding and export from the ER, and delivery via the Golgi complex to secretory granules for conversion to insulin and ultimate hormone storage. All of these steps are needed for generation and maintenance of the total insulin granule pool, and defects in any of these steps may, weakly or strongly, perturb glycemic control. The foregoing considerations have obvious potential relevance to the pathogenesis of type 2 diabetes and some forms of monogenic diabetes; conceivably, several of these concepts might also have implications for β cell failure in type 1 diabetes.
Microthrombi as a Major Cause of Cardiac Injury in COVID-19
Authors: Dario Pellegrini, Rika Kawakami, Giulio Guagliumi, Atsushi Sakamoto, Kenji Kawai, Andrea Gianatti, Ahmed Nasr, Robert Kutys, Liang Guo, Anne Cornelissen, Lara Faggi, Masayuki Mori, Yu Sato, Irene Pescetelli, Matteo Brivio, Maria Romero, Renu Virmani, Aloke V. Finn
Journal: Circulation (2021)

Background: Cardiac injury is common in patients who are hospitalized with coronavirus disease 2019 (COVID-19) and portends poorer prognosis. However, the mechanism and the type of myocardial damage associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain uncertain. Methods: We conducted a systematic pathological analysis of 40 hearts from hospitalized patients dying of COVID-19 in Bergamo, Italy, to determine the pathological mechanisms of cardiac injury. We divided the hearts according to presence or absence of acute myocyte necrosis and then determined the underlying mechanisms of cardiac injury. Results: Of the 40 hearts examined, 14 (35%) had evidence of myocyte necrosis, predominantly of the left ventricle. Compared with subjects without necrosis, subjects with necrosis tended to be female, have chronic kidney disease, and have shorter symptom onset to admission. The incidence of severe coronary artery disease (ie, &gt;75% cross-sectional narrowing) was not significantly different between those with and without necrosis. Three of 14 (21.4%) subjects with myocyte necrosis showed evidence of acute myocardial infarction, defined as ≥1 cm 2 area of necrosis, whereas 11 of 14 (78.6%) showed evidence of focal (&gt;20 necrotic myocytes with an area of ≥0.05 mm 2 but &lt;1 cm 2 ) myocyte necrosis. Cardiac thrombi were present in 11 of 14 (78.6%) cases with necrosis, with 2 of 14 (14.2%) having epicardial coronary artery thrombi, whereas 9 of 14 (64.3%) had microthrombi in myocardial capillaries, arterioles, and small muscular arteries. We compared cardiac microthrombi from COVID-19–positive autopsy cases to intramyocardial thromboemboli from COVID-19 cases as well as to aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19–infected patients presenting with ST-segment–elevation myocardial infarction. Microthrombi had significantly greater fibrin and terminal complement C5b-9 immunostaining compared with intramyocardial thromboemboli from COVID-19–negative subjects and with aspirated thrombi. There were no significant differences between the constituents of thrombi aspirated from COVID-19–positive and –negative patients with ST-segment–elevation myocardial infarction. Conclusions: The most common pathological cause of myocyte necrosis was microthrombi. Microthrombi were different in composition from intramyocardial thromboemboli from COVID-19–negative subjects and from coronary thrombi retrieved from COVID-19–positive and –negative patients with ST-segment–elevation myocardial infarction. Tailored antithrombotic strategies may be useful to counteract the cardiac effects of COVID-19 infection.
Digital health during COVID-19: lessons from operationalising new models of care in ophthalmology
Authors: Dinesh V Gunasekeran, Yih-Chung Tham, Daniel S W Ting, Gavin S W Tan, Tien Y Wong
Journal: The Lancet Digital Health (2021)

The COVID-19 pandemic has resulted in massive disruptions within health care, both directly as a result of the infectious disease outbreak, and indirectly because of public health measures to mitigate against transmission. This disruption has caused rapid dynamic fluctuations in demand, capacity, and even contextual aspects of health care. Therefore, the traditional face-to-face patient–physician care model has had to be re-examined in many countries, with digital technology and new models of care being rapidly deployed to meet the various challenges of the pandemic. This Viewpoint highlights new models in ophthalmology that have adapted to incorporate digital health solutions such as telehealth, artificial intelligence decision support for triaging and clinical care, and home monitoring. These models can be operationalised for different clinical applications based on the technology, clinical need, demand from patients, and manpower availability, ranging from out-of-hospital models including the hub-and-spoke pre-hospital model, to front-line models such as the inflow funnel model and monitoring models such as the so-called lighthouse model for provider-led monitoring. Lessons learnt from operationalising these models for ophthalmology in the context of COVID-19 are discussed, along with their relevance for other specialty domains.
A novel approach to the basophil activation test for characterizing peanut allergic patients in the clinical setting
Authors: Amanda Agyemang, Maria Suprun, Mayte Suárez‐Fariñas, Faouria Boina, Rihane Arif‐Lusson, Alexander Grishin, Jean‐Marc Busnel, Hugh A. Sampson
Journal: Allergy (2021)

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