tbuckley/cabot-search huggingface dataset:
Variability in the expression of a β2-microglobulin epitope on hepatocytes in chronic type C hepatitis on treatment with interferon
Authors: L García-Buey
Journal: Hepatology (1993)

Cytotoxic CD8+ T lymphocytes recognize viral antigens in the context of human leukocyte antigen class I molecule coexpression by target cells. Analysis of β2-microglobulin reactivity is useful in evaluating changes in human leukocyte antigen class I antigen distribution. In this study we analyzed liver biopsy specimens obtained from 15 patients with chronic active hepatitis type C who underwent a clinical trial with recombinant interferon-α2b. We comparatively studied by immunohistochemical analysis the expression of human leukocyte antigen class I antigens in frozen liver samples obtained before entry in the protocol and in specimens taken 8 mo after initiation of treatment. Six normal liver samples were used as controls. For immunohistochemical analysis, a panel of several human leukocyte antigen class I monoclonal antibodies, specific for β2-microglobulin or different heavy-chain determinants, was used. In addition, we included a novel monoclonal antibody (HP-1H8), characterized in this report, which is specific for a distinct β2-microglobulin epitope. On entry, mean serum ALT was 240 ± 89 IU/L and mean Knodell's index was 9.9 ± 2.4, whereas at the time of the second biopsy mean values had diminished to 45 ± 22 IU/L and 4.7 ± 3.0, respectively. Liver sections from controls and patients expressed human leukocyte antigen class I light- and heavy-chain determinants in hepatocytes, biliary duct epithelium, sinusoidal lining cells and lymphocytes. Remarkably, the β2-microglobulin epitope recognized by the HP-1H8 monoclonal antibody was undetectable on hepatocytes from normal livers but clearly evident on hepatocytes from patients with chronic active hepatitis C before interferon treatment. Positive staining was more intense in areas of piecemeal and lobular necrosis. Double immunostaining with a CD2 monoclonal antibody demonstrated that labeling with HP-1H8 was predominantly associated with T-cell infiltration. Interestingly, the reactivity of HP-1H8 with hepatocytes was diminished or disappeared in specimens obtained during interferon treatment; the pattern of reactivity then resembled that of samples from normal controls. Our data indirectly suggest that, in addition to the increased expression of human leukocyte antigen class I molecules on hepatocytes in viral infections, conformational changes may take place in these antigens. These changes can be revealed by immunostaining with the HP-1H8 monoclonal antibody. Interferon therapy could down-regulate this expression through its effect in reducing the histological activity resulting from the lysis of virus-infected hepatocytes by cytotoxic T cells. (HEPATOLOGY 1993;17:372–382.)
P14.45 The incidence of major subtypes of primary brain tumours in adults in England 1995–2017
Authors: H Wanis
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Primary brain tumours are a complex heterogenous group of benign and malignant tumours. Reports on their occurrence in the English population by sex, age, and morphological subtype and on their incidence are currently not available. Using data from the National Cancer Registration and Analysis Service (NCRAS), the incidence of adult primary brain tumour by major subtypes in England will be described. METHODS Data on all adult English patients diagnosed with primary brain tumour between 1995 and 2017, excluding spinal, endocrinal and other CNS tumours, were extracted from NCRAS. Incidence rates were standardised to the 2013 European Standard Population. Results are presented by sex, age, and morphological subtype. RESULTS Between 1995 and 2017, a total of 133,669 cases of adult primary brain tumour were registered in England. Glioblastoma was the most frequent tumour subtype (31.8%), followed by meningioma (27.3%). The age-standardised incidence for glioblastoma increased from 3.27 per 100,000 population per year in 1995 to 7.34 in men in 2013 and from 2.00 to 4.45 in women. Meningioma incidence also increased from 1.89 to 3.41 per 100,000 in men and from 3.40 to 7.46 in women. The incidence of other astrocytic and unclassified brain tumours declined between 1995 and 2007 and remained stable thereafter. CONCLUSION Part of the increase in the incidence of major subtypes of brain tumours in England could be explained by advances in clinical practice including the adoption of new diagnostic tools, classifications and molecular testing, and improved cancer registration practices.
Continuous Glucose Monitoring in Adults With Type 1 Diabetes With 35 Years Duration From the DCCT/EDIC Study
Authors: Rose A. Gubitosi-Klug, Barbara H. Braffett, Ionut Bebu, Mary L. Johnson, Kaleigh Farrell, David Kenny, Victoria R. Trapani, Lynne Meadema-Mayer, Elsayed Z. Soliman, Rodica Pop-Busui, John M. Lachin, Richard M. Bergenstal, William V. Tamborlane
Journal: Diabetes Care (2022)

We evaluated blinded continuous glucose monitoring (CGM) profiles in a subset of adults with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study to characterize the frequency of glycemic excursions and contributing factors.CGM-derived metrics were compared for daytime and nighttime periods using blinded CGM for a minimum of 6.5 days (average 11.9 days) and correlated with HbA1c levels, routine use of diabetes devices, and other characteristics in 765 participants.Participants were 58.9 ± 6.5 years of age with diabetes duration 36.8 ± 4.9 years and HbA1c 7.8 ± 1.2%; 58% used insulin pumps, and 27% used personal, unblinded CGM. Compared with daytime, nighttime mean sensor glucose was lower, percent time in range 70-180 mg/dL (TIR) was similar, and hypoglycemia was more common. Over the entire recording period, only 9% of the 765 participants achieved >70% TIR and only 28% achieved <1% of observations of <54 mg/dL. Indeed, participants with the highest percentage of hypoglycemia had the lowest HbA1c levels. However, use of insulin pumps and CGM decreased the percent time at <54 mg/dL.In adults with long-standing type 1 diabetes, short-term blinded CGM profiles revealed frequent clinically significant hypoglycemia (<54 mg/dL) during the night and more time in hyperglycemia during the day. The small subset of participants using routine CGM and insulin pumps had fewer hypoglycemic and hyperglycemic excursions and lower HbA1c levels. Thus, strategies to lower meal-stimulated hyperglycemia during the day and prevent hypoglycemia at night are relevant clinical goals in older patients with type 1 diabetes.
Targeting pancreatic cancer by TAK-981: a SUMOylation inhibitor that activates the immune system and blocks cancer cell cycle progression in a preclinical model
Authors: Sumit Kumar, Mark J A Schoonderwoerd, Jessie S Kroonen, Ilona J de Graaf, Marjolein Sluijter, Dina Ruano, Román González-Prieto, Matty Verlaan-de Vries, Jasper Rip, Ramon Arens, Noel F C C de Miranda, Lukas J A C Hawinkels, Thorbald van Hall, Alfred C O Vertegaal
Journal: Gut (2022)

Pancreatic ductal adenocarcinoma (PDAC) has the characteristics of high-density desmoplastic stroma, a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemotherapy and immunotherapy, leading to a 5-year survival rate of 9%. Our study aims to add novel small molecule therapeutics for the treatment of PDAC.We have studied whether TAK-981, a novel highly selective and potent small molecule inhibitor of the small ubiquitin like modifier (SUMO) activating enzyme E1 could be used to treat a preclinical syngeneic PDAC mouse model and we have studied the mode of action of TAK-981.We found that SUMOylation, a reversible post-translational modification required for cell cycle progression, is increased in PDAC patient samples compared with normal pancreatic tissue. TAK-981 decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. TAK-981 efficiently limited tumour burden in the KPC3 syngeneic mouse model without evidence of systemic toxicity. In vivo treatment with TAK-981 enhanced the proportions of activated CD8 T cells and natural killer (NK) cells but transiently decreased B cell numbers in tumour, peripheral blood, spleen and lymph nodes. Single cell RNA sequencing revealed activation of the interferon response on TAK-981 treatment in lymphocytes including T, B and NK cells. TAK-981 treatment of CD8 T cells ex vivo induced activation of STAT1 and interferon target genes.Our findings indicate that pharmacological inhibition of the SUMO pathway represents a potential strategy to target PDAC via a dual mechanism: inhibiting cancer cell cycle progression and activating anti-tumour immunity by inducing interferon signalling.
Prostate cancer specific mortality in the ERSPC trial: What is the role of screening result and adherence
Authors: C. Wetterauer, S. Remmers, J. Hugosson, T. Tammela, M. Zappa, V. Nelen, M. Lujan, L.J. Denis, A. Paez, D. Puliti, V. Arnaud, X. Rebillard, R. Ansrud Godtman, C. Bangma, F.H. Schröder, A. Auvinen, L. Manka, L.W. Prause, H.H. Seifert, S.F. Wyler, M.J. Roobol, M. Kwiatkowski
Journal: European Urology (2021)
SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response
Authors: Shunya Tsuji, Shohei Minami, Rina Hashimoto, Yusuke Konishi, Tatsuya Suzuki, Tamae Kondo, Miwa Sasai, Shiho Torii, Chikako Ono, Shintaro Shichinohe, Shintaro Sato, Masahiro Wakita, Shintaro Okumura, Sosuke Nakano, Tatsuyuki Matsudaira, Tomonori Matsumoto, Shimpei Kawamoto, Masahiro Yamamoto, Tokiko Watanabe, Yoshiharu Matsuura, Kazuo Takayama, Takeshi Kobayashi, Toru Okamoto, Eiji Hara
Journal: Nature Aging (2022)

Abstract Reports of post-acute COVID-19 syndrome, in which the inflammatory response persists even after SARS-CoV-2 has disappeared, are increasing 1 , but the underlying mechanisms of post-acute COVID-19 syndrome remain unknown. Here, we show that SARS-CoV-2-infected cells trigger senescence-like cell-cycle arrest 2,3 in neighboring uninfected cells in a paracrine manner via virus-induced cytokine production. In cultured human cells or bronchial organoids, these SASR-CoV-2 infection-induced senescent cells express high levels of a series of inflammatory factors known as senescence-associated secretory phenotypes (SASPs) 4 in a sustained manner, even after SARS-CoV-2 is no longer detectable. We also show that the expression of the senescence marker CDKN2A (refs. 5,6 ) and various SASP factor 4 genes is increased in the pulmonary cells of patients with severe post-acute COVID-19 syndrome. Furthermore, we find that mice exposed to a mouse-adapted strain of SARS-CoV-2 exhibit prolonged signs of cellular senescence and SASP in the lung at 14 days after infection when the virus was undetectable, which could be substantially reduced by the administration of senolytic drugs 7 . The sustained infection-induced paracrine senescence described here may be involved in the long-term inflammation caused by SARS-CoV-2 infection.
Comorbidity Burden and Use of Concomitant Medications at CML Diagnosis: A Retrospective Analysis of 470 Patients from the Polish Adult Leukemia Group (PALG) Registry
Authors: Joanna Gora-Tybor, Tomasz Sacha, Joanna Waclaw, Joanna Niesiobedzka, Olga Grzybowska-Izydorczyk, Ewa Medras, Izabela Deren-Wagemann, Elzbieta Patkowska, Ilona Seferynska, Krzysztof Lewandowski, Anna Wache, Beata Blajer-Olszewska, Marzena Watek, Krzysztof Warzocha, Krzysztof Jamroziak
Journal: Blood (2016)
Letter to the editor: Circulating thrombospondin‐2 as a biomarker in patients with NAFLD with and without diabetes—Are we convinced yet?
Authors: Chi Ho Lee, David T. W. Lui, Karen S. L. Lam
Journal: Hepatology (2022)

To the editor, We read with interest the study by Kozumi et al. which demonstrated, using hepatic transcriptome profiling of liver tissues from patients with NAFLD, that the thrombospondin‐2 (TSP2) gene was most significantly up‐regulated in NASH and that its expression exhibited a stepwise increase along with fibrosis severity.[1] The authors highlighted the utility of circulating TSP2 as a noninvasive diagnostic biomarker of NASH and advanced fibrosis (AF) on histology. Notably, while most patients with NAFLD do not progress, type 2 diabetes (T2D) doubles the risk of developing advanced liver disease in NAFLD.[2] Therefore, there is a more pressing need for prognostic biomarkers in patients with T2D and fatty liver, especially when hepatic steatosis is highly prevalent in T2D. Interestingly, our group recently also reported significant associations between circulating TSP2 and the presence of AF in 820 exclusive patients with T2D and NAFLD using vibration‐controlled transient elastography (VCTE). More importantly, our prospective analysis found that the baseline circulating TSP2 level was independently associated with incident AF.[3] However, in contrast to the study by Kozumi et al., which found comparable performance between circulating TSP2 and conventional noninvasive fibrosis scores including the NAFLD fibrosis score (NFS) and Fibrosis‐4 (FIB‐4) index, we demonstrated significant superiority of circulating TSP2 over NFS and FIB‐4 in identifying AF among patients with T2D. Although the two studies differ in the methods of fibrosis assessment, VCTE is accurate in detecting histological fibrosis. Rather, it might be related to the suboptimal performance of these conventional fibrosis scores in T2D, as reported.[4] Moreover, the higher tissue TSP2 expression previously observed in T2D could have possibly led to its better discriminatory ability for AF in patients with T2D.[5] A subgroup analysis with participants stratified by T2D in the study by Kozumi et al. would be helpful to address this question. Nonetheless, we found that the two studies complement each other and have provided convincing evidence that circulating TSP2 is a clinically useful fibrosis biomarker in NAFLD. However, because most cases of HCC in Southeast Asia are related to viral hepatitis, further studies from Western populations are required to clarify the role of TSP2 in NAFLD‐related HCC. CONFLICT OF INTEREST Dr. Lam is an advisory board member of Merck Sharp and Dohme. Dr. Lee received speaker's fees from AstraZeneca, Bayer, and Sanofi Aventis. The remaining author has no conflict of interests.
How do dermatologists’ personal models inform a patient‐centred approach to management: a qualitative study using the example of prescribing a new treatment (Apremilast)*
Authors: Rachael M. Hewitt, Chris Bundy, Antonia‐Luise Newi, Evangelos Chachos, Rachel Sommer, C. Elise Kleyn, Matthias Augustin, Christopher E.M. Griffiths, Christine Blome
Journal: British Journal of Dermatology (2022)

The quality of dermatology consultations is partly determined by how clinicians approach patient care. The term 'Personal Models' describes the explanatory frameworks of thoughts, feelings and experiences that drive behaviour. One study found that clinicians' personal models, specifically their beliefs about autonomy and patient self-management, influenced the degree to which clinicians engage patients in shared decision making during consultations. Further research is needed to further explore how clinicians' personal models inform and affect the quality of patient care.
Connecting nutritional deprivation and pubertal inhibition via GRK2-mediated repression of kisspeptin actions in GnRH neurons
Authors: Cecilia Perdices-Lopez, María S Avendaño, Alexia Barroso, Francisco Gaytán, Francisco Ruiz-Pino, Maria J Vázquez, Silvia Leon, Yong Bhum Song, Veronica Sobrino, Violeta Heras, Antonio Romero-Ruiz, Juan Roa, Federico Mayor, Cristina Murga, Leonor Pinilla, Ursula B Kaiser, Manuel Tena-Sempere
Journal: Metabolism (2022)
Insights on the mutational landscape of the SARS-CoV-2 Omicron variant receptor-binding domain
Authors: Nathaniel L. Miller, Thomas Clark, Rahul Raman, Ram Sasisekharan
Journal: Cell Reports Medicine (2022)

The Omicron variant features enhanced transmissibility and antibody escape. Here, we describe the Omicron receptor-binding domain (RBD) mutational landscape using amino acid interaction (AAI) networks, which are well suited for interrogating constellations of mutations that function in an epistatic manner. Using AAI, we map Omicron mutations directly and indirectly driving increased escape breadth and depth in class 1-4 antibody epitopes. Further, we present epitope networks for authorized therapeutic antibodies and assess perturbations to each antibody's epitope. Since our initial modeling following the identification of Omicron, these predictions have been realized by experimental findings of Omicron neutralization escape from therapeutic antibodies ADG20, AZD8895, and AZD1061. Importantly, the AAI predicted escape resulting from indirect epitope perturbations was not captured by previous sequence or point mutation analyses. Finally, for several Omicron RBD mutations, we find evidence for a plausible role in enhanced transmissibility via disruption of RBD-down conformational stability at the RBDdown-RBDdown interface.
Holmium laser enucleation of the prostate with virtual basket tool: Faster and better control on bleeding
Authors: M. Maltagliati, L. Berti, U. Besana, A. Calori, C. Buizza, L. Rivolta, C. Gastaldi, G. Autieri, M.C. Sighinolfi, S. Micali, B. Rocco, G. Bozzini
Journal: European Urology (2021)
TCTAP A-011 Comparison of Timing of Non-culprit Lesion Percutaneous Coronary Intervention in Myocardial Infarction Patients
Authors: Hyung Oh Kim, Weon Kim, Soo-Joong Kim, Jong Shin Woo, Hyemoon Chung, Jae Min Kim
Journal: Journal of the American College of Cardiology (2017)
Vulnerability to acid reflux of the airway epithelium in severe asthma
Authors: Jeanne-Marie Perotin, Gabrielle Wheway, Kamran Tariq, Adnan Azim, Robert A. Ridley, Jonathan A. Ward, James P.R. Schofield, Clair Barber, Peter Howarth, Donna E. Davies, Ratko Djukanovic
Journal: European Respiratory Journal (2022)

Background Severe asthma is associated with multiple comorbidities, including gastro-oesophageal reflux disease (GORD), which can contribute to exacerbation frequency and poor quality of life. Since epithelial dysfunction is an important feature in asthma, we hypothesised that in severe asthma the bronchial epithelium is more susceptible to the effects of acid reflux. Methods We developed an in vitro model of GORD using differentiated bronchial epithelial cells (BECs) from normal or severe asthmatic donors exposed to a combination of pepsin, acid pH and bile acids using a multiple challenge protocol (MCP-PAB). In addition, we analysed bronchial biopsies and undertook RNA sequencing of bronchial brushings from controls and severe asthmatics without or with GORD. Results Exposure of BECs to the MCP-PAB caused structural disruption, increased permeability, interleukin (IL)-33 expression, inflammatory mediator release and changes in gene expression for multiple biological processes. Cultures from severe asthmatics were significantly more affected than those from healthy donors. Analysis of bronchial biopsies confirmed increased IL-33 expression in severe asthmatics with GORD. RNA sequencing of bronchial brushings from this group identified 15 of the top 37 dysregulated genes found in MCP-PAB treated BECs, including genes involved in oxidative stress responses. Conclusions and clinical implication By affecting epithelial permeability, GORD may increase exposure of the airway submucosa to allergens and pathogens, resulting in increased risk of inflammation and exacerbations. These results suggest the need for research into alternative therapeutic management of GORD in severe asthma.
Cost-effectiveness of Physical Therapy vs Intra-articular Glucocorticoid Injection for Knee Osteoarthritis
Authors: Daniel I. Rhon, Minchul Kim, Carl V. Asche, Stephen C. Allison, Chris S. Allen, Gail D. Deyle
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Physical therapy and glucocorticoid injections are initial treatment options for knee osteoarthritis, but available data indicate that most patients receive one or the other, suggesting they may be competing interventions. The initial cost difference for treatment can be substantial, with physical therapy often being more expensive at the outset, and cost-effectiveness analysis can aid patients and clinicians in making decisions. <h3>Objective</h3> To investigate the incremental cost-effectiveness between physical therapy and intra-articular glucocorticoid injection as initial treatment strategies for knee osteoarthritis. <h3>Design, Setting, and Participants</h3> This economic evaluation is a secondary analysis of a randomized clinical trial performed from October 1, 2012, to May 4, 2017. Health economists were blinded to study outcomes and treatment allocation. A randomized sample of patients seen in primary care and physical therapy clinics with a radiographically confirmed diagnosis of knee osteoarthritis were evaluated from the clinical trial with 96.2% follow-up at 1 year. <h3>Interventions</h3> Physical therapy or glucocorticoid injection <h3>Main Outcomes and Measures</h3> The main outcome was incremental cost-effectiveness between 2 alternative treatments. Acceptability curves of bootstrapped incremental cost-effectiveness ratios (ICERs) were used to identify the proportion of ICERs under the specific willingness-to-pay level ($50 000-$100 000). Health care system costs (total and knee related) and health-related quality-of-life based on quality-adjusted life-years (QALYs) were obtained. <h3>Results</h3> A total of 156 participants (mean [SD] age, 56.1 [8.7] years; 81 [51.9%] male) were randomized 1:1 and followed up for 1 year. Mean (SD) 1-year knee-related medical costs were $2113 ($4224) in the glucocorticoid injection group and $2131 ($1015) in the physical therapy group. The mean difference in QALY significantly favored physical therapy at 1 year (0.076; 95% CI, 0.02-0.126;<i>P</i> = .003). Physical therapy was the more cost-effective intervention, with an ICER of $8103 for knee-related medical costs, with a 99.2% probability that results fall below the willingness-to-pay threshold of $100 000. <h3>Conclusions and Relevance</h3> A course of physical therapy was cost-effective compared with a course of glucocorticoid injections for patients with knee osteoarthritis. These results suggest that, although the initial cost of delivering physical therapy may be higher than an initial course of glucocorticoid injections, 1-year total knee-related costs are equivalent, and greater improvement in QALYs may justify the initial higher costs. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01427153
Monocytes as a convergent nanoparticle therapeutic target for cardiovascular diseases
Authors: Dasia Aldarondo, Elizabeth Wayne
Journal: Advanced Drug Delivery Reviews (2022)

Due to the increasing population of individuals with cardiovascular diseases and related comorbidities, there is an increasing need for development of synergistic therapeutics. Monocytes are implicated in a broad spectrum of diseases and can serve as a focal point for therapeutic targeting. This review discusses the role of monocytes in cardiovascular diseases and highlights trends in monocyte targets nanoparticles in three cardiovascular-related diseases: Diabetes, Atherosclerosis, and HIV. Finally, the review offers perspectives on how to develop nanoparticle monocyte targeting strategies that can be beneficial for treating co-morbidities.