tbuckley/cabot-search huggingface dataset:
THU0165 Longterm outcome of austrian patients with rheumatoid arthritis
Authors: M Skoumal, G Kolarz, A Wottawa
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Rheumatoid Arthritis (RA) is a progressive disease and is characterised by increased work disability, functional declines and radiographic damages. To prevent irreversible joint damage, Disease Modifying Antirheumatic Drugs (DMARDs) and recently available biologics should be given as soon as possible. Prospective long-term studies are difficult to organise and may have a minimal relevance for current clinical practice at the end of the study. <h3>Objectives</h3> To examine retrospectively the long-term outcome of patients with RA in Austria. <h3>Methods</h3> 81 indoor patients with seropositve RA (RA+) and seronegative RA (RA-) completed a standardised clinical and laboratory blood examination 3 ? 8× between 1978 ? 1999. The course of the disease was assessed by determining of Disease Activity Score (DAS), 28 Joint Count (28JC), 30 Swollen Joint Count (30SJC), Proximal Interphalangeal joint score (PIP), Ritchie Index, Stoke Index, Steinbrocker stage and Larson score. <h3>Results</h3> Over 21 years with a mean duration of follow up of 10 years we observed a statistically significant improvement of PIP, of Ritchie Index, of Stoke Index and of DAS. Steinbrocker stage and Larson Score increased significantly. With respect to DMARDs we noted that a high percentage of the patients did not receive any DMARDs within the first two years of disease. From all used drugs Methotrexate (MTX) was continued much longer and was the preferred DMARD since the early nineties. Referring to extraarticular manifestations the most frequent was Sicca Syndrome in relation with positive Antinuclear Antibodies (ANA). We found two cases of vasculitis and one case of lung fibrosis; however we did not find a case of amyloidosis. <h3>Conclusion</h3> In our long-term follow up a change of treatment with rather weak DMARDs at the onset of the disease to a more aggressive treatment within the last decade was remarkable. With respect to the significant increase of Steinbrocker stage and Larson score as well an early aggressive therapy is however required With respect to the association of ANA and extrarticular manifestations elevated ANA should give rise for an exact organ screening. The development of predicting factors for the outcome of patients with RA would be helpful to refer patients to specialist care as soon as possible. <h3>References</h3> Wolfe F, Hawley DJ, Cathey MA. Termination of slow acting antirheumatic therapy in rheumatoid arthritis: a 14 year prospective evaluation of 1024 consecutive starts. J Rheumatol. 1990;17:994–1002 Scott DL. Prognostic factors in early rheumatoid arthritis. Rheumatology 2000;39(Suppl 1):24–9 Pincus T, Callahan LF, Sale WG, Brooks AL, Payne LE, Vaughn WK. Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. Arthritis Rheum. 1984;27:864–72
More evidences on which biologic and which pathway is key in severe-critical COVID-19 pneumonia
Authors: Gianfranco Ferraccioli
Journal: Annals of the Rheumatic Diseases (2020)

I read with great interest the paper by Della Torre et al on the effects of sarilumab in severe acute respiratory syndrome coronavirus 2 severe-critical pneumonia. They show that sarilumab treated and standard of care (SOC) treated patients present a mortality rate which is statistically not different (n 28 SARI=7% vs n 28 SOC=18%; p=NS).1 These data confirm previous data from the same group; when analysing patients treated with tocilizumab, they showed no statistically significant differences (n 33 SOC=33%, mortality vs tocilizumab (TOCI) n 32=16%, p=NS).2 These data seem to suggest that interleukin (IL)-6 is not the main target. Indeed out of more than 20 studies reported so far in the literature, only half reported clinically significant results (paper submitted). The various studies have so many bias and differences that a definite conclusion is impossible. However, since the approach with biologics has a strong rationale in controlling the …
Phase II study of dovitinib in first line metastatic or (nonresectable primary) adrenocortical carcinoma (ACC): SOGUG study 2011-03.
Authors: Jesús García-Donas, Susana Hernando Polo, Marta Guix, Miguel Angel Climent Duran, Maria Jose Mendez Vidal, Paula Jiménez, Luis Leon Mateos, Juan Francisco Rodriguez-Moreno, Fernando Moreno, Eduardo Segura, Ignacio Duran, Sonia Maciá, Jose Angel Arranz Arija, Sergio Vazquez-Estevez, Francisco Javier Perez, Nuria Lainez, Daniel E. Castellano
Journal: Journal of Clinical Oncology (2013)

4587 Background: Dovitinib is a novel targeted therapy that inhibits the fribroblast growth factor receptor (FGFR). Preclinical studies have pointed to a major role of this pathway in adrenocortical carcinoma (ACC) thus we aimed to test its clinical efficacy in this tumor. Methods: A phase II proof of concept trial was designed. Since this is an extremely infrequent disease sample size calculation was done taking as a basis the first stage of a two-stage Gehan model. Thus 15 patients needed to be included to show a treatment efficacy of at least 15% (probability of Type I error α = 0.05, power [1 – β] = 0.8). Main inclusion criteria was advanced non-resectable ACC, histologically confirmed, with no prior therapy other than mitotane. Primary endpoint was response rate (RR) by RECIST 1.1 assessed by an independent radiologist. Secondary endpoints included clinical benefit (RR plus stable disease), progression free (PFS) and overall survival (OS). Dovitinib was administered at 500mg daily dose 5 days on 2 days off for 6 months. Continuation of therapy was permitted at physician criteria. Results: From January 2012 to August 2012, 17 patients (5 male and 12 female) have been included in 7 institutions. Median age was 53 years (range 26-72); ECOG was 0-1 in 15 patients, 2 in one patient and N/A in one patient. 77 cycles, defined as one month on treatment, have been administered with dose reductions in 6 (7.8%). Grade 3-4 adverse events deemed as related to the drug were: rash (6%), asthenia (12%), diarrhea (6%), GGT elevation (18%), nausea (6%), hypertriglyceridemia (6%), hypertension (6%), hyperkalemia (6%). 13 patients withdrew treatment because of disease progression and 4 remain on dovitinib. No toxic death was reported. After a median follow-up of 5, 2 months (range 2,27 – 9,7) no objective response has been observed. Median PFS was 1,8 months (CI 95% [ 1,35 -2,25]), median OS has not been reached and clinical benefit has been achieved in 35% of patients with long lasting stable disease (&gt;6 months) in 23%. Conclusions: Though no objective response was observed, a significant number of long lasting stabilizations have been achieved with an acceptable toxicity. These encouraging results merit further study. Clinical trial information: NCT01514526.
Cytokeratin-19 (CK19) and mammaglobin (MGB1) gene expression in circulating tumor cells (CTCs) from metastatic breast cancer patients enrolled in the NCCTG trials, N0436 and N0437
Authors: M. M. Reinholz, K. A. Kitzmann, T. J. Hobday, D. W. Northfelt, B. LaPlant, J. B. Allred, A. C. Dueck, P. J. Stella, W. L. Lingle, E. A. Perez
Journal: Journal of Clinical Oncology (2009)

11095 Background: Biologic characterization of CTCs is increasingly important in determining metastatic breast cancer (MBC) patient (pt) prognosis and treatment prediction. Combined preliminary results from two earlier metastatic BC NCCTG trials, N0234 &amp; N0336, suggested that the change in CTC mammaglobin (MGB1) gene expression between baseline and two cycles of chemotherapy predicted tumor response (p=0.04). The objectives of this study were to 1) determine CTC gene expression of CK19 and MGB1 before, during, and after treatment in N0436 &amp; N0437 and 2) determine associations between baseline and post-treatment gene expression and treatment response. Methods: CTCs were enriched using CD45-depletion from ∼10ml EDTA blood obtained from metastatic BC pts before, after two cycles, and at end of treatment with either first/second-line irinotecan plus cetuximab (N0436) or first-line paclitaxel poliglumex and capecitabine (N0437). CK19 and MGB1 mRNA levels were determined using quantitative RT-PCR in baseline and serial CTC samples of up to 19 pts from N0436 and 40 pts from N0437. The relative gene expressions were normalized to β 2 -microglobulin and calibrated to healthy blood using the 2 -ΔΔCt algorithm; a value of 2 was defined as positive for the respective marker. Results: CK19+ mRNA was detected in 58% of baseline samples from N0436 (11/19) and N0437 (23/40). MGB1+ mRNA was detected in 32% (6/19) and 38% (15/40) of N0436 and N0437 baseline samples, respectively. CK19+ mRNA was detected in 50% (7/14) and 56% (29/52) of N0436 and N0437 serial CTC samples, respectively. MGB1+ mRNA was detected in 29% (4/14) and 27% (14/52) of N0436 and N0437 serial CTC samples, respectively. Of the 66 serial samples, 27% of samples (18/66) had turned positive from baseline for CK19 or MGB1. CK19 mRNA was detected in 85% (33/39) of MGB1+ mRNA samples but their baseline mRNA levels were not correlated. Conclusions: CK19 mRNA was detected in MBC pts with similar frequencies to the CellSearch imaging system. CK19 was detected at a higher frequency than MGB1. In the majority of cases, MGB1 was co-expressed with CK19. Associations between gene expression and treatment response using Chi-Squared analyses and Cox regression models will be presented. No significant financial relationships to disclose.
Abstract #3215: Characterization of breast cancer and disseminated medulloblastoma leptomeningeal tumor models
Authors: Leslie Muldoon, Daniel Guillaume, Seymur Gahramonov, Seth Lewin, Sheila Taylor, Edward Neuwelt
Journal: Cancer Research (2009)

INTRODUCTION. Seeding of cerebrospinal fluid (CSF) and leptomeninges by human tumor cells is associated with hydrocephalus and poor prognosis. CSF tumor spread is most commonly found in breast carcinoma in adults, and medulloblastoma in children. We evaluated breast cancer and medulloblastoma leptomeningeal (LM) tumor models as assessed by magnetic resonance imaging (MRI), histology, and survival. METHODS. MDA-MB231BR human breast carcinoma cells expressing HER2 (1 x 106 cells) and DAOY human medulloblastoma cells (1.5 x 106 or 5 x 106) were injected into the right lateral cerebral ventricle or the cisterna magna of adult female or male nude rats, respectively. Animals underwent weekly MRI (T2-weighted and T1-weighted with or without gadolinium). Ventricular volume and ventricular/cerebral ratio were measured as markers of hydrocephalus. Rat brains were harvested 1-4 weeks after tumor cell injection, or followed for survival, and coronal sections were evaluated by histology and immunohistochemistry for tumor markers. RESULTS. Standard MRI did not demonstrate enhancing or non-enhancing tumor nodules in either LM model, similar to what is seen clinically. MRI with iron oxide nanoparticles at 12 tesla showed evidence of inflammatory infiltration in the brain stem in the breast cancer LM model. In this model, rats showed clinical symptoms by 2 weeks post inoculation and survival time was 20 ± 2.5 days (n = 16). Mild hydrocephalus was detected on histology in 7 of 16 animals at sacrifice while the remaining animals showed no ventricular enlargement. In the medulloblastoma LM model, moderate to severe hydrocephalus was detected within 1 week in 15/23 rats, suggesting that DAOY cells in the CSF space interfere with CSF clearance. The time course and magnitude of hydrocephalus formation correlated with the time from injection. Despite extensive hydrocephalus, survival in the medulloblastoma model was at least 4-6 weeks. In both models, tumor cells were found disseminated throughout the leptomeningeal CSF space, with tumor growth along the leptomeninges of the brain stem and around the anterior spinal cord beneath the cerebellar folia, with some vascular invasion. CONCLUSION. This radiographic and histological analysis demonstrates that the breast cancer and disseminated medulloblastoma LM tumor models are clinically relevant, with diffuse leptomeningeal tumor spread and absence of enhancing or non-enhancing tumor nodules on MRI. The models showed marked differences in terms of hydrocephalus, survival, and inflammatory infiltration.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3215.
Evaluation of a Patient-Collected Audio Audit and Feedback Quality Improvement Program on Clinician Attention to Patient Life Context and Health Care Costs in the Veterans Affairs Health Care System
Authors: Saul Weiner, Alan Schwartz, Lisa Altman, Sherry Ball, Brian Bartle, Amy Binns-Calvey, Carolyn Chan, Corinna Falck-Ytter, Meghana Frenchman, Bryan Gee, Jeffrey L. Jackson, Neil Jordan, Benjamin Kass, Brendan Kelly, Nasia Safdar, Cecilia Scholcoff, Gunjan Sharma, Frances Weaver, Maria Wopat
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Evidence-based care plans can fail when they do not consider relevant patient life circumstances, termed<i>contextual factors</i>, such as a loss of social support or financial hardship. Preventing these contextual errors can reduce obstacles to effective care. <h3>Objective</h3> To evaluate the effectiveness of a quality improvement program in which clinicians receive ongoing feedback on their attention to patient contextual factors. <h3>Design, Setting, and Participants</h3> In this quality improvement study, patients at 6 Department of Veterans Affairs outpatient facilities audio recorded their primary care visits from May 2017 to May 2019. Encounters were analyzed using the Content Coding for Contextualization of Care (4C) method. A feedback intervention based on the 4C coded analysis was introduced using a stepped wedge design. In the 4C coding schema, clues that patients are struggling with contextual factors are termed<i>contextual red flags</i>(eg, sudden loss of control of a chronic condition), and a positive outcome is prospectively defined for each encounter as a quantifiable improvement of the contextual red flag. Data analysis was performed from May to October 2019. <h3>Interventions</h3> Clinicians received feedback at 2 intensity levels on their attention to patient contextual factors and on predefined patient outcomes at 4 to 6 months. <h3>Main Outcomes and Measures</h3> Contextual error rates, patient outcomes, and hospitalization rates and costs were measured. <h3>Results</h3> The patients (mean age, 62.0 years; 92% male) recorded 4496 encounters with 666 clinicians. At baseline, clinicians addressed 413 of 618 contextual factors in their care plans (67%). After either standard or enhanced feedback, they addressed 1707 of 2367 contextual factors (72%), a significant difference (odds ratio, 1.3; 95% CI, 1.1-1.6;<i>P</i> = .01). In a mixed-effects logistic regression model, contextualized care planning was associated with a greater likelihood of improved outcomes (adjusted odds ratio, 2.5; 95% CI, 1.5-4.1;<i>P</i> &lt; .001). In a budget analysis, estimated savings from avoided hospitalizations were $25.2 million (95% CI, $23.9-$26.6 million), at a cost of $337 242 for the intervention. <h3>Conclusions and Relevance</h3> These findings suggest that patient-collected audio recordings of the medical encounter with feedback may enhance clinician attention to contextual factors, improve outcomes, and reduce hospitalizations. In addition, the intervention is associated with substantial cost savings.
Erratum to: ‘Cross-genotype AR3-specific neutralizing antibodies confer long-term protection in injecting drug users after HCV clearance’ (J Hepatol 2019; 71(1): 14-24)
Authors: Sabrina J. Merat, Camille Bru, Dorien van de Berg, Richard Molenkamp, Alexander W. Tarr, Sylvie Koekkoek, Neeltje A. Kootstra, Maria Prins, Jonathan K. Ball, Arjen Q. Bakker, Menno D. de Jong, Hergen Spits, Tim Beaumont, Janke Schinkel
Journal: Journal of Hepatology (2020)
DCAF1 regulates Treg senescence via the ROS axis during immunological aging
Authors: Zengli Guo, Gang Wang, Bing Wu, Wei-Chun Chou, Liang Cheng, Chenlin Zhou, Jitong Lou, Di Wu, Lishan Su, Junnian Zheng, Jenny P.-Y. Ting, Yisong Y. Wan
Journal: Journal of Clinical Investigation (2020)

As a hallmark of immunological aging, low-grade, chronic inflammation with accumulation of effector memory T cells contributes to increased susceptibility to many aging-related diseases. While the proinflammatory state of aged T cells indicates a dysregulation of immune homeostasis, whether and how aging drives regulatory T cell (Treg) aging and alters Treg function are not fully understood owing to a lack of specific aging markers. Here, by a combination of cellular, molecular, and bioinformatic approaches, we discovered that Tregs senesce more severely than conventional T (Tconv) cells during aging. We found that Tregs from aged mice were less efficient than young Tregs in suppressing Tconv cell function in an inflammatory bowel disease model and in preventing Tconv cell aging in an irradiation-induced aging model. Furthermore, we revealed that DDB1- and CUL4-associated factor 1 (DCAF1) was downregulated in aged Tregs and was critical to restrain Treg aging via reactive oxygen species (ROS) regulated by glutathione-S-transferase P (GSTP1). Importantly, interfering with GSTP1 and ROS pathways reinvigorated the proliferation and function of aged Tregs. Therefore, our studies uncover an important role of the DCAF1/GSTP1/ROS axis in Treg senescence, which leads to uncontrolled inflammation and immunological aging.
Methods to evaluate serogroup B meningococcal vaccines: From predictions to real-world evidence
Authors: Ray Borrow, Muhamed-Kheir Taha, Marzia Monica Giuliani, Mariagrazia Pizza, Angelika Banzhoff, Rafik Bekkat-Berkani
Journal: Journal of Infection (2020)

Serogroup B meningococci (MenB) remain a prominent cause of invasive meningococcal disease (IMD). The protein-based multicomponent 4CMenB and the bivalent MenB-FHbp are the only currently available vaccines against MenB-caused IMD. Efficacy studies are not possible, due to the low incidence of IMD. Therefore, the vaccines' immunogenicity has been evaluated against several target strains chosen to quantify complement-mediated killing induced by each vaccine component in the serum bactericidal antibody assay. However, due to the wide genetic diversity and different expression levels of vaccine antigens across MenB strains, vaccine performance may differ from one strain to another. Here, we review the methods used to predict MenB strain coverage for 4CMenB and MenB-FHbp. Phenotypic assays such as the meningococcal antigen typing system (MATS, 4CMenB-specific) and the flow cytometric meningococcal antigen surface expression assay (MEASURE; MenB-FHbp-specific) were developed. Genomic approaches are also available, such as genetic MATS (gMATS) and the Bexsero antigen sequence type (BAST) scheme, both 4CMenB-specific. All methods allow tentative predictions of coverage across MenB strains, including that afforded by each vaccine antigen, and are rapid and reproducible. Real-world data on vaccine effectiveness are needed to confirm predictions obtained by these methods.
Corrigendum to “Isavuconazole is highly active in vitro against Candida species isolates but shows trailing effect” [Clin Microbiol Infect 24 (12) (December 2018) 1343.e1-1343.e4]
Authors: L.J. Marcos-Zambrano, A. Gómez, C. Sánchez-Carrillo, E. Bouza, P. Muñoz, P. Escribano, J. Guinea
Journal: Clinical Microbiology and Infection (2020)
Abstract 5476: Hepatic Over-Expression of Cholesteryl Ester Hydrolase Enhances Cholesterol Elimination and in vivo Reverse Cholesterol Transport
Authors: Bin Zhao, Jingmei Song, Shobha Ghosh
Journal: Circulation (2008)

Neutral Cholesteryl ester hydrolase (CEH) mediated hydrolysis of cellular cholesteryl esters (CE) is required not only to generate free cholesterol for efflux from macrophages but also to release FC from lipoprotein delivered CE in the liver for bile acid synthesis or direct secretion into the bile. We hypothesized that hepatic expression of CEH will regulate the hydrolysis of lipoprotein derived CE and enhance reverse cholesterol transport (RCT). Adenoviral mediated CEH over-expression led to a significant increase (&gt;3 fold) in bile acid output (see Figure ). To assess the role of hepatic CEH in promoting flux of cholesterol from macrophages to feces, cholesterol loaded and [ 3 H]-cholesterol labeled J774 macrophages were injected intraperitoneally into mice and appearance of [ 3 H]-cholesterol in gall bladder bile and feces over 48 hours was quantified. Mice over-expressing CEH had significantly higher [ 3 H]-cholesterol in bile and feces and it was associated with bile acids. This CEH-mediated increased movement of [ 3 H]-cholesterol from macrophages to bile and feces was significantly attenuated in SR-BI−/−mice. These studies demonstrate that similar to macrophage CEH that rate limits the first step, hepatic CEH regulates the last step of RCT by promoting the flux of cholesterol entering the liver via SR-BI and increasing hepatic bile acid output. This research has received full or partial funding support from the American Heart Association, AHA Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia &amp; Washington, DC).
Characterisation of γδ T cells infiltrating colorectal cancer
Authors: Elena Lo Presti, Anna Maria Corsale, Marta Di Simone, Francesco Dieli, Serena Meraviglia
Journal: Gut (2020)

We have read with great interest the paper by de Vries et al 1 reporting on the immune landscape of colorectal cancer (CRC) by high-dimensional mass cytometry, flow cytometry and single cell RNA sequencing. Among clusters of immune cells infiltrating CRC, authors have identified two populations of γδ T cells: one programmed cell death protein 1 (PD-1)+ population is almost exclusively found in DNA mismatch repair (MMR)-deficient (d) tumours, constitutes up to 8.4% of CD45+ cells and has an activated phenotype, and a PD-1− counterpart with a resting phenotype, which is also found in colorectal normal mucosa and MMR-proficient (p) tumours.

Using deconvolution of transcriptomic datasets and single cell RNA sequencing, we have detected γδ cells in many different human tumours, including CRC,2 3 but it is important to know also their subset distribution, maturation states and functional profiles. In fact, there are two subsets of γδ T cells, those expressing Vδ1 which reside at mucosal sites and those expressing Vδ2 which are found in the blood but are recruited to the tumour site.4

Our previous study5 in tissue specimens of n=70 patients with CRC using flow cytometry has shown that γδ T cells account for around 4.5% of CD45+ cells both in normal and in CRC mucosa, and these data have been confirmed by data-mining of …
Peter John Lewis Hunter
Authors: Gillian Williamson
Journal: BMJ (2020)

After qualifying Peter John Lewis Hunter decided to specialise in ophthalmology, and in 1947 he took up post in the eye department of the Royal Victoria Infirmary, Newcastle-upon-Tyne.

Peter was called to do his army service in 1949 and was posted to Hanover, Germany. After demobilisation he was appointed to Bradford Eye and Ear Hospital and a year later returned to the …