tbuckley/cabot-search huggingface dataset:
THU0062 Assessing inflammatory activity in rheumatoid arthritis and ankylosing spondylitis. serum amyloid a or c-reactive protein?
Authors: A Gómez, R Sanmartí, L Álvarez, G Salvador, JD Cañete, X Filella, J Gratacós, J Muñoz-Gómez
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Serum amyloid A (SAA) protein has been suggested to be a more sensitive marker of disease activity than CRP in rheumatoid arthritis (RA). Few studies are carried out in patients with ankylosing spondylitis (AS). <h3>Objectives</h3> To analyse if SAA correlates with other markers of inflammatory activity such as CRP, ESR and serum levels of IL-6 in both RA and AS. To evaluate if SAA is the most sensitive marker of clinical disease activity in RA. <h3>Methods</h3> Using a sensitive ELISA test (N-latex SA, Dadde Behring), SAA was measured in the serum of 51 patients with RA and 44 patients with AS. CRP, ESR and serum IL-6 (ELISA) were measured simultaneously. Clinical parameters of disease activity (number of painful and swollen joints) and Thompson's articular index were analysed also in RA patients. <h3>Results</h3> The magnitude of the SSA response was greater than the CRP (x ± SD: SAA = 32.7 ± 56.7 mg/l vs CRP = 18.8 ± 26.3 mg/l p &lt; 0.001). Patients with RA showed higher SAA levels than AS (x ± SD: 44.8 ± 64 mg/l vs 13.6 ± 18.9 mg/l p &lt; 0.001). In both RA and AS, SAA correlates significantly with ESR (r = 0.51; p = 0.0001 in RA and r = 0.61; p = 0.0001 in AS), CRP (r = 0.70; p = 0.0001 in RA and r = 0.66; p = 0.0001 in AS) and IL-6 (r = 0.58 in RA; p = 0.0001, and r = 0.48 in AS; p = 0.001). In patients with RA, SAA but not CRP, ESR or IL-6, showed a positive, although weak correlation with the number of painful joints (r = 0.31; p = 0.03). Thompson articular index, but not the swollen joint count, correlates with the four parameters analysed; this correlation was better for CRP (r = 0.51; p = 0.0001) than for SAA (r = 0.39; p = 0.007) ESR (r = 0.35; p = 0.02) or IL-6 (r = 0.37; p = 0.01). <h3>Conclusion</h3> In both RA and AS, SAA correlates well with other laboratory markers (mainly with CRP) of inflammation. However SAA is not a better marker of clinical disease activity than CRP in RA.
BAALC‐AS1/G3BP2/c‐Myc feedback loop promotes cell proliferation in esophageal squamous cell carcinoma
Authors: Hongyue Zhang, Yan Wang, Weimin Zhang, Qingnan Wu, Jiawen Fan, Qimin Zhan
Journal: Cancer Communications (2021)

Abstract Background Long non‐coding RNAs (lncRNAs) have been found to be involved in the development of many cancers. In this study, we aimed to identify the molecular mechanisms of lncRNA BAALC antisense RNA 1 (BAALC‐AS1) in regulating the malignancy of esophageal squamous cell carcinoma (ESCC). Methods The expression of BAALC‐AS1 in cancer patients was analyzed using a tissue microarray. The protein and RNA levels of BAALC‐AS1 were determined by Western blotting analysis and quantitative reverse transcription‐PCR (RT‐qPCR), respectively. The cell proliferation was determined by cell viability assays, bromodeoxyuridine incorporation, and flow cytometry. The relationships among BAALC‐AS1, RasGAPSH3 domain‐binding protein 2 (G3BP2), and c‐Myc were determined using RNA immunoprecipitation, RNA pull‐down assays, and luciferase assays. Results The expression of BAALC‐AS1 was highly up‐regulated and associated with malignant phenotypes in ESCC tissues and cell lines. In vivo and in vitro assays showed that BAALC‐AS1 promoted ESCC cell proliferation, migration, and invasion. BAALC‐AS1 directly interacted with G3BP2, and thereby inhibited the degradation of c‐Myc RNA 3'‐UTR by G3BP2, thus leading to the accumulation of c‐Myc expression. Additionally, c‐Myc acted as a transcription factor that can induce the expression of BAALC‐AS1 by directly binding to its promoter region. Conclusions BAALC‐AS1/G3BP2/c‐Myc feedback loop plays a critical role in the development of ESCC, which might provide a novel therapeutic target and facilitate the development of new therapeutic strategies for the treatment of ESCC.
FRI0075 Comp levels in serum lowered after six months treatment with etanercept in patients with rheumatoid arthritis
Authors: Å Thörner, C Freiburghaus, S Ernestam, J Bratt
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> The aim of this study was to evaluate Cartilage Oligometric Matrix Protein (COMP) levels during TNFalfa-blocking therapy with Etanercept (Enbrel) in patients with rheumatoid arthritis (RA). Previous studies have suggested that serum COMP levels is a marker for joint destruction in RA. <h3>Methods</h3> 38 patients (34 female, 4 male) with active, longstanding RA were treated with Etanercept 25 mg x2/week. The efficacy measures included ACR response rates after treatment for 3 and 6 months. COMP was measured in serum using sandwich ELISA from AnaMar Med. Lund. Wilcoxon Matched Paired Test was used for statistical analysis. <h3>Results</h3> ACR 20, 50 and 70 responses were demonstrated for 79%, 29% and 5% of the patients, respectively, at 3 months and 68%, 35% and 11% at 6 months. 21% of the patients were still non-responders to Etanercept at 3 months and 32% after 6 months. The ACR response rates at 12 months will be presented at the meeting. A significant decrease (p &lt; 0,05) in serum COMP levels was seen after 6 and 12 months treatment with Etanercept but not after 3 months. At 3 months COMP levels showed a high degree of variability. <h3>Conclusion</h3> Significant reduction in serum COMP levels were seen after six months TNFalfa-blocking therapy and was maintained after 12 months. The COMP levels at 3 months gave no indication regarding outcome of treatment.
LRIG1, a regulator of stem cell quiescence and a pleiotropic feedback tumor suppressor
Authors: Yibing Ji, Rahul Kumar, Abhiram Gokhale, Hseu-Ping Chao, Kiera Rycaj, Xin Chen, Qiuhui Li, Dean G. Tang
Journal: Seminars in Cancer Biology (2021)

LRIG1, leucine-rich repeats and immunoglobulin-like domains protein 1, was discovered more than 20 years ago and has been shown to be downregulated or lost, and to function as a tumor suppressor in several cancers. Another well-reported biological function of LRIG1 is to regulate and help enforce the quiescence of adult stem cells (SCs). In both contexts, LRIG1 regulates SC quiescence and represses tumor growth via, primarily, antagonizing the expression and activities of ERBB and other receptor tyrosine kinases (RTKs). We have recently reported that in treatment-naïve human prostate cancer (PCa), LRIG1 is primarily regulated by androgen receptor (AR) and is prominently overexpressed. In castration-resistant PCa (CRPC), both LRIG1 and AR expression becomes heterogeneous and, frequently, discordant. Importantly, in both androgen-dependent PCa and CRPC models, LRIG1 exhibits tumor-suppressive functions. Moreover, LRIG1 induction inhibits the growth of pre-established AR+ and AR- PCa. Here, upon a brief introduction of the LRIG1 and the LRIG family, we provide an updated overview on LRIG1 functions in regulating SC quiescence and repressing tumor development. We further highlight the expression, regulation and functions of LRIG1 in treatment-naïve PCa and CRPC. We conclude by offering the perspectives of identifying novel cancer-specific LRIG1-interacting signaling partners and developing LRIG1-based anti-cancer therapeutics and diagnostic/prognostic biomarkers.
Treatment dependence of prognostic gene expression signatures in de novo follicular lymphoma
Authors: Christopher R. Bolen, Federico Mattiello, Michael Herold, Wolfgang Hiddemann, Sarah Huet, Wolfram Klapper, Robert Marcus, Farheen Mir, Gilles Salles, Oliver Weigert, Tina Nielsen, Mikkel Z. Oestergaard, Jeffrey M. Venstrom
Journal: Blood (2021)
The impact of prior therapies on outcomes with trifluridine/tipiracil (FTD/TPI) in the phase III TAGS trial.
Authors: Kohei Shitara, Ben George, Julien Taieb, Raghav Sundar, Marwan Fakih, Lukas Makris, Karim A. Benhadji, Michele Ghidini
Journal: Journal of Clinical Oncology (2021)

247 Background: It is unclear whether prior treatment with ramucirumab (RAM) or RAM plus paclitaxel (PAC), standard second-line treatments for metastatic gastric or gastroesophageal junction cancer (mGC/GEJC), can influence outcomes with third-line chemotherapy in this patient (pt) population (pop). In the phase 3 TAGS trial, FTD/TPI showed a survival benefit vs placebo (PBO) in pts with mGC/GEJC who had received ≥2 prior chemotherapy regimens. Post hoc analyses were performed to assess the impact of prior RAM, PAC or RAM+PAC treatment on the efficacy and safety of FTD/TPI in TAGS. Methods: Pts in the TAGS trial were categorized into 5 subgroups based on prior treatment received as follows: A) RAM (alone or combined with other agents), B) no RAM, C) PAC (but no RAM), D) RAM+PAC (sequentially or in combination) and E) neither PAC nor RAM. While subgroups A and B were prespecified, all other subgroups were identified post hoc. Efficacy (overall survival [OS] and progression-free survival [PFS]) and safety were assessed in these subgroups. Results: In the overall pop (N=507), 33% had received prior RAM (alone/combined); 30% prior RAM+PAC; 27% prior PAC but no RAM; and 40% had received neither PAC nor RAM. As only 3% of all pts received prior RAM but no PAC, that subgroup was not considered in this analysis. FTD/TPI treatment was consistently associated with benefits in OS and PFS vs placebo across all pt subgroups (Table). Among pts randomized to FTD/TPI, OS benefit was similar between pts who received RAM+PAC vs those who received neither (HR, 1.15; 95% CI, 0.84–1.58) and between pts who received PAC (but no RAM) vs those who received neither (HR, 0.91; 95% CI, 0.66–1.25). The FTD/TPI safety profile was consistent across all subgroups, with similar overall incidences of grade ≥3 adverse events (AEs). Minor variations in hematologic toxicities were noted (Table). Conclusions: In the phase 3 TAGS trial, FTD/TPI treatment in the third or later line provided efficacy benefits vs PBO and demonstrated a consistent safety profile in pts with mGC/GEJC regardless of prior treatments. Clinical trial information: NCT02500043. [Table: see text]
Association of Potent and Very Potent Topical Corticosteroids and the Risk of Osteoporosis and Major Osteoporotic Fractures
Authors: Alexander Egeberg, Peter Schwarz, Torben Harsløf, Yuki M. F. Andersen, Anton Pottegård, Jesper Hallas, Jacob P. Thyssen
Journal: JAMA Dermatology (2021)

Systemic and inhaled corticosteroids negatively affect bone remodeling and cause osteoporosis and bone fracture when given continuously or in high doses. However, risk of osteoporosis and major osteoporotic fracture (MOF) after application of topical corticosteroids (TCSs) is largely unexplored.To examine the association between cumulative exposure to potent and very potent TCSs and risk of osteoporosis and MOF.This nationwide retrospective cohort study included 723 251 Danish adults treated with potent or very potent TCSs from January 1, 2003, to December 31, 2017. Data were obtained from Danish nationwide registries. Filled prescription data were converted in equipotent doses to mometasone furoate (1 mg/g). Data were analyzed from June 1 to August 31, 2019.Patients were considered exposed when they had filled prescriptions of cumulative amounts corresponding to the equivalent of at least 500 g of mometasone, using filled prescriptions of 200 to 499 g as the reference group.The co-primary outcomes were a diagnosis of osteoporosis or MOF. Hazard ratios (HRs) adjusted for age, sex, socioeconomic status, medication use, and comorbidity were calculated with 95% CIs using Cox proportional hazards regression models.A total of 723 251 adults treated with the equivalent of at least 200 g of mometasone were included in the analysis (52.8% women; mean [SD] age, 52.8 [19.2] years). Dose-response associations were found between increased use of potent or very potent TCSs and the risk of osteoporosis and MOF. For example, HRs of MOF were 1.01 (95% CI, 0.99-1.03) for exposure to 500 to 999 g, 1.05 (95% CI, 1.02-1.08) for exposure to 1000 to 1999 g, 1.10 (95% CI, 1.07-1.13) for exposure to 2000 to 9999 g, and 1.27 (95% CI, 1.19-1.35) for exposure to at least 10 000 g. A 3% relative risk increase of osteoporosis and MOF was observed per doubling of the cumulative TCS dose (HR, 1.03 [95% CI, 1.02-1.04] for both). The overall population-attributable risk was 4.3% (95% CI, 2.7%-5.8%) for osteoporosis and 2.7% (95% CI, 1.7%-3.8%) for MOF. The lowest exposure needed for 1 additional patient to be harmed (454 person-years) was observed for MOF with exposure of at least 10 000 g.These findings demonstrate that use of high cumulative amounts of potent or very potent TCSs was associated with an increased risk of osteoporosis and MOF.
Gut microbiota mediates the absorption of FLZ, a new drug for Parkinson's disease treatment
Authors: Junmei Shang, Shurong Ma, Caixia Zang, Xiuqi Bao, Yan Wang, Dan Zhang
Journal: Acta Pharmaceutica Sinica B (2021)

The gut microbiota plays an important role in regulating the pharmacokinetics and pharmacodynamics of many drugs. FLZ, a novel squamosamide derivative, has been shown to have neuroprotective effects on experimental Parkinson's disease (PD) models. FLZ is under phase Ⅰ clinical trial now, while the underlying mechanisms contributing to the absorption of FLZ are still not fully elucidated. Due to the main metabolite of FLZ was abundant in feces but rare in urine and bile of mice, we focused on the gut microbiota to address how FLZ was metabolized and absorbed. In vitro studies revealed that FLZ could be exclusively metabolized to its major metabolite M1 by the lanosterol 14 alpha-demethylase (CYP51) in the gut microbiota, but was almost not metabolized by any other metabolism-related organs, such as liver, kidney, and small intestine. M1 was quickly absorbed into the blood and then remethylated to FLZ by catechol O-methyltransferase (COMT). Notably, dysbacteriosis reduced the therapeutic efficacy of FLZ on the PD mouse model by inhibiting its absorption. The results show that the gut microbiota mediate the absorption of FLZ through a FLZ–M1–FLZ circulation. Our research elucidates the vital role of the gut microbiota in the absorption of FLZ and provides a theoretical basis for clinical pharmacokinetic studies and clinical application of FLZ in the treatment of PD.
PASTUL questionnaire: a tool for self-assessment of scleroderma skin during the COVID-19 pandemic
Authors: Julia Spierings, Voon Ong, Christopher P Denton
Journal: Annals of the Rheumatic Diseases (2021)

COVID-19 pandemic heralds the biggest challenge faced by health services worldwide and remote consultations are now widely implemented. Evaluation of skin involvement with modified Rodnan Skin Score (mRSS) is central in systemic sclerosis (SSc) as it is associated with internal organ manifestations and mortality, and an increase in mRSS requires attention in all SSc subsets.1 To monitor skin activity remotely during this pandemic we developed the PASTUL (Patient self-Assessment of Skin Thickness in Upper Limb) questionnaire. The questionnaire specifies a grading of skin (normal (0), mild (1), moderate (2), severely (3) thickened) at eight sites corresponding to mRSS with maximum score assigned to each site.2

We evaluated the PASTUL questionnaire on feasibility and validity in patients with SSc who had either a remote or face-to-face appointment at the Royal Free Hospital London, UK. Informed consent was obtained and patient instructions were provided.

Scleroderma Skin Patient Reported Outcome (SSPRO),3 Scleroderma Health Assessment (SHAQ),4 the Scleroderma Functional Score (SFS)5 and the mRSS were collected to evaluate construct validity. The …
Systemic Inflammation in Acute SARS-CoV-2 Infection May Lead to Elevated Cardiac Cytokines and Adverse Remodeling
Authors: M. Sayegh, K. A. Cooney, L. F. Wang, T. Hoang, E. Viox, M. Pino, F. Schneider, R. Geller, M. Paiardini, R. Levit
Journal: Circulation Research (2020)

COVID-19, the clinical syndrome caused by severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) infection, has affected 15 million people globally as of August 2020  Myocardial injury, as evidenced by troponin elevation, is common during early SARS-CoV-2 infection and is predictive of poor outcomes  However, studying the effects of SARS-CoV-2 on the heart is difficult as tissue is generally only available from autopsy specimens late in the disease course  The non-human primate Rhesus macaque (RM) shares 91% homology of the ACE2 receptor to humans and has a similar susceptibility to infection and organ involvement as humans  Here, we sought to assess the acute effects of SARS-CoV-2 infection on the heart  Four (4) adult RM were infected with SARSCoV- 2 by intratracheal and intranasal inoculation and followed for 10 days  The virus was undetectable in cardiac tissue 10 days post inoculation (DPI), but we observed systemic inflammation at 4/5 DPI, with elevated CRP and ferritin levels  Immune cell infiltration was limited on flow cytometry of dissociated left ventricular tissue (n=1-2)  Leukocyte numbers were about 32 CD45+ cells/mg, split evenly between macrophages and neutrophils  Half the macrophages were M2 (CD163+)  About 71% of neutrophils were positive for the ACE2 receptor and CXCR2, and less than 10% had markers of NETosis  Surprisingly, we detected increased cardiac fibrosis assessed at necropsy (n=9), as well as elevated inflammatory cytokines IL-6 and TNF-alpha (n=5), compared to non-infected controls  In conclusion, while we saw no evidence of direct viral infection or significant immune response in the heart, the systemic inflammatory response to SARS-CoV-2 could be triggering adverse remodeling and fibrosis in the heart
OP0111 Treatment of established corticoid-induced osteoporosis by 3-monthly intravenous ibandronate injections
Authors: JD Ringe, A Dorst, H Faber
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Long-term anti-inflammatory therapy with corticosteroids (CS) leads to decreased formation and increased resorption of bone, i.e. to corticoid-induced osteoporosis (CIO). Several recent studies with etidronate, alendronate and risedronate has proven the efficacy of oral bisphosphonate (BP) treatment to increase bone mineral density (BMD) and reduce fracture risk in these patients. Since chronically ill patients with CIO often take multiple oral medications, an injectable BP may improve compliance and therapeutic results. <h3>Objectives</h3> <h3>Methods</h3> In a controlled, prospective, comparative two-arm study we treated 105 patients with established CIO (average age 65 years) over three years with either 2 mg ibandronate every 3 months iv (group A) or with a daily dose of 1 mg alfacalcidol orally (group B). All patients received a 500 mg calcium supplement per day. The patients had been on CS for an average time of 8 years. The initial mean BMD values were very low (T-score lumbar spine -3.8, femoral neck -3.1). 91% of the patients had 1 or more prevalent vertebral fractures (average: 3.8 fractures/patient). <h3>Results</h3> During the 36 months of observation there was a progressive reduction in back pain in both groups. No relevant adverse events were recorded. Mean BMD at the lumbar spine increased by 14.2% in the ibandronate cases and 2.3% in the 1-alpha group (p &lt; 0.0001). The corresponding changes after 3 years for the femoral neck were 5.1% and 1.6% (p = 0.0005). Six new vertebral fractures per 6 patients were observed in group A and 15 per 12 patients in group B. <h3>Conclusion</h3> We conclude that ibandronate is superior to alfacalcidol in the treatment of CIO. The data confirm the very positive effect of BP therapy on the course of CIO. The very good acceptance and excellent compliance with the 3 months bolus therapy in our trial, the scarcity of adverse events and the avoidance of poor intestinal absorption make ibandronate a very interesting alternative to oral BP treatment.
Abstract 2531: Altered Structure of Small Cerebral Arteries in Patients With Essential Hypertension
Authors: Enzo Porteri, Carolina De Ciuceis, Gianluca E Boari, Pietro Mortini, Claudio Cornali, Luigi Rodella, Marco Miclini, Francesca Zani, Nicola Rizzardi, Caterina Platto, Silvia Paiardi, Rita Rezzani, Rossella Bianchi, Damiano Rizzoni, Enrico Agabiti Rosei
Journal: Circulation (2007)

Objective Structural alterations in the microcirculation may be considered an important mechanism of organ damage. An increased media to lumen ratio of subcutaneous small resistance arteries (M/L) ...
Transcription Factors Drive Opposite Relationships between Gene Age and Tissue Specificity in Male and Female <i>Drosophila</i> Gonads
Authors: Evan Witt, Nicolas Svetec, Sigi Benjamin, Li Zhao
Journal: Molecular Biology and Evolution (2021)

Evolutionarily young genes are usually preferentially expressed in the testis across species. Although it is known that older genes are generally more broadly expressed than younger genes, the properties that shaped this pattern are unknown. Older genes may gain expression across other tissues uniformly, or faster in certain tissues than others. Using Drosophila gene expression data, we confirmed previous findings that younger genes are disproportionately testis biased and older genes are disproportionately ovary biased. We found that the relationship between gene age and expression is stronger in the ovary than any other tissue and weakest in testis. We performed ATAC-seq on Drosophila testis and found that although genes of all ages are more likely to have open promoter chromatin in testis than in ovary, promoter chromatin alone does not explain the ovary bias of older genes. Instead, we found that upstream transcription factor (TF) expression is highly predictive of gene expression in ovary but not in testis. In the ovary, TF expression is more predictive of gene expression than open promoter chromatin, whereas testis gene expression is similarly influenced by both TF expression and open promoter chromatin. We propose that the testis is uniquely able to express younger genes controlled by relatively few TFs, whereas older genes with more TF partners are broadly expressed with peak expression most likely in the ovary. The testis allows widespread baseline expression that is relatively unresponsive to regulatory changes, whereas the ovary transcriptome is more responsive to trans-regulation and has a higher ceiling for gene expression.
Diagnosis and management of Bartter syndrome: executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders
Authors: Martin Konrad, Tom Nijenhuis, Gema Ariceta, Aurelia Bertholet-Thomas, Lorenzo A. Calo, Giovambattista Capasso, Francesco Emma, Karl P. Schlingmann, Mandeep Singh, Francesco Trepiccione, Stephen B. Walsh, Kirsty Whitton, Rosa Vargas-Poussou, Detlef Bockenhauer
Journal: Kidney International (2021)

Bartter syndrome is a rare inherited salt-losing renal tubular disorder characterized by secondary hyperaldosteronism with hypokalemic and hypochloremic metabolic alkalosis and low to normal blood pressure. The primary pathogenic mechanism is defective salt reabsorption predominantly in the thick ascending limb of the loop of Henle. There is significant variability in the clinical expression of the disease, which is genetically heterogenous with 5 different genes described to date. Despite considerable phenotypic overlap, correlations of specific clinical characteristics with the underlying molecular defects have been demonstrated, generating gene-specific phenotypes. As with many other rare disease conditions, there is a paucity of clinical studies that could guide diagnosis and therapeutic interventions. In this expert consensus document, the authors have summarized the currently available knowledge and propose clinical indicators to assess and improve quality of care.