tbuckley/cabot-search huggingface dataset:
Rejuvenating old lungs: Ain’t no tonic like a drop of retinoic
Authors: Reinoud Gosens, John-Poul Ng-Blichfeldt
Journal: Thorax (2021)

One of the main challenges of experimental respiratory medicine today is the development of therapies that could support lung regeneration, leading to restoration of lung structure and function, in chronic lung diseases such as idiopathic pulmonary fibrosis (IPF). Current therapies such as pirfenidone and nintedanib slow down progression of the disease, but are insufficient to modify the underlying disease process to the extent that progression can be halted or that lung regeneration can be achieved.1 Accordingly, new regenerative therapies will need to be developed guided by insights into the mechanistic underpinnings of defective alveolar regeneration. This challenge is on, not just for IPF, but also for other chronic diseases such as chronic obstructive pulmonary disease (COPD), and is complicated by the limited endogenous regenerative capacity of the ageing lung as the background against which these diseases often develop.

Retinoids are among the most widely studied classes of drugs with putative proregenerative capacity. Retinoic acid signals by binding to nuclear retinoic acid receptors which form heterodimeric complexes with retinoid X receptors to effect gene expression in a variety of cells. Both retinoic acid derivatives and retinoid X receptor ligands have been studied for their proregenerative effects, mostly in experimental models of COPD, and were found to enhance alveolar regeneration in the emphysematous lung.2 Retinoic …
Development and validation of a targeted sequencing panel for application to treatment-refractory solid tumor.
Authors: Woo Sun Kwon, Jingmin Che, Sun Young Rha, Hyun Cheol Chung, Hyo Jun Han, Jaeyoung Kim, Erkhembayar Jadamba, Yunbeom Lee, Ernie Kim
Journal: Journal of Clinical Oncology (2021)

245 Background: Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted sequencing panel for application to treatment-refractory solid tumor types with particular focus on tumours of the stomach cancer, plus test for utility in FFPE, fluid sample and cancer cell lines. Methods: “CancerMaster” is custom RNA probes for target enrichment sequencing. It consists of all unions (7,811 regions, 2.5Mb) of reported exons of 524 tumor and immune related genes. The panel contains special RNA probes, which enables detection of microsatellite instability, Epstein-Barr virus and Human papillomavirus. Also, the CancerMaster panel analyzes 524 genes as well as genomic signatures including microsatellite instability (MSI), tumor mutational burden (TMB) and HLA allele. FFPE samples and 49 gastric cancer (GC) cell lines were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 117), and specificity by Sanger sequencing, pyrosequencing, FoundationOne CDx. Results: We achieved a mean coverage of 1,032x, with sensitivity and specificity of &gt;99% and precision of &gt;97%. In this study, we evaluated 26 Yonsei Cancer Center (YCC) GC cell lines and 23 GC cell lines from other sources (ATCC, KCLB, and JCRB). Application to 49 gastric cancers cell lines resulted in detection of copy number variant (CNV), single number variant (SNV) and small InDel aligned to whole exome sequencing data. In addition to previous novel EBV infected cell line (YCCEL1/YCC-10, J Gen Virol. 2013), we observed amplification and overexpression of receptor tyrosine kinase (RTK) including HER2 (YCC-19, 32, 33, 38), EGFR (YCC-11, 21), Met (YCC-31, 34), and FGFR2 (YCC-28, 30) in YCC GC cell lines; confirming that protein was overexpression by Western blot or Flow cytometry in 19/49 (38.8%). Interestingly, amplification of RTKs was detected mutually exclusive pattern with other RTK amplification. Conclusions: We have developed and validated an analytically-validated panel for application to cancers of treatment-refractory types.
Website of the week: Gay sex
Authors: Douglas Carnall
Journal: BMJ (2000)

This week the BMJ publishes a short report that shows an increase in the prevalence of high risk sexual behaviours for the transmission of HIV among gay men in London. As I start to look around for the web angle to this theme, my intuition suggests that entering the search term “unprotected anal intercourse” into a search engine may return sites whose orientation is not primarily medical.

So, not shirking, I discover that this search returns only one triple-X header on both Google and AltaVista and nine worthy sites. And what if one is too many? One approach is to use one of the various text based algorithms that lie behind censorware initiatives such as SurfWatch (www.surfwatch.com/). For example, AltaVista uses its index of problem terms to provide a “Family filter,” which effectively removes the triple-X offender but also all nine of the worthy sites that the unfiltered search found. The filtered results file also continued to invite me to “comparison shop for unprotected anal intercourse,” which may be something the filter's authors will correct in version 2.

In fact, asking experts may be a better way to track down sites: asked to pick only one URL, mine came up with www.safersex.org/. Here you can download video and audio clips that model safe behaviours for the decisive moments when health messages may take second place to more fundamental urges. And while you may not agree with the suggested dialogue in the audio clips, they at least form a good starting point for considering how you might adapt them to something you feel comfortable with yourself. The non-text content is mainly delivered as QuickTime files, which, while remarkable in their degree of compression (raw NTSC video (about 27 Mb/s) packs down to a file of less than 100 kb/s), may still prove frustrating to download on low bandwidth dial up connections.

There is also good advice for doctors on talking with gay men at www.gmhp.demon.co.uk/guides/gp/smalleffort.html
THU0168 Correlation between sf36 and indices of outcome in 121 rheumatoid arthritis (ra) patients
Authors: MC Lunic, MB Nishishinya, S Galceran, G Nasswetter
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The SF36 is a generic 36 items questionnaire which measures eight dimensions of health status, and permit to make direct comparisons with other disease states or with population norms. SF36 reflects a combination of physical and mental function, and well-being, the extent of social and role disability, and patients personal evaluation of health status. It has been used in several countries and its contents and construct validity, test retest reliability and responsiveness have also been reported. <h3>Objectives</h3> to evaluate the health related quality of life (HRQoL) of patients affected by rheumatoid arthritis (RA) through SF36, and to correlate the results with ACR core set activity index and with mHAQ disability index. <h3>Methods</h3> The study included 121 consecutive patients affected by RA attending the "Hospital de Clinicas", mean age 50(18-84) years, mean disease duration 91(3-480) months, erythrocyte sedimentation rate (ESR)34.71(8-105) mm/h, and mean mHAQ 0.68(0-3). The HRQoL was evaluated through SF36(100-0) eight domains, physical function (PF), physical role (PR), bodily pain (BP), general health (GH), vitality (V), social function (SF), emotional role (ER), and mental health (MH). Disease activity was assessed using ACR core set, swollen joint count (SJcount 0-28), tender joint count (TJ count 0-28), pain by visual analogue scale (VAS 0-100), patient global assessment by VAS, physician global assessment by VAS, acute phase reactant erythrocyte sedimentation rate (Westergren, mm/h), and disability by mHAQ(0-3). <h3>Results</h3> The mHAQ showed good correlation with PF, BP(r &gt; 0.61), SF(r &gt; 0.55), and correlated with PR, V(r &gt; 0.47). VAS pain correlated well with BP and V(r &gt; 0.60), and correlated with PF, PR, and GH(r &gt;o.41), patients global assessment correlated with BP, GH, V(r &gt; 0.48). All correlations had p &lt; 0.001. <h3>Conclusion</h3> SF36 showed to be a practical tool for use in RA patients and may facilitate to achieve burden of impact of disease and to compare with that of other chronic diseases. In this cohort mHAQ was significantly associated with physical and social function as well as bodily pain and vitality. VAS patients global assessment was associated with general health, vitality and bodily pain. No correlation were found with physical and mental role suggesting that different information is involved. Differences with others RA cohorts may be due to demographic characteristics and medical conditions in our group.
AB0008 Ceruloplasmin, transferrin and intracellular adhesion molecule-1 in patients with rheumatoid arthritis
Authors: S Cogalgil, K Yildirim, S Tayli, F Akcay
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> We studied serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), ceruloplasmin (CP) and transferrin (Tf) and investigated the correlation of these parameters with the disease activity. <h3>Methods</h3> Serum sICAM-1 levels were determined with sandwich enzime-linked immunosorbent assay (ELISA) in sera from 42 patients with RA and in 30 healthy controls. Erythtrocyte sedimentation rate (ESR) was determined according to the Westhergen method and C-reactive protein (CRP), CP and Tf by nephelometric method. Disease activity was assessed by disease activity criterias. <h3>Results</h3> Although decreased serum Tf level, serum levels of sICAM-1 and CP were significantly higher in patients with RA than in healthy controls. It was found that sICAM-1 had a negative correlation with Tf (r = ?0.47, p &lt; 0.01) and a positive correlation with CP (r = 0.49, p &lt; 0.001). There was a weak but statistically significant positive correlation between sICAM levels with Ritche articular index (RAI) score and CRP (r = 0.32, p &lt; 0.05; r = 0.44, p &lt; 0.01, respectively), whereas no significant correlation was observed between sICAM-1 levels with ESR, age and disease duration. There was no correlation between values of CRP, RAI and ESR with serum CP and Tf. <h3>Conclusion</h3> These data show that the decreases in serum CP and Tf levels and increases in sICAM-1, ESR and CRP levels are present in RA, and that the decrease in serum CP and Tf levels in RA might be due to increased sICAM-1, and increased levels of sICAM-1 and correlations with other parameters may be a significant and novel marker for evaluating the disease status and the activity of RA.
Role of ctDNA to predict risk of recurrence following potentially curative resection of biliary tract and pancreatic malignancies.
Authors: Angela Lamarca, Mairead Geraldine McNamara, Richard Hubner, Juan W. Valle
Journal: Journal of Clinical Oncology (2021)

336 Background: The potential role of ctDNA to identify residual disease after potentially curative resection has been suggested in some malignancies; its role in resected pancreatico(P)-biliary(B) malignancies is unknown. Methods: Patients diagnosed with PB malignancies underwent molecular profiling (ctDNA) using FoundationMedicine Liquid (72 cancer-related genes) following potentially curative resection. Baseline patient characteristics and molecular profiling outcomes, including mutant allele frequency (MAF) for pathological alterations were extracted. Primary objective: prevalence of ctDNA identification and its correlation with recurrence (relapse-free survival (RFS) and relapse rate). Results: Total of 11 individuals had ctDNA analysed following potentially curative resection for PB malignancies: 8 B (4 extra-hepatic cholangiocarcinoma (eCCA), 2 ampulla, 1 intrahepatic cholangiocarcinoma (iCCA), 1 gallbladder cancer (GBC)) and 3 P. Baseline characteristics: 6 female (54.55%), median age 71.59 years (range 39.98-81.19). Most were pT2 (45.45%), pN0 (54.55%) and R0 (63.64%). Following surgery, 6 patients were started on adjuvant chemotherapy; at the end of follow-up (data cut-off 25/6/2020; median follow-up 11.15 months (range 5.45-13.52); 5 relapsed (45.45%) and 2 died (18.18%). Estimated median RFS was 11.43 months (95% CI 2.28-not reached); median overall survival was not reached. No sample failed ctDNA analysis; presence of ctDNA was identified in 3/11 (27.27%) of the samples; 2 and 1 samples had 2 and 1 pathological alterations identified, respectively: ALK fusion (1 sample; GBC), TP53 mutation (2 samples; eCCA and GBC), CHEK2 mutation (1 sample; pancreas), IDH2 mutation (1 sample; eCCA). Mean maximum MAF was 1.47 (2 in biliary; 0.43 in pancreas). Variants of unknown significance were identified in 72.73% of the samples (87.5% in B; 33.33% in P; p-value 0.152). None of the baseline characteristics explored correlated with presence of ctDNA. There was a trend towards increased relapse risk in the patients with ctDNA present following potentially curative surgery; Cox regression for RFS [HR 2.64 (95% CI 0.36-19.31); median RFS 11.44 months (95% CI 2.28-not reached) vs 10.87 (95% CI 2.21-not reached)]; relapse rate 37.5% (ctDNA absent) vs 66.67% (ctDNA present); statistical significance was not reached (p-value 0.340 and p-value 0.545, respectively). Conclusions: This pilot study demonstrates the feasibility of testing for ctDNA following potentially curative resection in PB malignancies. Presence of ctDNA may be associated with increased relapse risk; further studies are required to increase sample size and assess clinical implications.
Supplemental Vitamins and Minerals for Cardiovascular Disease Prevention and Treatment
Authors: David J.A. Jenkins, J. David Spence, Edward L. Giovannucci, Young-in Kim, Robert G. Josse, Reinhold Vieth, Sandhya Sahye-Pudaruth, Melanie Paquette, Darshna Patel, Sonia Blanco Mejia, Effie Viguiliouk, Stephanie K. Nishi, Meaghan Kavanagh, Tom Tsirakis, Cyril W.C. Kendall, Sathish C. Pichika, John L. Sievenpiper
Journal: Journal of the American College of Cardiology (2021)
Ruxolitinib for the Treatment of Steroid-Refractory Chronic Graft-vs-Host Disease—Another Hopeful Step Forward
Authors: Joseph Clemente Alvarnas
Journal: JAMA Network Open (2021)

Hengwei Wu, MD; Jimin Shi, MD; Yi Luo, MD; Yamin Tan, MD; Mingming Zhang, MD; Xiaoyu Lai, PhD; Jian Yu, PhD; Lizhen Liu, MD; Huarui Fu, MD; He Huang, PhD, MD; Yanmin Zhao, MD
Phospholipase A2 receptor 1 promotes lung cell senescence and emphysema in obstructive lung disease
Authors: Delphine Beaulieu, Aya Attwe, Marielle Breau, Larissa Lipskaia, Elisabeth Marcos, Emmanuelle Born, Jin Huang, Shariq Abid, Geneviève Derumeaux, Amal Houssaini, Bernard Maitre, Marine Lefevre, Nora Vienney, Philippe Bertolino, Sara Jaber, Hiba Noureddine, Delphine Goehrig, David Vindrieux, David Bernard, Serge Adnot
Journal: European Respiratory Journal (2021)

Cell senescence is a key process in age-associated dysfunction and diseases, notably chronic obstructive pulmonary disease (COPD). We previously identified phospholipase A2 receptor 1 (PLA2R1) as a positive regulator of cell senescence acting via Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling. Its role in pathology, however, remains unknown. Here, we assessed PLA2R1-induced senescence in COPD and lung emphysema pathogenesis.We assessed cell senescence in lungs and cultured lung cells from patients with COPD and controls subjected to PLA2R1 knockdown, PLA2R1 gene transduction and treatment with the JAK1/2 inhibitor ruxolitinib. To assess whether PLA2R1 upregulation caused lung lesions, we developed transgenic mice overexpressing PLA2R1 (PLA2R1-TG) and intratracheally injected wild-type mice with a lentiviral vector carrying the Pla2r1 gene (LV-PLA2R1 mice).We found that PLA2R1 was overexpressed in various cell types exhibiting senescence characteristics in COPD lungs. PLA2R1 knockdown extended the population doubling capacity of these cells and inhibited their pro-inflammatory senescence-associated secretory phenotype (SASP). PLA2R1-mediated cell senescence in COPD was largely reversed by treatment with the potent JAK1/2 inhibitor ruxolitinib. Five-month-old PLA2R1-TG mice exhibited lung cell senescence, and developed lung emphysema and lung fibrosis together with pulmonary hypertension. Treatment with ruxolitinib induced reversal of lung emphysema and fibrosis. LV-PLA2R1-treated mice developed lung emphysema within 4 weeks and this was markedly attenuated by concomitant ruxolitinib treatment.Our data support a major role for PLA2R1 activation in driving lung cell senescence and lung alterations in COPD. Targeting JAK1/2 may represent a promising therapeutic approach for COPD.
Influenza Causes MLKL-Driven Cardiac Proteome Remodeling During Convalescence
Authors: Yi-Han Lin, Maryann P. Platt, Ryan P. Gilley, David Brown, Peter H. Dube, Yanbao Yu, Norberto Gonzalez-Juarbe
Journal: Circulation Research (2021)

Patients with and without cardiovascular diseases have been shown to be at risk of influenza-mediated cardiac complications. Recent clinical reports support the notion of a direct link between laboratory-confirmed influenza virus infections and adverse cardiac events.Define the molecular mechanisms underlying influenza virus-induced cardiac pathogenesis after resolution of pulmonary infection and the role of necroptosis in this process.Hearts from wild-type and necroptosis-deficient (MLKL [mixed lineage kinase domain-like protein]-KO) mice were dissected 12 days after initial influenza A virus (IAV) infection when viral titers were undetectable in the lungs. Immunofluorescence microscopy and plaque assays showed presence of viable IAV particles in the myocardium without generation of interferon responses. Global proteome and phosphoproteome analyses using high-resolution accurate mass-based LC-MS/MS and label-free quantitation showed that the global proteome as well as the phosphoproteome profiles were significantly altered in IAV-infected mouse hearts in a strain-independent manner. Necroptosis-deficient mice had increased survival and reduced weight loss post-IAV infection, as well as increased antioxidant and mitochondrial function, indicating partial protection to IAV infection. These findings were confirmed in vitro by pretreatment of human and rat myocytes with antioxidants or necroptosis inhibitors, which blunted oxidative stress and mitochondrial damage after IAV infection.This study provides the first evidence that the cardiac proteome and phosphoproteome are significantly altered post-pulmonary influenza infection. Moreover, viral particles can persist in the heart after lung clearance, altering mitochondrial function and promoting cell death without active replication and interferon responses. Finally, our findings show inhibition of necroptosis or prevention of mitochondrial damage as possible therapeutic interventions to reduce cardiac damage during influenza infections. Graphic Abstract: A graphic abstract is available for this article.
OP0114 Beneficial effects of risedronate treatment on bmd and vertebral fracture risk in men on gc therapy
Authors: P Thompson, RF Laan, G Weryha, C Hrncirik
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Of the 518 patients enrolled in studies of patients initiating or on maintenance of glucocorticoid (GC) therapy (Prevention: less than 3 months on GC therapy and Treatment: greater than 6 months GC therapy), 186 were men. There were 77 men in the Prevention study and 109 in the Treatment study. The mean ages and lumbar spine T-scores were 59.5, -0.38 for the Prevention study and 56.2 and ?1.67 for the Treatment study respectively. <h3>Objectives</h3> <h3>Methods</h3> Patients were randomised to receive placebo, or risedronate (RIS) 2.5 mg, or RIS 5 mg daily for 1 year in both studies. Patients were supplemented with elemental calcium 500 mg/day or elemental calcium 1 g/day and vitamin D 400 IU/day. Most men in the studies were taking GC therapy for either rheumatoid arthritis (38%) or lung disease (22%). <h3>Results</h3> RIS 5 mg significantly increased BMD or prevented bone loss at both the spine and the hip in men (Table 1 Year BMD Mean (SE)% Change from Baseline in Men Taking Glucocorticoids). 23% (9 out of 38) of placebo patients had a new vertebral fracture compared with 5% in the risedronate 2.5 and 5 mg/day treated group (3 out of 58). The vertebral fracture risk reduction was 82% (p = 0.008) for pooled risedronate doses. <h3>Conclusion</h3> In summary, these studies demonstrate that risedronate is effective in preventing bone loss in men recently on glucocorticoids and can increase BMD in men on long term glucocorticoid therapy.
FRI0051 Decrease of disease activity and disability and improvement of quality of life in patients with refractory long-standing rheumatoid arthritis treated with monoclonal anti-tumour necrosis factor-alpha antibody
Authors: F Fantini, L Sinigaglia, S Zeni, M Cagnoli, P Colombelli, E Favalli, C Arnoldi, A Soldi
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Anti-tumour necrosis factor-alpha; (TNF-alpha) antibody has been recently introduced for the treatment of Rheumatoid Arthritis (RA). <h3>Objectives</h3> To evaluate the efficacy of anti-tumour necrosis factor-alpha (TNF-alpha) antibody associated with low-dose methotrexate (MTX) on disease activity, disability and quality of life in a group of RA patients non responder to traditional DMARDs. <h3>Methods</h3> Forty-five non responder patients (42 F, 3 M; age 52 ± 11.7) with long-standing refractory active (DAS28 &gt;4) rheumatoid arthritis (disease duration 15.5 ± 8.8 years) were included in an open study. Before entry most of the patients were on a combination DMARDs regimen. Patients were treated with slow i.v. infusions (at day 0, 15, 45 and then every 45 days) with monoclonal anti-TNF-alpha antibody (Infliximab, 3 mg/Kg) associated with low-dose weekly MTX (median dose 13 mg). Symptomatic treatment was stable during the observation. At every control the following parameters were evaluated: number of tender and swollen joints, pain VAS, General Health assessment VAS (GH VAS), ESR, CRP, haemoglobin level, DAS index, Health Assessment Questionnaire (HAQ), Short Form 36 (SF-36). Until now 37 patients completed a 6 months (6 infusions) whereas 11 patients completed a 12 months (10 infusions) course of treatment. <h3>Results</h3> After 45 days a statistically significant improvement of all the parameters with the exception of CRP and haemoglobin level was observed. The long-term observation, up to month 6 (37 pts) and month 12 (11 pts), showed a statistically significant decrease of DAS, number of tender joints and pain VAS. The same statistically significant trend was observed also for parameters related to quality of life. The infusion was generally well tolerated. Major side effects leading to drug withdrawal were registered in 6 patients (hiperpyrexia in 2 patients, allergic reactions in 3 patients and pulmonary tuberculosis in 1 patient). <h3>Conclusion</h3> Monoclonal anti-TNF-alpha antibody in association with MTX induced a prompt and long-lasting (at least one year) symptomatic response with a significant decrease of disease activity and disability and an improvement of quality of life in a series of patients with rheumatoid arthritis refractory to traditional DMARDs.