tbuckley/cabot-search huggingface dataset:
Antibodies to IgG4 Hinge Can Be Found in Rheumatoid Arthritis Patients During All Stages of Disease and May Exacerbate Chronic Antibody-Mediated Inflammation
Authors: Lotte A. van de Stadt, Henk de Vrieze, Ninotska I. L. Derksen, Mieke Brouwer, Diana Wouters, Dirkjan van Schaardenburg, Gertjan Wolbink, Theo Rispens
Journal: Arthritis & Rheumatology (2013)

In rheumatoid arthritis (RA), autoantibodies such as anti-citrullinated protein antibodies (ACPAs) develop in response to neoepitopes that are formed under conditions of chronic inflammation. These autoantibodies may subsequently be fragmented by inflammation-associated proteases, leading to the formation of F(ab')2 fragments. The hinge of F(ab')2 fragments can serve as a neoepitope, and so-called antihinge antibodies (AHAs) can be found in RA patients, which might modulate the function of (fragmented) autoantibodies. We undertook this study to investigate the presence and specificities of AHAs in different stages of RA and to study their function.The presence of AHAs was assessed by radioimmunoassay in healthy controls, blood donors who later developed RA, patients with arthralgia, patients with early RA, and patients with established RA. Specificity of the AHAs was analyzed with inhibition assays, and complement-activating ability was studied with a C4b deposition assay.Antibodies to IgG1 hinge, IgG2 hinge, and IgG4 hinge were detected in patients with established RA, with anti-IgG4 hinge antibodies being most specific (appearing in 1% of healthy controls, 3.8% of blood donors who later developed RA, 13% of arthralgia patients, 19% of early RA patients, and 16% of established RA patients). Anti-IgG4 hinge antibodies were subclass specific and were able to restore C4b deposition by IgG4 F(ab')2 fragments. In patients with arthralgia and patients with early RA, anti-IgG4 hinge antibodies were associated with rheumatoid factors and ACPAs.Anti-IgG4 hinge antibodies are present in RA patients and have low sensitivity but high specificity for RA. Since a significant proportion of ACPAs can be of the IgG4 subclass, the formation of anti-IgG4 hinge antibodies may represent one mechanism of ACPA-mediated inflammation.
Interferon regulatory factor 3 constrains IKKβ/NF-κB signaling to alleviate hepatic steatosis and insulin resistance
Authors: Xin-An Wang, Ran Zhang, Zhi-Gang She, Xiao-Fei Zhang, Ding-Sheng Jiang, Tao Wang, Lu Gao, Wei Deng, Shu-Min Zhang, Li-Hua Zhu, Sen Guo, Ke Chen, Xiao-Dong Zhang, De-Pei Liu, Hongliang Li
Journal: Hepatology (2013)

Obesity and related metabolic diseases associated with chronic low-grade inflammation greatly compromise human health. Previous observations on the roles of interferon regulatory factors (IRFs) in the regulation of metabolism prompted investigation of the involvement of a key family member, IRF3, in metabolic disorders. IRF3 expression in the liver is decreased in animals with diet-induced and genetic obesity. The global knockout (KO) of IRF3 significantly promotes chronic high-fat diet (HFD)-induced hepatic insulin resistance and steatosis; in contrast, adenoviral-mediated hepatic IRF3 overexpression preserves glucose and lipid homeostasis. Furthermore, systemic and hepatic inflammation, which is increased in IRF3 KO mice, is attenuated by the overexpression of hepatic IRF3. Importantly, inhibitor of nuclear factor kappa B kinase beta subunit / nuclear factor kappa B (IKKβ/NF-κB) signaling is repressed by IRF3, and hepatic overexpression of the inhibitor of κB-α (IκBα) reverses HFD-induced insulin resistance and steatosis in IRF3 KO mice. Mechanistically, IRF3 interacts with the kinase domain of IKKβ in the cytoplasm and inhibits its downstream signaling. Moreover, deletion of the region of IRF3 responsible for the IRF3/IKKβ interaction inhibits the capacity of IRF3 to preserve glucose and lipid homeostasis. Conclusion: IRF3 interacts with IKKβ in the cytoplasm to inhibit IKKβ/NF-κB signaling, thus alleviating hepatic inflammation, insulin resistance, and hepatic steatosis. (Hepatology 2014;59:870–885)
6-minute walk test predicts pulmonary artery pressure in patients with collagen vascular disease associated interstitial pneumonia
Authors: Kota Takahashi, Hiroyuki Taniguchi, Yasuhiro Kondoh, Tomoki Kimura, Kensuke Kataoka
Journal: European Respiratory Journal (2012)

[Objective] It has been reported clinical importance of pulmonary hypertension(PH) in collagen vascular disease(CVD), however the role of PH in interstitial pneumonia related CVD(CVD-IP) has been scarcely evaluated. We sought to determine the prediction factor of mean pulmonary artery pressure(MPAP) in patients with CVD-IP.

[Method]Patients with CVD-IP underwent right heart catheterization(RHC) within 3 months of initial evaluation at our institution. Patients with left ventricular dysfunction, incomplete follow-up, and patients with respiratory failure were excluded.

[Results] We studied 44 patients, (19 male, mean age 59.8±11.0years). They were 13 with RA, 13 with SSc, 9 with PM/DM, and 9 with others. PaO2 at rest was 83.1±9.6mmHg,MPAP was 17.2±5.5mmHg (>20mmHg, 13(29.5%)), cardiac index(CI) was 3.6±0.8L/min/m2, pulmonary vascular resistance index(PARI) was 223±102 Wood units/m2, %vital capacity(%VC) was 78.4±21.0%, percentage of carbon monoxide diffusing capacity (%DLco) was 50.9±17.6%, and 6-min walk distance(6MWD) was 502±142 m, and minimum SpO2 at 6-min walking test (mSpO2) was 85.6±5.9%, respectively. The median observation period was 31.8 months with 11 patients died. In the univariable model, MPAP was significantly correlated with %DLco (r=-0.377,P=0.013), and mSpO2 (r=-0.552, P=0.0001). In the multivariable model, MPAP was significantly correlated with 6MWD (r=-0.360,P=0.019) and mSpO2 (r=-0.595,P<0.001).

Conclusion] 6MWD and mSpO2 were independent predictors of MPAP in CVD-IP.
Short- and medium-term efficacy of specific hydrotherapy in inherited ichthyosis
Authors: C. Bodemer, E. Bourrat, J. Mazereeuw-Hautier, F. Boralevi, S. Barbarot, D. Bessis, C. Blanchet-Bardon, E. Bourdon-Lanoy, J.-F. Stalder, V. Ribet, D. Guerrero, V. Sibaud
Journal: British Journal of Dermatology (2011)

Summary Background Management of inherited ichthyoses is symptomatic. Despite treatment, skin symptoms have a major impact on patients’ quality of life (QoL). Objectives To assess the short- and medium-term efficacy of hydrotherapy on QoL and clinical symptoms of patients with inherited ichthyosis. Methods In this 9-month prospective, open-label, multicentre study, 20 children and 24 adults with ichthyosis were enrolled in several French reference and competence centres, 2 months before undergoing a 3-week treatment with specific hydrotherapeutic management at Avène Hydrotherapy Centre. At baseline (2 months before hydrotherapy), beginning (D0) and end of hydrotherapy (D18), and 3 and 6 months later at the reference and competence centres, patients self-assessed QoL using the Dermatology Life Quality Index (DLQI) or its paediatric version (Children’s DLQI), and investigators evaluated ichthyosis severity using a specific clinical ichthyosis score. Results The DLQI scores were significantly improved not only at the end of the hydrotherapy treatment (−56% vs. baseline; mean ± SD 3·59 ± 4·30 at D18 vs. 8·35 ± 5·71 at D0; P &amp;lt;0·0001), but also at 3 months (−28% vs. baseline; P =0·01) and 6 months after hydrotherapy (−26% vs. baseline; mean ± SD 5·21 ± 5·11 vs. 6·89 ± 5·38; P =0·03) (primary criterion). Clinical symptoms were also significantly improved at all post-treatment visits, with a decrease of the mean clinical ichthyosis score by −38% between D0 and D18, by −30% at 3 months and by −31% at 6 months vs. baseline. Conclusions A 3-week treatment at Avène Hydrotherapy Centre provided significant and persisting improvement of QoL and clinical symptoms in patients with inherited ichthyoses.
Abstract 3597: Malignancy of bladder cancer cells is enhanced by tumor associated fibroblasts through a cytokine-chemokine loop
Authors: Susanne Grimm, Susanne Jennek, Jens Bratsch, Andreas Wohlmann, Vrinda Mohta, Kerstin Junker, Karlheinz Friedrich
Journal: Cancer Research (2014)

Abstract The tumor microenvironment plays an important role in cancer progression. In particular, stromal fibroblasts have profound influence on migration and invasiveness of tumor cells. We employ bladder carcinoma cell lines of different de-differentiation grade to pursue the hypothesis that tumor cell malignancy correlates with the cells' potential to recruit support by tumor associated fibroblasts (TAFs). Bladder cancer cell lines RT112 and Cal29 were used as models for tumor cells of low or high de-differentiation grade, respectively. They were grown separately or in co-culture with tumor-associated fibroblast isolated from kidney carcinomas. Migratory and invasive cell properties were quantified by Boyden chamber (Matrigel) and wound healing assays. Cytokine production of cells was measured by intracellular staining followed by cytometry, by semi-quantitative PCR, or by subjecting conditioned medium to ELISA and Western blot analysis. Migration and invasiveness of bladder cancer cell lines Cal29 and RT112 was enhanced by co-cultivation with TAFs. The low grade cell line RT112, however, was much more dependent on TAF-derived signals to increase the malignancy parameters. Conditioned medium from tumor cells induced the secretion of Matrix Metalloproteinases (MMPs) and the release of GM-CSF, HGF, and Monocyte Chemotactic Protein (MCP-1, CCL2) by TAFs. We could identify tumor cell-derived IL-1α and β as well as TGF-β as stimuli responsible for the upregulation of GM-CSF and MCP-1, respectively, in fibroblasts. MCP-1 is implicated in inflammatory disease states characterized by monocytic infiltrates and was shown to promote cell migration of both bladder cancer cell lines under investigation. Employing pathway-specific reporter gene constructs we are currently addressing signal transduction reactions in both tumor cells and fibroblasts underlying this crosstalk. Supported by: IZKF Jena, European Regional Development Fund ERDF. Citation Format: Susanne Grimm, Susanne Jennek, Jens Bratsch, Andreas Wohlmann, Vrinda Mohta, Kerstin Junker, Karlheinz Friedrich. Malignancy of bladder cancer cells is enhanced by tumor associated fibroblasts through a cytokine-chemokine loop. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3597. doi:10.1158/1538-7445.AM2014-3597
Real-time Imaging of the Resection Bed Using a Handheld Probe to Reduce Incidence of Microscopic Positive Margins in Cancer Surgery
Authors: Sarah J. Erickson-Bhatt, Ryan M. Nolan, Nathan D. Shemonski, Steven G. Adie, Jeffrey Putney, Donald Darga, Daniel T. McCormick, Andrew J. Cittadine, Adam M. Zysk, Marina Marjanovic, Eric J. Chaney, Guillermo L. Monroy, Fredrick A. South, Kimberly A. Cradock, Z. George Liu, Magesh Sundaram, Partha S. Ray, Stephen A. Boppart
Journal: Cancer Research (2015)

Abstract Wide local excision (WLE) is a common surgical intervention for solid tumors such as those in melanoma, breast, pancreatic, and gastrointestinal cancer. However, adequate margin assessment during WLE remains a significant challenge, resulting in surgical reinterventions to achieve adequate local control. Currently, no label-free imaging method is available for surgeons to examine the resection bed in vivo for microscopic residual cancer. Optical coherence tomography (OCT) enables real-time high-resolution imaging of tissue microstructure. Previous studies have demonstrated that OCT analysis of excised tissue specimens can distinguish between normal and cancerous tissues by identifying the heterogeneous and disorganized microscopic tissue structures indicative of malignancy. In this translational study involving 35 patients, a handheld surgical OCT imaging probe was developed for in vivo use to assess margins both in the resection bed and on excised specimens for the microscopic presence of cancer. The image results from OCT showed structural differences between normal and cancerous tissue within the resection bed following WLE of the human breast. The ex vivo images were compared with standard postoperative histopathology to yield sensitivity of 91.7% [95% confidence interval (CI), 62.5%–100%] and specificity of 92.1% (95% CI, 78.4%–98%). This study demonstrates in vivo OCT imaging of the resection bed during WLE with the potential for real-time microscopic image-guided surgery. Cancer Res; 75(18); 3706–12. ©2015 AACR.
Prolongation of the Antiemetic Action of P6 Acupuncture by Acupressure in Patients Having Cancer Chemotherapy
Authors: J W Dundee, J Yang
Journal: Journal of the Royal Society of Medicine (1990)

Previous work from our department has shown that P6 acupuncture is an effective adjuvant to conventional antiemetic therapy for patients having cytotoxic drugs. However, its efficacy is limited to about 8 h. The current studies show that the application of an elasticized wrist band with a stud placed over the acupuncture point, and pressed regularly every 2 h, will prolong the antiemetic action for 24 h. This proved more effective in hospitalized patients (20/20) than in outpatients (15/20), presumably due to the encouragement given to regularly press the stud. Nausea and vomiting remain problems with cancer chemotherapy despite the use of antiemetics. Following encouraging results with P6 acupuncture (ACP) in postoperative sickness this has been shown to be effective in cancer chemotherapy in 105 patients who, despite the use of conventional antiemetics had been sick following the previous treatment. Electrical stimulation (10 Hz DC) of P6 point for 5 min before administration of the cytotoxic drugs was effective in preventing sickness in 66% and only 6% got no benefit. The ACP was given with the antiemetics which the patients had been receiving. Although there were no side effects with the ACP, the benefit only lasted 6-8 h. This was not important in hospitalized patients where the treatment could be repeated, but was a problem with outpatients. It has been shown that pressure on the P6 point (acupressure) has an antiemetic action. A commercially available elasticized band with a plastic stud (Sea Band) is an effective method of applying pressure to P6 point.(ABSTRACT TRUNCATED AT 250 WORDS)
Acupuncture versus combined acupuncture and nicotine substituting therapy for the treatment of nicotinism
Authors: Sofia Angelova, Dora Marinova
Journal: European Respiratory Journal (2011)

Aim:  To compare the effectiveness of two different approaches for smoking cessation: acupuncture and combination of acupuncture and nicotine substituting therapy.   Methods:  We use two main approaches - acupuncture and combination of acupuncture and nicotine substituting therapy with Tabex (Cytisine, original Bulgarian product). The patients, 50 active smokers (mean age 45 years), highly motivated in smoking cessation, were divided into two groups of 25 people each. The participants in both groups had mean 25 years of smoking history and mean use of 20 cigarettes daily. Acupuncture was performed with standart and micro needles on acupunctural ear and nose points. Tabex was administred for 20 days, according to the following regimen: 1 tablet is sucked out in the morning, 1 tablet orally at noon and one in the evening after meals. The rest 3 tablets are taken on demand, maximaly 6 tablets daily. Treatment effect-smoking cessation-was checked on the 10th day, 20th day, 3rd and 6th month after onset.  The results showed that the combined method (acupuncture+Tabex) has more significant long-lasting effect (depletion or significant reduction of abstinence, and smoking cessation in 65% of the mild and heavily nicotine dependant patients) at the end of the 6th month than the acupuncture separately (32%).  In conclusion we recommend the combination of acupuncture and nicotine substituting therapy with Tabex for the treatment of mild and heavily nicotine dependent smokers.
Phase II study of topotecan in metastatic non-small-cell lung cancer.
Authors: T J Lynch, L Kalish, G Strauss, A Elias, A Skarin, L N Shulman, M Posner, E Frei
Journal: Journal of Clinical Oncology (1994)

PURPOSE Topotecan is an inhibitor of topoisomerase I that has shown preclinical activity against non-small-cell lung cancer (NSCLC). This phase II study was designed to determine the clinical activity and toxicity spectrum of topotecan in untreated patients with metastatic NSCLC. PATIENTS AND METHODS Twenty previously untreated patients received topotecan every 21 days at the dose of 2 mg/m2/d intravenously (IV) for 5 days for two cycles, at which point response was assessed. Patients with either clinical response or stable disease (SD) received additional cycles of the drug until toxicity developed or disease progression (PRG) occurred. RESULTS This study was designed to enter 30 patients. However, because no clinical responses were seen in the first 20 patients entered onto the study, the early-stopping rule was invoked and patient accrual was halted. Eleven patients (55%) had SD on topotecan, and nine (45%) had PRG. Toxicity included neutropenia and rash. The median survival duration for all patients was 7.6 months. CONCLUSION We observed no objective clinical responses despite producing high-grade neutropenia. Phase II trials of topotecan using different schedules or higher doses supported by growth factors may clarify the role of topotecan in the treatment of NSCLC. The combination of topotecan with cisplatin and topoisomerase II inhibitors such as etoposide should be explored. Finally, the median survival duration of 7.6 months for 20 patients treated with an agent that failed to produce any obvious clinical responses compares favorably to the survival obtained with combinations of existing agents. This supports the further study of novel compounds in this clinical setting.
Acquired mutations in MAPK signaling pathway following initial pharmacological response in <i>BRAF</i>-mutated metastatic colorectal cancer (mCRC).
Authors: Van Karlyle Morris, Brian James, Feng Tian, Zhi-Qin Jiang, Michael J. Overman, Dipen M. Maru, David Menter, Garth Powis, Scott Kopetz
Journal: Journal of Clinical Oncology (2015)

629 Background: BRAF V600 mutations are associated with inferior survival and limited responses to standard therapies. Blockade of BRAF by vemurafenib generates reflexive activation of EGFR, whose activity can be overcome by concomitant addition of cetuximab. Early-phase clinical trials have demonstrated objective responses with the combination of vemurafenib and cetuximab in patients with BRAF mut mCRC. Mechanisms of resistance following initial anti-tumor response have not yet been described. Methods: Patient-derived xenograft (PDX) models of BRAF mut mCRC have been established at our institution by subcutaneous implantation of tumor into NSG female mice. Here, two different models of BRAF mut mCRC, one with innate sensitivity to vemurafenib and another with innate resistance, were selected for further study. Mice were given vemurafenib chow (417 mg/kg) and/or intraperitoneal cetuximab (1 mg/kg twice a week). Tumor dimensions were serially measured. Tumor resistance developed after a median of 35 days. Tumor DNA was extracted, and whole exome sequencing was performed and compared to untreated controls. Results: In one model of BRAF mut mCRC, 8 mice treated with vemurafenib demonstrated an initial complete response but later developed resistance despite continued treatment. Exome sequencing of the resistant tumors from 6 of 8 mice revealed novel mutations in EGFR, KRAS, NRAS, and MEK not detected in untreated controls (Table). All mutations are predicted to be damaging in COSMIC. Expansion of tumors with acquired NRAS G13D mutation into another generation of mice showed cross-resistance with the combination of BRAF and EGFR inhibition in vivo. In contrast, another PDX model with innate resistance to vemurafenib did not acquire additional mutations in MAPK oncogenes. Conclusions: Acquired activating mutations in oncogenes critical to MAPK signaling have not been described in BRAF mut mCRC after initial pharmacological response. Such mutations, if present as low-frequency clones prior to treatment, may generate resistance following treatment with BRAF and EGFR inhibitors. [Table: see text]
Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcome of early-stage Hodgkin's disease: a meta-analysis of 23 randomized trials involving 3,888 patients. International Hodgkin's Disease Collaborative Group.
Authors: L Specht, R G Gray, M J Clarke, R Peto
Journal: Journal of Clinical Oncology (1998)

PURPOSE To assess the effect of more extensive radiotherapy and of adjuvant combination chemotherapy on long-term outcome of early-stage Hodgkin's disease. METHODS In a collaborative worldwide systematic overview, individual patient data were centrally reviewed on 1,974 patients in eight randomized trials of more versus less extensive radiotherapy and on 1,688 patients in 13 trials of radiotherapy plus chemotherapy versus radiotherapy alone. Crude mortality data on 226 patients in two other trials of chemotherapy were also reviewed. RESULTS More extensive radiotherapy reduced the risk of treatment failure (resistant or recurrent disease) at 10 years by more than one third (31.3% v 43.4% failures; P &lt; .00001), but there was no apparent improvement in overall 10-year survival (77.1 % v 77.0% alive). The addition of chemotherapy to radiotherapy halved the 10-year risk of failure (15.8% v 32.7%; P &lt; .00001), with a small, nonsignificant improvement in survival (79.4% v 76.5% alive). This involved a reduction of borderline significance for deaths from Hodgkin's disease (12.3% v 15.4% dead at 10 years; P = .07), which was partly counterbalanced by a nonsignificant excess of deaths from other causes (12.4% v 10.0% 10-year risk). CONCLUSION More extensive radiotherapy fields or the addition of chemotherapy to radiotherapy in the initial treatment of early-stage Hodgkin's disease had a large effect on disease control, but only a small effect on overall survival. Recurrences could be prevented by more extensive radiotherapy or by additional chemotherapy. However, if chemotherapy had not been given initially, recurrences were generally salvageable by re-treatment with chemotherapy. Hence, less intensive primary treatment--particularly a reduction in radiotherapy fields--appears to achieve similar survival rates as more intensive treatment, although more randomized evidence is needed to confirm this.