tbuckley/cabot-search huggingface dataset:
Influence of Disease Activity in Rheumatoid Arthritis on Radiographic Progression of Concomitant Interphalangeal Joint Osteoarthritis
Authors: Christian A. Lechtenboehmer, Veronika K. Jaeger, Diego Kyburz, Ulrich A. Walker, Thomas Hügle
Journal: Arthritis & Rheumatology (2018)

Distal interphalangeal (DIP) joints are commonly considered to be unaffected by rheumatoid arthritis (RA). Despite synovitis and bone marrow edema being associated with radiographic progression in hand osteoarthritis (OA) and hand RA, radiographic courses differ substantially. This study was undertaken to analyze incidence and progression of radiographically evident DIP joint OA in RA patients, in relation to RA activity and patient characteristics.In sequential radiographs of 1,988 RA patients in the Swiss Clinical Quality Management in Rheumatic Diseases registry, we evaluated and scored 15,904 DIP joints. Scoring was based on the presence of central erosions and subchondral sclerosis and on the severity of osteophytes and joint space narrowing, according to the modified Kellgren/Lawrence (K/L) grade. The presence of DIP joint OA was defined as ≥1 joint with a K/L grade of ≥2, and progression was defined as an increase in a summed K/L grade. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.The median follow-up time was 4.5 years (interquartile range 3.1-7.0), and the mean ± SD age was 56.1 ± 11.1 years. DIP joint OA was present in 60% of patients at baseline. Higher mean age (OR 1.09 [95% CI 1.08-1.10]), female sex (OR 1.37 [95% CI 1.08-1.74]), and higher mean body mass index (OR 1.03 [95% CI 1.00-1.06]) were associated with the presence of DIP joint OA, but neither the presence of anti-citrullinated protein antibodies (ACPAs) (OR 0.72 [95% CI 0.50-1.03]) nor the presence of rheumatoid factor (OR 1.01 [95% CI 0.74-1.38]) were associated with it. Disease Activity Score using the erythrocyte sedimentation rate and metacarpophalangeal (MCP) joint erosions were not associated with DIP joint OA progression. RA disease duration had no relevant effect size associated with DIP joint OA progression (OR 0.97 [95% CI 0.96-0.99]).Known risk factors for DIP joint OA were replicated in patients with RA. The observation that RA activity, the presence of ACPA, and MCP joint erosions were not associated with the prevalence or progression of DIP joint OA indicates that there are distinct roles of inflammation in the pathogenesis of RA and DIP joint OA.
Abstract P117: Day to Day Variation in Self-Efficacy Associated with Weight Loss and Risk of Dietary Lapses
Authors: Lora E Burke, Linda J Ewing, Saul Shiffman, Dan Siewiorek, Asim Smailagic, Andrea Kriska, Steven Rathbun
Journal: Circulation (2015)

Introduction: Ecological momentary assessment (EMA) assesses individuals' experiences, behaviors, and moods as they occur in real time and in their own environment, making it useful to understand the processes of behavior change. We report the use of EMA to study the triggers of lapses after intentional weight loss in a 12-mo. study that includes a standard behavioral weight loss intervention. Purpose: We examined daily self-reports of self-efficacy and how they were related to unplanned eating episodes (‘lapses’) and weight change over the first 6 mos. of the study. Hypothesis: Higher self-efficacy is related to fewer “lapses” and better weight loss over time. Methods: Participants were provided a smartphone app programmed to administer EMA assessments up to 5 randomly-selected times/day. Each assessment included the self-efficacy query, How confident are you that if you have an urge to go off your healthy lifestyle plan, you can resist the urge? measured on a scale of 1-10. Participants were weighed at weekly, and after 3 months bi-weekly, group sessions. To account for replicate observations among subjects, generalized estimating equations were used to fit logistic regression models predicting lapses as a function of self-efficacy, adjusting for location (e.g., home, work, restaurant) and social setting (e.g., with others, alone). Results: The sample (N = 151) was 90.7% female and 79.5% White, and on average, 51.18 (10.22) years of age with a mean BMI of 34.0 (4.6) kg/m2. Of the 59,913 random assessments conducted over 6 mos., eating episodes were recorded in 7,991 (13.34%) of those assessments, of which 881 (11.03%) were not planned. Most of the 7,991 planned and unplanned eating episodes were captured when individuals were with others who were eating (49%), or when completely alone (24%). After adjusting for location and social setting, self-efficacy remained a significant predictor of a lapse (p &lt; 0.001). The odds of a lapse decreased by 70% (95% CI, 64%, 76%) for every unit increase in self efficacy. After controlling for social setting, participants were estimated to lose 0.35 more lbs/mo. (SE = 0.14; p = 0.02) for each unit increase in self efficacy. Self-efficacy maintained a stable level between 7.3 and 7.4 for the first 4 mos., before decreasing at a rate of 0.11 points/month (SE = 0.04; p = 0.002) in the last 2 mos. This temporal trend in self-efficacy was paralleled by a similar trend in participants’ weights; they lost an average of 3.26 lbs/mo. (SE = 0.18) in the first 4 mos. compared to only 0.59 lbs/mo. (SE = 0.29) in the last 2 mos. Conclusions: The data suggest that as self-efficacy decreased to near 7.0, individuals were at greater risk to experience a lapse in their diet, an integral part of the healthy lifestyle plan. Targeting enhanced and sustained levels of self-efficacy above 7 may enable a person to resist lapses and prevent weight regain.
Synthetic Retinoid Am80 Suppresses Smooth Muscle Phenotypic Modulation and In-Stent Neointima Formation by Inhibiting KLF5
Authors: KatsuhitoFujiu, IchiroManabe, AtsushiIshihara, YumikoOishi, HiroshiIwata, GoNishimura, TakayukiShindo, KojiMaemura, HiroyukiKagechika, KoichiShudo, RyozoNagai
Journal: Circulation Research (2005)

Modulation of smooth muscle cell (SMC) phenotype plays a central role in neointima formation. We recently demonstrated that Am80, a synthetic retinoic acid receptor α-specific agonist, inhibits the activity of the transcription factor KLF5, which is essential for neointima formation after vascular injury. In the present study, we aimed to further analyze the mechanism by which Am80 inhibits KLF5 and the effects of inhibiting KLF5 on SMCs and vascular lesion formation, as well as to evaluate potential of Am80 for use in the prevention of in-stent neointima formation. We found that Am80 inhibited both the expression and transcriptional function of KLF5. Of particular interest was our finding that KLF5 forms a transcriptionally active complex with unliganded RAR/RXR heterodimer on the PDGF-A promoter; Am80 disrupts this complex, thereby inhibiting KLF5-dependent transcriptional activation. Knocking down KLF5 using small interfering RNA suppressed serum-induced downregulation of SMC differentiation marker gen...
Abstract 2214: Impact of comorbidities at diagnosis on prostate cancer treatment and survival
Authors: Katarina L. Matthes, Manuela Limam, Giulia Pestoni, Leonhard Held, Dimitri Korol, Sabine Rohrmann
Journal: Cancer Research (2018)

Abstract Background: For Switzerland, it is currently unclear in which way comorbidities influence the choice of primary treatment in prostate cancer (PCa) patients and how comorbidities affect long-term survival of PCa patients. Thus, the aim of this study was to assess the associations of comorbidities with primary treatment of PCa patients and of comorbidities with PCa-specific mortality (PCSM) compared to other-cause mortality (OCM) in Switzerland. Patients and Methods: We included 1527 men diagnosed with PCa in 2000 and 2001 in the canton of Zurich. Comorbidities at time of diagnosis were based on the Charlson Comorbidity Index (CCI). For each patient, the scores of the respective comorbidities were summed up and classified into three groups: CCI 0 = no comorbidities, CCI 1 = sum of scores equals to 1, CCI 2+ = sum of scores equals to 2 or larger. Multiple imputation methods were applied to missing data for stage, grade and comorbidities. Multinomial logistic regression analyses were used to explore the associations of comorbidities with treatment. Cox regression models were used to estimate all-cause mortality, and Fine and Gray competing risk regression models to estimate sub-distribution hazard ratios for the outcomes PCSM and OCM. Results: Increasing age was associated with a decreasing probability of receiving curative treatment, whereas an increasing CCI did not influence the treatment decision as strongly as age. The probability of OCM was significantly higher for patients with comorbidities compared to those without comorbidities (CCI 1: 2.07 [95% CI 1.51 - 2.85], CCI 2+: 2.34 [1.59 - 3.44]); this was not observed for PCSM (CCI 1: 0.79 [0.50 - 1.23], CCI 2+: 0.97 [0.59 - 1.59]). In addition, comorbidities had a greater impact on the patients' mortality than age. Conclusions: The results of the current study suggest that the chronological age is a stronger predictor of treatment choices than comorbidities. This study supports the inclusion of comorbidities in treatment choices in order to offer more appropriate treatment for PCa patients to counteract over- or undertreatment. Citation Format: Katarina L. Matthes, Manuela Limam, Giulia Pestoni, Leonhard Held, Dimitri Korol, Sabine Rohrmann. Impact of comorbidities at diagnosis on prostate cancer treatment and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2214.
Unveiling the Mechanism of Surface Hydrophilicity‐Modulated Macrophage Polarization
Authors: Lin Lv, Youtao Xie, Kai Li, Tao Hu, Xiang Lu, Yunzhen Cao, Xuebin Zheng
Journal: Advanced Healthcare Materials (2018)

Abstract With inflammation increasingly recognized as a key factor that influences fracture healing, the immunologic response is considered to play a pivotal role in determining implant‐mediated osteogenesis. Herein, this paper demonstrates that modification of the surface hydrophilicity of Ti surface oxides can be utilized to control immune response by steering the macrophage polarization toward pro‐ or anti‐inflammation phenotype. Enhanced anti‐inflammatory and prohealing performance of macrophages is observed on hydrophilic surfaces compared to hydrophobic ones. Further study on the detailed mechanism demonstrates that the surface hydrophilicity controls specific proteins (fibronectin and fibrinogen) adsorption and conformation, which activate different signaling pathways (PI3K and NF‐κB) through selective expression of integrin β1 or β2 to influence the behaviors of macrophages. Thus, this study presents a mechanism of macrophage polarization modulated by surface hydrophilicity for the surface design of advanced implant materials with satisfactory anti‐inflammatory and osteogenesis‐promoting properties.
Abstract 11907: Choice of Antihypertensive Combination Therapy Based on Daily Salt Intake
Authors: Shigeru Toyoda, Shu Inami, Toru Kato, Kinji Tsukada, Akiya Nakamoto, Yoshinobu Kikegawa, Akihiro Suzuki, Yukitaka Anraku, Koichi Node, Teruo Inoue
Journal: Circulation (2016)

Introduction: To achieve strict blood pressure control, combination therapy with multiple antihypertensive agents, including angiotensin receptor blockers (ARBs) are recommended. Recently, various ARB combination pills have been developed, including ARBs combined with thiazide diuretics (TZs) and calcium channel blockers (CCBs). However, it has yet to be determined which drug class, the TZs or the CCBs, is more efficacious as add-on therapy to ARBs in controlling hypertension. Hypothesis: This study was designed to test our hypothesis that the combination treatment with ARB/TZ would be better in hypertensive patients with high salt diet intake to lower blood pressure, compared to that with ARB/CCB. Methods: Hypertensive patients who failed to reach blood pressure goals despite treatment with ARBs alone were randomly assigned to receive either ARB/TZ or ARB/CCB combination therapy. Estimated daily sodium intake was calculated from spot urine values of sodium and creatinine. Blood pressure was measured at baseline, and at 4, 8 and 12 weeks after starting combination therapy. Results: For all study patients (n=87), diastolic blood pressure (DBP) reduction was greater in 49 patients receiving ARB/CCB treatment, compared to 38 patients receiving ARB/TZ treatment (11±10 vs. 6±12 mmHg, P&lt;0.05 at 4 weeks; 12±11 vs. 5±11 mmHg, P&lt;0.05 at 8 weeks; 13±11 vs. 7±9 mmHg, P&lt;0.05 at 12 weeks, respectively), although the magnitude of the SBP reduction was similar in each group. In the 37 patients with a baseline estimated daily salt intake greater than 10 g and baseline systolic blood pressure (SBP) ranging from 150 to 200 mmHg, SBP was lower (130±12 vs. 141±17 mmHg , P&lt;0.05) and SBP reduction was greater (35±17 vs. 24±17 mmHg , P&lt;0.05) at 4 weeks in patients receiving ARB/TZ treatment, compared to patients receiving ARB/CCB treatment. In the 31 patients whose estimated daily salt intake increased at 12 weeks compared to baseline, SBP at 12 weeks was lower in patients receiving ARB/TZ treatment, compared to patients receiving ARB/CCB treatment (131±8 vs. 139±10 mmHg, P&lt;0.05). Conclusion: Estimated daily salt intake is a useful tool for guiding antihypertensive therapy and should be measured repeatedly during the therapeutic course.
Abstract 12917: Model of End-stage Liver Disease Excluding INR (MELD-XI) Scoring System Provides the Additional Long-Term Prognostic Information to Malnutrition in Patients Admitted With Acute Decompensated Heart Failure
Authors: Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Shunsuke Tamaki, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Takumi Kondo, Masashi Ishimi, Hideyuki Hakui, Tatsuhisa Ozaki, Yoshihiro Satoh, Masahiro Seo, Iyo Ikeda, Masatake Fukunami
Journal: Circulation (2015)

Backgrounds: Hospitalization for acute decompensated heart failure (ADHF) is associated with a high mortality after discharge. Liver dysfunction has a prognostic impact on the outcome of patients with advanced heart failure. A model of end-stage liver disease excluding INR (MELD-XI), a robust scoring system of liver dysfunction, has been shown to provide prognostic information in heart failure patients. Malnutrition is also associated with poor outcome in ADHF pts. However, there is no information available on the long-term prognostic significance of MELD-XI score in patients admitted with acute decompensated heart failure (ADHF), relating to malnutrition. Methods and Results: We studied 303 consecutive ADHF patients discharged with survival. MELD-XI score was calculated by the following formula: 5.11·ln(bilirubin)+11.79·ln(creatinine)+9.44. Nutritional status was evaluated by Geriatric Nutritional Risk Index (GNRI) calculated as follows: 14.89·serumalbumin (g/dl) + 41.7·BMI/22. During a follow-up period of 5.0±4.3 yrs, 75 patients had cardiovascular death (CVD). At multivariate Cox analysis, MELD-XI score (p=0.0025) and GNRI (p=0.0025) were significantly independently associated with CVD, independently of systolic blood pressure, serum sodium level and prior heart failure hospitalization. ROC analysis revealed that MELD-XI score of 12 was a fair discriminator for CVD (AUC 0.70 [0.64-0.77]). In group with malnutrition (GNRI&lt;96.5: median value), patients with high MELD-XI score (≥12) had a higher risk of CVD than those with low MELD score (43% vs 25%, p=0.02, HR 1.9 [1.1-3.3]). In group without hyponatremia (GNRI≥96.5), patients with high MELD-XI score also had a higher risk of CVD (38% vs 11%, p&lt;0.0001, HR 4.4 [2.0-10.0]). Conclusion: A MELD-XI scoring system could provide the additional long-term prognostic information to malnutrition in ADHF patients.
Tuberculosis after a borderline QuantiFERON result during screening before infliximab
Authors: Jonathan W. Uzorka, Nathalie M. Delfos, Anne M.C. Witte, Henk Scheper, Dick van Soolingen, Sandra M. Arend
Journal: European Respiratory Journal (2018)

Patients who are eligible for treatment with immunosuppressive drugs such as antagonists of tumour necrosis factor (TNF)-α must be screened for latent tuberculosis infection (LTBI), as stated in the recent European standards for tuberculosis (TB) care [1]. Although there are controversies regarding optimal screening [2], interferon-γ release assays such as QuantiFERON-TB Gold (QFT) (Qiagen, Hilden, Germany) are nowadays frequently used. The formal cut-off for a positive QFT is ≥0.35 IU·mL−1 interferon-γ. However, a recent study published in the European Respiratory Journal found that a significant proportion of results just below this cut-off, so called borderline results, represented true infection with Mycobacterium tuberculosis [3]. We present a patient who clearly illustrates the clinical significance of borderline QFT results in patients screened before immunosuppression. Development of tuberculosis after a borderline QuantiFERON result during screening before TNF-α antagonist therapy <http://ow.ly/zW1u30kw2Qv>
Abstract 5624: Development of novel bispecific immune modulating antibodies
Authors: Laura A. Vitale, Lawrence J. Thomas, Li-Zhen He, Thomas O'Neill, Jenifer Widger, Andrea Crocker, James Testa, Karuna Sundarapandiyan, Eric Forsberg, James Boyer, James Storey, Joel Goldstein, Henry C. Marsh, Tibor Keler
Journal: Cancer Research (2018)

Abstract The initial success with checkpoint blocking antibodies has evolved into a tremendous effort in combination therapy to further improve outcome in responsive cancers and to overcome resistance. There is strong rationale for this approach, as the cancer-immunity cycle has many points for intervention, and the immune system has developed multiple pathways to the same end. The use of bispecific antibodies provides opportunities to engage two pathways simultaneously that can result in greater efficacy, improved safety profile, and simplified development compared to separately administered antibodies. To generate bispecific antibodies that blocked the PD-1 signaling pathway, we developed and characterized fully human PD-L1 specific antibodies generated using human Ig transgenic mice. A lead antibody was chosen for its potent activity in functional assays and good manufacturing properties. Our initial bispecific construct couples our CD27 agonist antibody with the PD-L1 antibody (αCD27xαPD-L1) as we have previously shown that this combination led to improved therapeutic activity in the BCL1 disseminated lymphoma model. We found that the αCD27xαPD-L1 was more potent in CD27 costimulation assays such as NFkB activation, and T cell cytokine production compared to the parental antibodies. Similarly, αCD27xαPD-L1 was more efficacious in vivo as measured by Ag-specific T cell IFN-γ production and antitumor activity. Importantly, the bispecific antibody was more effective than the combination of anti-CD27 and anti-PD-L1 antibodies in the BCL1 lymphoma model. The enhanced efficacy was attributed to more efficient cross-linking of the bispecific antibody/CD27 receptor, resulting in stronger T cell activation. In addition, we observed that CD27 signaling increased PD-L1 expression on both tumor and immune cells, which may further enhance the activity of the bispecific antibody. The use of bispecific antibodies can improve the efficacy and profile of immunotherapeutic monoclonal antibodies by combining complementary functionalities and enhancing target cross-linking in the relevant tissues. We are currently exploring this approach with multiple antibodies from our pipeline. Citation Format: Laura A. Vitale, Lawrence J. Thomas, Li-Zhen He, Thomas O'Neill, Jenifer Widger, Andrea Crocker, James Testa, Karuna Sundarapandiyan, Eric Forsberg, James Boyer, James Storey, Joel Goldstein, Henry C. Marsh, Tibor Keler. Development of novel bispecific immune modulating antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5624.
Abstract LB-254: Combined inhibition of MEK and autophagy promotes regression of pancreatic cancer
Authors: Conan Kinsey, Katrin Guillen, Soledad Camolotto, Amelie Boespflug, Jill Shea, Michael Seipp, Courtney Scaife, Martin McMahon
Journal: Cancer Research (2018)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a recalcitrant disease responsible for ~43,000 deaths in the USA in 2017. Despite an advanced understanding of the genetics, biochemistry and biology of pancreatic cancer, there is no effective pathway-targeted therapy for PDAC such that the standard of care treatment for most patients remains conventional cytotoxic chemotherapy. Although the clinical picture remains grim, progress has been made in understanding how alterations in tumor suppressors and proto-oncogenes contribute to PDAC initiation and progression. Whereas initiating mutations in KRAS promote the growth of premalignant pancreatic intra-epithelial neoplasia, progression to cancer malignancy requires cooperating alterations of tumor suppressors such as TP53, CDKN2A, and/or SMAD4. Downstream of KRAS oncoproteins, the RAF→MEK→ERK MAP kinase signaling pathway plays a central role in the genesis and maintenance of PDAC. However, to date, pharmacological inhibition of this pathway has demonstrated little clinical benefit in PDAC patients. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling in PDAC cell lines elicits autophagy, a process of cellular self-consumption, which protects pancreatic cancer cells from the potentially cytotoxic effects of pathway inhibition. Mechanistically, inhibition of MEK1/2 leads to activation of ULK1 through the LKB1-AMPK-ULK1 axis. Combined inhibition of MEK1/2 and autophagy (with chloroquine) displays synergistic anti-proliferative effects against PDAC cell lines in vitro. Most strikingly, whereas single agent therapy had modest effects, combined treatment of xenografted patient-derived PDAC tumors with trametinib plus chloroquine/hydroxychloroquine elicited striking tumor regression. Finally, the observed anti-tumor effects of combination trametinib plus chloroquine were observed against a NRAS mutated melanoma and a BRAF mutated colorectal patient-derived xenografts. These data may warrant testing this combination therapy in patients with KRAS mutated pancreatic cancers, a disease for which new pathway-targeted therapies are urgently required. Citation Format: Conan Kinsey, Katrin Guillen, Soledad Camolotto, Amelie Boespflug, Jill Shea, Michael Seipp, Courtney Scaife, Martin McMahon. Combined inhibition of MEK and autophagy promotes regression of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-254.