tbuckley/cabot-search huggingface dataset:
THU0127 The evaluation of disease outcome measures in 225 rheumatoid arthritis lithuanian patients
Authors: JJ Jankauskiene, S Stropuviene, J Dadoniene, A Luksiene, A Jurgelenas
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> It is commonly recognised that outcome measures in rheumatoid arthritis depend on the duration of disease and especially disability index reveals that link while the others demonstrate minor changes in the course of disease. <h3>Objectives</h3> To test the latter hypotheses we performed the study which aimed to measure long-term outcomes of rheumatoid arthritis in 225 patients – Vilnius city inhabitants. <h3>Methods</h3> The patients were asked to fill in the self-administered questioners as follows: Stanford HAQ (0–3,3 worth health), AIMS(1–6, 6 worth), SF-36 (0–100, 0 worth health). The entire cohort was subdivided into three groups depending on the disease duration. The first cohort with the short disease less than 5 years encountered 70 patients, second cohort between 5 to 10 years of disease duration encountered 56 patients and 99 patients with long standing disease more than 10 years duration consisted the third cohort. The differences between means (SD) of the variables were measured by F-ratio and qualified as significant if p &lt; 0.05. <h3>Results</h3> The significant differences between the cohorts were found in disability indices measured by health assessment questioner: 1,21(0,75), 1,17(0,69) and 1,45(0,83) respectively with F-ratio higher than critical value (p = 0,048). Aims depression and anxiety measures were not significantly different between the cohorts, the same as quality of life indices measured by SF-36. The study was found to be powerful enough -0,7- to reveal the possible differences. <h3>Conclusion</h3> The only differences between disease duration cohorts were revealed in measuring disability indices which tended to grow with increasing disease duration while the other measures were not sensitive to change. This large enough study showed that psychological distress and quality of life measures do not depend on disease duration and the disease impact is particularly visible on disease indices.
Physiological and pathological roles of protein kinase A in the heart
Authors: Yuening Liu, Jingrui Chen, Shayne K Fontes, Erika N Bautista, Zhaokang Cheng
Journal: Cardiovascular Research (2021)

Abstract Protein kinase A (PKA) is a central regulator of cardiac performance and morphology. Myocardial PKA activation is induced by a variety of hormones, neurotransmitters, and stress signals, most notably catecholamines secreted by the sympathetic nervous system. Catecholamines bind β-adrenergic receptors to stimulate cAMP-dependent PKA activation in cardiomyocytes. Elevated PKA activity enhances Ca2+ cycling and increases cardiac muscle contractility. Dynamic control of PKA is essential for cardiac homeostasis, as dysregulation of PKA signalling is associated with a broad range of heart diseases. Specifically, abnormal PKA activation or inactivation contributes to the pathogenesis of myocardial ischaemia, hypertrophy, heart failure, as well as diabetic, takotsubo, or anthracycline cardiomyopathies. PKA may also determine sex-dependent differences in contractile function and heart disease predisposition. Here, we describe the recent advances regarding the roles of PKA in cardiac physiology and pathology, highlighting previous study limitations and future research directions. Moreover, we discuss the therapeutic strategies and molecular mechanisms associated with cardiac PKA biology. In summary, PKA could serve as a promising drug target for cardioprotection. Depending on disease types and mechanisms, therapeutic intervention may require either inhibition or activation of PKA. Therefore, specific PKA inhibitors or activators may represent valuable drug candidates for the treatment of heart diseases.
Metabolic surgery versus conventional medical therapy in patients with type 2 diabetes: 10-year follow-up of an open-label, single-centre, randomised controlled trial
Authors: Geltrude Mingrone, Simona Panunzi, Andrea De Gaetano, Caterina Guidone, Amerigo Iaconelli, Esmeralda Capristo, Ghassan Chamseddine, Stefan R Bornstein, Francesco Rubino
Journal: The Lancet (2021)
Localized diffuse-type gastric adenocarcinoma: Influence of baseline positron emission tomography on survival and therapy response.
Authors: Ahmed Abdelhakeem, Xuemei Wang, Rebecca E Waters, Madhavi Patnana, Jeannelyn Estrella, Mariela A. Blum-Murphy, Allison Trail, Yang Lu, Catherine E Devine, Naruhiko Ikoma, Brian D. Badgwell, Jane Elizabeth Rogers, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2021)

176 Background: Diffuse type of gastric adenocarcinoma (dGAC) confers a poor but variable prognosis compared to intestinal type of GAC. The value of baseline uptake of FDG-PET in localized dGAC is unclear and ~40% are not FDG-PET avid. We analyzed outcomes based on the avidity (high with SUV &gt; 3.5 or low with SUV ≤3.5) of the primary on baseline FDG-PET. Methods: We retrospectively selected 111 localized dGAC cases who had baseline FDG-PET for staging. We compared the FDG-PET avidity with overall survival (OS) and response to preoperative therapy. Standard statistical methods were utilized. Results: The mean age was 59.4 years and with many female patients (47.7%). All patients had dGAC. The high-SUV group (58 [52.3%] patients) and the low-SUV group (53 [47.7%] patients) were equally divided. While the median OS for all patients was 49.5 months (95% CI: 38.5 – 98.8 months), it was 98.0 months for the low-SUV group and 36.0 months for the high-SUV ( p value = 0.003). While the median PFS for all patients was 38.2 months (95%CI: 27.7 – 97.6 months), it was 98.0 months for the low-SUV group was and 27.0 months for the high-SUV group ( p value = 0.005). Clinical responses before surgery were more common in the low-SUV group but there were only 4 patients with pathologic complete response in the entire cohort. Conclusions: Our unique data suggest that localized dGAC patients with low SUV fare better than those with high SUV meaning highly metabolic GACs consuming glucose confer poor prognosis and overall all dGACs seem resistant to therapy.
The association of renal function with safety and efficacy of cisplatin plus S-1 (CS) therapy and docetaxel plus cisplatin plus S-1 (DCS) therapy in patients with advanced gastric cancer (AGC): An exploratory analysis of JCOG1013.
Authors: Shuichi Hironaka, Ryo Sadachi, Tadayoshi Hashimoto, Nozomu Machida, Satoru Iwasa, Yasuhide Yamada, Mitsuru Sasako, Narikazu Boku, Takaki Yoshikawa, Masanori Terashima
Journal: Journal of Clinical Oncology (2021)

197 Background: JCOG1013, a phase III study comparing CS therapy with DCS therapy for AGC, failed to demonstrate the superiority of DCS to CS in overall survival (OS) (Yamada Y, Lancet GH 2019). Because cisplatin and gimeracil (an inhibitor of dihydropyrimidine dehydrogenase contained in S-1) are excreted in urine, it is speculated that renal dysfunction may affect the safety and efficacy of CS and DCS in patients (pts) with AGC. Methods: Among 741 all randomized pts, pts with serum creatinine level &lt; 1.2 mg/dL were included in this study. Pts were categorized by creatinine clearance (CrCl) and treatment into A1 (CrCl ≥ 80 mL/min, CS), A2 (60 &lt; CrCl &lt; 80, CS), A3 (CrCl &lt; 60, CS), B1 (CrCl ≥ 80, DCS), B2 (60 &lt; CrCl &lt; 80, DCS), and B3 (CrCl &lt; 60, DCS). Adverse events, OS, progression-free survival (PFS), objective response rate (ORR) were compared by CrCl in group A (A1 vs. A2 vs. A3) and group B (B1 vs B2 vs B3), respectively, and between the treatment groups according to CrCl (A1 vs. B1, A2 vs. B2, A3 vs. B3). Results: Of 723 pts (169/136/57 in A1/A2/A3 and 170/138/53 in B1/B2/B3), the median CrCl was 94.1/71.9/53.4 mL/min in A1/A2/A3 and 98.2/70.0/55.6 mL/min in B1/B2/B3 group. The incidence of Grade (G) 4 hematological toxicity was 7.8/16.3/25.9% in A1/A2/A3 (P &lt; 0.01), and 29.1/29.3/22.0% in B1/B2/B3 (P = 0.44), and that of G3-4 non-hematological toxicity was 46.1/64.4/64.3% in A1/A2/A3 (P &lt; 0.01) and 54.6/64.7/74.5% in B1/B2/B3 (P &lt; 0.01), respectively. The median OS was 15.4/15.5/15.4 months in A1/A2/A3 (P = 0.89) and 15.3/13.7/13.7 months in B1/B2/B3 (P = 0.72). The median PFS was comparable in A1/A2/A3 (7.1/6.8/6.2 months, P = 0.88) and B1/B2/B3 groups (7.5/7.2/7.8 months, P = 0.85). ORR showed no significant difference in A1/A2/A3 (58.9/57.8/46.9%, P = 0.31) and B1/B2/B3 groups (62.0/61.5/51.5%, P = 0.36). Comparisons between treatment arms according to CrCl (A1 vs. B1, A2 vs. B2, A3 vs. B3) did not show any significant difference in OS (P = 0.88, 0.65, 0.83) and PFS (P = 0.91, 0.63, 0.46). Conclusions: In this exploratory analysis of JCOG1013, CrCl might be associated with safety (G4 hematological toxicity for CS, and G3-4 non-hematological toxicity for CS and DCS), but not with efficacy in either group. Clinical trial information: 000007652.
Site of Recurrence and Survival After Surgery for Colorectal Peritoneal Metastasis
Authors: Eva Breuer, Monika Hebeisen, Marcel André Schneider, Lilian Roth, Chantal Pauli, Katharina Frischer-Ordu, Janina Eden, Basile Pache, Thomas Steffen, Martin Hübner, Laurent Villeneuve, Vahan Kepenekian, Guillaume Passot, Philippe Gertsch, Anurag Gupta, Olivier Glehen, Kuno Lehmann
Journal: JNCI Journal of the National Cancer Institute (2021)

Abstract Background Multimodal treatment, including systemic treatment and surgery, improved the prognosis of peritoneal metastasis (PM). Despite all efforts, recurrence rates remain high, and little data are available about clinical behavior or molecular patterns of PM in comparison to hematogenous metastasis. Here, we aimed to analyze recurrence patterns after multimodal treatment for PM from colorectal cancer. Methods Patients with colorectal PM undergoing multimodal treatment including systemic chemotherapy and cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) between 2005 and 2017 at 4 centers were analyzed retrospectively. Results A total of 505 patients undergoing CRS/HIPEC were analyzed. Of the patients, 82.1% received preoperative chemotherapy. Median peritoneal cancer index was 6 (interquartile range = 3-11). Median disease-free and overall survival was 12 (95% confidence interval [CI] = 11 to 14) months and 51 (95% CI = 43 to 62) months, respectively. Disease recurred in 361 (71.5%) patients, presenting as isolated peritoneal recurrence in 24.6%, isolated hematogenous recurrence in 28.3%, and mixed recurrence in 13.9% of patients. Recurrence to the peritoneum was associated with an impaired time from recurrence to death of 21 (95% CI = 18 to 31) months for isolated peritoneal and 22 (95% CI = 16 to 30) months for mixed recurrence, compared with 43 (95% CI = 31 to &amp;gt;121) months for hematogenous recurrence (hazard ratio [HR] = 1.79, 95% CI = 1.27 to 2.53; P = .001; and HR = 2.44, 95% CI = 1.61 to 3.79; P &amp;lt; .001). On multiple logistic regression analysis, RAS mutational status (odds ratio [OR] = 2.42, 95% CI = 1.11 to 5.47; P = .03) and positive nodal stage of the primary (OR = 3.88, 95% CI = 1.40 to 11.86; P = .01) were identified as predictive factors for peritoneal recurrence. Conclusions This study highlights the heterogeneity of peritoneal metastasis in patients with colorectal cancer. Recurrent peritoneal metastasis after radical treatment represents a more aggressive subset of metastatic colorectal cancer.
OP0103 Systemic lupus erythematosus is associated with more mortality and tissue damage in men than in women
Authors: FJ López-Longo, CM González, M Moreno-Zazo, CA Montilla, R Del Castillo, N Caro, L Cebrián, C González-Montagut, S Gómez, E Carmona, I Monteagudo, L Carreño
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Systemic lupus erythematosus (SLE) is less frequent in men than in women, but it can be more severe. <h3>Objectives</h3> To determine if the outcome of SLE and its treatment differ between men and women. <h3>Methods</h3> We calculated the SLICC scores (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) of 236 patients diagnosed as SLE between 1988 and 2000. Anti-ENA antibodies (U1-RNP, Sm, Ro, and La) were studied by ELISA in the first available serum sample for each patient. The SLE disease activity index (SLEDAI) of the first hospital study was calculated retrospectively. <h3>Results</h3> Twenty-five (10.5%) of the 236 patients were men. Age, age at onset of SLE, duration of the disease, and SLEDAI score at the onset of the disease were similar in the men and women. There was no difference in the frequency of anti-ENA antibodies between the sexes. The SLICC cumulative tissue damage score obtained at the last follow-up visit was significantly higher in men (2.24; SD 1.89) than in women (1.40; SD 1.86) (Mann-Whitney p:0.009). Kidney disease, whether characterised by clearance of less than 50% of normal (9 of 25; 36% vs 23 of 211; 10.9%) (OR: 4.5) or proteinuria over 3.5 g/day and need for dialysis and transplantation (14 of 25; 56% vs 49 of 211; 23.2%) (OR: 4.2), was significantly more frequent in men (OR: 3.8). Cardiomyopathy (3 of 25; 12% vs 3 of 211; 1.4%) (OR: 9.4), avascular necrosis (3 of 25; 12% vs 3 of 211; 1.4%) (OR: 9.4), and retinal disorders (2 of 25; 8% vs 1 of 211; 0.5%) (OR: 18.2) also were more frequent in men than women. In the follow-up period, 5 of the 25 men died (20%) but only 3 of the 211 women died (1.4%) (Fisher p:0.005; OR: 17.33; IC 95%: 3.8–77.9). <h3>Conclusion</h3> Mortality and the tissue damage scores were significantly greater in men with SLE than in women. The higher SLICC score was due mainly to the greater frequency of kidney and heart disease.
Early detection and localization of multiple cancers using a blood-based methylation assay (ELSA-seq).
Authors: Qiang Gao, Bingsi Li, Shangli Cai, Jiayue Xu, Chenyang Wang, Jing Su, Shuai Fang, Fujun Qiu, Xiaofang Wen, Yuzi Zhang, Guoqiang Wang, Hao Liu, Zhihong Zhang
Journal: Journal of Clinical Oncology (2021)

459 Background: Early detection of cancer can potentially offer clinical benefits, particularly for those without effective screening methods. The PREDICT study (pan-cancer early detection project, NCT 04383353) is a prospective, multi-center, longitudinal study that aims to identify multiple cancers non-invasively before symptoms become apparent. As a pilot project, the THUNDER (the unintrusive detection of early-stage cancer) study is designed for development and validation of ELSA-seq, a sensitive targeted methylation sequencing assay that interrogates epigenetic alterations from circulating cell-free DNA (cfDNA). Herein we report results from the second THUNDER sub study (THUNDER-II), which focused on malignancies developed in liver, colon/rectum, esophagus, pancreas, lung and ovary, of which four are gastrointestinal (GI) cancer types. Methods: THUNDER-II comprises four independent steps: marker discovery, model training, validation, and single-blind test. The marker discovery work was conducted by profiling 5.5 million CpG sites in 247 tissue samples (116 cancer, 131 normal/benign, 6 cancer types) using a SeqCap Epi CpGiant system (Roche). By combining data generated in-house and from public sources, a custom hybridization capture panel was designed to target 161,984 CpG sites. For cfDNA applications, 625 patients and 483 non-cancer controls were enrolled and divided into a training set (274 cancer and 195 non-cancer) and an independent validation set (351 cancer and 288 non-cancer). Results: The cancer patients and non-cancer controls were generally comparable with respect to age, gender, and smoking status. Various stages were represented in the cancer group, and 79.5% patients were diagnosed at early stages (I-III). At 99.5% training specificity (95%CI: 96.7-100%), the cross-validated sensitivity was 79.9% (95%CI: 74.6-84.4%). The results were consistent in the validation set, with 98.3% specificity (95%CI: 95.8-99.4%) and 80.6% (76.0-84.6%) sensitivity across stages and cancer types. In terms of tracking diseased organ(s), the classifier returned a tissue-of-origin (TOO) result in 98.6% cases, and 81.0% (95%CI: 77.2-84.3%) of these predictions were correct. Conclusions: Results from the THUNDER-II study demonstrated that early cancer signals could be identified by ELSA-seq with high specificity. This method also enabled accurate prediction of TOO, offering guidance for subsequent diagnostic work-up. Together these findings highlight the potential implementation of this sensitive and robust assay as a multi-cancer detection test.
Single nucleotide polymorphisms (SNPs) in endoplasmic reticulum (ER) stress response genes to predict first-line treatment outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from the MAVERICC and FIRE-3 trials.
Authors: Francesca Battaglin, Hiroyuki Arai, Joshua Millstein, Sebastian Stintzing, Aparna Raj Parikh, Jingyuan Wang, Natsuko Kawanishi, Shivani Soni, Zhang Wu, Christoph Mancao, Volker Heinemann, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2021)

103 Background: ER stress, triggered by the disruption of intracellular protein homeostasis, promotes the activation of a highly conserved adaptive program called unfolded protein response (UPR). UPR signaling has been reported to contribute to tumor initiation and progression, as well as microenvironment remodeling and chemoresistance in multiple cancer types, including CRC. Several studies point to a direct role of the UPR in tumor angiogenesis and an interaction with EGFR signaling. We therefore hypothesized that genetic variants in ER stress response genes may predict first-line treatment outcome in mCRC pts. Methods: The impact on outcome of 17 functional SNPs in 8 core genes of the ER stress response pathway ( IRE1, PERK, ATF6, XBP1, CHOP, GRP78, GADD34, ATF4) was analyzed on a total of 560 pts enrolled in two independent randomized first-line trials: MAVERICC (FOLFIRI/bevacizumab, [bev] n = 163; FOLFOX6/bev, n = 161), and FIRE-3 (FOLFIRI/bev, n = 107; FOLFIRI/cetuximab [cet], n = 129). Genomic DNA from blood samples of pts was genotyped through the OncoArray, a custom array manufactured by Illumina. The association between SNPs and clinical outcomes was evaluated using Cox regression and log-rank tests. The SNP*treatment interaction was assessed in both trials. Results: IRE1 rs16947383 any T allele variant was associated with shorter progression free survival (PFS) and overall survival (OS) compared to the C/C genotype in pts treated with FOLFIRI/bev in the MAVERICC trial both in uni- and multivariate analysis: 10.5 vs 14.1 months for PFS, adjusted hazard ratio (HR) 1.83, 95% confidence interval (CI) 1.12-2.99, adjusted P-value = 0.02; 23.8 vs 38.4 months for OS, adjusted HR 2.12, 95%CI 1.1-4.09, adjusted P-value = 0.02. The association with OS was validated in the FIRE-3 FOLFIRI/bev arm where any T allele carriers showed significantly shorter OS compared to the C/C genotype in both uni- and multivariate analysis: 21.1 vs 44.2 months, adjusted HR 2.06, 95%CI 1.01-4.18, adjusted P-value = 0.05. This effect was not observed in MAVERICC FOLFOX6 and FIRE-3 cet cohorts. A significant interaction was found between IRE1 rs16947383 and treatment on OS in both trials: P = 0.04 in MAVERICC (FOLFIRI vs FOLFOX6), and P = 0.03 in FIRE-3 (bev vs cet). In the MAVERICC FOLFOX6/bev arm, XBP1 rs2239815 and PERK rs6731022 SNPs were associated with shorter PFS and OS, while GADD34 rs610308 with longer OS, in multivariable analysis ( P &lt; 0.05). Conclusions: Our results provide evidence that germline polymorphisms in ER stress response genes may have a predictive value in mCRC pts receiving first-line bev-based treatment and contribute to modulate anti-VEGF efficacy.
Self‐Limiting Mussel Inspired Thin Antifouling Coating with Broad‐Spectrum Resistance to Biofilm Formation to Prevent Catheter‐Associated Infection in Mouse and Porcine Models
Authors: Kai Yu, Amal Alzahrani, Sara Khoddami, Demian Ferreira, Kymora B. Scotland, John T. J. Cheng, Hossein Yazdani‐Ahmadabadi, Yan Mei, Arshdeep Gill, Lily E. Takeuchi, Edbert Yeung, Dana Grecov, Robert E. W. Hancock, Ben H. Chew, Dirk Lange, Jayachandran N. Kizhakkedathu
Journal: Advanced Healthcare Materials (2021)

Catheter-associated urinary tract infections (CAUTIs) are one of the most commonly occurring hospital-acquired infections. Current coating strategies to prevent catheter-associated biofilm formation are limited by their poor long-term efficiency and limited applicability to diverse materials. Here, the authors report a highly effective non-fouling coating with long-term biofilm prevention activity and is applicable to diverse catheters. The thin coating is lubricous, stable, highly uniform, and shows broad spectrum prevention of biofilm formation of nine different bacterial strains and prevents the migration of bacteria on catheter surface. The coating method is adapted to human-sized catheters (both intraluminal and extraluminal) and demonstrates long-term biofilm prevention activity over 30 days in challenging conditions. The coated catheters are tested in a mouse CAUTI model and demonstrate high efficiency in preventing bacterial colonization of both Gram-positive and Gram-negative bacteria. Furthermore, the coated human-sized Foley catheters are evaluated in a porcine CAUTI model and show consistent efficiency in reducing biofilm formation by Escherichia coli (E. coli) over 95%. The simplicity of the coating method, the ability to apply this coating on diverse materials, and the high efficiency in preventing bacterial adhesion increase the potential of this method for the development of next generation infection resistant medical devices.