tbuckley/cabot-search huggingface dataset:
Phase I trial of p28 (NSC745104), a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in pediatric patients with recurrent or progressive central nervous system tumors: A Pediatric Brain Tumor Consortium Study
Authors: Rishi R. Lulla, Stewart Goldman, Tohru Yamada, Craig W. Beattie, Linda Bressler, Michael Pacini, Ian F. Pollack, Paul Graham Fisher, Roger J. Packer, Ira J. Dunkel, Girish Dhall, Shengjie Wu, Arzu Onar, James M. Boyett, Maryam Fouladi
Journal: Neuro-Oncology (2016)

p53 is a promising target in human cancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G2/M. We conducted a phase I study to determine the maximum-tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) and pharmacokinetics (PKs) of p28 in children. Children aged 3–21 years with recurrent or progressive central nervous system tumors were eligible. Intravenous p28 was administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult recommended phase II dose) using a rolling-6 study design. Expression status of p53 was characterized by immunohistochemistry, and serum PK parameters were established on the second dose. Of the 18 eligible patients enrolled in the study, 12 completed the DLT monitoring period and were evaluable for toxicity. p28 was well-tolerated; 7 participants received ≥2 courses, and the most common adverse event attributed to the drug was transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults; however, an increased area under the curve was observed in pediatric patients. High p53 expression in tumor cell nuclei was observed in 6 of 12 available tissue samples. There were no objective responses; 2 participants remained stable on the study for >4 cycles. This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose.
PTU-038 Long term follow-up of patients with non-alcoholic steatohepatitis
Authors: H Lafferty, C D Evans, K A Oien, P R Mills
Journal: Gut (2012)

Introduction Non-alcoholic steatohepatitis (NASH) is an increasingly common cause for liver disease. More evidence is needed to determine the natural history and prognosis of this condition. The aim of the study was to conduct a prospective follow-up of a group of patients with NASH confirmed on liver biopsy over a period of up to 26 years. Methods A study of 62 patients who had NASH on liver biopsy performed during the period 1985 to 1994 was published in 2002.1 Biopsies were scored according to Brunt's system2 by a single pathologist. 59 of these patients were now traceable. Information on long-term outcome was obtained by review of case notes, electronic patient records and data from NHS Information Services Division and the Registrar General for Scotland. Follow-up duration was defined as the time between diagnosis by initial liver biopsy and last hospital attendance or death. 1 patient subsequently tested positive for hepatitis C and was excluded from further analysis. Results 17 of the 58 patients were male, with an overall mean age at diagnosis of 44 (range 17–74 years). 56 were Caucasian and 2 Asian and mean follow-up in years was 15 (range 0–26). Mean body mass index at diagnosis was 27.6 (range 21.1–41.3). At diagnosis, 6 (10.3%) had diabetes mellitus (DM), 14 (24.1%) hypertension (HTN) and 4 (6.9%) ischaemic heart disease (IHD). On follow-up a total of 21 (36.2%) patients had a diagnosis of DM and 30 (51.7%) HTN. On initial biopsy none of the patients had cirrhosis. During follow-up 15 (25.8%) patients developed cirrhosis (3 biopsy proven and 12 clinical). 5 (8.6%) patients developed hepatic decompensation with jaundice (2), ascites (2), encephalopathy (1), variceal haemorrhage (1) and hepatoma (1). 28 (48.3%) of the patients have died at a mean age of 70.4 years (range 33–97). Time to death from diagnosis was 0.5 to 24 years (mean 14). Two patients died of liver failure (7.1%), 4 from non-hepatic malignancy (14.3%), 6 from IHD (21.4%), 3 of infectious causes (10.7%), 3 of cerebrovascular disease (10.7%) and 10 of “other causes” (2 chronic obstructive pulmonary disease, 1 DM, 1 alcohol, 1 pancreatitis, 5 unknown). Conclusion This observational study shows that the outcome of NASH is not benign with a significant mortality over a mean of 15 years, largely due to vascular disease and malignancy as expected. Progression to cirrhosis occurred in 26% of patients causing considerable clinical morbidity, but death from liver disease over this time period was uncommon. Competing interests None declared. References 1. J Clin Path 2002; 55 :689–692. 2. Am J Gastroenterol 1999; 94 :2467–74.
Scintigraphic Findings of Multiple Focal Nodular Hyperplasias in Type 1 Glycogen Storage Disease
Authors: KAZUYOSHI SUGA, AKIKO HARA, NOBUHIKO OGASAWARA, NAOFUMI MATSUNAGA, FUMIE KUROKAWA, KIWAMI OKITA
Journal: Clinical Nuclear Medicine (2002)

SUGA, KAZUYOSHI M.D.; HARA, AKIKO M.D.; OGASAWARA, NOBUHIKO M.D.; MATSUNAGA, NAOFUMI M.D.; KUROKAWA, FUMIE M.D.; OKITA, KIWAMI M.D. Author Information
THU0230 Response to treatment with azathioprine in behcet’s syndrome patients with different organ involvement and documentation of improvement using patient reported outcomes in routine clinical care:
Authors: Y. Yazici, A.L. Regens, C.J. Swearingen
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Behcet's syndrome (BS) is a systemic vasculitis that may different pathogenic mechanisms leading to different manifestations, such as eye, mucocutaneous and GI disease. We started a dedicated Behcet's clinic in 2004 and have treated over 850 patients to date. <h3>Objectives</h3> To determine the response to therapy depending on type of organ involvement and documentation of improvement with patient reported outcomes. <h3>Methods</h3> All patients seen at the Center complete MDHAQ, medical history, medication use, Behcet's specific history, ethnic and demographic information forms. In addition a Behcet Syndrome Activity Score (BSAS) is also completed by all Behcet patients. These data are prospectively collected and updated each visit. Patients were divided into eye disease only, GI only, both or none groups and compared for disease activity and medication, specifically azathioprine, use. They could have mucocutaneous disease in addition to above manifestations <h3>Results</h3> 484 patients (78% female, disease duration 4.8 (7.1) years, age 35.3 (13.8)) were analyzed. 244 patients had no eye or GI disease, 83 had eye, 111 GI and 46 both eye and GI involvement. Both groups of azathioprine treated and untreated patients showed improvement in their disease activity scores but the improvement were more pronounced for GI disease by BSAS. RAPID3 responses were more in the azathioprine treated group with eye and both eye and GI disease. Patients with no eye or GI disease did similarly with or without azathioprine. <h3>Conclusions</h3> In this cohort of 484 Behcet patients, some treatment response differences were noted between patients with eye or GI involvement vs those who did not have these. Overall, azathioprine, led to better outcomes regardless of organ involvement. It was possible to demonstrate these improvements using patient reported outcomes, RAPID3 and BSAS, as part of routine clinical care. <h3>Disclosure of Interest</h3> Y. Yazici Grant/Research support from: Abbott, BMS, Celgene, Genentech, Consultant for: Abbott, BMS, Centocor, Celgene, Pfizer, genentech, UCB, Takeda, A. Regens: None Declared, C. Swearingen: None Declared
Macrophages are modulated by factors secreted by adipocytes
Authors: I R Klein-Wieringa, S N Andersen, J C Kwekkeboom, B J E de Lange, M Kloppenburg, R E M Toes
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> Obesity has been associated with development and progression of osteoarthritis. Although the biological mechanisms underlying this association are unknown, several studies have indicated that adipose tissue secretes a large variety of soluble factors that can influence whole-body metabolism. The authors have recently shown that the infrapatellar fat pad (IFP), an adipose tissue organ in the knee joint, is a source of inflammatory mediators that could influence joint pathology. Moreover, the authors identified obesity-related changes in cytokine release by IFP. Both adipocytes and immune cells present in IFP could constitute the source of these inflammatory mediators. Among IFP-infiltrating immune cells, macrophages are the most abundant and previous studies have indicated that cytokine release by adipose tissue macrophages depends on adiposity. However, the mechanism underlying this association is unknown. In the present study, the authors explored the possibility that adipocytes modulate the phenotype of macrophages, thereby contributing to obesity-induced changes in adipose tissue. <h3>Materials and methods</h3> Adipocyte conditioned media (ACM) were generated by culturing adipocytes from IFP (OA patients) or subcutaneous adipose tissue (ScAT, healthy donors) for 24 h. Protein and lipid fractions were isolated using TBME and resuspended in medium. Macrophages were obtained by differentiating purified CD14<sup>+</sup> monocytes of healthy individuals in the presence of GM-CSF for 7 days. ACM or different fractions were added for the last 48 h, while LPS was added during the last 24 h of culture. IL-12 and tumour necrosis factor α (TNFα) cytokine secretion was measured by ELISA. The T cell stimulatory capacity of ACM-conditioned macrophages was measured in a 4-day mixed lymphocyte reaction. T cell proliferation was measured by tritium-thymidine incorporation. <h3>Results</h3> Treatment of macrophages with ACM resulted in a strong reduction in IL-12 secretion upon LPS stimulation, whereas TNFα remained unaffected. In addition, ACM-conditioned macrophages had an increased T cell stimulatory capacity. These effects were observed with both IFP- and ScAT-derived ACM. Interestingly, the inhibition of IL-12 release correlated to the Body Mass Index (BMI) of the IFP adipocyte donor. Separation of protein and lipid fractions of ACM indicated that the IL-12 inhibition was mediated by the lipid fraction. Current research investigates the lipid(s) responsible for the observed effects. <h3>Conclusion</h3> Macrophage function is modulated by soluble factors secreted by adipocytes. These factors appear to reside in the lipid fraction of the ACM. Interestingly, the inhibition of IL-12 release correlates with BMI of the adipocytes donor, indicating that obesity-related changes in macrophage phenotype could be mediated by adipocytes.
THU0478 Genome-Wide Association Analysis of Pain Reduction in Rheumatoid Arthritis Patients Treated with TNF Inhibitors
Authors: M. Coenen, M. Umićević Mirkov, S.B. Krintel, J.S. Johansen, C. Miceli-Richard, H. Källberg, L. Padyukov, H. Scheffer, W. Kievit, M.A. van de Laar, P.L. van Riel, X. Mariette, S. Saevarsdottir, M.L. Hetland, S.H. Vermeulen, C.A. Albers
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Pain is the dominant and prevailing symptom of rheumatoid arthritis (RA). Tumor necrosis factor inihibitors (TNFi) have proven very successful in pain reduction. Interestingly, improvement of pain, is notable rapidly after administration of TNFi agents, and well before anti-inflammatory effects of treatment can be observed. The vast majority of pharmacogenetic studies of response to TNFi utilized the clinical outcome measure, disease activity score 28 (DAS28). This measure is very useful for clinical practice, however it might be less heritable as compared to individual, potentially more homogeneous, disease measures. Usage of less complex phenotypes, such as pain (heritability 28-71%), might significantly aid the identification of genetic markers predicting differential response to TNFi. <h3>Objectives</h3> We aimed to identify and replicate genetic factors predicting pain reduction upon TNFi treatment in patients with RA using genome-wide association approach. <h3>Methods</h3> We included 508 TNFi treated RA patients. Association analysis of change of visual analogue scale of pain (VAS-pain) after 14 weeks of treatment was performed on imputed genome-wide genotyping data under additive genetic model with adjustment for baseline VAS-pain. We also conducted a meta-analysis including 1287 RA patients. Gene-based analysis was performed using VEGAS. <h3>Results</h3> No findings reached the threshold for genome-wide significance (P-value≤1x10<sup>–8</sup>) in the discovery cohort. Meta-analysis revealed 213 SNPs suggestively associated (P&lt;10<sup>–4</sup>) with change in VAS-pain after fourteen weeks of TNFi treatment. The most significant SNP rs2295739 (p=2.21x10<sup>–6</sup>), located ∼50kb upstream from the <i>KCNK10</i> gene, which belongs to a family of genes involved in sensory perception. The top hit in the gene-based analysis was RET, known to regulate ion channels and receptors participating in detection and transduction of sensory stimuli. Besides Ret-deficient mice show elevated pain responses. <h3>Conclusions</h3> We have identified several suggestive genomic regions, further studies are required to validate if these regions play a role in pain reduction upon TNFi treatment. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4094
Abstract 764: 6-Bromoindirubin-3′-oxime induces apoptosis of human melanoma cells associated with inhibition of JAK/STAT3 signaling
Authors: Xiangli Liu, Sangkil Nam, Yan Tian, Marina Kritsanida, Prokpios Magiatis, Leandros Skaltsounis, Richard Jove
Journal: Cancer Research (2010)

Abstract Signal Transducer and Activator of Transcription 3 (STAT3) is constitutively activated in many diverse human tumors and contributes to malignant progression in part by preventing apoptosis. Janus kinases (JAKs), which are receptor-associated tyrosine kinases, phosphorylate STAT3 in normal as well as tumor cells in response to stimulation with cytokines or growth factors. Thus, the JAK/STAT3 signaling pathway has emerged as a promising new target for development of anti-cancer therapeutics. Previous studies demonstrated that bromoindirubin derivatives have anti-cancer activity with enhanced solubility and bioavailability compared to indirubin, which is a natural product with anti-tumor activity found in traditional herbal medicines. The marine natural product derivative 6-bromoindirubin-3′-oxime (6-BIO) has been shown to inhibit kinase activity of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3β (GSK-3β). Here, we report that 6-BIO induces apoptosis of A2058 melanoma cells, associated with inhibition of JAK/STAT3 signaling. Our data show that 6-BIO inhibits viability and induces apoptosis of melanoma cells with an IC50 value of 5 µM, consistent with reduction of phosphorylation of JAK family kinases (JAK1, JAK2 and TYK2) and STAT3 in both dose- and time-dependent manners. Expression of STAT3 downstream targets involved in preventing apoptosis, particularly Mcl-1, was decreased through inactivation of STAT3 by 6-BIO at similar IC50 values. In contrast to the decreased levels of phosphorylation of JAKs and STAT3, phosphorylation levels of the AKT and MAPK signaling proteins were not inhibited in the cells treated with 6-BIO. Taken together, these data demonstrate that JAK/STAT3 signaling was selectively inhibited by 6-BIO associated with induction of tumor cell apoptosis. Our findings support further development of 6-BIO as a potential anti-cancer therapeutic agent that targets JAK/STAT3 signaling in tumor cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 764.
Abstract P1-15-02: Febrile neutropenia (FN) risk assessment and granulocyte colony-stimulating factor (G-CSF) guideline adherence in patients with breast cancer – results from a German prospective multicentre observational study (PROTECT)
Authors: C-C Steffens, H Eschenburg, C Kurbacher, T Goehler, M Schmidt, H Eustermann, M Schaffrik, B Otremba
Journal: Cancer Research (2012)

Abstract Background: FN is a dose-limiting toxicity of chemotherapy which can affect patient (pt) outcomes. EORTC guidelines recommend G-CSF primary prophylaxis when the overall FN risk assessment is ≥20%. We evaluated risk assessment and guideline adherence (prophylaxis in high-risk pts) in clinical practice among breast cancer patients. Methods: Eligible pts were enrolled consecutively at centres selected based on experience and geographical spread. Key inclusion criteria were diagnosis of solid tumour or lymphoma, physician-assessed overall FN risk ≥10% (chemotherapy risk plus individual risk factors per EORTC guidelines), and planned primary (PPP) or secondary (PSP) prophylaxis with pegfilgrastim. Pegfilgrastim administered &amp;gt;3 days after chemotherapy completion was classified as therapeutic use. The primary objective was to describe the proportion of pts with an investigator-assessed overall FN risk of &amp;gt;20% or 10–20% receiving PPP or PSP. Secondary objectives included evaluating FN incidence and chemotherapy dose reductions/delays. Data from breast cancer patients only are reported, and prophylaxis in high-risk patients was determined to evaluate guideline adherence. Results: 1003 pts were enrolled from Nov 2007 to Sept 2010. Mean (±SD) age was 54.4 (±11.2) years, almost all pts (99%) were female. Treatment intent was deemed curative by the investigator in 91% of pts. The investigator-assessed FN risk was &amp;gt;20% in 505 (50%) pts and 10–20% in 414 (41%) pts. Despite eligibility criteria, 84 (8%) pts were assessed by investigators as &amp;lt;10% risk; reasons for inclusion of low-risk pts were not documented. Measured baseline patient risk factors were similar between PPP and PSP pts, and PPP and PSP pts were equally likely to receive chemotherapy with curative intent (92% vs 89%) and less likely to have received prior chemotherapy (11% vs 20%). 100 pts (10%) experienced FN, 43/680 (6%) in the PPP and 53/254 (21%) in the PSP group. 45 (4%) pts experienced FN-related dose reductions or dose delays, with 22/680 (3%) in the PPP group and 22/254 (9%) in the PSP group. In the subgroup of pts assessed as high FN risk, PPP was administered to fewer pts than planned and PSP to more pts than planned (Table). Conclusion: Adherence to G-CSF guidelines, and reasons for differences between planned and administered prophylaxis warrants further investigation. Comparison of outcomes between prophylaxis groups should be interpreted with caution; however, FN incidence remained low with pegfilgrastim PP among breast cancer pts in German clinical practice. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-02.
Endoscopic ultrasound-guided fine-needle aspiration diagnosis of mixed endocrine somatostatinoma of the minor papilla in von Recklinghausen disease
Authors: Luca Barresi, Ilaria Tarantino, Dario Ligresti, Rosa Liotta, Gabriele Curcio, Antonino Granata, Gianluca Marrone, Mario Traina
Journal: Endoscopy (2014)

Von Recklinghausen disease (VRD) is an autosomal-dominant disorder with variable penetrance. VRD is associated with a variety of benign and malignant neoplastic lesions [1]. The association with duodenal neuroendocrine tumors, particularly somatostatinomas, is widely recognized [1] [2] [3]. Mixed endocrine tumors are a particular category of neuroendocrine tumors and include at least two distinct tumor populations, one of which is endocrine [3] [4]. We describe a case of mixed neuroendocrine tumor with somatostatin expression arising from the minor papilla in a patient with VRD, diagnosed by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA).
THU0558 Role of Physical Exercise in Patients with Hip Osteoarthritis
Authors: R. I. Marcu, S. Patru, A. C. Bighea, R. S. Popescu
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Hip osteoarthritis evolution is slow, but progressive, with increasing degradation of the joint, worsening instability, with permanent pain and reduced walk perimeter. <h3>Objectives</h3> The purpose of this study was to examine the effects of a 3 weeks kinetic program on pain and the functional status of patients with hip osteoarthritis. <h3>Methods</h3> We conducted an observational, prospective, randomized study on a sample of 80 patients previously diagnosed with hip osteoarthritis. The patients were randomly assigned to a control group (40 patients) who received electrotherapy, physical therapy and massage (group 1) and a study group (40 patients) whose therapeutic program included electrotherapy, physical therapy, massage and daily physical exercise (group 2). Rehabilitation program of patients had the following general objectives: increase the function or maintenance of the existing function and prevent failures and disability by reducing pain and inflammation, maintaining or increasing muscular strength and joint mobility. Evaluation of patients was done on day1 and after 3 weeks of rehabilitation treatment. The clinical and functional parameters assessed were: pain on a visual analogue scale (100 mmVAS), physical impairments (muscular strength, static disorders and mobility of hip joint), and disabilities (Tinetti Gait Scale, ADL 24, D'Aubigné Scale and movement capacity). <h3>Results</h3> After the 3 weeks rehabilitation program, the scores for functional parameters improved as follows: pain- 43.5% (group 2) and 32.9% (group 1) and the results were high statistic significant (p=0.000054); physical impairments : muscular strength- 9.7% (group 2), without improving by group 1, static disorders- 24.6% (group 2) and 13.6% (group 1), mobility of hip joint: 34.8% (group2) and 23.2% (group 1); disabilities: Tinetti Gait Scale- 36.3% (group 2) and 22.1% (group 1), ADL- 53.6% (group 2) and 40.2% (group 1), D'Aubigné Scale- 34.7% (group 2) and 25.9% (group 1), movement capacity- 45.7% (group2) and 32.7% (group 1). The results were also statistic significant (p&lt;0.05). The compliance of the study participants was very good: only three patients did not complete the 3 weeks rehabilitation program. <h3>Conclusions</h3> Improvement of pain, physical impairments and disabilities for the study group certifies the efficacy of the rehabilitation program including physical exercise for the patients suffering from hip osteoarthritis and motivates the continuation of the study on a longer period of time and on a larger number of patients. <h3>Disclosure of Interest</h3> None Declared
An Endoscopic View of Appendicitis
Authors: Anil Minocha
Journal: New England Journal of Medicine (1998)

To the Editor: The diagnosis of acute appendicitis is often, but not always, straightforward. Imaging studies, such as ultrasonography and computed tomography, may be helpful. When other diagnoses seem more likely, colonoscopy may be performed,1,2 although acute appendicitis may occur as a complication of colonoscopy.3,4 I describe a patient in whom appendicitis was diagnosed by colonoscopy. A 42-year-old man was evaluated in the emergency department because of the sudden onset of poorly localized, right-sided abdominal pain with nausea and vomiting. He was afebrile, and there was no change in bowel motion. He had a history of intermittent hematochezia . . .
TERMINATION OF A LEFT ATRIAL TACHYCARDIA BY LEFT ATRIAL APPENDAGE LIGATION
Authors: Moustapha Atoui, Sampath Gunda, Jayasree Pillarisetti, Muhammad Afzal, Donita Atkins, Madhu Reddy, Dhanunjaya Lakkireddy
Journal: Journal of the American College of Cardiology (2015)