tbuckley/cabot-search huggingface dataset:
Abstract 1752: Nonclinical safety and pharmacokinetics of Sym004: A synergistic anti-EGF receptor antibody mixture
Authors: Niels Jørgen Skartved, Mikkel W. Pedersen, Helle Jacobsen, Thomas K. Jørgensen, Michael Kragh
Journal: Cancer Research (2011)

Abstract Epidermal growth factor receptor (EGFR) is a well validated oncology target for monoclonal antibodies (mAb's). Symphogen is developing a novel and more efficacious anti-EGFR therapy to treat cancer patients with EGFR-dependent tumors. Sym004 is a recombinant antibody product consisting of a 1:1 mixture of two chimeric IgG1 mAb's targeting non-overlapping epitopes of EGFR. Preclinical proof-of-concept studies have shown that the Sym004 mixture is superior to existing anti-EGFR mAb's currently in clinical use (1). The nonclinical safety data of Sym004 are presented. The studies were designed to evaluate toxicity and pharmacokinetics of Sym004 as well as the individual antibodies comprising Sym004. No apparent accumulation was observed upon weekly dosing of Sym004 to non-human primates for eight consecutive weeks, whereas, a prolonged half life and accumulation were noted for both of the individual antibodies if these were administered alone. Weekly administration of Sym004 to non-human primates was well tolerated although dose limiting toxicity was observed in a dose-range-finding toxicology study. In a head-to-head comparison with the licensed anti-EGFR mAb, cetuximab (Erbitux®), weekly administration of Sym004 did not induce any distinct or novel adverse findings in the animals. However, and in accordance with the enhanced pharmacological profile of Sym004, an accelerated onset of anticipated anti-EGFR-mediated effects (skin rash and liquid faeces) was observed compared to cetuximab. None or only minor effects were observed in the animals treated with the individual antibodies comprising Sym004. All experimental observations, except a single case of rash, showed reversibility during the 4-week treatment free recovery period. In tissue cross reactivity studies, Sym004 had a staining pattern similar to cetuximab in a full tissue panel from both human and non human primates. In conclusion, Sym004 is considered to be safe, and the nonclinical safety data supported the initiation of the currently ongoing Phase I/II trial. 1. Pedersen MW et al. Cancer Res; 70(2) January 15, 2010 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1752. doi:10.1158/1538-7445.AM2011-1752
Abstract 506: Mechanisms of microvesicle-mediated communication in cancer
Authors: Katrin J. Svensson, Helena C. Christianson, Anders Wittrup, Maria C. Johansson, Matthias Mörgelin, Mattias Belting
Journal: Cancer Research (2011)

Abstract The many functional roles of microvesicles (MVs) in tumor development and progression have lately become a subject of intense investigation. Cancer cell derived genetic material and signaling proteins residing in MVs can be transferred to recipient cells by as yet ill-defined mechanisms. We have found that heparan sulfate proteoglycans (HSPGs), which previously have been implicated as receptors of various macromolecular ligands, also can mediate the uptake of MVs. Our data suggest that MV uptake involves membrane raft, non-caveolin dependent endocytosis. These findings are consistent with recent data from our group on HSPG-mediated uptake of antibody-conjugated nanoparticles. Furthermore, MVs were found to be sorted to CD63-containing, vesicular compartments through intracellular transport that appeared highly dependent on an intact microtubule network. Intriguingly, preliminary findings support the concept of intracellular exchange of MV cargo, thus giving rise, in a single transporting vesicle, to a signal that integrates information from multiple cells. The presented results reveal a novel receptor that mediates MV uptake, and advance our general understanding of MV-dependent transfer of molecular information. Finally, the finding that MVs can potentially harbor molecules from multiple cells residing in the tumor environment opens up new, exciting roles of MVs as information carriers in cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 506. doi:10.1158/1538-7445.AM2011-506
Diffuse Splenic F-18 FDG Uptake in Visceral Leishmaniasis
Authors: Ali Fuat Yapar, Mehmet Reyhan, Nazim Emrah Kocer, Mehmet Aydin, Gül Nihal Nursal
Journal: Clinical Nuclear Medicine (2011)

A 51-year-old woman had splenomegaly and enlarged multiple splenic hilar lymph nodes. The patient was referred to our department for F-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) evaluation to determine the metabolic activity of lymph nodes and define a biopsy site. PET/CT images showed diffuse increased FDG uptake in an enlarged spleen and hypermetabolic splenic hilar lymph nodes. The metabolic activity in bone marrow also seemed diffusely increased. After splenectomy, histopathologic analysis showed the growth of Leishmania amastigotes in splenic tissue, and bone marrow biopsy did not reveal any significant pathology but only mild hypercellularity.
Abstract 1750: Reduced xpression of Reelin (RELN) gene is associated with high recurrence rate of hepatocellular carcinoma
Authors: Yukiyasu Okamura, Shuji Nomoto, Mitsuro Kanda, Masamichi Hayashi, Tsutomu Fujii, Hiroyuki Sugimito, Shin Takeda, Akimasa Nakao
Journal: Cancer Research (2010)

Abstract Background and Aims: Hepatocellular carcinoma (HCC) is one of the world's top five causes of cancer-related deaths and has limited treatment options. HCC is one of the few cancers for which the etiology of the underlying disease is known in most cases. However, the molecular pathogenesis of HCC has not been fully elucidated. Recently described genome-wide approaches robustly detect many candidate genes that are regulated in HCC. Here we attempt to identify the novel genes with altered expressions related to clinical factors using a double-combination array, which contains an expression array and a single nucleotide polymorphism (SNP) array. Moreover, we analyzed the identified gene, using quantitative reverse transcription polymerase chain reaction (RT-PCR) and methylation-specific PCR. Samples and Methods: A 68-year-old woman with chronic hepatitis C was diagnosed with HCC and underwent liver resection. On the same HCC sample, we performed double-combination array analysis. We consequently analyzed the identified gene, using quantitative RT-PCR, methylation-specific PCR, and un-methylated specific PCR in five HCC cell lines, together with 48 pairs of HCC tissues (HTs) and adjacent non-tumorous tissues (NTs) obtained from patients who underwent hepatectomy. The results were compared with the clinico-pathological data. Results: There was decreased expression of the Reelin (RELN) gene in HT at the level of −3.0. We then used the SNP-Chip array to confirm that the copy number of chromosome 7 where RELN is located did not show any abnormalities. These results suggest that RELN expression was reduced without LOH or deletion. We then examined the sequence of the promoter region of RELN gene and found many CpG islands. Therefore, we hypothesized that hypermethylation of the CpG islands was the mechanism for its decreased expression in HT. Thirty-four of 48 (79.2%) samples had decreased RELN expression level in HTs and the expression level of HTs was clearly reduced compared with that of NTs (P &amp;lt; 0.002). We found that 18 of 48 (37.5%) HTs had promoter hypermethylation of the RELN gene. In regard to clinical data, the patients with reduced expression in HTs have a high recurrence rate (P = 0.028). Conclusion. The present study suggests that our method is able to detect novel genes with altered expression and that RELN is a novel gene associated with recurrence of HCC. 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 1750.
Tl-201 Uptake in Chronic Hypertrophic Pachymeningitis
Authors: HITOYA OHTA, HIROKI TAKEUCHI, TAKAO SUZUKI, MASAYUKI SHINTAKU
Journal: Clinical Nuclear Medicine (2003)

OHTA, HITOYA M.D.; TAKEUCHI, HIROKI M.D.; SUZUKI, TAKAO; SHINTAKU, MASAYUKI M.D. Author Information
Abstract 4019: Identification of SOX4 transcriptional target genes in human lung cancer
Authors: Sandra D. Castillo, Pedro P. Medina, Niccolò Mariani, Montse Sanchez-Cespedes
Journal: Cancer Research (2011)

Abstract The search for novel oncogenes is becoming increasingly important in cancer genetics because they are suitable targets for therapeutic intervention. Our current work lays in study the role of the SOX4 transcription factor in human lung carcinogenesis. The SOX4 gene belongs to a large family of transcription factors related by homology in their DNA-binding domain and is predominantly expressed during embryonic development in heart, central nervous system, lung and thymus. SOX4 has been proposed as a candidate oncogene in many types of cancer such as bladder, prostate, colon, urothelial, adenoid cystic carcinoma and lung because of its increased expression in those tumors. Previous studies in our lab uncovered SOX4 gene amplification and concomitant over-expression in a subset of lung primary tumors and cancer cell lines. Interestingly, SOX4 expression was significantly greater in the SCLC cell lines. Little is known about the transcriptional targets and pathways orchestrated by SOX4 during lung carcinogenesis. To further investigate SOX4 contribution to lung carcinogenesis we developed an inducible short-hairpin system in the NCI-H522 lung cancer cell line, which is known to carry SOX4 gene amplification and over-expression, in order to abrogate SOX4 expression in an inducible manner. Then, we performed an expression analysis using the Whole Human Genome Oligo Microarray platform from Agilent which represents over 41000 genes and transcripts to elucidate the differential gene expression when knocking down SOX4. We found about 150 genes and transcripts with more than 2 fold-change of expression. Afterwards, we confirmed the array data by real time quantitative PCR (RT-qPCR) of the genes with a decreased expression when interfering SOX4 mRNA. Within these genes, we could confirm direct transcriptional targets of SOX4 by means of binding site computation and quantitative chromatin immunoprecipitation (qChIP). This integrated approach helps us to better understand the role of SOX4 in lung carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4019. doi:10.1158/1538-7445.AM2011-4019
A Deficient Diagnosis
Authors: Dina Hafez, Sanjay Saint, Julius Griauzde, Rajen Mody, Jennifer Meddings
Journal: New England Journal of Medicine (2016)

A previously healthy boy, 2 1/2 years old, presented with a 6-week history of progressive inability to bear weight on his right leg. His mother noted no recent trauma. His medical history was notable only for speech delay.
FRI0443 Bone loss in patients with early spondyloarthritis
Authors: E. E. Gubar, A. G. Bochkova, A. V. Smirnov, T. V. Dubinina, A. B. Demina, O. A. Krichevskaya, O. A. Rumyantseva, S. V. Shubin, E. V. Volnukhin, S. F. Erdes
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To examine bone mineral density (BMD) at the femoral neck and lumbar spine and to look for the association between bone loss and disease activity in patients with early spondyloarthritis (SpA). <h3>Methods</h3> 30 pts (14 men and 16 women) with early SpA were included in this study; mean age 28.9±6.3 years, disease duration &lt;24 months (15.3±8.1), mean BASDAI 4.4±3.9. Clinical data were collected and BMD was measured using dual energy X-ray absorptiometry (DXA) of the femoral neck and lumbar spine. Magnetic resonance imaging (MRI) of the sacroiliac joints (SIJs), and lumbar spine (L2–4) was performed. <h3>Results</h3> The reduction in BMD was found in 18 (60%) pts. All of them had osteopenia (-1&gt;T-score&gt;-2.5). 6 pts (20%) had osteopenia of lumbar spine, 4 pts (13.3%) had osteopenia of the femoral neck, osteopenia in both areas was found in 8 pts (26.7%). In all pts with osteopenia mean T-score was -1.68±0.47 at the femoral neck and -1.92±0.46 for the lumbar spine. Femoral neck and/or lumbar spine bone loss was found to be associated with bone marrow oedema of the SIJs and/or lumbar spine (p=0.029). No association was found between bone loss and raised C-reactive protein levels (p=0.184) or high disease activity according to BASDAI scores (p=0.703). <h3>Conclusions</h3> MRI bone marrow oedema of the SIJs and lumbar spine was found to be associated with bone loss in lumbar spine and femoral neck. <h3>Disclosure of Interest</h3> None Declared
A3.02 Antibodies to self and exogenous citrullinated antigens in the pre-symptomatic stage of rheumatoid arthritis
Authors: L Johansson, F Pratesi, M Brink, P Migliorini, S Rantapää-Dahlqvist
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> ACPA have been detected in individuals predating onset of rheumatoid arthritis (RA), with an initially limited spectrum of reactivities that gradually broadens to the wide recognition of different citrullinated substrates typical of established RA. Among the targets of ACPA, viral deiminated (citrullinated) proteins and antigens derived from neutrophil extracellular traps like histone H4 have been described. The aim of this study is to analyse the evolution of antibody response in pre-RA using citrullinated exogenous (viral peptides) and self (H4 peptides) antigens as substrates to detect ACPA. <h3>Patients and methods</h3> 521&nbsp;individuals sampled before any symptoms of RA and 272 population controls were identified as donors to the Medical Biobank of Northern Sweden; 241 plasma of early RA-patients were also collected. ACPA were detected by ELISA on viral citrullinated peptides derived from EBNA 1 and EBNA2 (VCP1 and VCP2) and on histones 4 (H4) derived peptides (HCP1 and HCP2). <h3>Results</h3> Anti-VCP1 antibodies were detected in 10.4% of the pre-symptomatic individuals as compared with 36.1% in early RA; anti-VCP2 in 17.1% vs. 52.3%; anti-HCP1 in 10.2% vs. 37.3%; anti-HCP216.3% vs. 48.5%. Anti-VCP and anti-HCP concentrations were significantly increased in pre-symptomatic individuals as compared with controls (p &lt; 0.001). Mean antibody concentration and frequency of positivityincreased steadily approaching symptom onset. ACPA specific for HCP or VCP appeared at the same time (median (Q1-Q3) 5.3 (2.9–8.9) years before symptom onset); positivity for anti-VCP2, HCP1 and HCP2 was associated with disease development. Combination of anti-VCP1, anti-VCP2 and anti–HCP2 and negativity for anti-HCP1 yielded a highrisk ratio (OR=18.70; 95% CI 2.53–138.47; p &lt; 0.004). Anti-VCP2 and anti-HCP2 antibodies were associated in presymptomatic individuals with HLA-SE but not with PTPN22 T-allele. <h3>Conclusions</h3> Anti-VCP and anti-HCP antibodies start to appear long before disease onset and predict disease development, butno hierarchy of citrullinated epitopes can be drawn in the building up of the ACPA response. Taken together with previous findings, these results suggest that no inciting citrullinated antigen so far described is common to all RA patients; data are rather compatible with a stochastic mechanism in ACPA production.
Successful nonoperative treatment of extensive extramammary Paget’s disease
Authors: T. J. Hieken, A. Lasser
Journal: Journal of Clinical Oncology (2005)

2584 Introduction: Extramammary Paget’s disease (EMPD) is a rare cutaneous neoplasm characterized by a variable clinical appearance and propensity for recurrence. Current accepted treatments include wide local excision, Mohs’ surgery, and, in some cases, radiation and chemotherapy. We report on our experience with the application of a topical immune response modifier for the treatment of extensive inguinal and perianal EMPD. Patient & Methods: A 69-year-old white male presented with a 6 month history of a pruritic erythematous eruption in both groins and the perianum. Multiple biopsies were performed and demonstrated intraepidermal EMPD. The lesions were confluent on both sides from groin to perianum and circumferentially encircled the anus. The patient had no clinically evident lymphadenopathy, normal laboratory tests including a CEA, clear chest and abdominal CT Scans and negative cystoscopic, anoscopic and colonoscopic examinations. The patient was offered daily self-administered topical treatment with 5% imiquimod cream as an alternative to staged excision and reconstruction. Results: The patient completed a 10 week course of therapy, with one mid-course break for 10 days secondary to erythema, irritation and discomfort of the adjacent scrotum. He had no systemic symptoms or hematologic from treatment. At the cessation of treatment he had mild skin discoloration. At eight months follow-up the patient is well without evidence of local, regional or distant disease or any concomitant genitourinary or gastrointestinal malignancy. Multiple repeated biopsies have shown no evidence of tumor. Conclusions: Imiquimod, a biologic response modifier known to stimulate both innate and acquired immune function, via induction of cytokines and activation of antigen-presenting cells, was effective treatment of extensive inguinal and perianal EMPD in our patient. In this case, the advantages of this nonsurgical treatment include tissue sparing and functional preservation as well as avoidance of a morbid procedure associated with a prolonged recovery. The long term success of this approach and its applicability to invasive malignancy remains to be determined. No significant financial relationships to disclose.
Pneumatosis cystoides intestinalis secondary to increased intraluminal air pressure of previous colonoscopies
Authors: Eduardo Rodrigues-Pinto, Rosa Ramalho, Helena Baldaia, Guilherme Macedo
Journal: Endoscopy (2014)

A 67-year-old man was referred for surveillance colonoscopy because of his past medical history of a segmental colonic resection in 2010 for colorectal adenocarcinoma. He underwent colonoscopy in 2011 and again in 2013, with endoscopic polypectomy carried out during both procedures. He was asymptomatic. In 2014, multiple sessile, ball-shaped subepithelial nodules were identified at the colonic anastomosis, suggestive of pneumatosis cystoides intestinalis ([Fig. 1]). Some of the nodules were covered with a reddish mucosa ([Fig. 2]), but the mucosa overlying most of the nodules was normal ([Fig. 3]). Biopsies were done to confirm the nature of the cystic lesions ([Fig. 4]), and an injection needle was used to puncture the cyst and determine the nature of the target, with the release of “air” and cyst collapse ([Video 1]). Mucosal histology confirmed the diagnosis ([Fig. 5]).
Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia
Authors: John C. Byrd, Bonnie Harrington, Susan O’Brien, Jeffrey A. Jones, Anna Schuh, Steve Devereux, Jorge Chaves, William G. Wierda, Farrukh T. Awan, Jennifer R. Brown, Peter Hillmen, Deborah M. Stephens, Paolo Ghia, Jacqueline C. Barrientos, John M. Pagel, Jennifer Woyach, Dave Johnson, Jane Huang, Xiaolin Wang, Allard Kaptein, Brian J. Lannutti, Todd Covey, Maria Fardis, Jesse McGreivy, Ahmed Hamdy, Wayne Rothbaum, Raquel Izumi, Thomas G. Diacovo, Amy J. Johnson, Richard R. Furman
Journal: New England Journal of Medicine (2015)

Irreversible inhibition of Bruton's tyrosine kinase (BTK) by ibrutinib represents an important therapeutic advance for the treatment of chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromises its therapeutic index. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors.In this uncontrolled, phase 1-2, multicenter study, we administered oral acalabrutinib to 61 patients who had relapsed CLL to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib. Patients were treated with acalabrutinib at a dose of 100 to 400 mg once daily in the dose-escalation (phase 1) portion of the study and 100 mg twice daily in the expansion (phase 2) portion.The median age of the patients was 62 years, and patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletion, and 75% had unmutated immunoglobulin heavy-chain variable genes. No dose-limiting toxic effects occurred during the dose-escalation portion of the study. The most common adverse events observed were headache (in 43% of the patients), diarrhea (in 39%), and increased weight (in 26%). Most adverse events were of grade 1 or 2. At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response with lymphocytosis; the remaining 5% of patients had stable disease. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%. No cases of Richter's transformation (CLL that has evolved into large-cell lymphoma) and only one case of CLL progression have occurred.In this study, the selective BTK inhibitor acalabrutinib had promising safety and efficacy profiles in patients with relapsed CLL, including those with chromosome 17p13.1 deletion. (Funded by the Acerta Pharma and others; ClinicalTrials.gov number, NCT02029443.).
556miR-23b and miR-199a regulate atrioventricular cushion epithelial-to-mesenchymal transition in chickens
Authors: F Bonet, A Aranega, D Franco
Journal: Cardiovascular Research (2014)

Valve development is a multistep process involving the activation of the cardiac endothelium, an epithelial-mesenchymal transition (EMT) and the progressive lining and differentiation of distinct mesenchymal cell types into the fibrosa and spongiosa layers. Several pathways such as Notch/delta, Tbf-beta and/or Vegf signalling have been involved in a crucial steps of valvulogenesis. We have previously demonstrated that discrete changes on microRNAs expression occur during ventricular chamber development. Several of these microRNAs were predicted to target Bmp- and Tgf-beta signalling, which are crucial steps during valvulogenesis. We have therefore analyzed the expression profile of candidate microRNAs in the atrial, ventricular and atrioventricular canal regions at four different developmental stages, HH13, HH19, HH27 and HH32. qRT-PCR analyses of microRNAs demonstrated a highly dynamic and distinct expression profile within the atrial, ventricular and atrioventricular canal regions of the developing chicken heart. Several microRNAs, such as miR-23b displayed increased expression at early but not late AVC developmental stages as compared to the atrial and ventricular chambers, whereas others such as miR-130a display decreased expression levels. Furthermore, we have implemented an in vitro EMT model to study microRNA function. Our results demonstrated that over-expression of miR-23b or miR-199 significantly blocks EMT in a similar fashion as high glucose administration controls, yet the analyses of the distinct signalling pathways involved in valvulogenesis suggest microRNA-specific control mechanisms. We shall provide a working model as how microRNA impact EMT during atrioventricular valve development.