tbuckley/cabot-search huggingface dataset:
Abstract 5079: A mathematical approach to earlier cancer detection: Using blood biomarker assays to monitor growth of a tumor from a single cell
Authors: Sharon S. Hori, Sanjiv S. Gambhir
Journal: Cancer Research (2011)

Abstract Early cancer detection may eventually be enabled by a quick, highly sensitive assay to monitor abnormal cancer biomarker levels in blood, followed by a localized imaging scan to visualize tumor burden. To improve screening of high-risk patients prior to imaging, blood assay sensitivity/specificity is being increased and biomarker secretion processes are being studied, but it is not clear which strategies will provide better detection of smaller tumors. To address this, we developed a linear 1-compartment model with 9 parameters to describe plasma biomarker kinetics in relation to the growth of cancer, beginning with a single tumor cell. In this model, plasma biomarker levels are dependent on the number of biomarker-secreting cells (cancerous and healthy), the biomarker secretion rate, the percent of biomarker entering plasma from the interstitium, and the elimination rate of plasma biomarker. To exemplify a realistic case, we based parameter values on ovarian cancer and CA125 secretion because CA125 secretion rates and assay sensitivities are readily available in published literature. Gompertzian tumor growth was modeled using published human ovarian carcinoma growth rates. The model predicted that tumor burden must grow to a volume of (20.4 mm)3 to reach plasma biomarker levels that are greater than in 99.9% of healthy patients; this may require &amp;gt;10 years after the birth of the initial tumor cell. These predictions are consistent with published cancer progression timelines recently uncovered from sequencing of metastatic genome data. Furthermore, by perturbing parameter values over log-orders of magnitude, we identified alternative strategies that could allow detection of &amp;lt;1 mm diameter tumors (Table). Applying this model to other cancers and associated biomarkers may pinpoint characteristics of ideal biomarkers and the assays used to detect them, thereby helping to identify cancers at earlier stages, when they can be more effectively treated. 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 5079. doi:10.1158/1538-7445.AM2011-5079
Abstract 3254: Novel bivalent Smac mimetics as a new class of anticancer agents
Authors: Haiying Sun, Jianfeng Lu, Liu Liu, Donna McEachern, Longchuan Bai, Chao-Yie Yang, Shaomeng Wang
Journal: Cancer Research (2011)

Abstract Second mitochondria-derived activator of caspase (Smac) is a protein released from mitochondria in response to apoptotic stimuli which functions as an endogenous inhibitor of several members of inhibitor of apoptotic proteins (IAPs), including XIAP, cIAP-1 and cIAP-2. Smac interacts with IAPs by binding of its N-terminal AVPI tetrapeptide to one or more BIR domains in IAPs. We designed and synthesized a series of non-peptidic, cell-permeable, bivalent small-molecules which mimic the dimeric Smac protein for targeting IAPs (bivalent Smac mimetics) and performed extensive evaluations of these bivalent Smac mimetics for their interaction with IAP proteins and their activity and mechanism of function in cancer cells. Our studies show that these Smac mimetics bind to XIAP, cIAP-1 and cIAP-2 with low nano-molar affinities. They function as extremely potent XIAP antagonists by concurrently targeting both the BIR2 and BIR3 domains of XIAP and nullify its inhibition to both caspase-9 and caspase-3/-7 and potently and effectively induce rapid degradation of these two proteins in cancer cells. The most potent bivalent Smac mimetics inhibit cell growth with IC50 values at low nanomolar and effectively induce apoptosis in a subset of cancer cell lines through TNFα dependent mechanism. Furthermore, bivalent Smac mimetics can dramatically enhance the antitumor activity of TRAIL in both TRAIL-sensitive and -resistant cancer cell lines. The combination of one such bivalent Smac mimetic, SM-164 with TRAIL induces rapid tumor regression in vivo in a breast cancer xenograft model in which either agent is ineffective. Mechanistic studies demonstrate that while RIP1 plays a minimal role in TRAIL's activity as a single agent, it is required for the synergistic interaction between TRAIL and SM-164. XIAP and cIAP1 work in concert to attenuate the activity of TRAIL and SM-164 strongly sensitizes TRAIL by concurrently targeting XIAP and cIAP1. Taken together, our data suggest that bivalent Smac mimetics may have a great therapeutic potential for the treatment of human cancer by targeting multiple IAPs, either alone or in combination with TRAIL. 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 3254. doi:10.1158/1538-7445.AM2011-3254
Abstract 2601: ROCK1 as a potential therapeutic target in pancreatic cancer
Authors: Clifford Whatcott, Aprill Watanabe, Joseph Demirjian, Michael Barrett, Galen Hostetter, Daniel Von Hoff, Haiyong Han
Journal: Cancer Research (2011)

Abstract ROCK1, or Rho-associated coiled coil-containing protein kinase 1, is a multifunctional member of the AGC (protein kinase A/G/C) kinase family that has been implicated in the modulation of stress-fiber assembly, cell-cell adhesion, cell contraction, apoptosis, cytokinesis, and in the migration and invasion of multiple cell types. Increased ROCK1 expression has been observed in a number of pathological conditions, including cancer. We identified a low frequency (4/34) amplification of the ROCK1 gene locus at chromosome 18q11.1 in pancreatic ductal adenocarcinoma (PDA) patient tissue samples by aCGH analysis. We therefore hypothesized that ROCK1 might play an important role in pancreatic cancer progression, and may serve as a suitable target in pancreatic cancer treatment. Consistent with findings in other tumor types, we observed increased expression of ROCK1 in pancreatic epithelial cells relative to the surrounding stromal cells, or adjacent normal pancreatic ductal cells, in an immunohistochemical (IHC) analysis of a pancreatic cancer tissue array. In our study, 76% (53/70) of tumor samples exhibited 2+ or greater (scale 0-3+) in staining intensity by IHC analysis, versus 40% (19/47) of adjacent normal tissue samples (P&amp;lt;0.0001). This same increased expression of ROCK1 in cancer cells was also observed in a coculture model of human PDA cells and primary myofibroblast cells derived from PDA tissues. Inhibition of ROCK kinase activity by small molecule inhibitors (Fasudil and Y27632) demonstrated moderate (IC50s range from 2-30 μM) inhibition of PDA cell proliferation. An increased sensitivity to ROCK1 inhibition was observed in PDA myofibroblasts, which corresponded with a decreased expression of Collagen I. These results suggest that ROCK1 may play a role in pancreatic cancer, both in the proliferation of tumor epithelial cells, as well as the development of the stromal compartment. Based on these findings we feel that ROCK1 is a potential therapeutic target in both the tumor and stromal cells in pancreatic cancer, and may provide an effective means to enhance current treatment regimens. 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 2601. doi:10.1158/1538-7445.AM2011-2601
AB0410 Non-thromboembolic risk in sle associated antiphospholipid syndrome
Authors: M. Deak, M. Bocskai, S. Burcsár, O. Dányi, Z. Fekete, L. Kovács
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Antiphospholipid syndrome (APS) is frequently associated with systemic lupus erythematosus (SLE). In addition to an increased thromboembolic risk, it may alter the disease course of SLE. Our aim was to study the impact of secondary antiphospholipid syndrome and antiphospholipid antibody (APA) positivity on the clinical presentation of SLE. <h3>Methods</h3> Data of 224 SLE patients (204 females, average age: 49 /20-92/ years) were analised retrospectively. Various SLE and APS related clinical and laboratory features were compared between patients without APA (n=119) and those with APA-positivity (n=105). Of these 105 APA-positive patients, 53 fulfilled the criteria for APS. Data on SLE+APS patients were also compared with those on SLE patients without APA-positivity. Central nervous system, cardiac, pulmonary and renal symptoms were considered major organ manifestations. <h3>Results</h3> Significantly higher proportion of the APA-positive versus APA-negative SLE patients developed thromboembolic events, Coombs-positive haemolytic anaemia, thrombocytopenia and endocarditis. In addition, when APS complicated SLE, several non-thromboembolic symptoms occurred more often, than in the absence of APS: pleuritis, interstitial lung disease, myocarditis, nephritis and organic brain syndrome. The total number of major organ manifestations (1,2 vs 0,5) and also the sum of the organ manifestations ever occurred in an individual patient (8,1 vs 6,9) were higher in the SLE+APS patients than in those without APA (p&lt;0.05). In the presence of secondary APS, SLE patients required more frequently iv. corticosteroid, iv. cyclophosphamide and azathioprine threatment, than the non-APA patients (p&lt;0,05). <h3>Conclusions</h3> The SLE patients with APA positivity or with secondary APS have a higher risk to develop non-thromboembolic disease manifestations in addition to the APA-related symptoms. Moreover, the SLE+APS patients have a predisposition to more severe SLE-manifestations, with the necessity of powerful immunosuppressive therapies. <h3>Disclosure of Interest</h3> None Declared
P-199 Degradation of CONNEXIN 43 in the plasma membrane by autophagy in colon cancer
Authors: J. Paulo, J. Balça, M. Areias, L. André, S. Catarino, M. Zuzarte, A. Cadime, H. Gervásio, U. Schmidt Strassburger, H. Girão
Journal: Annals of Oncology (2015)
Abstract 417: SMAD3 upregulation is a novel biomarker of poor prognosis and epithelial-mesenchymal transition in pancreatic cancer.
Authors: Ken Yamazaki, Yohei Masugi, Kathryn Effendi, Michiie Sakamoto
Journal: Cancer Research (2013)

Abstract Pancreatic cancer has one of the worst survival rates among all cancers. Features like epithelial-mesenchymal transition (EMT) are often seen in pancreatic tumors and correlate with poor prognosis. The purpose of this study was to identify factors involved in EMT in pancreatic cancer that may serve as prognostic indicators. Gene-expression profiling identified overexpression of SMAD3 in pancreatic cancer with high-grade solitary cell infiltration, one of the EMT-like features. SMAD3 expression was then evaluated through immunohistochemical analysis using clinical specimens. SMAD3 was accumulated in the nuclei of tumor cells (positive rate ranging from 0% to 75%), but was not detected in most of the epithelial cells in the pancreatic duct. Upregulated SMAD3 (≥15% positive in nuclei of tumor cells) correlated with malignant characteristics, such as higher tumor grade (P = 0.001) and lymph node metastasis (P &amp;lt;0.001), as well as with EMT-like features, such as reduced E-cadherin (P = 0.013) and elevated vimentin (P = 0.032). SMAD3 knockdown in pancreatic cancer cells resulted in increased E-cadherin expression, decreased vimentin expression and decreased cell motility. The suppressed EMT-like features by SMAD3 knockdown were observed even in SMAD4-inactivated pancreatic cancer cells, suggesting that SMAD3 is involved in EMT induction, regardless of SMAD4 status. In clinical cases, SMAD3 upregulation and EMT-like features correlated with shorter survival time. Moreover, SMAD3 and E-cadherin were identified as independent prognostic factors by multivariate analysis, and the group of patients with both upregulated SMAD3 and reduced E-cadherin had the least favorable prognosis compared with other groups. Taken together, SMAD3 seems to play an important role in malignant progression of pancreatic cancer, and may provide a potential biomarker for poor prognosis of pancreatic cancer. Citation Format: Ken Yamazaki, Yohei Masugi, Kathryn Effendi, Michiie Sakamoto. SMAD3 upregulation is a novel biomarker of poor prognosis and epithelial-mesenchymal transition in pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 417. doi:10.1158/1538-7445.AM2013-417
Abstract 3442: Olaparib increases antitumor effects on epigenetically RAD51C-deficient human cancer cells.
Authors: Ahrum Min, Seongyeong Kim, Seock-Ah Im, Young-Kwang Yoon, Sang-Hyun Song, Hyun-Jin Nam, Hyung-Seok Hur, Kyung-Hun Lee, Sae-Won Han, Do-Youn Oh, Tae-You Kim, Mark J. O'Connor, Woo-Ho Kim, Yung-Jue Bang
Journal: Cancer Research (2013)

Abstract Background: The poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib, has been found to have a therapeutic potential for treating cancers that have an impaired DNA repair ability. RAD51C has been reported to play an essential role in DNA repair mediated by homologous recombination. In addition, RAD51C is a gene that affects human cancer susceptibility, similar to BRCA1 and BRCA2. RAD51C-defective cancers can therefore be potentially treated with olaparib because DNA damage induced by olaparib cannot be effectively repaired by HR since RAD51C deficiency interferes with RAD51-mediated HR. Materials and Methods: We studied the growth inhibitory effects of olaparib on human cancer cell lines using clonogenic survival assays. Cell cycle analysis and molecular changed induced by olaparib were also performed. DNA methylation status in cancer cells and tumor tissue samples was also determined by using bisulfate sequencing. Results: Olaparib is effective to RAD51C-defective cells. Olaparib leads to the accumulation of unrepaired DSBs due to dysfunctional RAD51 foci formation along with increased caspase 3-dependent cell death and G2/M arrest in RAD51C-defective cells. Moreover, the growth of RAD51C-deficient SNU601 tumor cells in a xenograft model decreased significantly following treatment with olaparib. Furthermore, RAD51C expression was significantly decreased in cancer and the lack of RAD51C was attributed to DNA methylation and histone modification. Our findings showed that the loss of RAD51C expression due to epigenetic silencing leads to olaparib sensitivity in cancer cells. Conclusion: The loss of RAD51C expression was frequently associated with human cancers. We used a novel synthetic lethal approach using PARP inhibitors and observed that RAD51C was a participant in the DNA repair pathway. Our findings have potential clinical application for treating cancers with RAD51C deficiencies. Furthermore, we determined that RAD51C may serve as a novel biomarker for identifying olaparib-sensitive patients, thereby allowing physicians to select the most effective modalities for treating these individuals. Citation Format: Ahrum Min, Seongyeong Kim, Seock-Ah Im, Young-Kwang Yoon, Sang-Hyun Song, Hyun-Jin Nam, Hyung-Seok Hur, Kyung-Hun Lee, Sae-Won Han, Do-Youn Oh, Tae-You Kim, Mark J. O`Connor, Woo-Ho Kim, Yung-Jue Bang. Olaparib increases antitumor effects on epigenetically RAD51C-deficient human cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3442. doi:10.1158/1538-7445.AM2013-3442
FRI0175 Anti-drug-antibodies but not igg-4 antibodies against tnf blockers influence the activity of anti-tnf drugs in rheumatoid arthritis
Authors: M. Benucci, M. Infantino, M. Manfredi, B. Olivito, P. Sarzi-Puttini, F. Atzeni
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Anti-TNF drugs have changed the clinical course of rheumatoid arthritis (RA), but the survival rate and the resistance to the therapy showed that about 30% of RA patients fail to respond to these drugs. <h3>Objectives</h3> The aim of our study was to evaluate the correlation between the development of anti-drug antibodies and specific IgG-4 antibodies against TNF inhibitors and the resistance to this therapy in RA patients. <h3>Methods</h3> The retrospective study involved 130 established RA patients [98 females and 32 males, mean age 56,7±12,3 years, disease duration 6,3±1.2] who fail to respond to conventional DMARDs treated with anti-TNF agents [32 pts with INF, 58 pts. with ETN, 40 pts with ADA] with a baseline DAS28 range between 3.2-5.6. After 6 months of treatment according to DAS28 values the patients were classified in remission for DAS28 &lt;2.6 (R) and having low disease activity (LDA) for DAS28 range between 2.6-3.2 or non responder (NR)&gt;3.2. The patients were tested for serum anti-drugs antibodies (Anti TNF-α Blocker ELISA kit Immundiagnostik AG, Bensheim - Listarfish, Milan, Italy) and IgG4 specific antibodies against TNF- inhibitors (ImmunoCAP® Assay fluoroenzyme immuno assay Kit for ImmunoCAP250, Phadia, Uppsala, Sweden). <h3>Results</h3> After a mean of 6 months in IFN group: 15.65% of the patients were in remission (R ), 31.2 % in LDA and 53.12% NRs; in ETN group 22.41% of the patients in R, 41.37% in LDA, 36.20% NRs, in ADA group 30% of the patients in R, 25% in LDA and 45% NRs. In the INF group the anti-drug antibodies were detected in 21. 87% of the patients and specific IgG-4 antibodies in18%, in ETN group the anti-drug antibodies were detected in 10.34% and specific IgG-4 antibodies in 8.67%, in ADA group the anti-drugs antibodies in 25% and specific IgG-4 antibodies in 5%. The presence of anti-drug antibodies in INF e ADA group correlate with the high percentage of NRs (R:0.032 ;R:0.039). No correlation with the specific IgG-4 antibodies against TNF and clinical response was observed. <h3>Conclusions</h3> In patients with RA the presence of all anti-drug antibodies but not the specific IgG-4 antibodies against TNF could influence the activity of TNFblockers in particular in INF and ADA group. This study also confirmed the low immunogenecity of ETN. <h3>Disclosure of Interest</h3> None Declared
P09 * CAN RAPIDARC(R) IMPROVE THE OUTCOME OF GLIOMAS TREATED WITH RADIOTHERAPY?
Authors: D. R. Crossley, M. Henshaw, M. Hill, D. B. Foran
Journal: Neuro-Oncology (2014)

INTRODUCTION:Radiotherapy is used to treat high and low grade gliomas either as primary therapy or as an adjunct following surgery. However, long term side effects in patients with low grade gliomas, and complete tumour coverage in high grade gliomas is a concern due to the proximity of sensitive structures in the central nervous system. RapidArc® Volumetric arc therapy is a type of rotational intensity modulated radiotherapy (IMRT) used to reduce dose to organs at risk (OARs) and improve dose and coverage of the target. Could this improve outcomes and toxicity in gliomas treated with radiotherapy? We will discuss the experience of using RapidArc® in our centre for the treatment of gliomas over a 2 year period. METHOD:We compared radiotherapy treatment plans for gliomas before and after the establishment of RapidArc® planning. Treatment volumes, beam arrangements with colourwashes and dose-volume histograms were analysed for comparison. RESULTS: Planning with RapidArc® as compared to conventionally planned radiotherapy results in a significant reduction in the area treated to a higher dose, especially to the optic lenses and the normal surrounding brain. It does however, result in a larger area receiving a low dose of radiation.The dose distribution and homogeneity across the PTV was significantly better with RapidArc® as compared to conventionally planned radiotherapy. Tumours close to OARs (e.g. chiasm) received much better coverage with RapidArc®. CONCLUSION: RapidArc® is a modern IMRT technique that results in better coverage of the target and reduced doses to the OARs when treating gliomas. Longer term follow up ideally within a clinical trial is needed to confirm the improvements in long term outcomes and toxicity.
Potential Gene Therapy for AIDS Described
Authors: L. F. Anderson
Journal: JNCI Journal of the National Cancer Institute (1989)

Potential Gene Therapy for AIDS Described Get access Linda F. Anderson Linda F. Anderson Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 14, 19 July 1989, Pages 1055–1056, https://doi.org/10.1093/jnci/81.14.1055 Published: 19 July 1989
DIFFERENTIAL NEURONAL REMODELING IN PORCINE INTRINSIC CARDIAC GANGLIA FOLLOWING MYOCARDIAL INFARCTION
Authors: Keijiro Nakamura, Olujimi Ajijola, Pradeep Rajendran, Eileen So, Kentaro Yamakawa, Tadanobu Irie, David Hamon, Marmar Vaseghi, Jeffrey Ardell, Kalyanam Shivkumar
Journal: Journal of the American College of Cardiology (2015)
A9.1 Macrophage activation syndrome after mycoplasma pneumoniae infection
Authors: Blanca Szolga, Ileana Filipescu, Laura Damian, Simona Rednic, Nicolae Rednic
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Introduction</h3> Macrophage activation syndrome is a rare and potentially life threatening condition, triggered by various events like bacterial and viral illness and sometimes it can be a complication of childhood rheumatic disorders. Physical and laboratory results usually show non-remitting fever, hepatosplenomegaly, lymphadenopathy, bleeding diathesis, altered mental status, rash, pancytopenia and impaired liver and renal function tests, elevated triglyceride and serum ferritin levels. Corticosteroids and Cyclosporine are the drugs commonly used in its management. Early diagnosis and prompt treatment can be life saving. <h3>Objective</h3> To present a case of Macrofage activation syndrome triggered by a Mycoplasma pneumoniae infection. <h3>Background</h3> A 18 years old male pacient presented with high fever, tachycardia, lethargy, leucopenia and artharlgias after having a Mycoplasma pneumoniae infection treated in the Infectious disease department. <h3>Investigations </h3> Physical and laboratory results showed hepatosplenomegaly, high fever, tachycardia, low levels of Ig G and Ig M, leucopenia and the bone marrow aspiration showed cells phagocytosing hematopoietic elements. Also, on the basis of the effectuated investigations ( CBC; biochemistry and immunology tests; cultures of boold, urine, stool; abdomen and heart ultrasonography; thoracic CT) other infectious, malignant or rheumatic diseases were exclused. <h3>Diagnosis</h3> Macrophage activation syndrome triggered by a Mycoplasma pneumoniae infection. <h3>Management</h3> The patient9s disease was successfully controlled following the treatement with Methyprednisolone and Cyclosporine. <h3>Discussion and conclusion</h3> This case illustrates this rare, but potentially life-threatening condition sometimes associated with chronic rheumatic disorders with various triggering events like bacterial and viral illness. Differentiation from a disease flare of a rheumatic disorder is difficult and that is why pacients with this condition need further investigation and careful monitoring. In conclusion, MAS is a severe, potentially life-threatening complication of chronic rheumatic disease; therefore it is essential for clinicians to have a high threshold of suspicion, make an early diagnosis, and start prompt treatment to have success.