tbuckley/cabot-search huggingface dataset:
Abstract P4-01-06: The Role of the PI3K/AKT, RAS/MAPK and Novel Signaling Pathways in Resistance to HER2-Targeted Therapy
Authors: NA O'Brien, K Wilcox, M McDermott, J Crown, N O'Donovan, DJ. Slamon
Journal: Cancer Research (2010)

Abstract Despite the proven clinical benefits of HER2-targeted therapy, resistance to trastuzumab and lapatinib exists. Understanding the molecular mechanisms responsible for resistance is critical to improving the survival rates of patients with this aggressive subtype of breast cancer. Currently, there are no clinically validated biomarkers of resistance to therapy. To address this issue, we measured the responses of a panel of 18 HER2-amplified breast cancer cell lines to both trastuzumab and lapatinib and evaluated the activity of PI3K/AKT/mTOR and RAS/MAPK/ERK signaling in resistance. Eight of the cell lines were identified as resistant to trastuzumab and seven as resistant to lapatinib by both two and three dimensional response assays. Five of the trastuzumab resistant cell lines remained sensitive to lapatinib (IC50 &amp;lt; 1 μM), indicating that these two agents have at least partially non-overlapping mechanisms of resistance. The combination of low PTEN or the presence of activating mutations of PI3K, and thus increased activity of PI3K/AKT signaling, is a strong predictor of resistance to trastuzumab. However, this is not the case with lapatinib, two of the cell lines with activating mutations of PI3K (MDA-361 and HCC-202) were resistant to lapatinib whereas two other PI3K mutant cells lines (SUM-190 and HCC-1954) were lapatinib sensitive, indicating that lapatinib resistance can occurindependently of increased PI3K/AKT signaling. To further investigate these mechanisms, we measured the effects of trastuzumab and lapatinib treatment on AKT/mTOR and ERK activation. Cell lines sensitive to trastuzumab or lapatinib showed a marked reduction in pAKT, pS6K and pERK in response to either agent, whereas the resistant cells maintained high pAKT, pS6K and pERK levels in the presence of trastuzumab and lapatinib. In cell lines resistant to trastuzumab yet sensitive to lapatinib, treatment with lapatinib significantly reduced the phosphorylation of AKT, S6K and ERK. Thus in a subpopulation of cell lines lapatinib can overcome trastuzumab resistance via continued deactivation of PI3K/AKT/mTOR and MAPK/ERK signaling. However, there still remains a subgroup of HER2-positive cells that are resistant to both trastuzumab and lapatinib. We used global expression analysis by both mRNA microarray and proteomic screening to identify a set of genes and proteins that are consistently altered in these innately resistant cells relative to the sensitive cell lines. In vitro validation of these targets will reveal which are playing a functional role in resistance and are thus potentially druggable targets to be used in improving the survival of patients with HER2-positive disease. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-01-06.
Abstract LB-324: A toll-like receptor 4 agonist enhances the efficacy of trastuzumab therapy and promotes adaptive immunity and long-term protection against a human ErbB-2 (HER2)-transfected syngeneic tumor in a human HER2 transgenic mouse model
Authors: Shangzi Wang, Wei Xu, Yong Tang, Rishi Surana, Catherine Bingham, Igor A. Astsaturov, Kenneth McCarthy, R. Katherine Alpaugh, Bruce A. Littlefield, Lynn D. Hawkins, Sally T. Ishizaka, Louis M. Weiner
Journal: Cancer Research (2010)

Abstract Antibodies against cancer-relevant targets can recruit Fc receptor-bearing myeloid and natural killer cells to mediate antibody dependent cellular cytotoxicity (ADCC). Toll-like receptors are potent activators of the innate immune system and generate signals leading to the initiation of an adaptive immune response that can be utilized for therapeutic purposes. We tested the efficacy of E6020, a TLR4 agonist, administered in combination with the clinically approved anti-HER2 antibody trastuzumab. A four-week course of therapy with trastuzumab and E6020 protected against the outgrowth of syngeneic D5 melanoma cells transfected with the human tumor antigen HER2 in immunodeficient C57BL/6 SCID mice, in immunocompetent wild-type C57BL/6 mice as well as in human HER2-tolerant C57BL/6 hmHER2 transgenic mice. In each tested strain of mice, the addition of E6020 to trastuzumab significantly increased the proportion of animals that survived initial tumor challenge compared to trastuzumab treatment alone (83% vs. 33% in C57BL/6 hmHER2 transgenic mice; p &amp;lt; 0.05). To determine if apparently cured mice had been effectively immunized against human HER2, the transgenic mice were inoculated subcutaneously with 103 D5-HER2 cells and then received a 4-week course of trastuzumab+E6020, or trastuzumab alone. Animals that survived the primary tumor challenge were followed for at least 120 days and then rechallenged with 5 × 103 D5-HER2 or unmodified D5 cells and followed for a minimum of 60 additional days. Mice that had been initially treated with the combination of trastuzumab and E6020 demonstrated superior protection (22/30; 73%) to those treated with trastuzumab alone (16/36; 44%; p &amp;lt; 0.05) against rechallenge with D5-HER2, but no protection was seen against D5 challenge. Both CD4 and CD8 T-cells were required for full protection against rechallenge. These findings suggest that trastuzumab therapy can induce a host-protective adaptive immune response. Moreover, combined treatment with trastuzumab and a TLR4 agonist enhances both the direct anti-tumor effects of trastuzumab and a host-protective human HER2-directed adaptive immune response. 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 LB-324.
Foreshortening affects both uphill and downhill slope perception at far distances
Authors: Helen E. Ross
Journal: Behavioral and Brain Sciences (2013)

Abstract Perceived slope varies with the viewing distance, and is consistent with the effects of foreshortening. Distant viewing makes uphill slopes appear steeper and downhill slopes flatter than does near viewing. These effects are obvious to skiers and climbers in mountainous country. They have also been measured in outdoor experiments with controlled viewing distances. There are many other sources of slope illusions.
Abstract 5720: Chromosomal instability predicts the progression of premalignant oral lesions
Authors: Rinske MPT Hamers, Theke JH Siebers, Annick Haesevoets, Iris R. Zwijnenberg, Adri C. Voogd, Frans CS Ramaekers, Bernd Kremer, Thijs MAW Merkx, Pieter J. Slootweg, Ernst-Jan M. Speel
Journal: Cancer Research (2010)

Abstract A major dilemma in the management of patients with precursor lesions of the oral mucosa lies in deciding which lesions will progress into carcinoma. Because a strong association between histological differentiation and clinical prognosis is lacking, the aim of this study was to evaluate the value of chromosomal instability (CIN) detected by fluorescence in situ hybridization (FISH) for the identification of oral premalignant lesions at risk for progression. We examined a series of premalignant oral mucosa lesions of 106 patients by means of FISH on paraffin-embedded tissue sections using biotin- and digoxigenin-labeled probes specific for the centromeric regions of chromosomes 1 and 7. CIN was indicated by the presence of chromosome imbalances and/or polyploidization for chromosomes 1 and 7. Results were correlated with histopathological data as well as with clinical follow up data. The 5-year progression-free survival rate was 83%. Outcome of routine histopathology did only predict malignant progression when comparing severe dysplasia with lower stage precursor lesions (hyperplasia, mild en moderate dysplasia) (p&amp;lt;0.001). CIN was detected in all different subgroups of histopathological differentiation. Moreover, the percentage of precursor lesions harboring CIN increased with progressing histopathological stage. CIN was significantly associated with a lower progression-free survival as compared with lesions without CIN (p&amp;lt;0.001). In conclusion, tumorigenesis of the oral mucosa is associated with the development of CIN, which can reliably identify lesions at risk for progression. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 5720.
Care of the Asplenic Patient
Authors: Lorry G. Rubin, William Schaffner
Journal: New England Journal of Medicine (2014)

Asplenic patients are at risk for rapidly progressive septicemia and death. Such patients should be vaccinated against pneumococci, H. influenzae type b, meningococci, and influenza virus, and if fever develops, they should receive empirical antimicrobial therapy immediately.
Myeloid sarcoma of the duodenum: a rare cause of bowel obstruction and gastrointestinal bleeding
Authors: Yen-I Chen, Philippe Paci, René Michel, Talat Bessissow
Journal: Endoscopy (2015)

A 78-year-old man with known relapsing acute myeloid leukemia (AML) presented to the emergency department with a 24-hour history of vomiting. On arrival, he had evidence of coffee ground emesis, his heart rate was 115 beats/minute, and his blood pressure was 135/89 mmHg. A computed tomography (CT) scan of the abdomen performed to rule out gastric outlet obstruction revealed an obstructive mass occupying the fourth part of the duodenum ([Fig. 1]). On enteroscopy, the mass was found to be friable, measuring 5 cm in diameter and occupying 75 % of the duodenal circumference ([Fig. 2]). The lesion bled on contact and on taking biopsies, but the bleeding was controlled by application of the hemostatic powder TC-325 (Hemospray; Cook Medical, Winston-Salem, North Carolina, USA).
A1.23 Macroautophagy deficiency in dendritic cells exacerbates antigen-induced arthritis
Authors: J Niven, G Palmer-Lourenco, D Talabot-Ayer, C Gabay, M Gannagé
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> Macroautophagy is a major catabolic pathway in cells, acting in parallel to the proteasome machinery. This pathway is an important contributor of cellular homeostasis, and therefore is active and up regulated in various conditions of cellular stress and inflammation. In this context, macroautophagy has been implicated in shaping the innate and adaptive immune responses by acting at multiple and diverse levels including cytokine secretion and antigen presentation. Our aim was to analyse the contribution of macroautophagy in the immune response during autoimmune arthritis, using mice that are deficient in autophagy in their dendritic cells. <h3>Materials and methods</h3> Mice: CD11c-Cre mice (C57BL/6), (Jackson Laboratory) were crossed with Atg5<sup>flox/flox</sup>mice (C57BL/6) provided by Dr. Noboru Mizushima (Japan). Since ATG5 is an essential autophagy gene, its targeted deletion in dendritic cells completely abolished a functional autophagy pathway in these cells. For the Antigen induced arthritis mice model, mice were immunised with methylated BSA (mBSA) and CFA, with a boost at day 7. Monoarthritis was induced at day 21 by injection of mBSA into the knee joint. Animals were sacrificed at day 28. Sections from knees were stained with hematoxylin and eosin and macroscopic scoring of the cellular infiltrate was performed. In parallel, toluidine blue staining was used for cartilage damage scoring. ELISA was used to determine the antibody titers against mBSA. T cell function was monitored by cytokine production, after <i>in vitro</i> re-stimulation with mBSA, using single cell suspensions from lymph nodes and spleens. mRNA levels of inflammatory cytokines were measured by quantitative PCR, after RNA extraction from the immunised hind limbs. <h3>Results</h3> We found enhanced cartilage destruction in mice lacking autophagy in their dendritic cells (DC/ATG5<sup>-/-</sup>). Interestingly, the TH1/TH17 response in DC/ATG5<sup>-/-</sup> mice was significantly increased. Indeed, T cells derived from spleens and lymph nodes of DC/ATG5<sup>-/-</sup> mice and their wild type littermate controls (DC/ATG5 <sup>+/+</sup>) were cultured <i>in vitro</i> for 48 h, with mBSA or CD3/CD28. A significant increase in INF-gamma and IL-17 production was assessed in T cell cultures from DC/ATG5<sup>-/-</sup> mice. In parallel, <i>in vivo</i>, pro-inflammatory cytokines production was locally enhanced since IL-1 beta, IL-23, and IL-17 transcripts levels were significantly higher in DC/ATG5<sup>-/-</sup> mice compare to their littermate controls. <h3>Conclusions</h3> Autophagy deficiency in dendritic cells enhances the TH1/TH17 inflammatory response in the AIA model, resulting in increased cartilage destruction. The precise mechanism behind this regulation is under investigation.
Abstract 3864: Evaluation of expression of antigens cancer/testis (CTAs) in head and neck squamous cell carcinoma
Authors: Fernando T. Zamunér, Bruno Takao Real Karia, André Lopes Carvalho, André Luiz Vettore de Oliveira
Journal: Cancer Research (2011)

Abstract Background: Among the ten most common cancers are the head and neck tumors with more than 500,000 new cases diagnosed annually worldwide, the majority (90%) represented by squamous cell carcinomas (HNSCC). Despite of the many strategies used in the treatment for HNSCC, the 5 years overall survival rate is close to 50%, and the development of loco-regional recurrence is the main reason for treatment failure. The head and neck cancer surgery is often mutilating and require extensive reconstruction. The development of new therapies and their integration into the current forms of treatment (including surgery, radiotherapy and chemotherapy) is of great interest to improve the therapeutic efficacy. Immunotherapy may provide an alternative for current treatment scheme, since the natural immune response can be stimulated by active immunotherapeutic interventions which may help control tumor progression and recurrence. A requirement for the development of immunotherapeutic approaches is the identification of immunogenic gene products expressed predominantly in tumor cells. Cancer/testis antigens (CTAs) fulfills this prerequisite as their expression is restricted to tumors with no expression in normal tissues, except germ line cells. Methods: In this study we performed a search on Oncomine, SAGE, CTdatabase and PubMed databases to select among 153 CTAs genes those that might be expressed in HNSCC. The expression of selected genes was investigated in 93 HNSCC samples and 10 normal mucosa samples from healthy individuals using reverse-transcription polymerase chain reaction (RT-PCR). The in silico analysis allowed the selection of 30 CTAs genes to be evaluated in tumors and control samples. The RT-PCR assays identified 6 CTAs with high specificity (100%) and frequently expressed in HNSCC samples (39 – 85%). Noteworthy, 99% of the tumor samples expressed at least one of the 6 CTAS, 91% expressed at least two of them, and 71% expressed at least three of these antigens. The six CTAs were expressed simultaneously in 13% of cases. Conclusion: We identified 6 CTAs genes with high expression and specificity in head and neck cancer. This result could be important for the development of immunotherapy strategies for treating HNSCC patients. 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 3864. doi:10.1158/1538-7445.AM2011-3864
Website of the week: Detaining people with personality disorders
Authors: D Carnall
Journal: BMJ (1999)

This week the Home Office and the Department of Health demonstrated their capacity for “joined up government” by proposing new powers to detain people with personality disorders who are a danger to the public. But it's not good news at www.open.gov.uk: its “What's new” page opens with a warning about congestion on its server, which the Government Information Service frankly …
Abstract 1506: Up-regulation of stromal matrilin-3 expression in advanced stage high-grade serous ovarian cancer
Authors: Zachary P. Yeung, Melissa S. Thompson, Tsz L. Yeung, Tarrik M. Zaid, Kwong K. Wong, Samuel C. Mok
Journal: Cancer Research (2011)

Abstract Objective: Transcriptome profiling performed on RNA isolated from microdissected epithelial and stromal fibroblastic components of advanced stage high-grade serous ovarian cancer (HGSC) and normal ovarian epithelial tissue identified a set of genes coding for secretory proteins that were significantly up-regulated in ovarian cancer associated fibroblasts (CAFs). One of the most significant differentially expressed genes is matrilin-3 (MATN3), which has been shown to play an important role in cartilage morphogenesis. The purpose of this study is to validate the differential expression patterns of MATN3 and its role in ovarian cancer progression. Methods: Validation studies on MATN3 expression were carried out using quantitative RT-PCR analysis on RNA samples isolated from the microdissected stromal and epithelial components of 44 HGSC samples and 10 normal ovaries. In addition, immunohistochemistry (IHC) was performed to determine over-expression of MATN3 in the stromal component of HGSCs. To assess the functional role of matrilin-3 in ovarian cancer pathogenesis, multiple ovarian cancer cells including SKOV3 ipluc, OVCA 432, OVCA 433, and ALST were treated with exogenous recombinant MATN3. Its effect on cell proliferation was evaluated by the WST-1 assay. Furthermore, the effect of MATN3 on invasion potential was determined by counting the number of cells migrating through a transwell membrane coated with a 0.1% type I collagen matrix containing 7.5 nM MATN3. Results: Quantitative RT-PCR analysis showed significantly over-expression of MATN3 in the stromal component of HGSC compared to the epithelial component and the normal ovaries (P=0.003). Immunohistochemistry (IHC) confirmed overexpression of MATN3 in a majority of ovarian cancer stromal specimens. When treated with recombinant exogenous matrilin-3, ALST and SKOV3 ip luc ovarian cancer cells showed a dose-dependent inhibition of proliferation by MATN3. Treatment of ovarian cancer cells SKOV3 and OVCA 432 with exogenous MATN3 significantly decreased the number of cells migrating through the transwell membrane (P&amp;lt;0.001). Conclusions: Over-expression of MATN3 in ovarian cancer stroma inhibits cell proliferation and invasion potential. Further evaluating the underlying molecular mechanism of MATN3 in ovarian cancer progression is warranted. 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 1506. doi:10.1158/1538-7445.AM2011-1506
ED-01 * MEDULLOBLASTOMA PRESENTING AS AN INTRACRANIAL HEMORRHAGE
Authors: A. Asante, J. Lin, M. Zagardo, M. Gujrati, K. Fernandez, R. Antony
Journal: Neuro-Oncology (2014)

CASE REPORT: Children with medulloblastoma usually present with ataxia, nystagmus, dysmetria, intention tremor, cranial nerve deficits or signs of elevated intra-cranial pressure. On MRI a midline non-homogenously enhancing lesion is seen often with associated brainstem compression, ventricular dilatation and transependymal CSF migration. We describe a 12 year old child who presented with dizziness, emesis, neck pain and occipital headache resulting from minor head trauma on the preceding day. Past history included recent onset intermittent diplopia corrected with lenses. Neurological examination was normal except for mild left hearing loss and decreased visual acuity. CT scan at admission revealed an acute subarachnoid hemorrhage in the left cerebellopontine angle (CPA) extending through the left foramina of Luschka and Magendie and compressing the adjacent cerebellum and brainstem. MRI /MRA/Cerebral angiogram did not uncover any underlying pathology. After observation for 3 days he was discharged with residual mild left hearing loss and left horizontal nystagmus. On follow up four months later he was found to have lost all hearing (left) and had difficulty with balance. MRI showed a 2.8 x 2.6 x 2.4 cm left CPA mass hypo-intense on T1 with hyperintense foci on T2. The mass extended into the internal auditory canal and compressed the brainstem without causing hydrocephalus. A peri-lesional hemorrhagic stain was observed. On repeat review of an MRI performed 2 months earlier the mass was noted to be present measuring 1.5 x 1.1 x 1.2 cm. Spinal cord MRI was negative. Gross total resection of the mass was complicated by left facial nerve palsy and severe obstructive hydrocephalus requiring temporary EVD placement. The patient is on treatment for medulloblastoma (classic histology/WNT subgroup).Hearing loss persists but his 7th CN palsy is improving. We seek to highlight that on MRI an acute intracranial hemorrhage can camouflage a neoplastic process.
PWE-041 Management Of Large Colonic Polyps In A Bowel Cancer Screening Programme
Authors: HY Lee, W Gashau, R Willert
Journal: Gut (2014)

Introduction Bowel cancer is the third most common cancer in the United Kingdom forming up to 13.6% of all newl1y diagnosed cancers (1). Bowel cancer screening colonoscopy allows early polyp detection at a curable stage. Complete resection and follow-up of large polyps is crucial to prevent malignant progression. The aim of this study was to review the management of polyps with diameters ≥2 cm, particularly of sessile polyps, to assess the enbloc resection rates, completeness of resection using endoscopic mucosal resection (EMR) vs surgery and the incidence of malignant polyps. Methods Patients were identified retrospectively from a regional bowel screening programme database. Details of index colonoscopy including polyp characteristics, method of resection and complications were recorded. Histology results were reviewed for all polyps. Outcomes from follow-up endoscopic surveillance were analysed. Results One hundred and fifty-eight patients (102 males, 56 females, mean age 66.2 years) with polyps ≥2 cm were identified from 2182 screening colonoscopies from January 2010 to August 2013. Caecal intubation rate was 96.8% in this group. Largest polyp size for each patient ranged from 20 to 60 mm (mean 26.6 mm). The incidence of adenocarcinoma was 11.9% (n = 19), all located within the left colon, with 12 requiring surgical resection. One hundred thirty nine patients (n = 139) had 155 non-malignant large polyps, mostly tubulovillous or villous histology (n = 110, 79%). Thirty-six patients had 37 sessile polyps which underwent primary resection by EMR (n = 26) or surgery (n = 11). Polyp diameter was larger in the surgery group with mean polyp diameter of 40.4 vs. 28.0 mm (p < 0.05). EMR enbloc resection rate was 11.5% (n = 3 out of 26). Completeness of excision was 38.4% (n = 10) at 3 months and 92.3% (n = 24) at 1 year. EMR complications included 1 perforation, 1 post polypectomy syndrome and 1 bleed. Surgical resection included: anterior resection in 2, TEMS excision in 7 and right hemicolectomy in 3. Conclusion Sessile polyps ≥2 cm are relatively uncommon in an asymptomatic bowel cancer screening programme (37 in 2182 colonoscopies). They can be successfully resected by EMR without recurrence in 92.3% at 1 year providing a 3 month site check is performed in all piecemeal polypectomies. Reference 1. Cancer for National Statistics 2010. Office for National Statistics. <http://www.ons.gov.uk/ons/dcp171778_263537.pdf> Disclosure of Interest None Declared.