tbuckley/cabot-search huggingface dataset:
GATA6 expression in Barrett’s metaplasia development and malignant progression.
Authors: Kirill Pavlov, Judith Honing, Coby Meijer, Wytske Boersma-van Ek, Frans Peters, Anke van den Berg, Arend Karrenbeld, John Theodorus Plukker, Frank Kruyt, Jan Kleibeuker
Journal: Journal of Clinical Oncology (2014)

26 Background: Barrett’s metaplasia is characterized by the presence of a columnar metaplastic epithelium in the esophagus. Barrett’s metaplasia can show malignant progression towards esophageal adenocarcinoma by a metaplasia-dysplasia-carcinoma sequence. The underlying mechanisms of Barrett’s metaplasia development and malignant progression are poorly understood. The transcription factor GATA-6 is known to be involved in columnar differentiation and carcinogenesis. GATA6 gene amplification was recently linked with aggressiveness in esophageal adenocarcinoma. Here, we studied GATA6 protein expression in normal squamous, metaplastic, dysplastic and esophageal adenocarcinoma tissues in order to identify a possible role of GATA-6 in the development and malignant progression of Barrett’s metaplasia. Methods: Samples of squamous epithelium (N=37), Barrett’s non-intestinal metaplasia (N=16), Barrett’s intestinal metaplasia (N=29), high-grade dysplasia (N= 39), in situ esophageal adenocarcinoma (N=29) and an esophageal adenocarcinoma tissue microarray (N=95) were stained with a polyclonal antibody against GATA6. Staining intensity was categorized as absent, weak, normal or strong. Scoring was performed by two independent observers and validated by a pathologist. Results: GATA6 expression was absent in squamous epithelium but expressed in all samples of Barrett’s metaplasia, preferentially in the lower half of the crypt. Expansion of GATA6-positive cells throughout the crypt was observed in high-grade dysplasia. While all cases of in situ esophageal adenocarcinoma showed GATA6 expression we observed complete loss of GATA6 expression in 17% of esophageal adenocarcinoma samples. Conclusions: GATA6 is absent in squamous epithelium but its expression increases along the metaplasia-dysplasia carcinoma sequence. GATA6 expression remains predominantly present in esophageal adenocarcinoma, however, its expression is lost in a subset of samples. Analysis of the relation between GATA6 expression and clinicopathological characteristics in esophageal adenocarcinoma is pending.
P174 CATCH - a year in profile and further reductions in 2WW referrals: Abstract P174 Table 1
Authors: VTY Ng, A Walsham, A Sharman, SCO Taggart
Journal: Thorax (2015)

<h3>Introduction</h3> In Salford, annual 2WW referrals rose from 235 in 2010/11 to 248 (2011/12) and 281 (2012/13) but fell to 249 in 2013/14 as the result of a 5 month pilot<sup>1</sup> of our CATCH protocol (<b>C</b>ommunity <b>A</b>ccess <b>T</b>o CT <b>Ch</b>est) allowing abnormal “low risk” CXR reports to trigger a GP request for a fast track CT scan. This audit reviews the performance of CATCH for a whole year of activity from 1<sup>st</sup> May 2014 to 30<sup>th</sup> April 2015. <h3>Methods</h3> The CATCH d-base and electronic patient record were used to identify the patients and dates of CXR and CT examinations in addition to CXR/CT scan reports and final diagnoses. The number of 2WW referrals was determined for the same time period using the cancer waiting times d-base. <h3>Results</h3> A total of 117 patients entered the CATCH protocol of which the majority of CXRs demonstrated the presence of a well-defined (47%) or ill-defined opacity (14%) and a further 18% revealed abnormality at the hilum. The remaining CXRs (21%) raised concerns about fat pads, atelectasis or pleural abnormality. For the 115 patients having a CT scan, the findings confirmed cancer in 9%, solitary pulmonary nodule (25%), infection/inflammation (15%), atelectasis (10%), pleural plaque (10%), fat pad (5%) and in 11% the CT scan was normal. Following CATCH CT scan, 53 (46%) patients required no follow up, 33 (29%) generated urgent referral, 16 (14%) non-urgent referral to the chest clinic, 11 (10%) required follow up surveillance imaging. Timelines for CATCH management are detailed in Table 1. Mean time from CT report to cancer diagnosis was 61.1 days (range 23 to 187) and total number of 2WW referrals for 2014/15 was 234. <h3>Conclusions</h3> Following the introduction of CATCH to the Salford Lung Cancer Service, 2WW referrals have fallen further to manageable numbers. The pick-up rate for cancer is only small and reflects the low risk abnormality detected on CXR. The relatively long diagnostic times for cancer reflect the processing of small nodules detected within this select group of patients. <h3>Reference</h3> 1 Moorcroft CS, Kamalatharen G, Elliot S, <i>et al</i>. CATCH - community access to CT chest. <i>Thorax</i> 2014;<b>69</b>:A115 doi:10.1136/thoraxjnl-2014-206260.231
Therapeutic Anticoagulation for Isolated Calf Deep Vein Thrombosis
Authors: Garth H. Utter, Tejveer S. Dhillon, Edgardo S. Salcedo, Daniel J. Shouldice, Cassandra L. Reynolds, Misty D. Humphries, Richard H. White
Journal: JAMA Surgery (2016)

Deep vein thrombosis (DVT) isolated to the calf veins (distal to the popliteal vein) is frequently detected with duplex ultrasonography and may result in proximal thrombosis or pulmonary embolism (PE).To evaluate whether therapeutic anticoagulation is associated with a decreased risk for proximal DVT or PE after diagnosis of an isolated calf DVT.All adult patients with ultrasonographic detection of an isolated calf DVT from January 1, 2010, to December 31, 2013, at the Vascular Laboratory of the University of California, Davis, Medical Center were included. Patients already receiving therapeutic anticoagulation and those with a chronic calf DVT, a contraindication to anticoagulation, prior venous thromboembolism within 180 days, or diagnosis of a PE suspected at the time of calf DVT diagnosis were excluded. Data were analyzed from August 18, 2015, to February 14, 2016.Intention to administer therapeutic anticoagulation.Proximal DVT or PE within 180 days of the diagnosis of the isolated calf DVT.From 14 056 lower-extremity venous duplex studies, we identified 697 patients with an isolated calf DVT and excluded 313 of these. The remaining 384 patients were available for analysis (222 men [57.8%]; 162 women [42.2%]; mean [SD] age, 60 [16] years). The calf DVT involved an axial vein (anterior tibial, posterior tibial, or peroneal) in 243 patients (63.2%) and a muscular branch (soleus or gastrocnemius) in 215 (56.0%). Physicians attempted to administer therapeutic anticoagulation in 243 patients (63.3%), leaving 141 control participants. Proximal DVT occurred in 7 controls (5.0%) and 4 anticoagulation recipients (1.6%); PE, in 6 controls (4.3%) and 4 anticoagulation recipients (1.6%). Therapeutic anticoagulation was associated with a decreased risk for proximal DVT or PE at 180 days (odds ratio [OR], 0.34; 95% CI, 0.14-0.83) but an increased risk for bleeding (OR, 4.35; 95% CI, 1.27-14.9), findings that persisted after adjustment for confounding factors (ORs, 0.33 [95% CI, 0.12-0.87] and 4.87 [95% CI, 1.37-17.3], respectively) and sensitivity analyses.Rates of proximal DVT or PE are low after isolated calf DVT. Therapeutic anticoagulation is associated with a reduction of these outcomes but an increase in bleeding.
Abstract 2368: Inhibition of epidermal growth factor receptor pathway by epidermal growth factor antibodies in non-small cell lung cancer
Authors: Jordi Codony-Servat, Miguel Angel Molina-Vila, Jordi Bertran-Alamillo, Rafael Rosell, Erik D’Hondt
Journal: Cancer Research (2016)

Abstract Introduction: The Epidermal Growth Factor Receptor (EGFR) signaling system is frequently unbalanced in non-small-cell lung cancer (NSCLC). Epidermal Growth Factor (EGF) could be an attractive target in these tumors. We used a “cancer vaccine” composed of human recombinant EGF conjugated to a carrier protein P64K. The vaccine is intended to induce antibodies against patients’ own EGF that would block EGF-EGFR interaction. Objectives: In NSCLC cell lines we assessed whether anti-EGF antibodies can inhibit the pathway activated by EGF-EGFR binding and whether sera from immunized patients can block downstream key signal transduction proteins. NSCLC cell lines were selected to determine whethergenetic alterations in EGFR, KRAS, ALK, BRAF or MET can have an impact on inhibition of EGFR pathway by anti-EGF antibodies. Experimental Procedures: Western blotting was used to evaluate the capacity of antibodies and sera from patients to inhibit EGFR activation pathway. MTT assays were performed to evaluate the effects on tumor cell proliferation. Results: The anti-EGF antibodies showed a dose-dependent inhibitory effect on EGF-induced activation of EGFR and downstream pathway molecules such as Akt and ERK 1/2. This inhibition was observed in all cell lines tested, including KRAS, EGFR and BRAF mutated cells as well as cells with ALK translocations or MET amplification. Sera from 10 patients immunized with the P64K-EGF vaccine were then tested. All sera reversed EGF-induced activation of EGFR and ERK 1/2, but some sera were significantly more potent than others. By contrast, two control sera from non-vaccinated patients failed to inhibit EGF-induced phosphorylation of EGFR and ERK 1/2. Finally, anti-EGF antibodies were also able to block the stimulatory effects of EGF on the growth of some NSCLC cell lines. Conclusions: Anti EGF antibodies and sera from patients immunized with an “EGF vaccine”, called otherwise EGF Pathway Targeted Immunization inhibits EGFR signaling in NSCLC cell line models. This effect is independent of cells’ genetic background. Citation Format: Jordi Codony-Servat, Miguel Angel Molina-Vila, Jordi Bertran-Alamillo, Rafael Rosell, Erik D’Hondt. Inhibition of epidermal growth factor receptor pathway by epidermal growth factor antibodies in non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2368.
PTH-148 Artificial nutrition support (ANS) after oesophagectomy for cancer – a review of practice: Abstract PTH-148 Table 1
Authors: O Hynes, A Champion, A Gardiner, A Davies, J Gossage
Journal: Gut (2015)

<h3>Introduction</h3> ANS is required after Oesophagectomy until resumption of oral intake. Jejunostomy tube (JT) feeding is associated with less post operative complications and shorter hospital length of stay LOS over Parenteral nutrition (PN). However, JT feeding comes with a risk of major complications including volvulus, bowel obstruction, bowel necrosis and mortality. It was routine at GSTFT to place a JT at Oesophagectomy. However, following the death of a patient due to small bowel volvulus/ischaemia this practice was suspended. Patients now receive PN. <h3>Method</h3> A retrospective observational study was carried out looking at post Oesophagectomy ANS practices at GSTFT in 2014. Data on feeding method used, postoperative LOS, readmissions, mortality, and use of JT after discharge was collated. <h3>Results</h3> Sixty three patients underwent an Oesophagectomy between January–December 2014; 31 received post operative feeding via a JT and 32 patients received PN. Table 1presents the demographics and descriptive statistics (using Microsoft Xcel) of results for both groups. Median LOS was shorter in the PN group, which is at odds with the literature. The introduction of enhanced recovery and increased dietetic personnel may have contributed this difference. Nine out of the 11 readmissions were for nutrition related problems and patients went home on JT or Nasojejunal tube feeding. One third of patients who had a JT insitu after discharge, did not use their tube again before removal. <h3>Conclusion</h3> The results of this study demonstrate the high requirements for ANS in patients following Oesophagectomy. ANS was key in the management of most readmissions. The advantage of JTs over PN is the potential for longterm use. However, given that a third of patients did not need to use their JT after discharge, is the risk of major complications too great that it outweighs the benefits? Prospective randomised studies are required to elucidate this. Better patient selection for JT insertion would prevent some patients undergoing an unnecessary additional risk at surgery. <h3>Disclosure of interest</h3> None Declared.
Benefit from next-generation ADT in AR-V7 positive patients.
Authors: Julie Steinestel, Thomas Schnoeller, Martin Boegemann, Andres Jan Schrader, Christof Bernemann
Journal: Journal of Clinical Oncology (2016)

e16532 Background: AR-V7 status is considered a predictive biomarker for non-response to next generation androgen deprivation therapy (ADT) such as abiraterone and enzalutamide. We recently identified an AR-V7 positive patient who responded to Abiraterone. Thus, we hypothesized that a subgroup of patients might benefit from next generation ADT despite expression of AR-V7 in CTCs. Methods: We assessed biochemichal response and stable disease in our cohort of AR-V7 positive, castration resistant prostate cancer patients who had received therapy with abiraterone or enzalutamide (n = 21). CTC collection was performed before therapy initiation with either abiraterone (N = 11) or enzalutamide (N = 10). We defined benefit from therapy as either stable disease ( < 50% PSA decrease to < 25% PSA increase from PSA nadir), or biochemical response (PSA decrease > 50%). Results: Six out of 21 AR-V7 positive patients who had been treated with abiraterone or enzalutamide had a benefit from the therapy. Four patients even displayed a biochemical response with a PSA decrease between 60% and 80%. The progression free survival of the six patients was between 26 – 188 days. Characteristics of the six AR-V7 positive patients who experienced benefit from next generation ADT did not differ significantly from the 15 AR-V7 positive patients showing no biochemical response. However, only one of the 6 responders (16.7%) but 9 of the 15 non-responders (60%) had received next generation ADT prior to CTC collection and inclusion in our study Conclusions: When reviewing the cohort for AR-V7 positive patient who had a benefit from unmatched next generation ADT (defined as < 25% increase of PSA) we found 6 of 21 patients. The findings strongly argue that the current portrayal of AR-V7 status in the literature should not be directly translated into clinical decision making.
Abstract 3586: Overexpression of Emi1 causes chromosomal instability and cancer
Authors: Srividya Vaidyanathan, Kathleen Cato, Sandra Pavey, Nikolas K. Haass, Brian G. Gabrielli, Pascal HG Duijf.
Journal: Cancer Research (2016)

Abstract Chromosomal Instability (CIN) is a common occurrence in solid cancer associated with poor survival in patients. A significant percentage of these tumors show abnormal chromosomes with near-triploid or tetraploid numbers exhibiting numerical CIN (nCIN). nCIN is caused mainly due to deregulation of cell cycle proteins. Early Mitotic Inhibitor 1 (Emi1) is a cell cycle protein that regulates the activity of E3 ubiquitin ligase, Anaphase Promoting Complex/Cyclosome (APC/C), which targets many cell cycle proteins for degradation. Emi1 is overexpressed in many solid tumors but not blood cancers. Unpublished data from our lab has shown that Emi1 overexpression in mouse models causes more penetrant and metastatic tumor than control tumors. Breast cancer tissues show significantly high expression of Emi1 at protein level as compared to control breast tissue samples, in agreement with the microarray data from The Cancer Genome Atlas (TCGA). In addition, Emi1 expression from breast cancer TCGA data strongly correlated with the chromosomal instability signature than many of the well-established genes known to promote CIN phenotype. To understand the mechanisms of CIN due to Emi1 overexpression, we overexpressed Emi1 in HeLa cells expressing GFP-tagged histone protein to monitor the cells during mitosis by live cell imaging. HeLa cells overexpressing Emi1 show CIN following delays in both chromosome alignment at the metaphase plate and, subsequently, anaphase onset (p = 0.0008 and p = 0.0028). There is a significant increase in CIN phenotypes and abnormal mitoses such as anaphase bridges/lagging chromosomes, mitotic arrest and cell death. These results indicate that Emi1 overexpression actively drives tumorigenesis. Citation Format: Srividya Vaidyanathan, Kathleen Cato, Sandra Pavey, Nikolas K. Haass, Brian G. Gabrielli, Pascal HG Duijf. Overexpression of Emi1 causes chromosomal instability and cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3586.
Abstract 4608: Survivin downregulation by α-santalol is not mediated through PI3K-Akt pathway in human breast cancer cells
Authors: AJAY BOMMAREDDY, KARRYN CRISAMORE, SARAH FILLMAN, SARAH BROZENA, JAMES STEIGERWALT, TERRA LANDIS, ADAM L. VANWERT, CHANDRADHAR DWIVEDI
Journal: Cancer Research (2016)

Abstract α-Santalol, a terpenoid found in sandalwood oil, has been shown to inhibit cancer cell growth in vitro by inducing apoptosis. This study was performed to investigate the anticancer properties of α-santalol associated with the induction of apoptosis in cultured MCF-7 (estrogen receptor (ER) positive, and wild type p53) and MDA-MB-231 (ER-negative and mutant p53) breast cancer cells. Expression of major proteins examined in the study were determined using standard Western blot protocol and analyzed by LICOR-Odyssey infra-red scanner. Total protein levels of survivin were confirmed by survivin ELISA kit. Cell viability was assessed by trypan blue dye exclusion assay, and caspase-3 activity was determined by caspase-3 (active) ELISA kit. Treatment of breast cancer cells for 6 and 9 hour time intervals with α-santalol (20, 40 μM) resulted in statistically significant concentration-dependent downregulation of survivin. pAkt levels were found to be slightly upregulated despite the downregulation of survivin. Pharmacological inhibition of the PI3K-Akt pathway did not result in a synergistic/additive increase in cell death or caspase-3 activity caused by α-santalol. The study reveals that survivin downregulation by α-santalol in breast cancer cells is not mediated through the PI3K-Akt pathway. Citation Format: AJAY BOMMAREDDY, KARRYN CRISAMORE, SARAH FILLMAN, SARAH BROZENA, JAMES STEIGERWALT, TERRA LANDIS, ADAM L. VANWERT, CHANDRADHAR DWIVEDI. Survivin downregulation by α-santalol is not mediated through PI3K-Akt pathway in human breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4608.
Loss-of-function mutations in the RNA biogenesis factor <i>NAF1</i> predispose to pulmonary fibrosis–emphysema
Authors: Susan E. Stanley, Dustin L. Gable, Christa L. Wagner, Thomas M. Carlile, Vidya Sagar Hanumanthu, Joshua D. Podlevsky, Sara E. Khalil, Amy E. DeZern, Maria F. Rojas-Duran, Carolyn D. Applegate, Jonathan K. Alder, Erin M. Parry, Wendy V. Gilbert, Mary Armanios
Journal: Science Translational Medicine (2016)

Chronic obstructive pulmonary disease and pulmonary fibrosis have been hypothesized to represent premature aging phenotypes. At times, they cluster in families, but the genetic basis is not understood. We identified rare, frameshift mutations in the gene for nuclear assembly factor 1, NAF1, a box H/ACA RNA biogenesis factor, in pulmonary fibrosis-emphysema patients. The mutations segregated with short telomere length, low telomerase RNA levels, and extrapulmonary manifestations including myelodysplastic syndrome and liver disease. A truncated NAF1 was detected in cells derived from patients, and, in cells in which the frameshift mutation was introduced by genome editing, telomerase RNA levels were reduced. The mutant NAF1 lacked a conserved carboxyl-terminal motif, which we show is required for nuclear localization. To understand the disease mechanism, we used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein-9 nuclease) to generate Naf1(+/-) mice and found that they had half the levels of telomerase RNA. Other box H/ACA RNA levels were also decreased, but rRNA pseudouridylation, which is guided by snoRNAs, was intact. Moreover, first-generation Naf1(+/-) mice showed no evidence of ribosomal pathology. Our data indicate that disease in NAF1 mutation carriers is telomere-mediated; they show that NAF1 haploinsufficiency selectively disturbs telomere length homeostasis by decreasing the levels of telomerase RNA while sparing rRNA pseudouridylation.
Micro-RNAs as positive biomarkers of pathological complete response after neoadjuvant chemoradiotherapy in locally advanced rectal carcinoma.
Authors: Erika B. Ruiz Garcia, Gilberto Lopez-Rosas, Cesar Lopez-Camarillo, Silvio Namendys-Silva, Leonardo Lino-Silva, Alicia Lopez-Yañez, Alette Ortega, German Caderillo-Ruiz, Dr. Consuelo Diaz, MaryTere Herrera, Laurence Marchat, Jesus Zamora Moreno, Itzel Vela Sarmiento, Abelardo Meneses-Garcia, Horacio Astudillo
Journal: Journal of Clinical Oncology (2016)

624 Background: Neoadjuvant chemoradiotherapy (nCRT) follow by surgery, as treatment for locally advanced rectal carcinoma (LARC), has improve local disease control, increase of complete pathological response (cPR) and preserve anal sphincter. cPR is associated with better prognosis. CRT act mainly through induction of DNA damage. MicroRNAs (miRNAs) are small non-coding RNAs able to regulate gene expression at post-transcriptional level. miRNAs are involved in the regulation of DNA damage/repair mechanism. Our goal was to measure expression of miRNAs involved in DNA damage/repair genes and correlated with cPR. Methods: Retrospectively, we analyzed the initial paraffin embedded tissue block of 20 Mexican patients with LARC treated with nCRT at National Cancer Institute of Mexico between 2010-2013. Treatment response was evaluated with Ryan Classification. Ten patients had cPR (Ryan Grade 0) meanwhile other 10 poor response (Ryan Grade 3). RNA extraction was done with RNeasy FFPE (Qiagen) Kit. RNA concentration and purity was assessed using NanoDrop 2000 Spectrophotometer. miRNAs expression were evaluated by real-time polymerase chain reaction (PCR) analysis with TaqMan Probes from Applied Biosystems. Statistical analysis was carried out with IBM SPSS Statistics 22.0. Differential expression between the two groups was performed with Chi square test. Results: There wasn’tsignificant difference betweenclinical/demographic features between the 2 groups. All patients received CRT at a total dose of 4500 cGy of pelvic irradiation, concomitantly with fluoropyrimidine. Surgical treatment was performed 14 weeks after completion of nCRT. The 2 miRNAs (188-5p and 590-5p) was overexpressed in the cPR group vs poor response group (p = 0.011 and p = 0.057, respectively). Conclusions: We evaluated the expression of miR590-5p and miR188-5p because they are related to DNA repair genes such as: MSH2, ERCC3, BRCC3 and XRCC5. We found overexpression in both miRNAs. Even though miR590 5p didn't reach statistical significance this maybe because of simple size.Our results now are been analyzed with a biological and functional genes network platform: Ingenuity Pathway Analysis.