tbuckley/cabot-search huggingface dataset:
A plausible mechanism for genome plasticity: lessons from parasitic wasps
Authors: Shijing Jia, Michael Gorin, Sofia Merajver
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4419 

Polydnaviruses are chromosomally incorporated and released via gene excision in parasitic wasps of the Ichneumonidae and Braconidae families. In this study, we utilized bioinformatics analysis and molecular biology methods to explore the possible existence of the ancestral hymenoptera gene excision mechanism in the human genome, as a plausible underlying mechanism of genome plasticity in oncogenesis. It was hypothesized that this mechanism of gene excision associated with polydnaviruses could be conserved amongst eukaryotic organisms. This hypothesis was tested in silico by comparisons of the recombinase binding site sequences of Cotesia congregata (3’: TTATTCAAAAAGCT; 5’: CAATCAAAAAAGCT) with the human genome using the National Center for Biotechnology Information’s BLAST Search and MapViewer Tool. The Ensembl Genome Browser and GeneCards were then employed to explore protein-encoding genes near potential sites. BLAST results indicate a high frequency of the excision sequences within the human genome. Though located over five megabasepairs apart, the most probable combination of 3’ and 5’ DRJ Cotesia congregata EP1 recombinase binding sites is located at 5: 160,949,945-160,949,958 and 5: 166,310,295-166,310,308 respectively. Disrupted genes upon potential excision include gamma-aminobutyric acid A receptor (GABRA6, GABRG2), cyclin G1(CCNG1), hyaluronan-mediated motility receptor (HMMR), and methionine adenosyltransferase II (MAT2B). Of particular interest is the cyclin-dependent protein kinases regulator gene cyclin G1, which has been found to be inducible by tumor protein p53 and has been associated with a plethora of cancers, including, retinoblastoma, malignant lymphoma, and hematopoietic neoplasms. Furthermore, despite the genetic distance between all potential pairs of 5’ and 3’ excision sites, the sheer number of present homologs is suggestive that analogous polydnaviral excision mechanisms could be viable within the human genome. The confirmation of such a genetically disruptive mechanism would be the next step to understanding innumerable oncogeneses. Continuing research employs molecular biology to examine the ability of human cancerous cells to excise or incorporate polydnaviral DNA. Current plans focus on molecular manipulation of Hyposoter didymator cells containing polydnavirus ichnovirus in combination with ovarian cancer cells in further investigation of the hypothesized presence of similar DNA excision mechanisms in humans.
Evidence for long-term survival in a sizeable proportion of good performance status (PS) patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: G. R. Simon, M. J. Schell, M. Begum, J. Kim, A. Chiappori, E. Haura, S. Antonia
Journal: Journal of Clinical Oncology (2009)

e19016 Background: Approximately 40% of NSCLC pts present with metastatic disease where treatment is considered palliative. Here we examine whether prolonged survival is possible in a sizeable proportion of NSCLC pts with good PS and stage IV disease particularly given the availability of personalized chemotherapy approaches. Methods: NSCLC pts with stage IV disease and an ECOG PS of 0/1 were prospectively accrued to four phase II clinical trials, at the H. Lee Moffitt Cancer Center and treated with the following regimens; Trial A) carboplatin/gemcitabine first-line followed by docetaxel second-line, Trial B) docetaxel and gefitinib combination therapy in patients aged 70 years or older, Trial C) combination therapy with carboplatin/paclitaxel/atrasentan, Trial D) personalized therapy (PT) based on ERCC1 and RRM1. Pts with low RRM1/low ERCC1 received gemcitabine/carboplatin; low RRM1/high ERCC1, gemcitabine/docetaxel; high RRM1/low ERCC, docetaxel/carboplatin; high RRM1/high ERCC1, vinorelbine/docetaxel. Data were updated as of 10/23 / 08. Overall survival was estimated using the piecewise exponential survival function which showed a dramatic shift at 29 months. Results: A total number of 181 pts were accrued. The median survival for the entire cohort was 10.5 months improving dramatically to 85.3 months, if alive at 29 months (adjusted P = 0.005). In the entire cohort, 16.7% of pts survived to 29 months compared to 25% of pts in the PT group. For pts who were alive at 29 months, the probabilities of surviving to 48, 60, 72 and 84 months were 79%, 68%, 59% and 51%, respectively. Conclusions: Long term survival is possible in a sizeable proportion of stage IV NSCLC with good PS. Our treatment paradigm should shift from palliation to achieving long term survival. Molecularly-based PT may be one way of achieving this goal. No significant financial relationships to disclose.
GSTP1 forms a stable, non-covalent complex with the tissue transglutaminase TGM2 in human glioblastoma cells
Authors: James Koh, Francis Ali-Osman
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4488 

In addition to its major role in cellular phase II metabolism and xenobiotic detoxification, the human glutathione S-transferase P1 (GSTP1) protein participates in a diverse array of cellular processes including stress and growth factor signaling, regulation of cellular proliferation, differentiation, transformation, and apoptosis. Here, we report that endogenously expressed GSTP1 can be recovered in a stable complex with the tissue transglutaminase TGM2 protein in the MGR3 human glioblastoma cell line. In contrast to an earlier report in which GSTP1 was found to interact with exogenously expressed TGM2 in cells undergoing TGM2-induced apoptosis, we have found that the GSTP1/TGM2 complex can be recovered from actively dividing cells in the absence of apoptotic stimuli. The GSTP1/TGM2 complex is not recovered under denaturing conditions, indicating that the interaction between the two proteins is non-covalent and thus not formed through the Iµ-(I³-glutamyl)lysine protein crosslinking activity of TGM2. When visualized through immunofluorescence, TGM2 is localized predominantly in the cytoplasm, whereas GSTP1 is found both in the nucleus and the cytoplasm. Subcellular fractionation experiments indicate that the GSTP1/TGM2 complex is found predominantly in the cytoplasm. siRNA-mediated down-regulation of TGM2 resulted in significantly decreased recovery of the TGM2/GSTP1 complex and an increased response to apoptotic stimuli. This report is the first to demonstrate that TGM2 can form a stable complex with GSTP1 in actively dividing tumor cells and establishes a direct physical link between two critical factors that are often found to be over-expressed in human breast and brain tumors. The data further suggest that the TGM2/GSTP1 interaction plays an important role in the survival of tumor cells and in their response to apoptosis-inducing anticancer agents. Further investigation of this complex should provide a deeper insight into the role of GSTP1 and of TGM2 in the biology and therapeutic response of malignant gliomas.

Supported by grants RSG MGO-103761 from the American Cancer Society (JK) and RO1 CA112519, RO1 CA 91438, P50 CA108786 (FAO).
The single-nucleotide polymorphism A&gt;G rs397768 in APC gene as a new biomarker of response to chemotherapy in advanced colorectal cancer.
Authors: J. Villa Guzman, R. Zarate, V. Boni, A. Gomez, J. De la Haba, E. Bandres, J. Garcia-Foncillas, E. Aranda
Journal: Journal of Clinical Oncology (2010)

10562 Background: Colorectal cancer is the third most common cancer and the second leading cause of cancer death in developed countries. It is widely accepted that genetic factors play key roles in the predisposition to colorectal cancer development, progression and can predict response to chemotherapy. The classical pathway of colorectal tumorigenesis includes stepwise or consecutive genetic and molecular changes, commencing with changes in adenomatous polyposis coli (APC). We hypothesize that the SNP A>G rs397768 could be a new predictive biomarker of response to chemotherapy in advanced colorectal cancer (CCR). Methods: We examined the SNP A>G in APC gene in 139 patients with advanced CCR. All patients had received first line of chemotherapy based in fluoropirimidines plus oxaliplatin or irinotecan. Time to progresion (TTP) and disease-control rate were (DCR) calculated. Genomic DNA was extracted from peripheral blood and genotyped by allelic discrimination. We explored the possible correlation of SNP A>G rs397768 with TTP and DCR using Kaplan-Meier model (log rank) and Chi-cuadrado test respectively. Results: The median age was 65 years (35-82). All patients were PS 0-1. Rectum localization was 42% while colon was 58%. SNP distribution among population was 12.1% (ancestral homozygous GG), 42.1% (variant homocygous AA) and 45.7% (heterocygous GA). The median TTP was 11 months (IC95%: 9.26-12.73); regarding APC polymorphism, there were not differences (p=0.87, log rank) while the high disease-control rate of chemotherapy was correlated significantly with variant homoygous AA (p=0.02) above all in regimens with irinotecan (p=0.021). Conclusions: The rs397768 A>G SNP in APC gene may be a new candidate predictor of chemoresponsiveness. Further characterization of APC SNPs may open new avenues for the study of cancer and therapeutic interventions. No significant financial relationships to disclose.
Predictive potential of angiogenic plasma biomarkers (PBs) in phase I trial with NGR-hTNF.
Authors: G. Rossoni, V. Gregorc, G. Citterio, A. Spreafico, G. Donadoni, G. Vitali, A. Borri, F. Caligaris-Cappio, A. Lambiase, C. Bordignon
Journal: Journal of Clinical Oncology (2010)

e13612 Background: NGR-hTNF is a vascular targeting agent consisting of TNF fused with the peptide NGR, a ligand of a CD13 overexpressed on tumor blood vessels. Methods: Fifteen refractory patients (pts) received 83 cycles (range, 1-29) of NGR-hTNF (0.2-1.6 μg/m2) given every 3 weeks until progression. Median progression-free (PFS) and overall survival (OS) were 3.4 and 6.9 months, respectively. Ninety PBs were tested at baseline and 2-h after first cycle (post-dosing). Significant post-dosing changes in IL1/IL8/IL10/MCP1/MIP1b were noted. Based on their angiogenic role, an additional four PBs were selected: VEGF, matrix metalloproteinase-9 (MMP9), vascular-cell and inter-cellular adhesion molecule-1 (VCAM1 and ICAM1). The associations between these nine PBs and treatment duration (TD; ≤2 v >2 cycles), OS and maximal changes in tumour vascularity (assessed every cycle by DCE-MRI) were investigated. Results: TD was associated with OS (Spearman's r=0.55, p=.04), baseline DCE-MRI values (r=0.86, p=.004) and moderately with changes in DCE-MRI (r=−0.51, p=.08). Baseline ICAM1 levels inversely correlated with both TD (r=−0.56, p=.03) and OS (r=−0.66, p=.01), as well as post-dosing ICAM1 levels (r=−0.55, p=.03 and r=−0.70, p=.009 for TD and OS, respectively). Post-dosing MMP9 levels correlated with OS (r=−0.57, p=.03) and moderately with TD (r=−0.46, p=.08). Greater decreases in DCE-MRI were associated with higher baseline IL10 levels (r=−0.65, p=.03). All the other PBs failed to show any correlation. By receiver operating characteristic analysis, baseline ICAM1 levels ≤171 ng/ml and post-dosing MMP9 levels ≤47 ng/ml yielded 87% sensitivity and 71% specificity in predicting TD. Pts with ICAM1 levels ≤ and >171 had median PFS of 8.2 and 2.4 months (p=.002) and median OS of 10.3 and 3.9 months (p=.008), respectively. Pts with MMP9 levels ≤ and >47 had median PFS of 5.8 and 2.0 months (p=.05) and median OS of 12.5 and 3.9 months (p=.005), respectively. Univariate Cox analysis confirmed significant associations with OS for both ICAM1 (p=.008) and MMP9 (p=.02). Conclusions: The lower the ICAM1 and MMP9 levels, the longer the clinical benefit. The predictive potential of these PBs for NGR-hTNF activity deserves further studies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MolMed
Even 'Bigger Gods' developed amongst the pastoralist followers of Moses and Mohammed : Consistent with uncertainty and disadvantage, but not prosociality. Commentary on Norensayan et al
Authors: Edward Dutton, Guy Madison
Journal: Behavioral and Brain Sciences (2015)

Even 'Bigger Gods' developed amongst the pastoralist followers of Moses and Mohammed : Consistent with uncertainty and disadvantage, but not prosociality. Commentary on Norensayan et al
Long term prognostic value of ER and PR in early stage breast cancer
Authors: C. E. Collen, V. Vinh-Hung
Journal: Journal of Clinical Oncology (2004)

771 Background: To examine the changes with time of the prognostic value of ER and PR, to evaluate if PR has more long term prognostic value than ER. Methods: Women aged between 25 and 95 years with T1-T2 breast carcinoma diagnosed in 1990–1997, treated curatively, were selected from the US Surveillance, Epidemiology and End Results public database. A total of 68313 patients were eligible for analysis. Median follow-up was 65 months(range 1–199). ER and PR positivity were found in 43829 and 37907 patients, respectively. The role of ER+ and PR+ were examined using multivariate proportional hazards (PH) models adjusting for other prognostic factors. Results: A check of hazards constancy in time showed that the favorable effect of ER+ was constant only during the first 3 years, then decreased progressively, ER+ had no more prognostic value after 6 years. The favorable effect of PR+ remained almost constant up to the maximum observed follow-up of 10 years. The test of hazards constancy confirmed a major departure for ER+ (p<0.0001), and a minor departure for PR+ (p=0.011). Conclusions: In this dataset, ER+ and PR+ in early breast cancer are both associated with a favorable outcome. However, PR+ status appears to have more long term prognostic value than ER+ status. No significant financial relationships to disclose.
Bronchiectasis is increasing in the UK, study shows
Authors: Susan Mayor
Journal: BMJ (2015)

The incidence and prevalence of bronchiectasis, a long term respiratory condition with persistent airway infection and recurrent exacerbations in people with structurally abnormal bronchi, has increased over the past decade and now affects more than 1% of people aged 70 and older, a UK study has shown.

The study, reported in the European Respiratory Journal , analysed anonymised primary care medical records for 14 million patients registered between 1 January 2004 and 31 December 2013.1 Researchers identified people aged 18 and over with a diagnosis of bronchiectasis and looked at trends in incidence, prevalence, and mortality over time. …
Abstract 20: Bystander Cardiopulmonary Resuscitation with Chest Compressions Only According to Dispatcher Telephone Instruction Status
Authors: Ken Nagao, Eizo Tachibana, Kei Nishikawa, Tukasa Yagi, Naohiro Yonemoto, Morimasa Takayama, Shinichi Shirai, Hiroshi Nonogi, Takeshi Kimura
Journal: Circulation (2012)

BACKGROUND The 2010 AHA guidelines for cardiopulmonary (CPR) recommended that untrained lay rescuers should continue chest compression-only CPR under dispatcher-telephone CPR instruction and trained lay rescuers should continue conventional CPR if he or she is able to perform rescue breaths. We assessed the effect of bystander CPR according to dispatcher-telephone CPR instruction status. METHODS From the data of the All-Japan Utstein Registry, a prospective, nationwide, population-based registry of out-of-hospital cardiac arrest, we extracted the adult patients with bystander-witnessed out-of hospital cardiac arrest due to cardiac etiology, and divided into groups according to the dispatcher-telephone CPR instruction status, inclusive of CPR techniques. The primary endpoint was 30-day favorable neurological outcome after cardiac arrest. RESULTS Of the 113,624 patients who met the inclusion criteria, 45,565 received dispatcher-telephone CPR instruction and 68,059 did not. Higher proportions in the instruction group than in the no instruction group were the performance of bystander CPR (chest-compression only CPR or conventional CPR) (68% [30,929/45,565] vs. 31% [20,900/68,059], p&lt;0.0001), especially that of chest-compression only CPR (46.2% [21,032/45,565] vs. 17.0% [11,541/68,059], p&lt;0.0001). Although frequencies of 30-day favorable neurological outcome in the instruction group were significantly lower than in the no instruction group for the whole cohorts (4.8% vs. 5.5%, p&lt;0.0001) and the subgroups of patients receiving bystander CPR (5.7% vs. 7.8%, p&lt;0.0001), chest-compression only CPR was equivalent or superior to conventional CPR in each group in terms of neurological benefit (5.7% vs. 5.9% in the instruction group, p=0.57, and 8.2% vs. 7.3% in the no instruction group, p=0.03). Among patents receiving bystander CPR, adjusted odds ratios of favorable neurological outcome were 1.2 (95% CI; 1.1 to 1.3) after no instruction group, and 1.1 (1.0 to 1.2) after chest-compression only CPR. CONCLUSIONS Bystander chest-compression only CPR was not inferior to conventional CPR in terms of neurological benefits, and dispatcher-telephone CPR instruction increased the performance rate of chest-compression only CPR.
Immunohistochemical test for MLH1 and MSH2 is an independent prognostic factor in sporadic colorectal cancer
Authors: K. Öhrling, D. Edler, M. Hallström, M. Karlberg, P. Ragnhammar
Journal: Journal of Clinical Oncology (2007)

4126 Background: Microsatellite instability (MSI) is the hallmark of a defective DNA mismatch repair (MMR) and occurs in 10- 20 % of sporadic colorectal cancer (CRC). The loss of the MLH1 protein is the cause of MSI in almost all sporadic colorectal MSI tumours. The second most common protein to be lost is MSH2. There is evidence that MSI is a prognostic factor in CRC. The role of MSI status as a predictive factor of benefit from adjuvant 5-fluorouracil (5-FU) based chemotherapy is controversial. Methods: Monoclonal antibodies that recognize the mismatch repair protein by immunohistochemistry (IHC) have been commercially available for several years. Previous reports have found a strong correlation between MMR results obtained by immunohistochemical and genetic analysis. This study included 1006 CRC patients (488 Stage II and 518 Stage III) with a median follow-up of 5 years. The patients were included in Nordic trials randomised between surgery alone and surgery plus adjuvant 5-FU. The MMR status was retrospectively assessed on paraffin-embedded formalin-fixed samples using IHC. Results: One hundred fifty seven patients (15.6 %) showed a loss of MMR protein expression (139 MLH1 negative, 15 MSH2 negative and 3 MLH1+MSH2 negative) and were classified as MMR protein negative. A normal MMR protein expression was found in 851 patients who were defined as MMR protein positive. The median overall survival (OS) was 84 months (range 2–181 months). MMR protein expression was a significant prognostic marker in the entire study group where a better OS was seen among patients with MMR protein negative carcinomas compared to patients with MMR protein positive tumours (p=0.005). In multivariate analysis the MMR protein expression was significantly associated with OS, (hazard ratio for death, 0.67 [95 per cent confidence interval, 0.38 to 0.96]; p=0.008). However, in this study the MMR status did not predict response to 5-FU adjuvant chemotherapy. Conclusions: This study reveals that immunohistochemical analysis of MLH1 and MSH2 expression can yield important prognostic information but is not a predictive factor in sporadic CRC. No significant financial relationships to disclose.
Tumor-associated proteolysis and prognosis: new functional risk factors in gastric cancer defined by the urokinase-type plasminogen activator system.
Authors: M M Heiss, R Babic, H Allgayer, K U Gruetzner, K W Jauch, U Loehrs, F W Schildberg
Journal: Journal of Clinical Oncology (1995)

PURPOSE The significance of tumor-associated proteolysis as reflected by parameters of the urokinase-type plasminogen activator (uPA) system for prognosis in cancer patients has been proposed because of evidence for its central role in basic mechanisms of invasion and metastasis. The aim of the present study was to evaluate whether the expression of the uPA parameters might be of clinical value in gastric cancer as a tumor/biologically defined risk factor. PATIENTS AND METHODS In a consecutive series of 203 patients resected for primary gastric cancer, the expression of uPA, uPA-receptor (uPA-R), plasminogen activator inhibitor (PAI)-1, and PAI-2 was determined immunohistochemically. The results were classified semiquantitatively (0 to 3). Patients were followed-up prospectively for a median of 31 months (range, 9 to 56 months). Disease-free and overall survival were analyzed according to Kaplan-Meier and with univariate and multivariate Cox analyses in relation to conventional prognostic factors. RESULTS Univariate analyses revealed a highly significant inverse correlation of uPA, uPA-R, and PAI-1 expression with survival time (P = .0008, P = .0002, and P = .0002, respectively), whereas PAI-2 demonstrated only a weak correlation. In multivariate analyses, PAI-1 was an independent and strong prognostic factor (P = .005; relative risk, 1.47 per staining degree; 95% confidence interval [CI], 1.31 to 1.64). In pT1/2 tumors and in Laurén's diffuse and mixed types, uPA, uPA-R, and PAI-1 added significant prognostic information. PAI-1 was also associated with survival in the subgroup of lymph node-positive patients. CONCLUSION PAI-1, uPA, and uPA-R are new functional risk factors reflecting clinical prognosis. In particular, PAI-1 is a new independent variable for the identification of patients at high risk after tumor resection. Our results support the hypothesis that the uPA system probably is of general importance for prognosis of patients with malignant disease, indicating an individual tumor's capacity for invasion and metastasis.