tbuckley/cabot-search huggingface dataset:
Abstract 780: Immune escape in colorectal carcinoma: role of the IFN-γ pathway
Authors: Nathalie Britzen-Laurent, Elisabeth Naschberger, Tilman Rau, Regine Schneider-Stock, Arndt Hartmann, Roland S. Croner, Michael Stürzl
Journal: Cancer Research (2011)

Abstract The presence of a Th1 adaptive immune response in colorectal carcinoma (CRC) has been associated with improved clinical outcome and survival of patients. The Th1 adaptive immune response is mediated by IFN-γ, a known anti-proliferative, pro-apoptotic and pro-immunogenic cytokine. We have previously identified the guanylate-binding protein 1 (GBP-1), one of the proteins the most highly induced by IFN-γ, as a sensitive marker for the detection of this immune response in CRC in vivo. In a tissue microarray study with 388 CRC tumors, 30% showed GBP-1 expression. Interestingly, in these tumors the expression of GBP-1 was only induced in the cells of the desmoplastic stroma and not observed in adjacent tumor cells. This suggested that CRC tumor cells might undergo an immune escape from the Th1 adaptive immune response, characterized by the loss of IFN-γ responsiveness. Therefore, we investigated the responsiveness to IFN-γ in sixth different CRC cell lines and in normal colon epithelial cells. After treatment with IFN-γ, three of the sixth CRC cell lines (DLD-1, SW480 and HCT116) failed to express GBP-1 as well as other IFN-induced proteins such as caspase-1 and MxA. On the contrary, a robust GBP-1 induction was present in normal colon epithelial cells, in T84, WiDr and HT29 cells. We then investigated whether the loss of expression of IFN-γ target genes was associated with phenotypic changes in CRC cells. In fact, we found that DLD-1, HCT116 and SW480 were resistant to IFN-γ-induced apoptosis. Furthermore, the loss of IFN-γ responsiveness correlated in SW480 and HCT116 with the absence of expression of the IFN-γ receptor alpha chain (IFNγRα). Tumor xenotransplant experiments using DLD-1 cells with reconstituted GBP-1 expression resulted in significantly reduced tumor growth as compared to xentotransplants with control vector transfected DLD-1 cells. This indicated that GBP-1 expression may mediate the anti-tumorigenic effects of the Th1 response. Overall, these data suggested that loss of IFN-γ responsiveness may be a common event in CRC and may protect tumor cells against the anti-tumorigenic (e.g. pro-apoptotic) effects of IFN-γ. The presence of an immune escape from the Th1 adaptive immune response may have important repercussions for prognosis and patients recruitment for immune-based therapy in CRC. 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 780. doi:10.1158/1538-7445.AM2011-780
GERIATRIC NUTRITIONAL RISK INDEX PREDICTS 2-YEAR MORTALITY IN PATIENTS WITH CRITICAL LIMB ISCHEMIA FOLLOWING ENDOVASCULAR THERAPY
Authors: Tatsuya Shiraki, Osamu Iida, Shin Okamoto, Takayuki Ishihara, Kiyonori Nanto, Takashi Kanda, Masashi Fujita, Masaaki Uematsu
Journal: Journal of the American College of Cardiology (2015)
RANOLAZINE PROTECTS VENTRICULAR FIBROBLAST FROM FAILING HUMAN HEART AGAINST DRONEDARONE-INDUCED TOXICITY
Authors: Larisa Emelyanova, Mingyuan Liu, Guangyuan Yang, Elizabeth Stoeckl, Milanka Petrovic, Ekhson Holmuhamedov, Farhan Rizvi, Gracious Ross, Frank X. Downey, A. Jamil Tajik, Arshad Jahangir
Journal: Journal of the American College of Cardiology (2016)
Abstract 2359: Modeling the kinetics of metastatic progression
Authors: Ananth Eleswarapu, Sung-Hyeok Hong, Arnulfo Mendoza, Chand Khanna
Journal: Cancer Research (2010)

Abstract Background: Metastasis has previously been described as an inefficient process - that is, many tumor cells do not survive the process of early metastasis. Metastatic cells must survive exposure to a foreign microenvironment, which can induce cell death, and to the circulation, which provides mechanical sheer stress and immune cells. By observing the kinetics of tumor growth in both ex vivo and in vivo models of metastasis, we hope to determine the relative contributions of circulatory flow and a foreign microenvironment to metastatic inefficiency. Methods: We have developed a novel Pulmonary Metastasis Assay (PuMA), in which we observe the progression of fluorescence-tagged tumor cells in an ex vivo whole organ lung culture. The PuMA model exposes metastatic cells to a foreign microenvironment, but not to the circulation. The intravital videomicroscopy (IVVM) model exposes tumor cells to both the circulation and a foreign microenvironment. We performed serial assessments of tumor burden for the first seven days after arrival of metastatic cells to the lungs, to compare kinetics of tumor growth in both circulation-dependent and circulation-independent models of metastasis. Results: Both the PuMA and IVVM models displayed metastatic inefficiency. The kinetics of metastatic inefficiency and recovery in the PuMA is similar to that seen in IVVM, with periods of 1) decline in tumor burden, 2) a plateau of several days, and 3) an escape, in which tumor burden grows beyond its baseline value. The magnitude of the initial decline in tumor burden, however, is greater in the IVVM model (85% decrease from baseline, at 24 hours after metastasis), than in the PuMA model (43% decrease at 24 hours). Conclusions: These data indicate that there is a significant circulation-independent contribution to metastatic inefficiency (as seen in the decrease in tumor burden in our PuMA model), as well a circulation-dependent contribution (as seen in the greater decrease in our IVVM model). We believe that the PuMA model will be a valuable tool in studying signaling pathways that affect survival in foreign environment. Studies are now underway to use the PuMA, in combination with pharmaceutical and genetic targeting, to study the effect of individual signaling pathways on survival during early metastasis. 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 2359.
Abstract 2963: Pharmacologic Chk2-inhibition promotes increased killing of human colorectal cancer cells and protects from gastrointestinal toxicity following Irinotecan/trail death-receptor agonists (TDRA)
Authors: Niklas K. Finnberg, Navaraj Arunasalam, Krystle Lang, George Cerniglia, Noboru Motoyama, Bin-Bing Zhou, Wafik S. El-Deiry
Journal: Cancer Research (2011)

Abstract Dose-limiting gastrointestinal toxicity following systemic chemotherapy-based treatment regimen is associated with increased cost and reduced cure-rate. Pharmacologic inhibition of Chk2 has the potential to sensitize cancer cells to cancer therapy while at the same time protect normal tissues from toxicity. Cell death in normal tissues and cells is blocked by inhibition or loss of chk2 in a DNA damage-specific manner whereas tumors cells with check-point aberrations are sensitized to death. We show that inhibiting Chk2-by the use the pharmacologic inhibitors of the Chk2-kinase “Chk2 Inhibitor II” (CI-II) and PV-1019 has the potential to both protect the GI mucosa and improve cell-kill of colorectal cancer cells when Irinotecan is combined with trail death-receptor agonists (TDRA). HCT116-Chk2-/- cells were increasingly sensitive to Irinotecan, TDRA and the combination thereof and PV-1019 had single agent activity towards SW620 cells at 10µM and caused sensitization to Irinotecan at lower doses. Gastrointestinal (GI) toxicity in mice following treatment with the TDRA-antibody MD5-1 in combination with high-dose Irinotecan is completely mediated by chk2 since Chk2-deficient mice are protected and pharmacologic inhibition of Chk2 using CI-II following Irinotecan/TDRA reduced the extent of weight loss and lethality associated with GI-toxicity in the mice. Interestingly, chk2-inhibition only conferred significant protection following Irinotecan/TDRA but not fluorouracil/TDRA, suggesting an Irinotecan-specific protection from GI-toxicity. Concomitant pharmacologic inhibition in conjunction with Irinotecan-based therapy may improve the therapeutic window by reducing GI-toxicity and increasingly promote colorectal cancers cell death. 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 2963. doi:10.1158/1538-7445.AM2011-2963
Quality Assurance of an Organised Screening Programme for Breast Cancer in Denmark 1991-2008.
Authors: M. von Euler-Chelpin, K. Jacobsen, I. Vejborg
Journal: Cancer Research (2009)

Abstract Background: The capital city of Copenhagen, Denmark, has had an organised programme for screening with mammography since 1991. All women resident within the area of uptake and aged 50-69, representing around 45000 women, are invited biennially, unless they actively have asked not to be invited. We have evaluated the programme with regard to the European guidelines for quality assurance in breast cancer screening and diagnosis, to assess performance and impact.Methods: The target population was identified through the national population register, identifying all women meeting the inclusion criteria in terms of age and place of residence, migration and death. The mammography programme supplied data on all invited women, participation and screening test results. Oncological data was retrieved from the National Cancer Register and the Danish Breast Cancer Group. Data was linked using the Danish unique personal identity number.Results: In the first invitation round (1991-1992) the invasive cancer detection rate was 10/1000 and was by the 8th invitation round (2006-2007) 8/1000. The in situ detection rate has been 1/1000 throughout the period. The programme sensitivity is approximately 70%. The detection rate of small tumours (≤ 10mm) was, on average, 39% over the first 4 invitation rounds and 62% by the 8th invitation round. The benign to malign ratio changed from 1:1.6 to 1:11.4, from the first to the 8th invitation round. Recall rates at initial screen dropped from 7% to 4% in the period, and for subsequent screens from 4% to 2%. The false positive rate was 5.5% in the first invitation round and had by the 8th invitation round dropped to 1.3%, with a cumulative risk of 15% over 8 rounds. In the 8th invitation round, there was 82% coverage, a participation rate of 61% and a long term adherence of 50%.Conclusions: The results for the majority of indicators were well within the recommended levels. There had been a significant improvement in the benign to malign ratio, despite that the false positive rate at assessment had decreased. The detection of small tumours had also improved significantly. Participation rates were, however, lower than recommended. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4005.
OC-061 Long-Term Survival of Patients with Systemic Sclerosis on home Parenteral Nutrition: 27-Years Experience: Abstract OC-061 Table 1
Authors: E Harrison, A L Herrick, J McLaughlin, S Lal
Journal: Gut (2013)

<h3>Introduction</h3> Patients with systemic sclerosis (SSc) may develop significant gastrointestinal involvement (GI) with associated nutritional impairment. When severe, this can progress to intestinal failure (IF) requiring home parenteral nutrition (HPN). Few outcome data are reported on these patients [1,2,3]. <h3>Methods</h3> Records were reviewed of all patients with SSc, who had been referred to a national IF centre and who required HPN between 1985 and 2012. Disease characteristics were evaluated and survival/outcome data compared to all patients requiring HPN in the IF centre. <h3>Results</h3> 25 patients (5 male, median age: 55 (range 24–76)) with SSc received HPN. Median time from SSc diagnosis to HPN was 58 months (range 0–378). 24/25 patients had small intestinal involvement. 1 patient had severe colonic and pharyngeal dysmotility but could not tolerate enteral feeding. 17 patients had bacterial overgrowth. 7 reported pseudo-obstruction episodes and 5 had intestinal resections. Prior to HPN, 7 patients had failed naso-enteric feeding. 10 had a gastrostomy or jejunostomy inserted; 7 of these patients received enteral feeding for &lt; 1 yr. The remaining patients were commenced directly on HPN without enteral tube feeding because of the severity of dysmotility/associated co-morbidity. Only 2 patients were weaned off HPN (after 8 and 29 months) following successful medical optimisation. Survival on HPN is shown in table 1. No patients died from HPN-related complications. 17/18 died from underlying SSc disease. 1/18 died from malignancy. 7 patients survive, 6 remain on HPN (median duration: 50 months, range 27–173). 8 patients were trained to manage their central venous catheters and self-administer HPN. 17 patients relied on others to administer their HPN. Reported catheter complications in SSc patients (37,600 catheter days) included occlusion (26), sepsis (7), fracture (3) and site calcification (2). Catheter sepsis rate equated to 0.19 episodes per 1000 days (vs. 0.39 per 1000 days for all HPN patients at this centre). No patient with SSc developed IF-associated liver disease. <h3>Conclusion</h3> This is the largest reported series of patients with SSc requiring HPN. Our data show that HPN offers a safe means of nutritional support for patients with severe SSc-related GI involvement, but that SSc-related mortality remains high. Notably, the SSc group had a lower catheter-related sepsis rate than all patients requiring HPN. Additionally, the majority relied on others for catheter care. <h3>Disclosure of Interest</h3> None Declared <h3>References</h3> Ng <i>et al.</i> Arthritis Rheum. 1989;32:212–6, Jawa <i>et al.</i> J. Rheum. 2012;39:1004–7, Brown <i>et al.</i> Rheumatology. 2008;47:176–9
TCTAP A-128 Impact of Regional Differences on Cardiovascular Outcome in Patients Undergoing Coronary Angiography or Intervention in Acute Coronary Syndrome: A Population-Based Study from NHIRD of Taiwan
Authors: Chun-Yuan Chu, Wen-Hsien Lee, Po-Chao Hsu, Ho-Ming Su, Hung-Hao Lee, Cheng-An Chiu, Tsung-Hsien Lin, Wen-Chol Voon, Wen-Ter Lai, Sheng-Hsiung Sheu
Journal: Journal of the American College of Cardiology (2015)
Reliable Detection of Mismatch Repair Deficiency in Colorectal Cancers Using Mutational Load in Next-Generation Sequencing Panels
Authors: Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, Leonard B. Saltz
Journal: Journal of Clinical Oncology (2016)

Tumor screening for Lynch syndrome is recommended in all or most patients with colorectal cancer (CRC). In metastatic CRC, sequencing of RAS/BRAF is necessary to guide clinical management. We hypothesized that a next-generation sequencing (NGS) panel that identifies RAS/BRAF and other actionable mutations could also reliably identify tumors with DNA mismatch repair protein deficiency (MMR-D) on the basis of increased mutational load.We identified all CRCs that underwent genomic mutation profiling with a custom NGS assay (MSK-IMPACT) between March 2014 and July 2015. Tumor mutational load, with exclusion of copy number changes, was determined for each case and compared with MMR status as determined by routine immunohistochemistry.Tumors from 224 patients with unique CRC analyzed for MMR status also underwent MSK-IMPACT. Thirteen percent (n = 28) exhibited MMR-D by immunohistochemistry. Using the 341-gene assay, 100% of the 193 tumors with < 20 mutations were MMR-proficient. Of 31 tumors with ≥ 20 mutations, 28 (90%) were MMR-D. The three remaining tumors were easily identified as being distinct from the MMR-D tumors with > 150 mutations each. Each of these tumors harbored the P286R hotspot POLE mutation consistent with the ultramutator phenotype. Among MMR-D tumors, the median number of mutations was 50 (range, 20 to 90) compared with six (range, 0 to 17) in MMR-proficient/POLE wild-type tumors (P < .001). With a mutational load cutoff of ≥ 20 and < 150 for MMR-D detection, sensitivity and specificity were both 1.0 (95% CI, 0.93 to 1.0).A cutoff for mutational load can be identified via multigene NGS tumor profiling, which provides a highly accurate means of screening for MMR-D in the same assay that is used for tumor genotyping.
Reality and revisionism: new evidence for Andrew C Ivy's claim to authorship of the Nuremberg Code
Authors: Allan Gaw
Journal: Journal of the Royal Society of Medicine (2014)

Maurice H Pappworth (1910–1994) was an English physician who had developed a deep concern for the ethics of human research. In 1966, while researching his book – Human Guinea Pigs, which would be published the following year1 – he wrote to Ivy regarding experimentation on prisoners. Andrew C Ivy (1893–1978) was an eminent physician and physiologist and according to Moreno2 ‘by the end of the war he was probably…the most famous doctor in the country [US]…the prototype of today’s media medical expert’. Perhaps because of this status, and the fact that he had been actively involved in research involving prison inmates, he had been invited to serve as the American Medical Association’s (AMA) adviser to the Nuremberg prosecutors (Figure 1). Ivy responded to Pappworth’s enquiry3 on 6 April 1966 and began by stating: 

I was considering the subject of your letter before I testified at Nuremberg and gave the Judges my Version of the Code

thus indicating from the outset his involvement. In his letter, he told Pappworth that he had been interested in research ethics since 1917 and that he had always tried to apply the ‘Golden Rule’ as a guiding principle in all his own research, that is that you should only do to others that which you would allow them to do to you. He indicated finally his belief that the natural extension of this principle was that you should always take your ‘own “Medicine” first’.3 This allusion to self-experimentation as a preliminary and necessary step in research becomes relevant when we consider Ivy’s appendix to the letter. 




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Figure 1.


Andrew C Ivy being sworn in at the Nuremberg Doctors’ Trial, June 1947.

Source: Photo courtesy of the National Archives RG 238 OMT-1-W-60.
Can I tell you something? I'm doping…
Authors: H P Dijkstra, N van Dyk, Y O Schumacher
Journal: British Journal of Sports Medicine (2015)

Doping in sport, particularly in track and field, is a reality.1 ,2 The WADA condemned a rife doping culture in Russian Athletics implicating athletes, coaches, doctors, managers, federations and even the Russian minister of sport.1 The prevalence of blood doping ranged from 1% to 48% for subpopulation samples (country, endurance, non-endurance) of a blood-testing programme by the international governing body for athletics (IAAF).3 In a study on Doping in Elite Sports Assessed by Randomized-Response Surveys, the prevalence of reported past-year doping was 29% at the 13th IAAF World Championships in Athletics in Daegu, South Korea, and 45% at the 12th Quadrennial Pan-Arab Games in Doha, Qatar.2 WADA published a list of 113 coaches, physicians and other support staff, guilty of violating anti-doping rules—athletes are not allowed to associate with any of these individuals.4 

How easy is it then for athletes to beat the system? What help do they get from team medical staff?

Consider this: you are a team physiotherapist at …
Tc-99m Sestamibi Imaging as an Indicator of P-Glycoprotein Expression in Metastatic Pheochromocytoma
Authors: E Derebek, G Capa, H Berk, B Sekeroğlu, H Havitçioğlu, B Değirmenci, M Alakavuklar, H Durak
Journal: Clinical Nuclear Medicine (1998)

A 73-year-old man with metastatic pheochromocytoma demonstrated areas of elevated I-131 MIBG uptake and no Tc-99m sestamibi uptake in the presence of marked blood flow, suggesting P-glycoprotein-mediated multidrug resistance. Tc-99m sestamibi scintigraphy may be used in predicting the chemotherapeutic response of P-glycoprotein-related cytotoxic drugs such as anthracyclines, vinca alkaloids, and epipodophyllotoxins. Moreover, in metastatic pheochromocytoma, it may change the therapy strategy, such as cytotoxic chemotherapy versus targeting therapy with I-131 MIBG or combined therapy with the addition of a P-glycoprotein-reversing agent, provided that the patient is surveyed first with Tc-99m sestamibi and I-131 MIBG.
Liposomal doxorubicin is less cardiotoxic than epirubicin in patients with breast cancer: evidence from a randomized clinical trial employing biological, tissue Doppler and standard echocardiographic endpoints.
Authors: M Lotrionte, G Palazzoni, G Comerci, A Abbate, G Biondi-Zoccai
Journal: Cancer Research (2009)

Abstract Abstract #6145 PURPOSE: Cardiomyopathy following anthracycline chemotherapy may have ominous clinical implications in cancer patients treated with this effective yet potentially toxic therapy. Liposomal anthracyclines (such as liposomal doxorubicin) have the potential for more selective uptake by cancer cells and reduced cardiac toxicity, but early detection at subclinical stage by means of non-invasive tests is pivotal to disclose treatment differences. We thus designed a randomized clinical trial, the Liposomal doxorubicin-Investigational chemotherapy-Tissue Doppler imaging Evaluation (LITE) pilot study to compare the safety of liposomal doxorubicin vs standard epirubicin in terms of clinical and subclinical cardiotoxicity.&amp;#x2028; METHODS: Women with breast cancer and indication to anthracycline chemotherapy were randomized to liposomal doxorubicin or standard epirubicin. Multimodality non-invasive tests, including serial troponin, NT-pro-B-type natriuretic peptide (NT-pro-BNP), standard and tissue Doppler echocardiography were used at baseline and then during follow-up visits to identify subclinical cardiotoxicity.&amp;#x2028; RESULTS: A total of 46 females were enrolled, with a follow-up of 11.0±1.4 months. Use of liposomal doxorubicin instead of epirubicin was associated, at follow-up, with significantly higher left ventricular systolic lateral wall velocities (9.89±2.00 cm/s vs 9.79±2.67 cm/s, P=0.011), and significantly smaller decreases in left ventricular ejection fraction (follow-up LVEF 60.8±4.8% vs 57.1±4.3%, P=0.038). In addition, we found significant correlations between peak NT-pro-BNP values and left ventricular ejection fraction (R=-0.451; P=0.021), and that early changes in diastolic and systolic tissue Doppler parameters could significantly predict much later changes in standard echocardiographic parameters, such as left ventricular ejection fraction (R=0.399; P=0.0035), end-diastolic diameter (R=-0.445; P=0.020), end-systolic diameter (R=-0.427; P=0.010), and deceleration time (R=-0.565; P=0.002).&amp;#x2028; CONCLUSIONS: The present randomized clinical trial, by exploiting tissue Doppler imaging parameters, suggests that a chemotherapy regimen based on liposomal doxorubicin is less cardiotoxic than one based on standard epirubicin in the treatment of patients with breast cancer. Moreover, prolonged follow-up from the overall study cohort shows that NT-pro-BNP values and early changes in tissue Doppler parameters can significantly predict later alterations in standard echocardiographic parameters, thus providing a potential tool for early detection of subclinical cardiotoxicity. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6145.