tbuckley/cabot-search huggingface dataset:
Somatic, hematologic phenotype, long‐term outcome, and effect of hematopoietic stem cell transplantation. An analysis of 97 Fanconi anemia patients from the Italian national database on behalf of the Marrow Failure Study Group of the AIEOP (Italian Association of Pediatric Hematology–Oncology)
Authors: Johanna Svahn, Francesca Bagnasco, Enrico Cappelli, Daniela Onofrillo, Silvia Caruso, Fabio Corsolini, Daniela De Rocco, Anna Savoia, Daniela Longoni, Marta Pillon, Nicoletta Marra, Ugo Ramenghi, Piero Farruggia, Anna Locasciulli, Carmen Addari, Carla Cerri, Elena Mastrodicasa, Gabriella Casazza, Federico Verzegnassi, Francesca Riccardi, Riccardo Haupt, Angelica Barone, Simone Cesaro, Chiara Cugno, Carlo Dufour
Journal: American Journal of Hematology (2016)

We analyzed 97 Fanconi anemia patients from a clinic/biological database for genotype, somatic, and hematologic phenotype, adverse hematological events, solid tumors, and treatment. Seventy‐two patients belonged to complementation group A. Eighty percent of patients presented with mild/moderate somatic phenotype and most with cytopenia. No correlation was seen between somatic/hematologic phenotype and number of missense mutations of FANCA alleles. Over follow‐up, 33% of patients improved or maintained mild/moderate cytopenia or normal blood count, whereas remaining worsened cytopenia. Eleven patients developed a hematological adverse event (MDS, AML, pathological cytogenetics) and three developed solid tumors. 10 years cumulative risk of death of the whole cohort was 25.6% with median follow‐up 5.8 years. In patients eligible to hematopoietic stem cell transplantation because of moderate cytopenia, mortality was significantly higher in subjects transplanted from matched unrelated donor over nontransplanted subjects, whereas there was no significant difference between matched sibling donor transplants and nontransplanted patients. In patients eligible to transplant because of severe cytopenia and clonal disease, mortality risk was not significantly different in transplanted from matched unrelated versus matched sibling donor versus nontransplanted subjects. The decision to transplant should rely on various elements including, type of donor, HLA matching, patient comorbidities, impairment, and clonal evolution of hematopoiesis. Am. J. Hematol. 91:666–671, 2016. © 2016 Wiley Periodicals, Inc.
BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis
Authors: Bobak Parang, Andrew M Kaz, Caitlyn W Barrett, Sarah P Short, Wei Ning, Cody E Keating, Mukul K Mittal, Rishi D Naik, Mary K Washington, Frank L Revetta, J Joshua Smith, Xi Chen, Keith T Wilson, Thomas Brand, David M Bader, William P Tansey, Ru Chen, Teresa A Brentnall, William M Grady, Christopher S Williams
Journal: Gut (2016)

<h3>Objective</h3> Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD. <h3>Design</h3> We determined <i>BVES</i> promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured <i>BVES</i> mRNA levels in a tissue microarray consisting of normal colons and CAC samples. <i>Bves<sup>−/−</sup></i> and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels. <h3>Results</h3> <i>BVES</i> mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, <i>BVES</i> promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, <i>Bves</i> was underexpressed in experimental inflammatory carcinogenesis, and <i>Bves<sup>−/−</sup></i> mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of <i>Bves</i><sup>−/−</sup> tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction. <h3>Conclusion</h3> Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. <i>BVES</i> promoter methylation status may serve as a CAC biomarker.
Abstract 15696: Inhibition of Mechanosensitive MicroRNA, mir-712 Decreases Endothelial Dysfunction and Atherosclerosis
Authors: Sandeep Kumar, Dong J Son, Wakako Takabe, Chanwoo Kim, Chih W Ni, Noah Alberts-Grill, Sang O Kim, Wan Kyu Kim, Jai Woong Seo, Katherine Ferrara, Hanjoong Jo
Journal: Circulation (2013)
Carcinogenicity and Mutagenicity Testing of Three Isomeric &lt;italic&gt;N&lt;/italic&gt;-Nitroso-&lt;italic&gt;N&lt;/italic&gt;-methylaminopyridines in Rats&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: R Preussmann, M Habs, B L Pool
Journal: JNCI Journal of the National Cancer Institute (1979)

Three isomeric N-nitroso-N-methylaminopyridines (NMPY's) were investigated for their carcinogenic activity in BD VI rats following chronic oral administration and for their mutagenic properties in the Ames assay. On the basis of postulated reaction mechanisms, it was expected that 3-NMPY would react differently than 2- and 4-NMPY, but the outcome of both carcinogenicity and mutagenicity assays did not show this. 2-NMPY induced tumors of the esophagus and possibly also of the liver; 3- and 4-NMPY had no activity as carcinogens under the experimental conditions used. Similarly, high concentrations of 2-NMPY showed mutagenic activity toward Salmonella typhimurium TA100, whereas 3- and 4-NMPY did not have such an effect.
Targeting colorectal cancer-associated bacteria: A new area of research for personalized treatments
Authors: T. Faïs, J. Delmas, A. Cougnoux, G. Dalmasso, R. Bonnet
Journal: Gut Microbes (2016)

Most cases of colorectal cancer (CRC) are sporadic, and numerous studies have suggested that gut microbiota may play a crucial role in CRC development. Escherichia coli is a member of the gut microbiota frequently associated with colorectal tumors. CRC-associated E. coli strains frequently harbor the pks genomic island. This genomic island is responsible for the synthesis of colibactin genotoxin, which increases tumor numbers in CRC mouse models. We recently showed that targeting ClbP, a key enzyme involved in colibactin synthesis, blocks the deleterious effect of this toxin in vitro and leads to a significant decrease in tumor numbers in vivo. Altogether, our results suggest that the personalized treatment of CRC should also take into consideration the bacteria associated with the tumor in order to limit their deleterious effects.
Abstract 13324: Outcomes of Endovascular Therapy and Intravascular Ultrasound Findings for Thromboangiitis Obliterans (Buerger’s Disease)
Authors: Osami Kawarada, Teruyoshi Kume, Koichiro Harada, Teruo Noguchi, Hisao Ogawa, Satoshi Yasuda
Journal: Circulation (2015)

Backgrounds: With the advancement of endovascular therapy for peripheral artery disease, thromboangiitis obliterans (TAO) patients might be able to benefit from endovascular therapy. We sought to investigate contemporary outcomes of endovascular therapy and intravascular ultrasound (IVUS) findings for TAO patients. Methods: This study included 21 consecutive limbs in 17 patients (mean age, 47±8 years) undergoing endovascular therapy between April 2007 and February 2015. Subjects’ clinical symptoms included a broad spectrum such as critical ischemia and claudication in the lower and upper limbs. Results: The extents of lesions were classified into crural type in 7, femorocrural type in 7, femoropopliteal type in 2, and radiopalmar/ulnopalmar type in 5. A total of 50 arteries and 1 graft were targeted. Successful revascularization was achieved in all limbs. Subacute thrombosis was observed in 4.8% (1 case) that was successfully managed by reintervention. Rutherford category significantly decreased after revascularization (Pre; 4.2±1.1, Post; 0.3±0.6, P&lt;0.001). During a mean follow-up of 18.2±19.9 months (range, 2-96), clinical benefits was sustained although 29% (6 limbs) required a clinically-driven reintervention. IVUS optionally performed in 15 limbs revealed unique findings including “bulls-eye appearance”, “lotus-root appearance” and “grape branch appearance”. Out of a variety of IVUS findings, dissection and undulation yielded a trend toward a higher incidence of reintervention or reocclusion. Conclusion: In our series, current endovascular therapy could serve as a potential option for TAO patients with lower and upper limb symptoms. Accumulating IVUS findings might lead to understand pathophysiology of TAO and predict the outcome of endovascular treatment.
Impaired dynamics of clot formation and hypofibrinolysis in severe sepsis are coexisting and strictly related
Authors: Mauro Panigada, Francesca Sampietro, Camilla L’Acqua, Lucia Zacchetti, Massimo Boscolo Anzoletti, Rossella Bader, Luciano Gattinoni, Armando D’Angelo
Journal: Intensive Care Medicine (2016)
An overview of pharmacologic treatment of cognitive decline in the aged
Authors: B Reisberg, S H Ferris, S Gershon
Journal: American Journal of Psychiatry (1981)

The most widely known substances that have been investigated for treating cognitive deterioration in the aged are cerebral vasodilators, Gerovital H3, psychostimulants, "nootropics," neuropeptides, and neurotransmitters. The rationale for the choice of specific agents has shifted as our conceptions regarding the origins of cognitive decline have changed; we now know that most cognitive deterioration occurs independently of arteriosclerotic vascular changes. Substances currently being investigated because of their effects on brain electrophysiology, on neurohumoral processes, or on central neurotransmitters show promise.
Attendance and diagnostic yield of repeated two-sample faecal immunochemical test screening for colorectal cancer
Authors: Atija Kapidzic, Aafke H C van Roon, Monique E van Leerdam, Anneke J van Vuuren, Marjolein van Ballegooijen, Iris Lansdorp-Vogelaar, Wolfert Spijker, Kirsten Izelaar, Lieke Hol, Ernst J Kuipers
Journal: Gut (2015)

<h3>Objective</h3> Limited data exist on attendance and additional yield of 2-sample faecal immunochemical testing (FIT) screening during multiple rounds. We therefore conducted a population-based colorectal cancer screening trial comparing attendance and yield of repeated 1-sample and 2-sample FIT screenings. <h3>Design</h3> Two randomly selected groups of average-risk subjects aged 50–74 years were invited for two rounds of either 1-sample (n=5007) or 2-sample (n=3197) FIT (OC-sensor Micro) screening. The test was considered positive if at least one sample was positive (cut-off 50 ng/mL; 10 µg haemoglobin/g). <h3>Results</h3> The cumulative attendance rate was similar for repeated 1-sample and 2-sample FIT screenings (1-sample FIT: 68.1%; 2-sample FIT: 67.1%, p=0.368). The positivity rate in the second round was lower for 1-sample FIT (6.2%, 95% CI 5.4% to 7.2%) than for 2-sample FIT (8.4%, 95% CI 7.1% to 9.8%, p=0.007), whereas the detection rate of advanced neoplasia (AN, 1-sample FIT: 1.9%, 95% CI 1.2% to 2.2%; 2-sample FIT: 1.7%, 95% CI 1.2% to 2.5%, p=0.861) and the positive predictive value (1-sample FIT: 32%, 95% CI 24% to 40%; 2-sample FIT: 21%, 95% CI 15% to 29%, p=0.075) did not differ. After two rounds of screening, the cumulative diagnostic yield of AN for 1-sample FIT was 29.3 per 1000 invitees, compared with 34.0 for 2-sample FIT (p=0.241). <h3>Conclusions</h3> Using 2-sample FIT instead of 1-sample FIT does not result in a higher detection rate of AN in the second round of repeated FIT screening. Furthermore, both strategies lead to a similar yield of AN over two rounds. These findings imply that 1-sample FIT screening is preferred over 2-sample FIT screening.
Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43–9006) in patients with advanced renal cell carcinoma (RCC)
Authors: B. Escudier, C. Szczylik, T. Eisen, W. M. Stadler, B. Schwartz, M. Shan, R. M. Bukowski
Journal: Journal of Clinical Oncology (2005)

LBA4510 Background: BAY 43–9006 (BAY), a dual-action Raf kinase and VEGFR inhibitor, inhibits tumor cell proliferation and angiogenesis. In Phase II trials, BAY has demonstrated activity in patients (pts) with metastatic RCC. The primary aim of this Phase III, double-blind trial was to assess overall survival (OS) in pts with confirmed advanced clear-cell RCC randomized to BAY vs best supportive care (BSC). Results of a planned analysis on the secondary endpoint, progression free survival (PFS) will be presented in this report. Methods: Pts (ECOG 0–1) who had received one prior systemic therapy for advanced RCC were stratified into intermediate- (1–2 risk factors) or low-risk (no risk factors) groups, according to the MSKCC prognostic index. Pts were randomized to receive continuous BAY 400 mg bid or matched placebo with BSC. Pts were withdrawn from the study if they met any of the following criteria: AEs requiring study drug termination; progressive disease (unless continued treatment was considered appropriate by the investigator); patient/sponsor request; pt lost to follow-up; or death. The primary efficacy endpoint is OS, for which an overall two-sided alpha of 0.04 will be used. Final analysis of OS will be performed after 540 events, required to detect 33% improvement with 90% power. Provided interim monitoring boundaries are not crossed, 884 pts (442 per treatment arm) will be randomized. PFS will be compared at a two-sided alpha level of 0.01 using a log-rank test stratified by prognostic group and country. Adverse events will be tabulated by NCI CTC version 3.0. Results: To date, 611 out of 884 pts have been randomized and 229 PFS events have occurred. PFS analysis will be performed after 363 progressive events have occurred. The results of the PFS analysis and the safety experience will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Healthcare Antigenics, Bayer, CFSB, Deutsche Bank, Genentech, Medacorp, Pfizer, Roche AstraZeneca, Bayer AG Antigenics, Bayer, Centocor, Genentech, Pfizer, Roche, Wyeth Amgen, Antigenics, Bayer, Celgene, Genentech, Pfizer, Wyeth
Norman Alan Green
Authors: Barry Ross
Journal: BMJ (2016)

Norman Alan Green was born in Leicester to Norman Green and Lilian Goins. He was educated at Wyggeston Grammer School, Leicester. He was house surgeon to Sir Edward Tuckwell and John Hosford and started his surgical training as anatomy demonstrator at Barts with Professor Cave, who wanted him to be a full time anatomist. Alan received a Fulbright scholarship to the USA. Under …
PWE-363 Bowelscope- results from the pilot sites: Abstract PWE-363 Table 1
Authors: LJ Neilson, R Bevan, C Nickerson, J Patnick, R Loke, BP Saunders, J Stebbing, R Tighe, A Veitch, CJ Rees
Journal: Gut (2015)

<h3>Introduction</h3> A large UK study of single flexible sigmoidoscopy with adenoma clearance in patients aged 55–64, demonstrated a reduction in CRC incidence by 23% and mortality by 31% in intention-to-treat analyses.<sup>1</sup>This provided the rationale for provision of a new arm of the Bowel Cancer Screening Programme (BCSP), offering a single flexible sigmoidoscopy (FS) to all 55 year olds in England, known as BowelScope screening. BowelScope was introduced to 6 pilot sites, beginning in May 2013. It is to be rolled out across the country by 2016. <h3>Method</h3> We aim to describe the findings, in terms of procedural data, from the first year of BowelScope screening at the pilot sites. Data were obtained from the Bowel Cancer Screening System database for all participants who underwent FS between May 2013–May 2014. Procedural data were recorded, including entonox use, adenoma detection rate (ADR), cancer detection, complications and colonoscopy conversion rates. <h3>Results</h3> Overall uptake was 44.1%. 1 cancer was detected. Mean ADR was 9.2%. The mean number of patients requiring colonoscopy conversion was 4.2%. Mean complication rate was 0.1%, including bleeding, discomfort, difficult polyp excision and unwell patient. There was wide variation in entonox use. (Table 1). <h3>Conclusion</h3> Uptake has improved since the six month data were presented but remains lower than for the FOB arm of the BCSP, and varies between sites. The ADR is 9.2% (range 7.6% - 11.1%). This is lower than reported in the UK FS screening trial (12.1%)<sup>1</sup>, however ADR calculations in BowelScope do not include adenomas not removed at FS but removed later at colonoscopy, whereas the FS trial did. The ADR is comparable to the BowelScope pathfinder project (9.6%).<sup>2</sup> Further work is necessary to explore the variation in uptake rates. Variation in ADR exists between centres. Further analysis of endoscopist factors and patient groups may explain this. Entonox use varies widely but does not appear to correlate with ADR- further work may be required to investigate this. <h3>Disclosure of interest</h3> None Declared. <h3>References</h3> Atkin WS <i>et al</i>. Lancet 2010;375:1624–33 Bevan R <i>et al</i>. Endoscopy 2015;47(3):225–31
Plasma levels of 4-OHT with topical tamoxifen gel (afimoxifene) and therapeutic local antiestrogenic effect in premenopausal women with cyclical mastalgia
Authors: A. Goyal, B. Baruah, E. Le Nestour, V. Masini-Etévé, R. Mansel
Journal: Journal of Clinical Oncology (2009)

e14598 Background: 4-hydroxytamoxifen(4-OHT) is a potent anti-estrogenic metabolite of tamoxifen with a much higher affinity for estrogen receptors than tamoxifen. Methods: Plasma levels of 4-OHT in 19 premenopausal women taking 20 mg/d oral tamoxifen for at least 2 months were compared with those of 16 premenopausal women assigned to apply 4mg 4-OHT in a 0.228% Afimoxifene gel daily for 21 days in a pharmacokinetic(PK) study. To evaluate the clinical effectiveness of the gel, premenopausal women experiencing moderate-to-severe mastalgia were randomized to receive placebo, 2mg or 4 mg of Afimoxifene daily delivered as a transdermal hydroalcoholic gel for 4 menstrual cycles. The primary efficacy parameter was change in mean pain intensity, as measured by the VAS for the 7 worst pain score days within a cycle, from baseline to the 4th cycle. Results: In the PK studies, the 4-OHT plasma levels following oral tamoxifen were 16–18 times higher than 4-OHT levels following 4mg 4-OHT administration by topical gel. At steady state, mean Cmax levels in the Afimoxifene group and oral tamoxifen group were 149+99 pg/mL and 2398+901 pg/mL respectively. The Cave concentrations, derived from AUC 0–24h /24, were 117+77 pg/mL (Afimoxifene) and 2078+811 pg/mL (oral tamoxifen). After 4 cycles of gel treatment, significant improvements relative to placebo were seen in mean VAS score in the 4-mg Afimoxifene group (-12.71 mm [95% confidence interval, -0.96 to -24.47; P = 0.034]). Patient global assessment of pain, physician assessment of pain, tenderness on palpation and nodularity following 4 cycles of treatment were significantly improved in the 4-mg group, compared with placebo (P = 0.010 [pain]; P = 0.012 [tenderness]; P = 0.017 [nodularity]). There were no changes in menstrual pattern or plasma hormone levels and no breakthrough vaginal bleeding in patients treated with Afimoxifene. Conclusion: Topical application avoids high systemic exposure to 4-OHT compared with oral tamoxifen, a 16–18-fold difference, thus reducing the risk of systemic side-effects. Afimoxifene is an effective treatment for moderate-to-severe mastalgia and potentially may be used for breast cancer chemoprevention and gynecomastia. No significant financial relationships to disclose.
Effect of dexamethasone on plasma prolactin and cortisol levels in psychiatric patients
Authors: H Y Meltzer, V S Fang, B J Tricou, A Robertson, S K Piyaka
Journal: American Journal of Psychiatry (1982)

In addition to its ability to decrease plasma cortisol levels, dexamethasone can also significantly decrease plasma prolactin levels. In 52 psychiatric patients, including 26 patients with primary major depression or schizoaffective depression, primarily affective type, there was a significant association between nonsuppression of plasma cortisol and prolactin after administration of dexamethasone. These results suggest that the abnormal cortisol response to dexamethasone in some psychiatric patients may be due to a pituitary gland abnormality rather than to a limbic system abnormality. The sensitivity and specificity of the dexamethasone suppression test for endogenous depression were less than previously reported.
Pathogenesis of Virus-Induced Rous Sarcoma. I. Distribution of Virus and Tumor Foci in Chicks and Turkeys&lt;xref ref-type="fn" rid="fn1"&gt;2&lt;/xref&gt;
Authors: Herbert J. Spencer, Vincent Groupé
Journal: JNCI Journal of the National Cancer Institute (1962)

Experiments were carried out to survey the distribution of tumor foci and the associated viral titers in chicks and turkeys infected with large doses of Rous sarcoma virus (RSV). The animals were infected either subcutane ously or intracerebrally with three different strains of RSV. In chicks, the tumors were of an open, myxosarcomatous structure, while in turkeys the growth appeared as a dense, spindle-cell sarcoma. These patterns predominated in both primary and secondary sites of malignancy, were a function of the host species, and were independent of the strain of RSV used. Secondary tumor foci occurred most frequently in the lungs, liver, and spleen of the infected animals, and high viral titers were always associated with areas of frank malignancy. However, appreciable titers were often found in tissues in which no tumor was apparent, either grossly or in single random sections. Following intracerebral inoculation, frank malignancy was found in the subarachnoid space and in association with the cerebral ventricles. Brains evidencing such pathology invariably yielded high viral titers. Following subcutaneous infection, these phenomena were absent in the brain. A brief review of the pertinent literature on the pathogenesis of Rous sarcoma is included.