tbuckley/cabot-search huggingface dataset:
Evolution of oesophageal adenocarcinoma from metaplastic columnar epithelium without goblet cells in Barrett's oesophagus
Authors: Danielle L Lavery, Pierre Martinez, Laura J Gay, Biancastella Cereser, Marco R Novelli, Manuel Rodriguez-Justo, Sybren L Meijer, Trevor A Graham, Stuart A C McDonald, Nicholas A Wright, Marnix Jansen
Journal: Gut (2015)

<h3>Objective</h3> Barrett9s oesophagus commonly presents as a patchwork of columnar metaplasia with and without goblet cells in the distal oesophagus. The presence of metaplastic columnar epithelium with goblet cells on oesophageal biopsy is a marker of cancer progression risk, but it is unclear whether clonal expansion and progression in Barrett9s oesophagus is exclusive to columnar epithelium with goblet cells. <h3>Design</h3> We developed a novel method to trace the clonal ancestry of an oesophageal adenocarcinoma across an entire Barrett9s segment. Clonal expansions in Barrett9s mucosa were identified using cytochrome c oxidase enzyme histochemistry. Somatic mutations were identified through mitochondrial DNA sequencing and single gland whole exome sequencing. <h3>Results</h3> By tracing the clonal origin of an oesophageal adenocarcinoma across an entire Barrett9s segment through a combination of histopathological spatial mapping and clonal ordering, we find that this cancer developed from a premalignant clonal expansion in non-dysplastic (‘cardia-type’) columnar metaplasia without goblet cells. <h3>Conclusion</h3> Our data demonstrate the premalignant potential of metaplastic columnar epithelium without goblet cells in the context of Barrett9s oesophagus.
대한간학회 학술연구기금 지원과제 결과 보고 : 독성 간손상 환자의 불안과 우울 성향에 관한 다기관연구
Authors: 서정일, 김강, 박정배, 사공정규, 이관, 이재동, 고순영, 서연석, 김병석, 김영석, 이헌주, 김인희, 이병석, 김석현, 김동준, 손주현, 김태엽, 안병민
Journal: Clinical and Molecular Hepatology (2011)
A polariser for on demand production of hyperpolarised 129Xe for human lung MRI
Authors: Graham Norquay, Steven Parnelll, Xiaojun Xu, Juan Parra-Robles, Jim Wild
Journal: European Respiratory Journal (2013)

Hyperpolarised 3He gas has been evaluated in clinical studies in different lung diseases, where it has been shown to have high sensitivity to early stage lung disease such as early smoking related emphysema and early obstruction of the airways in pediatric cystic fibrosis. Preliminary clinical studies with 129Xe gas lung MRI indicate comparable functional sensitivity to lung diseases as 3He MRI. Xenon is also soluble in blood and can be used to image lung ventilation-perfusion and alveolar-capillary gas exchange. Global supplies of 3He are limited, whilst 129Xe can be extracted from the air thus 129Xe lung MRI offers a potentially cheaper and more sustainable route to clinical translation than 3He as a lung imaging contrast agent. In this work we present a custom built 129Xe laser polariser capable of producing 129Xe gas on demand for human lung imaging studies. With just 300 ml of inhaled 129Xe gas (collected using cryogenic accumulation for ∼ 30 min with polarisations of > 10 %) from the polariser we are able to achieve lung images of a standard approaching the quality of 3He MRI. With regulatory approval of the polariser, the pathway for clinical research and future translation of 129Xe lung MRI is promising.
Phosphate depletion impairs leucine-induced insulin secretion.
Authors: H Y Oh, G Z Fadda, M Smogorzewski, H H Liou, S G Massry
Journal: Journal of the American Society of Nephrology (1994)

Phosphate depletion (PD) in vivo causes a sundry of abnormalities in pancreatic islets including a rise in cytosolic calcium, low ATP content, reduced Ca2+ ATPase and Na(+)-K+ ATPase activity, and impaired insulin secretion in response to glucose or potassium. L-Leucine is a strong secretagogue that triggers insulin secretion by deamination to alpha-ketoisocaproic acid (KIC) and the subsequent metabolism of the latter to ATP and by the activation of glutamate dehydrogenase (GLDH), which acts on glutamate to generate alpha-ketoglutarate, the metabolism of which results in ATP production. The generation of ATP triggers events that lead to insulin secretion. It is not known whether PD impairs leucine-induced insulin secretion, and the cellular derangements that are involved in such an abnormality are not defined. These issues were studied in PD rats and in pair-weighed normal animals as controls. D-Leucine uptake by islets from PD rats is normal, but both leucine- and KIC-induced insulin secretions are impaired and the activity of branched-chain keto acid dehydrogenase, which facilitates the metabolism of KIC, is reduced. Both leucine and 2-aminobicyclo (2-2-1) haptene failed to stimulate GLDH and to augment the generation of alpha-ketoglutarate in the islets of PD rats. Also, the concentration of basal alpha-ketoglutarate was significantly higher in the islets of PD rats, suggesting that its metabolism is impaired. In addition, the activity of glutaminase is significantly reduced, an abnormality that would result in decreased production of glutamate, the substrate for GLDH. The data show that PD impairs leucine-induced insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Low-calcium dialysate stimulates parathormone secretion and its long-term use worsens secondary hyperparathyroidism.
Authors: E Fernández, M Borràs, B Pais, J Montoliu
Journal: Journal of the American Society of Nephrology (1995)

The long-term clinical effects of the use of a low calcium concentration in the dialysate are largely unknown. For this reason, the influence of low-calcium dialysate on parathyroid hormone (PTH) secretion in hemodialysis patients and its long-term effect on the severity of secondary hyperparathyroidism were studied. In 35 hemodialysis patients, the dialysate calcium concentration was lowered from 1.75 to 1.25 mmol/L. Twelve months later, serum iPTH levels increased significantly from 18.6 to 33.2 pmol/L and so did alkaline phosphatase levels, from 210 to 330 IU/L, without significant changes in serum calcium or phosphorus levels. Hemodialysis with low-calcium dialysate (1.25 mmol/L) induced a net calcium loss in 10 patients, without modifications in ionized serum calcium levels. In addition, mean serum iPTH increased 20% over baseline levels, reaching the maximal level at 30 min after the start of hemodialysis with low-calcium dialysate. In contrast, mean serum iPTH levels drop dramatically at 30 min of hemodialysis with high-calcium dialysate (1.75 mmol/L). It was concluded that low-calcium dialysate worsens secondary hyperparathyroidism in hemodialysis patients, probably by inducing a negative calcium balance and causing repetitive stimulation of PTH secretion in each dialysis. The maintenance of normal serum calcium levels could be due to PTH-induced calcium mobilization from bone.
Defective monocyte oxidative burst predicts infection in alcoholic hepatitis and is associated with reduced expression of NADPH oxidase
Authors: Nikhil Vergis, Wafa Khamri, Kylie Beale, Fouzia Sadiq, Mina O Aletrari, Celia Moore, Stephen R Atkinson, Christine Bernsmeier, Lucia A Possamai, Gemma Petts, Jennifer M Ryan, Robin D Abeles, Sarah James, Matthew Foxton, Brian Hogan, Graham R Foster, Alastair J O'Brien, Yun Ma, Debbie L Shawcross, Julia A Wendon, Charalambos G Antoniades, Mark R Thursz
Journal: Gut (2016)

In order to explain the increased susceptibility to serious infection in alcoholic hepatitis, we evaluated monocyte phagocytosis, aberrations of associated signalling pathways and their reversibility, and whether phagocytic defects could predict subsequent infection.Monocytes were identified from blood samples of 42 patients with severe alcoholic hepatitis using monoclonal antibody to CD14. Phagocytosis and monocyte oxidative burst (MOB) were measured ex vivo using flow cytometry, luminometry and bacterial killing assays. Defects were related to the subsequent development of infection. Intracellular signalling pathways were investigated using western blotting and PCR. Interferon-γ (IFN-γ) was evaluated for its therapeutic potential in reversing phagocytic defects. Paired longitudinal samples were used to evaluate the effect of in vivo prednisolone therapy.MOB, production of superoxide and bacterial killing in response to Escherichia coli were markedly impaired in patients with alcoholic hepatitis. Pretreatment MOB predicted development of infection within two weeks with sensitivity and specificity that were superior to available clinical markers. Accordingly, defective MOB was associated with death at 28 and 90 days. Expression of the gp91 phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase was reduced in patients with alcoholic hepatitis demonstrating defective MOB. Monocytes were refractory to IFN-γ stimulation and showed high levels of a negative regulator of cytokine signalling, suppressor of cytokine signalling-1. MOB was unaffected by 7 days in vivo prednisolone therapy.Monocyte oxidative burst and bacterial killing is impaired in alcoholic hepatitis while bacterial uptake by phagocytosis is preserved. Defective MOB is associated with reduced expression of NADPH oxidase in these patients and predicts the development of infection and death.
Correlation of expression of circadian genes with liver metastasis and outcomes in colorectal cancer.
Authors: T. Oshima, C. Kunisaki, T. Sato, S. Fujii, N. Yamamoto, M. Shiozawa, M. Akaike, Y. Rino, M. Masuda, T. Imada
Journal: Journal of Clinical Oncology (2010)

10560 Background: Circadian rhythms are daily oscillations in various biological processes, generated by the feedback loops of eight core circadian genes. These eight genes are Clock, casein kinase I ϵ (CKIϵ), cryptochrome1 (Cry1), cryptochrome2 (Cry2), Period1 (Per1), Period2 (Per2), Period3 (Per3), and Bmal1. Recent studies have suggested that circadian genes participate in the growth and development of various cancers. This study examined the relations of circadian gene expression to clinicopathological factors and outcomes in patients with colorectal cancer. Methods: We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 202 patients with untreated colorectal cancer. The relative expression levels of the eight circadian genes in the specimens were measured by quantitative real-time, reverse-transcription polymerase chain reaction. Results: Expressions of the Clock gene and the CKIϵ gene in cancer tissue were significantly higher than those in adjacent normal mucosa (p < 0.0001, p < 0.0001). Expressions of the Per1 gene and the Per3 gene in cancer tissue were significantly lower than those in adjacent normal mucosa (p = 0.043, p = 0.010). Analysis of the relations between clinicopathological features and expressions of the eight circadian genes in cancer tissue showed that high expression of the Bmal1 gene and low expression of the Per1 gene correlated with liver metastasis. On analysis of the relations between outcomes and expressions of the eight circadian genes, high expression of the Per2 gene was associated with significantly better outcomes than low expression of the Per2 gene (p = 0.0038). Conclusions: Our results suggest that overexpression of the Bmal1 gene and reduced expression of the Per1 gene might promote liver metastasis, whereas reduced expression of the Per2 gene might shorten survival in patients with colorectal cancer. Overexpression of the Bmal1 gene and reduced expression of the Per1 gene may thus be useful predictors of liver metastasis. Moreover, reduced expression of the Per2 gene may also be a useful prognostic factor in patients with colorectal cancer. No significant financial relationships to disclose.
Assimilation of Amino Acid Analogues by a Virus-Induced Tumor&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: William C. Love, Alvin S. Levine, James Ashmore
Journal: JNCI Journal of the National Cancer Institute (1964)

The uptake of labeled amino acids was studied in vitro with the use of the chorio-allantoic membrane (CAM) of embryonated eggs and Rous sarcoma virus-induced tumors of CAM. The two amino acids studied were α-aminoisobutyric acid (AIB) and l-aminocyclopentane-l-carboxylic acid (ACC). Both AIB and ACC were concentrated in the intracellular fluid of tumor slices and CAM. Tumor tissue levels of these amino acids exceeded the level observed in the CAM. AIB and ACC concentration by Rous tumor and CAM was markedly inhibited by the presence of the natural amino acids, serine and valine. Both 2,4-dinitrophenol and anaerobiosis reduced AIB accumulation. Glucose suppressed the accumulation of AIB by tumor slices, but was without effect on the accumulation of the amino acid by CAM.
Abstract 15253: A Paradoxical Rise in Serum Copeptin After Non-Pulsatile LVAD: a New SIADH?
Authors: Cara M Statz, Aleksandra M Ras, Kevin D Ballard, Jason A Gluck, Detlef Wencker
Journal: Circulation (2014)

Introduction: Hyponatremia (Na&lt; 136 mmol/L) is prevalent (~28%) among hospitalized heart failure (HF) patients and a marker of advanced/end-stage HF(AHF) with increased mortality. Treatment of hyponatremia has no survival benefit in this population. In a prospective study of AHF patients, we sought to define the prevalence, pathophysiology and role of V2 vasoreceptor activity in the development of hyponatremia. Serum copeptin (S-COP), a surrogate marker for AVP activity, was assessed during AHF therapies (AHFT) which included axial-non-pulsatile left ventricular assist device (LVAD) and/or heart transplant (HTx). Methods: Serum samples were collected from AHF patients pre and post AHFT and compared with normal controls. S-COP levels were assessed using an enzyme linked immunosorbant assay and correlated to clinical variables, serum Sodium (S-Na) and glomerular filtration rate (eGFR). Results: Among 89 consecutive (mean age 56.2±15.35; M=69) patients awaiting AHFT, 54 (60%) were hyponatremic. Preop S-COP was elevated compared to controls (0.68±0.50 vs 0.53±0.13 ng/ml, P=.02) and inversely correlated to S-Na and eGFR (r=-0.23, P&lt;.05, r=-0.23, P&lt;.05; N=81); conversely, eGFR and S-Na were uncorrelated. AHFT (n=42) normalized S-Na (133.2±4.1 vs 136.1±3.5 mmol/l; P=.001) and improved eGFR (47.7±13.6 vs 52.7±9.7 mL/min/1.73sqm; P=.001); however, post LVAD (n=34) S-COP rose (0.67±0.21 vs 1.84±0.76 ng/ml; P&lt;.0001) with incomplete normalization of S-NA (132.9±4.3 vs 135.9±3.8 mmol/l; P&lt;.01). In contrast, post HTx (n=9) S-COP was unchanged to pre-AHFT (0.59±0.32 vs 0.65±0.16 ng/ml; P&gt;.1) and was lower compared to post LVAD (0.65±0.16 vs 1.84±0.76 ng/ml; P&lt;.0001). Elevated S-COP with LVAD as bridge to transplant (n=3) showed a marked decrease post HTx (2.7±0.50 vs 1.0±0.29 ng/ml; P&lt;.01). Conclusions: In AHF, the prevalence of hyponatremia is double compared to acute hospitalized HF and associated with S-COP surge prior to AHFT. Unexpectedly, LVAD but not HTx was associated with rising S-COP and incomplete S-Na recovery despite clinical improvement, suggesting inappropriate antidiuretic hormone release. The association of S-COP rise with non-pulsatile LVAD and potential benefit of long-term AVP inhibition post LVAD merits further studies.
Monitoring chronic myeloid leukemia (CML) response to tyrosine kinase inhibitors (TKI) and homoharringtonine (HHT) using peripheral blood (PB) fluorescence in situ hybridization (FISH) and quantitative RT-PCR (Q-PCR): Are bone marrow biopsies still needed?
Authors: H. J. Khoury, L. Lima, D. Saxe, K. P. Mann, M. Arellano, L. Heffner, L. Bernal-Mizrachi, M. McLemore, A. Langston, E. Winton
Journal: Journal of Clinical Oncology (2009)

7064 Background: The purpose of this study is to compare simultaneously obtained PB and bone marrow (BM) BCR-ABL FISH and Q-PCR to monitor response to TKI and HHT in CML. Methods: Between January 2005 and December 2008, 52 patients (pts) with chronic (n = 37, 80%), accelerated (n = 6, 7%), and blast phase (n = 9, 14%) CML had 112 simultaneous PB and BM FISH and Q-PCR before and/or after start of imatinib (IM, n = 27), dasatinib (n = 9), nilotinib (n = 1), bosutinib (n = 13), or HHT (n = 2) for newly diagnosed (n = 27), IM resistant (n = 20), or IM intolerant (n = 5) CML. 13 (26%) had chromosomal abnormalities in addition to the Philadelphia chromosome, and 10 (20%) had a detectable BCR-ABL mutation including the T315I in 2 pts. Results: 24 (46%) had simultaneous PB and BM FISH and/or Q-PCR measurements obtained at 1 time point, 9 (17%) at 2; 9 (17%) at 3; 10 (20%) at &gt; 4 time points before and/or post-initiation of TKI or HHT. Excellent concordance was observed between PB and BM at all time points for both FISH (r = 0.96; p = 0.0003) and Q-PCR (r = 0.88; p= 0.0015). Correlation was not affected by the presence of additional chromosomal abnormalities, phase of the disease, treatment (TKI or HHT), or the number of prior therapies. Conclusions: FISH and Q-PCR are reliable methods to monitor CML response to TKI and HHT in patients with CML and may render the need for BM biopsy monitoring obsolete. No significant financial relationships to disclose.
Hepatitis B Virus with Primary Resistance to Adefovir
Authors: Ting-Tsung Chang, Ching-Lung Lai
Journal: New England Journal of Medicine (2006)

included 183±482 and 135±434 ml of gas, respectively, and only 14±32 and 11±35 g of tissue, respectively, accounting for 1±3 percent and 1±2 percent of the total lung tissue.
A phase II randomized clinical trial of samarium-153 EDTMP (Sm-153) with or without PSA-TRICOM vaccine in metastatic castration-resistant prostate cancer (mCRPC) after docetaxel.
Authors: Christopher Ryan Heery, Ravi Amrit Madan, Marijo Bilusic, Joseph W. Kim, Nishith K. Singh, Myrna Rauckhorst, Seth M. Steinberg, William L. Dahut, Clara Chen, Robert S. DiPaola, Mark N. Stein, Dennis Panicali, James W. Hodge, Jeffrey Schlom, James L. Gulley
Journal: Journal of Clinical Oncology (2013)

102 Background: A prior randomized, placebo-controlled, multi-center phase 2 trial of PSA-TRICOM demonstrated survival benefit. Sm-153 is a radiopharmaceutical that targets osteoblastic lesions. Preclinical data indicated that Sm-153 could alter tumor phenotype, causing upregulation of Fas, MHC Class I, and tumor-associated antigens, making tumor cells more amenable to immune-mediated killing. This trial was intended to examine the safety and efficacy of the Sm-153 with PSA-TRICOM vs. Sm-153 alone. Methods: This phase 2 multi-center trial was designed to randomize 68 pts to Sm-153 with or without PSA-TRICOM. Eligibility included mCRPC, bone metastases, no visceral disease, prior docetaxel, ECOG ≤2, and normal organ function. Sm-153 was given at 1mCi/kg IV on day 8 and then every 12 weeks. PSA-TRICOM was given on days 1, 15, 29, then every 4 weeks. The 1° endpoint was comparison of progression-free survival at 4 months (mo) utilizing PCCWG, but not PSA criteria. A Fisher’s exact test, assuming a one-tailed alpha = 0.10, was used to compare these fractions. 2° endpoints were OS, ORR, PSA changes, immunologic, and toxicity. Results: 44 pts were enrolled, 5 were not evaluable for the 1° endpoint due to withdrawal prior to 4 mos (4 on Arm A, 1 on Arm B). PFS and PSA findings are provided below. Hematologic toxicities were most common, and were well matched. Conclusions: This final analysis suggests the combination of PSA-TRICOM and Sm-153 has a similar toxicity profile to Sm-153 alone. Despite early closure of this trial due to poor accrual, which may be related to recent approval of multiple agents for mCRPC, this analysis appears to demonstrate improvement in PFS with the combination. This may indicate synergy between PSA-TRICOM and bone-seeking radiopharmaceuticals. Based on the data presented here, we are exploring the potential to combine PSA-TRICOM with alpharadin (radium-223), a next generation bone-seeking radiopharmaceutical. Clinical trial information: NCT00450619. [Table: see text]
Immunomonitoring results of a pivotal phase II/III study with the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) in ovarian cancer patients with malignant ascites
Authors: M. J. Jaeger, A. M. Schoberth, M. M. Heiss, A. Lahr, H. Lindhofer
Journal: Journal of Clinical Oncology (2007)

3020 Background: Malignant ascites is a symptom of late-stage tumor disease and associated with a poor prognosis. The trifunctional antibody catumaxomab specifically binds to EpCAM+ tumor cells and redirects CD3+ T lymphocytes and FcγR I/III+ accessory cells simultaneously to the tumor site. Methods: 129 (85 catumaxomab; 44 control paracentesis) EpCAM-positive ovarian cancer patients with symptomatic malignant ascites were compared in an open-label, multicenter, randomized study for efficacy and tolerability of intraperitoneally given catumaxomab. Various in vivo and in vitro immunological and pharmacodynamic parameters were measured directly from ascites cell preparations. Results: During the course of catumaxomab treatment in the ascites fluid tumor cells dramatically decreased and leukocytes increased. Accordingly, the in vivo effector/target ratio (CD45+/EpCAM+) showed an drastic increase from a baseline of 6:1 to 10,000:1 already after the first infusion (all median). Leukocyte expansion was accompanied by in vivo upregulation of T cell activation marker CD69 on CD4+ and CD8+ T cells in the ascites fluid and an increase of IL-6 in serum at 24 hours after each infusion indicating systemic effects of catumaxomab. In vitro pharmacodynamic studies were carried out with screening samples to further validate the in vivo results. Similarly, the in vitro experiments showed efficient EpCAM+ tumor cell elimination, leukocyte expansion, drastical improvement of the effector/target ratio and activation of T cells. Additionally, a strong upregulation of activating cytokines IL-2 and IFN-γ (T H1 cytokine profile) and proliferation of CD4+, CD8+ T cells and CD11c+ accessory cells were demonstrated in the samples with catumaxomab compared to controls. Conclusions: Intraperitoneal catumaxomab treatment triggers activation and proliferation of different immune cells and leads to elimination of tumor cells within malignant ascites. These data confirm the postulated mode of action of trifunctional catumaxomab in vivo and correlate with clinical efficacy in patients with malignant ascites. [Table: see text]