tbuckley/cabot-search huggingface dataset:
Safety and efficacy of sequencing high-dose interleukin 2 (IL2) after tyrosine kinase inhibitor (TKI) therapy for metastatic renal cell carcinoma.
Authors: E. T. Lam, M. K. K. Wong, N. Agarwal, B. G. Redman, T. Logan, T. W. Flaig, J. P. Monk, A. Jarkowski, A. Sendilnathan, M. Bolden, T. Kuzel, T. Olencki
Journal: Journal of Clinical Oncology (2011)

e15079 Background: Although TKIs are the most common first-line therapy, IL2 remains the only agent that provides durable complete responses (CR). The optimal sequence of these agents is unknown. A single retrospective study of patients (pts) receiving IL2 after prior TKIs noted a high incidence of severe cardiovascular (CV) events and no responses. This study aimed to further determine the safety and efficacy of IL2 after TKI. Methods: After IRB approval, data relating to pt, disease, and treatment characteristics were retrospectively collected. Results: 34 pts treated consecutively at seven IL2 centers since 2005 met criteria for analysis. 23 (67%) and 11 (33%) pts had ≤ 2 or ≥ 3 cardiac risk factors (CRF), respectively. Median time from TKI to IL2 was 8 weeks (wks) (range 1.3 - 52). 22, 11, and 1 pt(s) received 1, 2, and 3 courses (C) of IL2, respectively. CV AEs (grade ≥ 3) included hypotension (26 pts, 76%), vascular leak syndrome (7, 21%), atrial fibrillation (afib) (2, 6%), and congestive heart failure (CHF) (2, 6%). Two pts had reversible non-cardiac respiratory failure. Two pts died within one month of receiving IL2 therapy. The first pt (with 2 CRFs, normal echo, 4 wk TKI to IL2 interval) died one month after C2 Wk1 due to afib and CHF. The second pt (with prior CAD, abnormal echo, 1.3 wk TKI to IL2 interval) died one wk after C1 Wk1 with severe anasarca and CHF. Best responses to IL2 included two CRs (6%), 3 partial responses (PRs, 9%), 10 stable disease (SD, 29%), 18 progressive disease (PD, 53%), and 1 unknown. Pts with CR, PR, SD, and PD had a median of 45, 32, 24.5, and 11.5 doses, respectively. Of the 32 pts with known survival status, 16 are still alive. Median overall survival was 13.5 months (range <1 to >62) from start of IL2, and 33.5 months from diagnosis of metastatic disease. Conclusions: IL2 after prior TKI produced a clinical benefit rate (CR+PR+SD) of 44%, with 18 month median duration of benefit. Although death from sudden cardiac arrest was not seen, as previously reported, two grade 5 CHFs occurred within a month of IL2 therapy. Careful selection of pts and diligent pre-treatment cardiac evaluation is critical. The optimal interval between TKI and IL2 requires further investigation.
Pancreatic Effects of Liraglutide or Sitagliptin in Overweight Patients With Type 2 Diabetes: A 12-Week Randomized, Placebo-Controlled Trial
Authors: Mark M. Smits, Lennart Tonneijck, Marcel H.A. Muskiet, Mark H.H. Kramer, Indra C. Pieters-van den Bos, Karuna E.W. Vendrik, Trynke Hoekstra, Marco J. Bruno, Michaela Diamant, Daniël H. van Raalte, Djuna L. Cahen
Journal: Diabetes Care (2016)

OBJECTIVE To assess the mechanistic effects of the glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide and the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin on (exocrine) pancreatic physiology and morphology. RESEARCH DESIGN AND METHODS For this randomized, double-blind, parallel-group trial, 55 patients with type 2 diabetes treated with metformin and/or sulfonylurea agents were included. Participants received liraglutide 1.8 mg (n = 19), sitagliptin 100 mg (n = 19), or matching placebos (n = 17) once daily for 12 weeks. The primary end point was change in exocrine function (intraduodenal pancreatic fluid secretion, lipase activity, fecal elastase-1, and chymotrypsin). Secondary end points included changes in plasma enzyme concentrations and pancreatic morphology (per MRI). RESULTS No patient developed pancreatitis. Sitagliptin increased intraduodenal pancreatic fluid secretion by 16.3 mL (95% CI −0.3 to 32.9; P = 0.05), whereas liraglutide did not change exocrine pancreatic function. Neither therapy increased lipase/amylase levels after 12 weeks. However, liraglutide increased lipase levels after 6 weeks (23.5 U/L [95% CI 2.1–44.8]; P = 0.03) and sitagliptin increased amylase levels after 2 and 6 weeks (13.7 U/L [95% CI 3.4–23.9]; P = 0.03). Both drugs increased plasma trypsinogen after 12 weeks (liraglutide: 34.6 µg/mL [95% CI 15.1–54.2], P = 0.001; sitagliptin: 23.9 µg/mL [95% CI 4.9–42.9], P = 0.01). Neither changed pancreatic morphology, although liraglutide tended to increase pancreatic volume (7.7 cm3 [95% CI −1.2 to 16.6]; P = 0.09). Treatment-induced volume expansion was associated with increased amylase levels. CONCLUSIONS A 12-week treatment with liraglutide or sitagliptin only resulted in a brief and modest increase of plasma pancreatic enzyme concentrations in patients with type 2 diabetes. Apart from a minimal sitagliptin-induced increase in intraduodenal fluid secretion, pancreatic exocrine function was unaffected. The long-term clinical consequences of these discrete changes require further study.
Abstract 5185: Identification of BRIP1 as a novel marker of breast tumor malignancy in the Omani population
Authors: Ishita Gupta, Allal Ouhtit, Marwa Al-Riyami, Adil Al Ajmi
Journal: Cancer Research (2015)

Abstract The rationale of the present study is based on the following observations made in Oman: 1) a significantly increasing number of younger females (25-40 years) present to the clinic with advanced stage of breast cancer (BC); 2) the rate of consanguinity is significantly high (∼50%); and 3) the transition from normal/benign to malignant phenotype of breast tumor requires the involvement of a subset of specific genes. The long-term objective of this study was to identify and validate the gene(s) that underpin BC malignant transformation using functional genomic approaches. RNA samples were isolated from 40 malignant breast tumor tissues and 40 normal/benign breast tissues and analyzed by microarray gene expression profiling. Among a number of differentially expressed genes, BRIP1 showing a 5-fold up-regulation was identified as a potential gene that might underpin the transition from the benign to the malignant phenotype. The differential expression of BRIP1 was structurally validated by RT-PCR using the remaining RNA of the same samples previously examined by microarray. Pathway analysis was carried out to predict the major functional pathways involving BRIP1 to other identified genes. Ongoing sequencing of these genes using DNA extracted from the same samples will ultimately identify any genetic alteration that can affect the normal function of these genes. Functional validation assays will validate further the physiological relevance of BRIP1 in tumor malignancy, and perhaps other novel gene(s) specific to BC in the Omani population. This study has identified BRIP1 as a novel potential marker for BC malignancy, and can be a potential biomarker for early diagnosis of BC and/or a target to pave the way towards the design of anti-BC therapeutic strategies. Citation Format: Ishita Gupta, Allal Ouhtit, Marwa Al-Riyami, Adil Al Ajmi. Identification of BRIP1 as a novel marker of breast tumor malignancy in the Omani population. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5185. doi:10.1158/1538-7445.AM2015-5185
Hypoxia-Inducible Factor-Alpha (HIF-α) Activation in Non-Hodgkin’s Lymphoma (NHL): Relationship to the Thioredoxin Family and Correlation with Survival by Tissue Microarray (TMA).
Authors: Andrew M. Evens, Paul T. Schumacker, Irene B. Helenowski, Amar Singh, Danijela Dokic, Anjeni Keswani, Elizabeth Kordeluk, Adekunle Raji, Jane N. Winter, Borko D. Jovanovic, Arne Holmgren, Beverly P. Nelson, Leo I. Gordon
Journal: Blood (2007)
Abstract 4424: Molecular diagnostics of drug resistant multiple myeloma cases using targeted next generation sequencing
Authors: Hiroshi Ikeda, Yasushi Sasaki, Tetsuyuki Igarashi, Yuka Aoki, Toshiaki Hayashi, Tadao Ishida, Takashi Tokino, Yasuhisa Sinomura
Journal: Cancer Research (2015)

Abstract In multiple myeloma (MM), there are two distinct genetic subtypes based on copy number alterations and translocations. About half of all MM cases are a hyperdiploid type, which is characterized by multiple trisomies of chromosomes 3, 5, 7, 9 11, 15, 19 and 21 and a lower prevalence of primary translocations involving the immunoglobulin heavy chain (IgH) locus at 14q32. The remaining cases are the non-hyperdiploid type, and chromosomes 8, 13, 14, and 16 are frequently lost. Non-hyperdiploid myeloma is strongly association with translocations of IgH alleles with various partner chromosomes, such as t(11;14)(q13;q32), t(4;14)(p16.3; q32), t(14;16)(q32;q23), t(6;14)(p21;q32) or t(14;20) (q32;q11). The copy number alterations in other chromosome regions such as 1q, 6q, 8p, and 16q occur in both subtypes. Overall, non-hyperdiploid MM is associated with worse survival than hyperdiploid MM. In this study, we sequenced all exons of 409 cancer-related genes in matched tumor and normal DNA from 5 non-hyperdiploid MM patients using a next-generation semiconductor sequencing protocol. DNA was extracted from magnetic bead-enriched bone marrow CD138 positive tumor cells from the patients and CD138 negative cells were used as matched normal cells. We detected both point mutations and copy number variations (CNVs). One individual with refractory MM (IgG λ type, ISS stage II) displayed 8 non-synonymous somatic mutations in addition to numbers of CNVs including CCND1 and RB1. We observed 2 point mutations and 3 CNVs, affecting NF-kB pathway genes: IKBKB, CYLD, IKBKE, CD79B and SYK. Although the basis of NF-kB pathway activation is only partially understood, our findings greatly expand the mechanisms by which NF-kB may be activated in this patient. We also detected several gene alterations, which may be associated with poor prognosis and poor response to chemotherapy in patients with refractory MM. Although its value should be further confirmed in larger samples, the targeted next generation sequencing is a valuable tool for high-throughput genetic testing in clinical research. Citation Format: Hiroshi Ikeda, Yasushi Sasaki, Tetsuyuki Igarashi, Yuka Aoki, Toshiaki Hayashi, Tadao Ishida, Takashi Tokino, Yasuhisa Sinomura. Molecular diagnostics of drug resistant multiple myeloma cases using targeted next generation sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4424. doi:10.1158/1538-7445.AM2015-4424
Commentary on the Paper “Anatomical Study of the Caudate Lobe with Special Reference to the Portal Venous and Biliary Branches Using Corrosion Liver Casts and Clinical Application” by Kumon
Authors: Guido Torzilli
Journal: Liver Cancer (2016)

This translation paper describes the anatomy of the caudate lobe using corrosion liver casts.It was originally published in Japanese more than 30 years ago [1] .Dr. Kumon studied 23 elaborative corrosion liver casts of autopsied livers.The corrosion liver casts were prepared by injecting colored silicone rubber into hepatic vessels and removing the hepatic parenchyma.Through the analysis, Dr. Kumon proposed that the caudate lobe can be partitioned into 3 regions by focusing on the type of the portal venous and biliary branches that are distributed in the caudate lobe: the Spiegel lobe, paracaval portion, and caudate process portion.In Europe, the anatomical concept of the caudate lobe was based on Couinaud's analysis [2] : he divided the caudate lobe into the left (segment 1l) and right (segment 1r) segments, although this definition had been slightly modified according to the period.In the US, Healey and Schroy [3] reported that the caudate lobe was partitioned into 3 portions that comprise the left portion, right portion, and caudate process.Finely prepared corrosion liver casts successfully demonstrated portal venous branches that ramified from the right and left portal veins (Fig. 1) and the extent of the caudate lobe (Fig. 2,4).Schematic images in Figure 4 depicted the anatomical concept of the caudate lobe by Kumon and colleagues, which comprised the Spiegel lobe, paracaval portion, and caudate process portion.This partition system influenced particularly the hepatobiliary teams in Japan in the 1990s and 2000s, but now is considered also by the European groups.In the event of surgery for hepatocellular carcinoma, the anatomic resection of Couinaud segment 1, using the counterstaining [4] or the counter-compression technique [5] , has been possible.Similarly, right trisectionectomy with full resection of segment 1 for hilar-cholangiocellular carcinoma [6] and left liver procurement including segment 1 for donor surgery [7] have also been described.Conservative surgery for anatomically removed large tumors in segment 1 has also been supported [8] .Based on this partition system, and on the evidence that, in the case of colorectal liver metastases, the tumor-vessel detachment is suitable [9] , the liver
EXTH-50. SPECIFIC KNOCKDOWN OF EGFR AND PLK1 GENE EXPRESSION IN U87 GBM CELLS WITH RADIOFREQUENCY ENERGY (RFE) DEVICE
Authors: Ilya Ulasov, Dhimankrishna Ghosh, Mike Butters, John Butters, Charles Cobbs
Journal: Neuro-Oncology (2016)

Every molecule contains a unique electromagnetic radiofrequency energy (RFE) potential. Using superconducting quantum interference device (SQUID) technology, we have developed a technique to specifically measure the RFE of a given molecule, and then expose living tissues to the specific and precise oscillating magnetic RFE field of that molecule. We discovered that exposure of a molecule’s unique RFE through a transmitting electromagnetic coil device can specifically impact biological systems as if the authentic molecule were present. We have recently acquired the RFE signals of siRNA oligonucleotide molecules. Here, we demonstrate for the first time that disruption of signaling pathway using RFE can significantly inhibit target mRNA and protein expression. EGFR and PLK1 blockade by RFE caused a 30-70% reduction of mRNA expression and ~40% protein expression vs control treated cells. Moreover, using RNA microarray and protein array we validated specificity of cellular EGFR knockdown. Finally, we demonstrated that RFE-mediated knockdown of EGFR and PLK1 was associated with decreased U87 GBM cell proliferation. These are the first results to demonstrate that specific RFE signals can be used to knock down specific cellular genes that can impact key pathways associated with cancer signaling.
Long-Term Valve Performance of TAVR and SAVR
Authors: Melissa A. Daubert, Neil J. Weissman, Rebecca T. Hahn, Philippe Pibarot, Rupa Parvataneni, Michael J. Mack, Lars G. Svensson, Deepika Gopal, Samir Kapadia, Robert J. Siegel, Susheel K. Kodali, Wilson Y. Szeto, Raj Makkar, Martin B. Leon, Pamela S. Douglas
Journal: JACC. Cardiovascular imaging (2016)
Abstract LB-029: Signal transduction in EGFR-amplified and NFKBIA-deleted human gliomas
Authors: Alok Mishra, Jun Kong, Daniel J. Brat
Journal: Cancer Research (2015)

Abstract Nuclear factor Kappa B (NF-κB)- a nuclear transcription factor that is retained in the cytoplasm by IKBα (encoded by NFKBIA)- is implicated as a mediator of aggressive behavior in all glioblastoma (GBM) subclasses. We are interested in elucidating molecular mechanisms that explain the relative mutual exclusivity of EGFR amplification and NFKBIA deletion in GBMs. Bioinformatics analysis of TCGA GBM data showed that NFKBIA hemizygous deletions were significantly depleted in samples with EGFR amplification (one-tailed p value of Fisher Exact test, P = 5.97e-4). Moreover, we showed by immunohistochemistry that IKBα was more highly expressed in EGFR-amplified than non-amplified GBMs. We use Ingenuity Pathway Analysis (IPA) to identify gene sets common to both EGFR amplification and NFKBIA hemizygous deletion to identity shared pathways that might explain mutual exclusivity and identified TNF, p53, PI3K, and NF-κB proliferation and apoptosis signaling pathways. We next genetically modeled glioma cell lines and GBM neurosphere cultures by transient transfection/stable viral transduction to recapitulate EGFR/NFKBIA combinations. qPCR of DNA and mRNA for EGFR and NFKBIA verified genotypes. Among the top hits predicted by our in silico studies, we identified sparcl1 and hgpx4 by RT-qPCR and immunoblots as concordantly upregulated in the EGFRamp/NFKBIA+/+ and EGFRnon-amp/NFKBIA+/- cell lines/neurospheres. We also showed differential DNA binding of NF-κB (by electro-mobility shift assay); target gene expression (eg. bcl-2, Il-6); and expression of upstream regulators of NF-κB pathways (viz. pAKT (S436) and IKKβ (Y466)) in GBM neurospheres with distinct EGFR/NFKBIA status. Moreover in U87MG cells (NFKBIA+/−), transiently silencing and overexpressing NFKBIA in different EGFR backgrounds (non-amplified and amplified) led to activation of PARP-dependent but caspase-3-independent apoptotic pathways. Interestingly, in U87MG cells and HPV E6/E7 transformed astrocytes, Annexin V/PI based FACS experiments indicated that NFKBIA overexpression suppressed necrosis. These data demonstrate a complex interplay of EGFR and IKBα/NF-κB in GBMs and identify shared pathways that might explain the relative mutual exclusivity of EGFR amplification and NFKBIA deletion. Citation Format: Alok Mishra, Jun Kong, Daniel J. Brat. Signal transduction in EGFR-amplified and NFKBIA-deleted human gliomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-029. doi:10.1158/1538-7445.AM2015-LB-029
Prognostic Significance of Circulating Epstein-Barr Virus (EBV) DNA in Non-Hodgkin's Lymphoma.
Authors: Myoung Joo Kang, Yoo Jin Cho, Heui June Ahn, Shin Kim, Dae Ho Lee, Sang We Kim, Hyun-Sook Chi, Cheolwon Suh
Journal: Blood (2009)
PTH-040 The effect of salivary nitrite on gastric emptying
Authors: J P Seenan, A A Wirz, A T Clarke, J J Manning, V Fyfe, A W Kelman, G Gillen, K E L McColl
Journal: Gut (2010)

<h3>Introduction</h3> Human saliva has a high nitrite concentration from the entero-salivary recirculation of dietary nitrate. Swallowed nitrite reacts with acidic gastric juice forming nitric oxide (NO). Increasing NO bioactivity, by inhibiting phosphodiesterase, enhances gastric accommodation and delays gastric emptying. <h3>Aims</h3> To determine (1) whether nitrite in saliva affects gastric emptying and (2) whether nitrite in saliva alters postprandial intragastric pressure (IGP). <h3>Methods</h3> 20 healthy subjects (11 males) were studied. On four separate days high-resolution manometry was performed during 15 min fasting and for 90 min following a standardised meal. Post-prandially, solutions of 0, 0.286, 2 and 14 mmol/l potassium nitrite were infused into the oral cavity. Solutions were randomised and double-blinded. Saliva was collected at baseline, 30, 60 and 90 min after the meal. Salivary nitrite concentrations were quantified by Griess reaction. Gastric emptying was assessed by means of a specially designed breath test. <sup>14</sup>C labelled sodium acetate was incorporated, during baking, into a rolled oats flapjack which constituted part of our standardised meal. Following consumption of the flapjack, breath samples were taken at regular intervals. The quantity of <sup>14</sup>C appearing in breath per unit time (μmol/minute) was calculated. A generalised linear regression method was used to estimate gastric half-emptying times (T½). Mean IGP was defined relative to atmospheric pressure as the lowest mean pressure recorded in the six most distal manometry sensors. Results are medians and ranges. <h3>Results</h3> Salivary nitrite concentrations at 60 min were 24.35 μmol/l (3.86–65.46), 80.42 μmol/l (20.88–158.79), 358.4 μmol/l (118.2–726.6) and 2694 μmol/l (600–8087) for the solutions containing 0, 0.286, 2 and 14 mmol/l nitrite, respectively. There was no significant difference in the rate of gastric emptying (T½) between the control solution (103.5 min, 56.2–239.1) and those containing 0.286 mmol/l (113.4 mins, 68.7–254.8, p=0.56), 2 mmol/l (121.7 min, 39.8–270.0, p=0.93) and 14 mmol/l (114.4 mins, 79.1–390.1, p=0.75). There was no difference in the increase in IGP recorded between the control solution (4.06 mm Hg, −2.64–7.31) and those containing 0.286 mmol/l (4.42 mm Hg, −4.55–8.45, p=0.61), 2 mmol/l (4.66 mm Hg, −0.94-9.16, p=0.27) and 14 mmol/l (4.24 mm Hg, −2.12–8.17, p=0.81) potassium nitrite. <h3>Conclusion</h3> Despite an excellent range of salivary nitrite concentrations, extending over and beyond the normal physiological range, no difference in the rate of gastric emptying or postprandial rise in IGP was seen. This suggests salivary nitrite does not affect gastric emptying.
P-Glycoprotein Is Downregulated in KG1a Primitive Leukaemia Cells by LDL Cholesterol Deprivation and by HMG-CoA Reductase Inhibitors.
Authors: Laura Connelly-Smith, Joanne Pattinson, Martin Grundy, Shili Shang, Claire Seedhouse, Nigel Russell, Monica Pallis
Journal: Blood (2007)
Phase II feasibility trial of a 3-week cycle of cisplatin plus radiation for post-operative high-risk head and neck cancer in a Japanese population.
Authors: N. Kiyota, M. Tahara, S. Okano, M. Kawashima, K. Matsuura, Y. Onozawa, K. Nibu, R. Hayashi, K. Yoshimura, A. Ohtsu
Journal: Journal of Clinical Oncology (2011)

e16007 Background: The current standard of care for post-operative high-risk head and neck squamous cell carcinoma (HNSCC) is a three-week cycle of cisplatin plus radiation (RT). In two pivotal trials (RTOG 9501 and EORTC 22931), however, the complete delivery rate of three cycles of cisplatin and RT was only about 60%. Here, we evaluated the feasibility and safety of adjuvant cisplatin plus RT in a Japanese population. Methods: Post-operative high-risk HNSCC patients were enrolled. Definitive surgery for locoregional recurrence was allowed. High-risk factors were a microscopically incomplete resection (ICR), extracapsular extension (ECE), and two or more lymph node metastases. Subjects received three cycles of cisplatin (100mg/m2) concomitant with RT (66Gy/33 Fr). Protocol treatment completion was defined as three cycles of cisplatin with a total dose of more than 240 mg/m2 with RT. Results: From August 2006 to May 2009, 25 eligible subjects were accrued, including 13 males, with a median age of 59 years, ECOG PS 0/1 (18/7), stage III/IVa/IVb/recurrent (1/18/1/5), oral cavity/oropharynx/hypopharynx/larynx (17/4/3/1), and ICR and/or ECE in 20. Protocol completion rate was 80%. Lower limit of the one-sided 90% CI was 66%, which met the predefined statistical criteria. Median relative DI of cisplatin was 0.83. Grade 3/4 acute toxicity included mucositis (44%), dysphagia (28%), dermatitis (24%), nausea/vomiting (16%), neutropenia (32%), and anemia (36%). Grade 3/4 late toxicity included dysphagia (10%), xerostomia (5%), and osteonecrosis (5%). 1-year feeding tube rate was 20%. No treatment-related deaths were observed. With a median follow-up of 25 months, 13 have had progression and 10 have died. Estimated 2-year OS and RFS were 58% and 47%. Univariate analysis revealed that oral cavity cancer and locoregional recurrence might be poor prognostic factors.Conclusions: This is the first phase II feasibility trial of a three-week cycle of cisplatin plus RT for post-operative high-risk HNSCC in an Asian population. Adjuvant three-week cycle of cisplatin plus RT was feasible and safety profile was identical to those in pivotal phase III trials.