tbuckley/cabot-search huggingface dataset:
Serum leucine-rich alpha-2-glycoprotein-1 with fucosylated triantennaryN-glycan as a novel tumor marker for colorectal cancer.
Authors: Eiji Shinozaki, Kazuhiro Tanabe, Takashi Akiyoshi, Tomohiro Tsuchida, Yuko Miyazaki, Nozomi Kojima, Masahiro Igarashi, Masashi Ueno, Mitsukuni Suenaga, Nobuyuki Mizunuma, Konosuke Nakayama, Sadayo Iijima, Toshiharu Yamaguchi
Journal: Journal of Clinical Oncology (2016)

595 Background: CEA and CA19-9 are measured widely in daily practice for colorectal cancer to monitor the condition of treatment, though its specificity and sensitivity is not satisfied enough. While, the innovation of mass spectrometry in this decade is dramatically. The revolutionized approach for the screening of glycomarkers provides a chance to discover more desirable tumor markers. We focused on glycan alterations of serum glycoproteins and tried to find new markers which are more specific and sensitive than the current markers. Methods: Sera of 80 CRC patients and 50 healthy volunteers were analyzed in this study. Glycopeptides were prepared from serum proteins by trypsin digestion, enriched by filtration and aleuria aurantia lectin(AAL), and then applied to liquid chromatography time-of flight mass spectrometry* (*LC-TOF-MS). Data was analyzed with our newly developed software, which calculates all of peak intensities and positions (m/z and elution time), aligns all peaks for all samples, and finally screens markers from a million of candidates. Results: Leucine-rich alpha-2-glycoprotein-1 with fucosylated triantennary N-glycan (LRG-FTG) was discovered as a new CRC marker from over 100,000 candidate glycopeptide peaks. The level of LRG-FTG in CRC patients (1.25 ± 0.973 U/ml) was much higher than that of healthy parsons (0.496 ± 0.433 U/ml, p &lt; 10-10). Its sensitivity and specificity exceeded those of CA19-9. CEA and LRG-FTG levels were moderately correlated (r = 0.61), however their relation was independent and complementary. Combination marker of LRG-FTG and CEA showed 84% of sensitivity, 90% of specificity and 0.91 of AUC (ROC analysis), and responded well to the efficacy of chemotherapy. Conclusions: Serum LRG-FTG was significantly elevated in CRC patients compared to healthy volunteers. The combination with CEA is expected to be an alternative diagnostic marker which distinguishes CRC from healthy persons and a sensitive monitoring marker for evaluation of efficacy during chemotherapy. Further validation study is warranted to evaluate serum LRG-FTG combination test compared with conventional tumor markers.
Treatment of childhood nasopharyngeal carcinoma (cNPC) with neoadjuvant chemotherapy (NAC) and concomitant chemoradiotherapy (CCRT): Results of the Children’s Oncology Group ARAR0331 study.
Authors: Carlos Rodriguez-Galindo, Mark D. Krailo, Matthew J. Krasin, Mary B McCarville, John Hicks, Farzana Pashankar, Alberto S. Pappo
Journal: Journal of Clinical Oncology (2016)

10513 Background: cNPC is a rare malignancy that typically presents as WHO type III histology in association with EBV infection, and has a higher incidence among African-American (AA) children. Treatment of cNPC has been adapted from adult NPC regimens; pediatric-specific studies are limited. The ARAR0331 study sought to evaluate the impact of NAC and CCRT. Methods: Patients with AJCC stages I-IIa (stratum A) were scheduled to receive radiation only, and patients with stages IIb-IV (stratum B) cNPC were scheduled to receive three cycles of NAC with cisplatin (80 mg/m2) and 5-FU (1000 mg/m2/day for four days), followed by CCRT with three cycles of cisplatin (100 mg/m2). Patients with complete or partial response to NAC received 61.2 Gy to the nasopharynx and neck, and patients with stable disease received 71.2 Gy. Amifostine (200 mg/m2) was given daily during radiation. Results: Between 2/2006 and 11/2013 111 patients (75 male) were enrolled. Median age was 14 years (range 3-18), and 46.8% of the patients were AA. No patients were enrolled on stratum A. Following a feasibility analysis, the study was amended in 5/2009 to reduce cisplatin to two cycles during CCRT. The 5-year EFS and OS estimates were 85.5% (77%-91%) and 88.2% (77%-94.1%), respectively. The 5-year EFS by stage were 100%, 85.8%, and 82.6% for stages IIb, III, and IV, respectively (p = 0.12, trend test). Patients treated before (N = 48) the amendment had greater 5-year EFS compared with those treated after the amendment (N = 56), although the difference was not significant (5-year EFS 91.5% vs. 81.3%, p = 0.18). Conclusions: cNPC presents with advanced disease and with a higher incidence among AA children and adolescents. Treatment of cNPC with NAC and CCRT results in excellent outcomes. A radiation dose reduction is possible for patients responding to NAC. While the outcomes are comparable, we observed a trend towards decreased EFS for patients receiving a reduced dose of cisplatin during CCRT. Future studies in cNPC should focus on further radiation reduction for patients responding to NAC and chemotherapy reduction for patients with stage IIb disease. Clinical trial information: NCT00274937.
Abstract 2456: Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain
Authors: Shuning He, Marc R. Mansour, Mark W. Zimmerman, Dong Hyuk Ki, Hillary M. Layden, Koshi Akahane, Eric D. de Groh, Antonio R. Perez-Atayde, Shizhen Zhu, Jonathan A. Epstein, A Thomas Look
Journal: Cancer Research (2016)

Abstract Earlier reports indicated that the role of Nf1 tumor suppressor gene in limiting sympathoadrenal cell growth during embryologic development is independent of its ability to down-modulate RAS-MAPK signaling. This finding raised the question of whether neuroblastoma pathogenesis was also accelerated by loss of a similar non-canonical function of NF1. To elucidate how loss of the NF1 tumor suppressor gene contributes to the development of high-risk neuroblastoma, we relied on a transgenic zebrafish model that overexpresses MYCN and harbors loss-of-function nf1 mutations. We show here that loss of nf1 leads to aberrant activation of RAS signaling in MYCN-induced neuroblastoma, promoting both increased tumor cell survival and rapid tumor cell proliferation. We demonstrate further that the GTPase-activating protein (GAP) activity of the (GAP)-related domain (GRD) is sufficient to suppress accelerated initiation of neuroblastoma in nf1-deficient zebrafish, even though this transgene is unable to restrict abnormal sympathoadrenal cell growth during embryologic development. Hence NF1 exhibits different activities in vivo in the normal development and tumorigenesis of the peripheral sympathetic nervous system. Our findings establish nf1-deficient zebrafish that overexpress MYCN as an ideal animal model system for investigating new strategies to improve treatment of very high risk neuroblastomas with aberrant RAS-MAPK activation. We are currently performing high-throughput in vivo drug analysis using these zebrafish with primary tumors. Citation Format: Shuning He, Marc R. Mansour, Mark W. Zimmerman, Dong Hyuk Ki, Hillary M. Layden, Koshi Akahane, Eric D. de Groh, Antonio R. Perez-Atayde, Shizhen Zhu, Jonathan A. Epstein, A Thomas Look. Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2456.
Effectiveness of High-Dose MTX Therapy for Adult Ph-Negative ALL By Randomized Trial: JALSG ALL202-O
Authors: Toru Sakura, Fumihiko Hayakawa, Isamu Sugiura, Kiyotoshi Imai, Noriko Usui, Shin Fujisawa, Tohru Murayama, Toshiaki Yujiri, Hitoshi Kiyoi, Kazunori Ohnishi, Yasushi Miyazaki, Shigeki Ohtake, Yukio Kobayashi, Keitaro Matsuo, Tomoki Naoe
Journal: Blood (2015)
Abstract 3492: Differential sensitivity of normal liver and hepatocarcinoma tissues to tBid induced apoptosis is determined by the abundance of VDAC2
Authors: Shamim Naghdi, Soumya Sinha Roy, Ludivine Walter, Gyorgy Hajnoczky
Journal: Cancer Research (2016)

Abstract A conserved step in extrinsic apoptosis is the outer mitochondrial membrane (OMM) permeabilization by truncated Bid (tBid) that is generated from Bid upon cleavage by Caspase-8 activated at death receptors. tBid directly or indirectly activate proapoptotic proteins i.e. Bak in OMM and/ or Bax in cytosol which is followed by a change in their conformation and oligomerization, leading to a pore formation in the OMM. To better understand the mitochondrial phase of this pathway we applied tBid to semi-permeabilized cells and isolated mitochondria. We monitored cytochrome c release, and the ensuing mitochondrial membrane potential collapse, using immunoblotting and fluorimetry as the markers for mitochondrial cell death. We found that normal liver tissue and normal hepatocytes (Rat, Mouse or Human) are unexpectedly resistant to tBid, whereas hepatocellular carcinoma (HCC) tissues and cell lines (e.g. PLC, Huh7) are greatly sensitized. Considering that the effect of tBid is most effectively mediated through Bak, its abundance in the mitochondria was tested. Bak level is significantly higher in tumor tissue/cell lines, whereas OMM-bound tBid and Bax levels are similar in both cancerous and normal tissue. Since we have recently found that voltage dependent anion channel 2 (V2), a pore forming OMM protein, is specifically required for Bak targeting to OMM, the abundance of V2 was also measured. V2 showed significant upregulation in HCC tissue/cell lines. Rescue studies using V2 sensitized normal hepatocytes and liver mitochondria to tBid. We propose that V2 might be the main regulator for the differential tBid sensitivity in normal liver and hepatocellular carcinoma. Citation Format: Shamim Naghdi, Soumya Sinha Roy, Ludivine Walter, Gyorgy Hajnoczky. Differential sensitivity of normal liver and hepatocarcinoma tissues to tBid induced apoptosis is determined by the abundance of VDAC2. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3492.
Abstract 1013: Quantification of NADPH balance in cancer
Authors: Ling Liu, Li Chen, Greg Ducker, Junyoung Park, Supriya Shah, Kathryn E. Wellen, Joshua D. Rabinowitz
Journal: Cancer Research (2016)

Abstract NADPH is a key cofactor involved in antioxidant defense and reductive biosynthesis. The quantitative contribution of different NADPH pathways, either in normal tissues or in tumors, remains unclear. Here we enable tracing of NADPH production using deuterium-labeled nutrients and mass spectrometry, providing methods that for the first time can track each of the major cytosolic pathways: malic enzyme, isocitrate dehydrogenase, folate metabolism, and the pentose phosphate pathway. This is achieved via a battery of different 2H-tracers. A linear algebra method for deducing the fractional contribution of each pathway, even when a specific tracer for that pathway is not available, will be described. Utility of these methods will be illustrated through examples drawn from both normal cellular physiology and cancer. Specifically, we find that most NADPH in differentiating adipocytes is made by malic enzyme. Examining cancer cells, we find that the pentose phosphate pathway is typically the largest cytosolic NADPH source, but that the collective contribution of alternative pathways is often larger than the pentose phosphate pathway. The specific other pathways involved differ strongly depending on the cancer cell type. We also provide examples where NADPH production routes in both normal and cancer cells vary with nutrient availability, including hypoxia. Given the heightened redox stress of cancer cells, understanding NADPH production routes is likely to illuminate new avenues for therapeutic intervention. Citation Format: Ling Liu, Li Chen, Greg Ducker, Junyoung Park, Supriya Shah, Kathryn E. Wellen, Joshua D. Rabinowitz. Quantification of NADPH balance in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1013.
MAVERICC, a phase II study of mFOLFOX6-bevacizumab (BV) vs FOLFIRI-BV as first-line (1L) chemotherapy (CT) in patients (pts) with metastatic colorectal cancer (mCRC): Outcomes by tumor location and KRAS status.
Authors: Heinz-Josef Lenz, Fa-Chyi Lee, Linda Yau, Han A. Koh, James A. Knost, Edith P. Mitchell, Ivan Bosanac, Christoph Mancao, Aparna Parikh
Journal: Journal of Clinical Oncology (2016)

3515 Background: Standard 1L mCRC treatment (tx) includes a CT backbone (e.g. modified leucovorin [LV]/5-fluorouracil [5-FU]/oxaliplatin [mFOLFOX6] or LV/ 5-FU/ irinotecan [FOLFIRI]) and a biologic (e.g. BV). The preferred CT backbone for anti-VEGF tx is unknown. MAVERICC (NCT01374425), a global, randomized, open-label, phase 2 trial, assessed efficacy and safety of mFOLFOX6-BV vs FOLFIRI-BV in pts with mCRC. PFS and OS were comparable between FOLFIRI-BV and mFOLFOX-BV (Lenz et al, ASCO GI 2016). Exploratory analyses compared clinical outcomes of the BV-containing tx groups by primary tumor location and baseline (BL) KRAS status. Methods: Pts with mCRC (≥1 measurable metastatic lesion, ECOG performance status ≤1) were randomized 1:1 to BV (5 mg/kg) + mFOLFOX6 or FOLFIRI every 2 wks. Time to PFS and OS for each tx group were estimated by Kaplan–Meier methods, hazard ratios (HR) were estimated by Cox regression, p-values were based on log-rank tests stratified by BL ERCC-1 status and region. Results: 376 pts were randomized: median age, 61 yr; white race, 83%; US region, 85%. BL: KRAS mutant (MUT), 34%; KRAS wild type (WT), 55%; KRAS unknown, 11%; left-sided primary tumor, 59%. Efficacy results are shown. Conclusions: There was a trend toward improved PFS and OS in the FOLFIRI-BV group, regardless of primary tumor location or BL KRAS status. PFS benefit from FOLFIRI-BV was statistically significant in left-sided tumors only. PFS and OS were numerically greater in pts with WT vs MUT KRAS status. Clinical trial information: NCT01374425. Median PFS (mo) Median OS (mo) ITT mFOLFOX6-BV (n=188) 10.1 23.9 FOLFIRI-BV (n=188) 12.6 27.5 HRa 0.79 0.76 Primary tumor location Right mFOLFOX6-BV (n=75) 10.0 22.7 FOLFIRI-BV (n=79) 11.2 27.4 HRa 0.88 0.76 Left mFOLFOX6-BV (n=113) 10.2 24.1 FOLFIRI-BV (n=109) 13.8 27.5 HRa 0.71b 0.86 KRAS Exon 2c (by tx) mFOLFOX6-BV (n=107) 11.2 26.1 FOLFIRI-BV (n=101) 14.0 36.7 HRa 0.83 0.77 MUT mFOLFOX6-BV (n=65) 9.5 22.5 FOLFIRI-BV (n=63) 12.3 26.9 HRa 0.72 0.83 KRAS Exon 2c (all tx) WT (n=208) 12.5 28.8 MUT (n=128) 10.9 24.6 HRa 1.29 1.34 a FOLFIRI vs mFOLFOX6 bp=0.040, others p>0.05 cKRAS status of 40 pts unknown
High Bone Turnover Is Present in Patients with Primary Systemic (AL) Amyloidosis and Increased Osteoprotegerin Identifies Patients with Poor Survival within Mayo Stage 1 Disease
Authors: Efstathios Kastritis, Maria Gavriatopoulou, Evangelos Eleutherakis-Papaiakovou, Nikolaos Kanellias, Maria Roussou, Constantinos Pamboucas, Savvas Th. Toumanidis, Evangelos Terpos, Meletios A. Dimopoulos
Journal: Blood (2014)
Transplantation Related Toxicity and Mortality in Older Autologous Hematopoietic Cell Transplantation Recipients
Authors: Hewan Belete, Linda J. Burns, Ryan Shanley, Manju Nayar, Brian McClune, Nishant Sahni, Aleksandr Lazaryan, Veronika Bachanova, Daniel J. Weisdorf, Mukta Arora
Journal: Blood (2014)
Abstract 4260: 3D colorectal cancer organoids as preclinical models for assessment of activity of RAF inhibitor BGB-283
Authors: Xiaoran Wu, Chunyan Fu, Xi Yuan, Lianhai Zhang, Xiaohong Wang, Jiafu Ji, Lusong Luo
Journal: Cancer Research (2016)

Abstract Tumor organoids are three-dimensional (3D) cultures of cancer cells. They can be derived from the tumor cell lines, patient-derived xenografts and tumor tissues from cancer patients, thereby providing an attractive in vitro assay to optimize anticancer treatment. Oncogenic B-RAF, which drives cell transformation and proliferation, has been detected in 5-15% of colorectal cancers (CRC). Despite the remarkable clinical activities achieved by vemurafenib in treating B-RAF V600E metastatic melanoma, their clinical efficacy in B-RAF V600E CRC is far less impressive. BGB-283, currently under clinical development for RAF and RAS mutated solid tumors, is a novel inhibitor of the RAF dimer with inhibitory activities against RAF family kinases. In this study, we evaluated the anti-proliferative effect of BGB-283 and compared it to BRAF inhibitor vemurafenib in CRC patient tumor derived organoids models. BGB-283 exhibited therapeutic potentials in tumors with mutations in the MAPK pathway. Herein, we reported the establishment of tumor organoid models from 19 CRC patients’ tumor tissues with a success rate of 83%. Organoids maintained many characteristics of their original tumors based on their histology. Our studies using primary CRC tumor organoids showed that in contrast to vemurafenib, which only inhibited B-RAF V600E CRC tumors, BGB-283 had inhibition effect on both B-RAF V600E and KRAS mutated tumors. These findings support BGB-283 as a promising clinical stage antitumor agent in treating CRC harboring B-RAF V600E and KRAS mutations. In addition, we showed that patient-derived organoids can be a valuable tool to test drug sensitivity in a personalized treatment and help to fill the gap between tumor genetics and patient trials. Citation Format: Xiaoran Wu, Chunyan Fu, Xi Yuan, Lianhai Zhang, Xiaohong Wang, Jiafu Ji, Lusong Luo. 3D colorectal cancer organoids as preclinical models for assessment of activity of RAF inhibitor BGB-283. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4260.
US proposes to expand fixed payments to cardiac care
Authors: Michael McCarthy
Journal: BMJ (2016)

The US Centers for Medicare and Medicaid Services has proposed the introduction of bundled payments to reimburse physicians and hospitals for cardiac care and to expand the payment model for the reimbursement of surgical treatment of hip and femur fractures.

The proposal, announced on 25 July, also includes incentive programs to promote the use of cardiac rehabilitation, which only about one in seven patients in the US who have had a heart attack receive.1

The initiative is part of President Obama’s plan to have 50% of Medicare payments disbursed through …
Are There Clinical Implications of Racial Differences in HbA1c? A Difference, to Be a Difference, Must Make a Difference
Authors: Elizabeth Selvin
Journal: Diabetes Care (2016)

Studies that have compared HbA1c levels by race have consistently demonstrated higher HbA1c levels in African Americans than in whites. These racial differences in HbA1c have not been explained by measured differences in glycemia, sociodemographic factors, clinical factors, access to care, or quality of care. Recently, a number of nonglycemic factors and several genetic polymorphisms that operate through nonglycemic mechanisms have been associated with HbA1c. Their distributions across racial groups and their impact on hemoglobin glycation need to be systematically explored. Thus, on the basis of evidence for racial differences in HbA1c, current clinical guidelines from the American Diabetes Association state: “It is important to take…race/ethnicity…into consideration when using the A1C to diagnose diabetes.” However, it is not clear from the guidelines how this recommendation might be actualized. So, the critical question is not whether racial differences in HbA1c exist between African Americans and whites; the important question is whether the observed differences in HbA1c level are clinically meaningful. Therefore, given the current controversy, we provide a Point-Counterpoint debate on this issue. In the preceding point narrative, Dr. Herman provides his argument that the failure to acknowledge that HbA1c might be a biased measure of average glycemia and an unwillingness to rigorously investigate this hypothesis will slow scientific progress and has the potential to do great harm. In the counterpoint narrative below, Dr. Selvin argues that there is no compelling evidence for racial differences in the validity of HbA1c as a measure of hyperglycemia and that race is a poor surrogate for differences in underlying causes of disease risk. —William T. Cefalu Editor in Chief, Diabetes Care
Abstract 3216: Anti-PD-1, Anti-PD-L1 and Anti-CTLA-4 checkpoint inhibitor treatment leads to different responses in syngeneic tumor models
Authors: Peter Jantscheff, Cynthia Schaefer-Obodozie, Sandra Moor, Holger Weber
Journal: Cancer Research (2016)

Abstract Checkpoint inhibitor treatment has already become a common therapy of various cancer types. Still there is a growing need for well-characterized preclinical mouse models, as clinical data indicate that patients only partially respond to this regiment. We examined the efficacy of anti-CTLA-4, anti-PD-1 and anti-PD-L1 therapy on 4T1, B16.F10, Clone M-3, CT26wt, LL/2, MC38-CEA and RENCA syngeneic tumor models. The outcome demonstrates a large variation in the response to the immune checkpoint therapy among the analyzed tumor models. Poorly immunogenic models like the LL/2 tumor did not respond to any given therapy, whereas highly immunogenic tumor models like CT26wt or MC38-CEA tumors were inhibited by all tested immunotherapies. The CT26wt tumor model was further characterized in a re-challenge experiment. Growth retardation was observed in CT26wt-tumor bearing mice treated with anti-PD-L1 antibody. A fraction of mice responded with a complete regression of the tumor. These mice were repeatedly challenged subcutaneously with a high number of fresh CT26wt tumor cells. No re-growth of CT26 tumors was observed, whereas challenging with fresh 4T1 tumor cells resulted in a rapid 4T1 growth in these mice, demonstrating a specific immune protection against CT26wt tumors. In addition all syngeneic tumor models were analyzed for the distribution of immune cells such as Treg cells, M1/M2 macrophages and M/PMN-MDSCs in tumor tissue based on multi-color flow-cytometric analysis. These data may help to select a suitable model for testing new drug candidates and define a sensitive combination therapy to support the anti-tumor immune defense in addition to checkpoint inhibitor treatment. Citation Format: Peter Jantscheff, Cynthia Schaefer-Obodozie, Sandra Moor, Holger Weber. Anti-PD-1, Anti-PD-L1 and Anti-CTLA-4 checkpoint inhibitor treatment leads to different responses in syngeneic tumor models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3216.