tbuckley/cabot-search huggingface dataset:
The health of the nation.
Authors: J. Gabbay
Journal: BMJ (1992)

<h3>Abstract</h3> Small molecule docking has proven to be invaluable for drug design and discovery. However, existing docking methods have several limitations, such as, improper treatment of the interactions of essential components in the chemical environment of the binding pocket (e.g. cofactors, metal-ions, <i>etc.</i>), incomplete sampling of chemically relevant ligand conformational space, and the inability to consistently correlate docking scores of the best binding pose with experimental binding affinities. We present CANDOCK, a novel docking algorithm that utilizes a hierarchical approach to reconstruct ligands from an atomic grid using graph theory and generalized statistical potential functions to sample biologically relevant ligand conformations. Our algorithm accounts for protein flexibility, solvent, metal ions and cofactors interactions in the binding pocket that are traditionally ignored by current methods. We evaluate the algorithm on the PDBbind and Astex proteins to show its ability to reproduce the binding mode of the ligands that is independent of the initial ligand conformation in these benchmarks. Finally, we identify the best selector and ranker potential functions, such that, the statistical score of best selected docked pose correlates with the experimental binding affinities of the ligands for any given protein target. Our results indicate that CANDOCK is a generalized flexible docking method that addresses several limitations of current docking methods by considering all interactions in the chemical environment of a binding pocket for correlating the best docked pose with biological activity.
Abstract 2074: Mangostin-encapsulated PLGA nanoparticles inhibit pancreatic cancer stem cell characteristics by suppressing sonic hedgehog pathway
Authors: Wei Yu, Yiming Ma, Sharmila Shankar, Rakesh K. Srivastava
Journal: Cancer Research (2016)

Abstract Pancreatic cancer is the fourth leading cause of cancer-related deaths in US, with a 5-year survival rate of approximately 6%. Patients develop resistance to currently used anticancer drugs which are mainly toxic and also demonstrate severe side effects. Cancer stem cells (CSCs) / tumor initiating cells (TICs) have been proposed for tumor initiation, promotion, metastasis, and chemotherapy failure. Thus, there is an urgent need to develop novel strategies for the management of pancreatic cancer. Sonic hedgehog (Shh) pathway has been implicated in pancreatic carcinogenesis and is constitutively active in CSCs. The α-Mangostin is derived from the plant mangosteen (Garcinia mangostana) which is a tropical evergreen tree. Mangosteen contains Mangnoids, such as α-Mangostin, and other phytochemicals. The main objective of the study was to demonstrate the biological activities of α-Mangostin-encapsulated PLGA nanoparticles (Mang-NPs) in human pancreatic CSCs and cells lines. We have also performed docking of α-Mangostin on to the DNA binding sites of Gli to assess whether α-Mangostin disrupts Gli-DNA binding and acts as a Gli inhibitor. Mang-NPs inhibited cell proliferation, colony formation, and induced apoptosis in pancreatic cancer AsPC-1, PANC-1 and Mia-Paca-2 cell lines, and CSCs. However, Mang-NPs had no effect on human pancreatic normal ductal epithelial cells. In addition, Mang-NPs inhibited epithelial to mesenchymal transition. α-Mangostin disrupted Gli-DNA binding activity. Western blot analysis has demonstrated that Mang-NPs inhibited pluripotency maintaining factors Nanog and c-Myc. Furthermore, Mang-NPs inhibited the expression of Gli1, Gli2, Patched1 and Patched2, and Gli transcriptional activity in pancreatic CSCs. Our data demonstrate that Mang-NPs can inhibit pancreatic CSC characteristics by disrupting Gli-DNA binding activity and may act as a Gli transcription inhibitor. Citation Format: Wei Yu, Yiming Ma, Sharmila Shankar, Rakesh K. Srivastava. Mangostin-encapsulated PLGA nanoparticles inhibit pancreatic cancer stem cell characteristics by suppressing sonic hedgehog pathway. [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 2074.
Abstract 1209: Istiratumab (MM-141), a bispecific antibody targeting IGF-1R and ErbB3, inhibits pro-survival signaling in vitro and potentiates the activity of standard of care chemotherapy in vivo in ovarian cancer models
Authors: Michael D. Curley, Gege Tan, Isabel Yannatos, Adam Camblin, Sergio Iadevaia, Chrystal Louis, Alexey Lugovskoy
Journal: Cancer Research (2016)

Abstract Insulin-like growth factor receptor 1 (IGF-1R) signaling has been implicated in the pathogenesis of ovarian cancer. However, clinical trials evaluating monospecific IGF-1R inhibitors have demonstrated limited clinical efficacy. Our data indicate that ErbB3, a member of the ErbB receptor tyrosine kinase family, can activate pro-survival AKT signaling in response to IGF-1R blockade and may represent a potential escape route in the development of resistance to therapy. Istiratumab (MM-141), an IGF-1R and ErbB3 directed bispecific antibody, inhibits ligand activation of these signaling pathways and degrades IGF-1R and ErbB3 receptor-containing complexes, leading to inhibition of downstream pro-survival signaling. Here we tested the activity of istiratumab, alone and in combination with chemotherapy, in in vitro and in vivo models of ovarian cancer. Anti-proliferative activity of istiratumab monotherapy was evaluated in a panel of ovarian cancer cell lines in vitro. The effects of istiratumab and the ligands IGF-1 and heregulin on IGF-1R- and ErbB3-mediated survival signaling were tested by ELISA and immunoblotting. Co-treatment assays with istiratumab and chemotherapy investigated mechanisms of synergy and additivity. Anti-tumor activity of istiratumab, alone and in combination with chemotherapy, was tested in in vivo ovarian xenograft tumor models. Our results indicated that istiratumab monotherapy inhibits ovarian cancer cell line proliferation in vitro. In addition, istiratumab blocked ligand-mediated resistance to chemotherapy. Co-treatment of istiratumab, ligands or chemotherapy indicated a strong correlation between drug activity and IGF-1R expression. Furthermore, co-treatment of chemotherapies and ligands potentiated AKT activation, which was inhibited by istiratumab. In vivo studies showed that istiratumab potentiates the activity of chemotherapy in ovarian xenograft tumor models. Our findings demonstrate that co-inhibition of IGF-1R and ErbB3 signaling with istiratumab can potentiate standard of care chemotherapies in ovarian tumor models and warrant further investigation of istiratumab as a potential therapy for ovarian cancer patients. Citation Format: Michael D. Curley, Gege Tan, Isabel Yannatos, Adam Camblin, Sergio Iadevaia, Chrystal Louis, Alexey Lugovskoy. Istiratumab (MM-141), a bispecific antibody targeting IGF-1R and ErbB3, inhibits pro-survival signaling in vitro and potentiates the activity of standard of care chemotherapy in vivo in ovarian cancer 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 1209.
Therapeutic vaccination with modified vaccinia Ankara (MVA) encoding Epstein-Barr virus (EBV) target antigens in EBV+ nasopharyngeal carcinoma (NPC)
Authors: E. P. Hui, B. B. Ma, S. L. Chan, R. Ho, W. L. Wong, G. S. Taylor, N. M. Steven, A. B. Rickinson, A. T. Chan
Journal: Journal of Clinical Oncology (2008)

3052 Background: EBV-associated tumors, including NPC, express the EBV-encoded proteins EBNA1 and LMP2. NPC patients demonstrate weak but nonetheless detectable CD8+ and CD4+ T cell responses to these proteins. We have developed a novel recombinant MVA vector encoding both the EBNA1 and LMP2 proteins to stimulate both the CD8+ and the CD4+ arms of the T cell immune response (J Virol 2004;78(2):768–78). Methods: This is a phase I dose escalation trial of recombinant MVA-EBNA1-LMP2 vaccine in EBV+ NPC patients (pts) in clinical remission and more than 12 weeks after completion of curative radiotherapy. Endpoints: (1) safety and toxicity, (2) immunogenicity by changes in the frequency of functional T-cell responses to MHC class I and II-restricted epitopes within EBNA1 & LMP2 in peripheral blood as quantitated by ELIspot assays at sequential time points, (3) changes in plasma EBV DNA levels. Each pts received three intradermal vaccinations at 3-weeks intervals. Cohorts of 3–6 pts will be treated at each dose level. Dose will be escalated from 5x107 to 5x108 pfu in 5 dose levels (starting dose, +100%, +100%, +67% and +50%) until maximum tolerated dose (MTD) or an immunogenic dose reached for phase II study. Results: Nine pts completed their vaccination course with three pts in each dose level up to dose level 3. No dose limiting toxicity (DLT) was observed. Main toxicities have been injection site reactions and systemic flu like symptoms. From screening of the first two vaccine recipients, T cell responses appear to have been induced to some of the relevant MHC class I and class II epitopes within the vaccine construct. Conclusions: We have developed a unique fused immunoconstruct of MHC class I (LMP2) and class II (EBNA1) epitopes delivered by MVA. This vaccine is well tolerated and even at the low initial doses tested so far appears to reactivate CD8+ and CD4+ T cell memory responses in EBV+ NPC patients. Determination of the immunogenic dose with minimal toxicity will lead to trials designed to demonstrate antitumor effects and prevention of recurrence following primary treatment. Acknowledgement: supported by Cancer Research UK and Hong Kong Cancer Fund. No significant financial relationships to disclose.
Abstract 2799: Exosomes from hypoxic pancreatic cancer cells confer resistance to subsequent hypoxia insult
Authors: Mary C. Patton, Haseeb Zubair, Girijesh K. Patel, Seema Singh, Ajay P. Singh
Journal: Cancer Research (2016)

Abstract Pancreatic cancer (PC) remains one of the leading causes of cancer-associated deaths in the US due to its highly aggressive nature and lack of effective treatments. Pancreatic tumors are characterized by a dense, desmoplastic reaction and poor vasculature leading to reduced oxygen levels within the tumor microenvironment. It is believed that this encounter of pancreatic tumor cells to intratumoral hypoxic condition is a major cause of their persistent survival under a variety of stresses, increased aggressiveness and therapeutic-resistance. However, underlying molecular mechanisms responsible for PC's adaptation to hypoxia (along with enhanced growth and aggressiveness) remain elusive. In this study, we examined the role of exosomes, which are nanoscale biological vesicles with a lipid bilayer membrane, in imparting survival benefit to PC cells. For this, we first examined the effect of conditioned media (CM) from PC cells cultured under hypoxic (0.1% O2, H-CM) or normoxic (21% O2, N-CM) conditions on the growth of fresh PC cells cultured under hypoxic (0.1% O2) conditions. We found that H-CM conferred significant survival benefit to cancer cells under hypoxia as compared to N-CM. Thereafter, we isolated exosomes from N-CM (N-exo) or H-CM (H-exo) and used them to treat pancreatic cancer cells under hypoxic culture conditions. We observed that H-exo imparted a significantly higher survival advantage to cancer cells under hypoxia as compared to N-exo. Interestingly, protein quantification indicated the presence of higher levels of exosomes from cells cultured under hypoxic conditions as compared to those grown in normoxic environment. Western blot analysis with anti-CD9 and anti-CD63 antibodies confirmed enrichment of exosomes. Moreover, Dynamic Light Scattering-based size distribution suggested that H-exo were smaller in size compared to N-exo. Further studies are underway to identify the molecular determinants in exosomes responsible for inducing growth-promoting effects under hypoxia. Overall, our data provides the first evidence that hypoxic PC cells secrete exosomes that enhance survivability under hypoxic conditions. Citation Format: Mary C. Patton, Haseeb Zubair, Girijesh K. Patel, Seema Singh, Ajay P. Singh. Exosomes from hypoxic pancreatic cancer cells confer resistance to subsequent hypoxia insult. [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 2799.
Biallelic inactivation of REV7 is associated with Fanconi anemia
Authors: Dominique Bluteau, Julien Masliah-Planchon, Connor Clairmont, Alix Rousseau, Raphael Ceccaldi, Catherine Dubois d’Enghien, Olivier Bluteau, Wendy Cuccuini, Stéphanie Gachet, Régis Peffault de Latour, Thierry Leblanc, Gérard Socié, André Baruchel, Dominique Stoppa-Lyonnet, Alan D. D’Andrea, Jean Soulier
Journal: Journal of Clinical Investigation (2016)

Fanconi anemia (FA) is a recessive genetic disease characterized by congenital abnormalities, chromosome instability, progressive bone marrow failure (BMF), and a strong predisposition to cancer. Twenty FA genes have been identified, and the FANC proteins they encode cooperate in a common pathway that regulates DNA crosslink repair and replication fork stability. We identified a child with severe BMF who harbored biallelic inactivating mutations of the translesion DNA synthesis (TLS) gene REV7 (also known as MAD2L2), which encodes the mutant REV7 protein REV7-V85E. Patient-derived cells demonstrated an extended FA phenotype, which included increased chromosome breaks and G2/M accumulation upon exposure to DNA crosslinking agents, γH2AX and 53BP1 foci accumulation, and enhanced p53/p21 activation relative to cells derived from healthy patients. Expression of WT REV7 restored normal cellular and functional phenotypes in the patient's cells, and CRISPR/Cas9 inactivation of REV7 in a non-FA human cell line produced an FA phenotype. Finally, silencing Rev7 in primary hematopoietic cells impaired progenitor function, suggesting that the DNA repair defect underlies the development of BMF in FA. Taken together, our genetic and functional analyses identified REV7 as a previously undescribed FA gene, which we term FANCV.
Case 40-1969
Authors: Stephen M. Krane, Sanford I. Roth
Journal: New England Journal of Medicine (1969)

Presentation of CaseA sixty-two-year-old woman was admitted to the hospital for treatment of left retinal detachment.Three years previously she was admitted to another hospital for repair of right retinal detachment. Urinalysis was negative, and the urea nitrogen was 9 mg per 100 ml. An x-ray film of the chest and an electrocardiogram were normal. Postoperatively, persistent vomiting, dehydration and delirium developed. Two weeks after the operation the sodium was 128 mEq, the chloride 87 mEq, the potassium 3.0 mEq, and the carbon dioxide 36 mEq per liter. The urea nitrogen was 42 mg, and the protein 6.8 gm . . .
Prognostic factor analysis of overall survival (OS) in gastric cancer from two phase III studies of second-line ramucirumab (RAM) (REGARD and RAINBOW) using pooled individual patient (pt) data.
Authors: Charles S. Fuchs, Kei Muro, Jiri Tomasek, Eric Van Cutsem, Jae Yong Cho, Sang Cheul Oh, Howard Safran, Gyorgy Bodoky, Ian Chau, Yasuhiro Shimada, Filip Dumitru, Salah-Eddin Al-Batran, Rodolfo Passalacqua, Atsushi Ohtsu, Michael Emig, David Ferry, Kumari Chandrawansa, Yanzhi Hsu, Andreas Sashegyi, Hansjochen Wilke
Journal: Journal of Clinical Oncology (2015)

4028 Background: From 2009-2012, 1020 pts were enrolled in two phase III, randomized, double-blind studies of RAM in metastatic gastroesophageal junction and gastric adenocarcinoma following progressive disease (PD) on first-line platinum- and/or fluoropyrimidine-containing therapy: REGARD (N = 355, RAM + best supportive care [BSC] vs placebo [PL] + BSC) and RAINBOW (N = 665, RAM + paclitaxel [PTX] vs PL + PTX). Methods: Individual pt data were pooled, and 41 key baseline covariates, common in both studies, were examined (19 clinical characteristics; 22 lab parameters). Lab tests were parameterized in two ways based on local lab abnormality assessments (high/normal/low): high vs normal or low; low vs normal or high. To identify prognostic factors for OS, univariate Cox models were first used to select covariates with p ≤ 0.05. For these covariates, a multivariate Cox model was used to make stepwise selection with both entry and exit p=0.01. All models were stratified by treatment and geographic region. Results: Of 1,020 pts, 953 (93%) were included in the stepwise Cox regression, after excluding pts with missing covariate values. We identified 12 independent prognostic factors (5 clinical; 7 lab). Conclusions: We identified 12 independent prognostic factors for pts with second-line gastric cancer from the largest randomized, controlled, global trial dataset. A simple prognostic index using these factors to divide pts into risk groups will be constructed and presented. This information may help clinical decision-making, pt risk stratification, and planning future clinical studies. Clinical trial information: NCT01170663 and NCT00917384. Poor Prognostic Factors HR (99% CI) for Mortality Peritoneal metastasis 1.49 (1.22, 1.83) Time-to-PD on prior therapy < 6 months 1.35 (1.10, 1.66) ECOG PS ≥ 1 1.39 (1.12, 1.73) Tumor differentiation (poor/unknown) 1.33 (1.08, 1.64) Primary tumor present 1.31 (1.05, 1.62) Alkaline phosphatase (high) 1.28 (1.03, 1.60) Sodium (low) 2.04 (1.54, 2.71) Lactate dehydrogenase (high) 1.31 (1.05, 1.63) Aspartate Aminotransferase (high) 1.37 (1.06, 1.76) Albumin (low) 1.33 (1.07, 1.65) Lymphocytes (low) 1.31 (1.05, 1.63) Neutrophils (high) 1.52 (1.17, 1.99)
Toxicity of EORTC 08031: phase 11 feasibility trial of induction chemotherapy (ICT) followed by extrapleural pneumonectomy (EPP) and postoperative radiotherapy (PORT) for malignant pleural mesothelioma (MPM) cT3N1M0 or less
Authors: PE Van Schil, P Baas, R Gaafar, AP Maat, M van de Pol, B Hasan, HM Klomp, AM Abdelrahman, J Welch, Jan Van Meerbeeck
Journal: Journal of Thoracic Oncology (2009)
The utility of neutrophil-to-lymphocyte ratio in determining survival outcomes in patients treated with neoadjuvant chemotherapy and radical cystectomy for high-risk bladder cancer.
Authors: Chinedu O. Mmeje, Austen Slade, Rebecca Slack, Neema Navai, Jianjun Gao, Arlene O. Siefker-Radtke, Ashish M. Kamat, Colin P. N. Dinney, Jay Bakul Shah
Journal: Journal of Clinical Oncology (2016)

419 Background: Pre-operative neutrophil-to-lymphocyte ratio (NLR) has been found to be associated with adverse pathological results and poor long-term outcomes in patients treated with radical cystectomy (RC) for urothelial carcinoma (UC). We aimed to evaluate the predictive utility of NLR in patients treated with neoadjuvant chemotherapy (NAC) and RC for high-risk UC. Methods: We reviewed the records of 585 patients treated with NAC and RC at our institution from 2000-2013. We calculated NLR before initiation of NAC (pre-chemo NLR) and during the recovery window between NAC and RC (post-chemo NLR).. We excluded patients with concomitant infection, blood disorder, or second malignancy. We used univariate and multivariate CART models to determine the optimal NLR cut-off for survival outcomes. We estimated disease-specific (DSS) and overall survival (OS) using the Kaplan-Meier method. We used Cox proportional hazards regression to explore the association of NLR with DSS and OS. Results: 584 patients had NLR information in our cohort. The median follow-up among survivors was 4.9 years (IQR 2.4 – 8.8 years). We identified optimal NLR cut-points of 7.1 for pre-chemo, 4.9 for post-chemo, and 1.9 for change in NLR [(post-chemo) – (pre-chemo)]. Post-chemo NLR showed the strongest association with OS and DSS. Patients with a post-chemo NLR ≥ 4.9 (n = 103) had a 5-yr DSS and OS of 42% and 33% respectively, compared to 69% and 58% for patients with an NLR &lt; 4.9 (n = 481). In the multivariable analysis, post-chemo NLR ≥ 4.9 was an independent predictor of DSS (HR = 2.5 [95% CI:1.8, 3.6] p &lt; 0.001 ), and OS (HR = 2.1 [95% CI:1.6, 2.8] p &lt; 0.001). Conclusions: A post-chemo NLR ≥ 4.9 is associated with poor DSS and OS in patients treated with NAC and RC. These findings may help guide treatment planning for adjuvant therapy following RC in patients with high-risk clinically localized bladder cancer.
Abstract 1253: Inhibition of FN14 to suppress KRAS-driven lung cancer migration and survival
Authors: Vashti M. Carson, Seungchan Kim, Landon J. Inge, Timothy G. Whitsett
Journal: Cancer Research (2016)

Abstract Lung cancer remains the leading cause of cancer related mortality throughout the world, and is estimated to kill more than one million people this year. Mutations in KRAS occur in about 1/3 of all lung adenocarcinomas, the most common histologic subtype of lung cancer. Mutations in KRAS are correlated with poor patient prognosis, advanced disease, therapeutic resistance and metastatic outcomes. There is an unmet clinical need to target KRAS-driven NSCLC towards abating the high mortality rate of this disease. We hypothesize that the tumor necrosis factor receptor, FN14 is induced and sustained by mutant KRAS signaling, and represents a therapeutic target in KRAS-driven NSCLC. Employing The Cancer Genome Atlas (TCGA) data, we showed that within a subgroup of adenocarcinoma patients harboring mutant KRAS, elevated FN14 expression conferred significantly worse survival outcomes compared to those with lower FN14 expression. Alone, elevated expression of FN14 conferred a poor prognosis in adenocarcinoma patients compared to lower expression of FN14. In lung cancer cell lines driven by mutant KRAS, elevated FN14 protein expression was observed. The ectopic induction of mutant KRAS in normal rat lung epithelial cells was sufficient to induce FN14 protein expression, an induction dependent on ERK signaling. In an animal model of mutant KRAS-driven NSCLC, FN14 protein was highly expressed and correlated with metastasis in vivo. TWEAK, the only known ligand for FN14, induced migration in NSCLC cell lines harboring mutant KRAS. Conversely, depletion of FN14 expression through siRNA suppressed KRAS-driven cell migration in vitro. We further demonstrated using a clonogenic assay that depletion of FN14 by siRNA was sufficient to reduce KRAS-driven NSCLC cell survival and significantly enhanced the cell killing effects of standard-of-care treatments such as radiation or cisplatin. These data suggest that NSCLC tumors harboring mutant KRAS may be vulnerable to inhibition of FN14 signaling. The recent development of FN14-targeted therapeutics provides an avenue towards clinical utility. As no therapeutics exist to target KRAS directly, a therapeutic strategy targeting FN14 might impact survival in KRAS-driven tumors and reduce the high mortality rate in this subgroup. Citation Format: Vashti M. Carson, Seungchan Kim, Landon J. Inge, Timothy G. Whitsett. Inhibition of FN14 to suppress KRAS-driven lung cancer migration and survival. [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 1253.