tbuckley/cabot-search huggingface dataset:
Effect of baseline (BL) biomarkers on overall survival (OS) in metastatic pancreatic cancer (mPC) patients (pts) treated with ganitumab (GAN; AMG 479) or placebo (P) in combination with gemcitabine (G).
Authors: I. McCaffery, Y. Tudor, H. Deng, R. Tang, S. Badola, H. L. Kindler, C. S. Fuchs, E. Loh, S. D. Patterson, L. Chen, J. L. Gansert
Journal: Journal of Clinical Oncology (2011)

4041 Background: GAN and conatumumab (CON) are investigational, fully human, monoclonal antibodies against type 1 insulin-like growth factor receptor (IGF1R) and death receptor 5, respectively. A 3-arm, P-controlled, phase 2 study randomized 125 mPC pts 1:1:1 to GAN + G, CON + G, or P + G. OS was improved (HR 0.67; 95%CI 0.41 to 1.12) in the GAN +G arm (N=42) vs P+ G arm (N=42) (Kindler et al, JCO 2010:28 abstr 4035). We hypothesized that high BL levels of the IGF1R ligands, IGF-1 and IGF-2; high BL levels of IGFBP-3 (stabilizes IGF-1 and -2); or low BL levels of IGFBP-1, -2, and -4 (sequester IGF-1 and -2) may predict improved OS with GAN treatment. Methods: BL serum or plasma was available from 30 to 33 pts in the GAN + G arm and 26 to 33 pts in the P + G arm. IGF-1 (free [f] and total [t]), tIGF-2 and IGFBP-1, -2, -3, and -4 were analyzed by immunoassay. Treatment effects on OS in high and low BL biomarker subgroups (defined by median BL levels) were evaluated by Cox proportional hazard models, and the interactions between treatment and BL biomarker subgroups were tested. Similar analyses were also conducted treating biomarkers as a continuous variable. Results: GAN +G was associated with significantly improved OS in the following BL biomarker groups: low IGFBP-2 (HR=0.19, 95% CI: 0.06 to 0.55; p=0.002); high tIGF-1 (HR=0.25, 95% CI: 0.09 to 0.67; p=0.006); high IGFBP-3 (HR = 0.28, 95% CI: 0.11 to 0.73; p=0.009); and high IGF-2 (HR=0.24, 95% CI: 0.09 to 0.68, p=0.007). p-values for testing differences in treatment effects among BL biomarker subgroups were 0.379 for IGFBP-2, 0.272 for tIGF-1, 0.11 for IGFBP-3 and 0.051 for IGF-2 (study not powered to detect these differences). Results were consistent when similar analyses for testing interactions were done treating BL biomarker levels as a continuous variable. Conclusions: In support of our hypothesis, low BL IGFBP-2 and high BL tIGF-1, IGF-2, or IGFBP-3 appeared to be associated with improved OS among patients treated with GAN + G. These results are informative for attempting to predict a biomarker-defined population enriched for GAN treatment effects and will be further tested in the ongoing GAN P3 trial.
Reduced-Intensity Stem Cell Transplantation for Adult T-Cell Leukemia: The Results of a Second Multi-Center Prospective Study and the Impact of Antithymocyte Globulin on Early Relapse.
Authors: Naokuni Uike, Ryuji Tanosaki, Atae Utsunomiya, Ilseung Choi, Masato Masuda, Yoshio Saburi, Masao Tomonaga, Tetsuya Etoh, Michihiro Hidaka, Mari Kannagi, Mine Harada, Jun Okamura
Journal: Blood (2006)
Effect of selenium supplemantation on anthracycline-induced cardiac toxicity in children treated for cancer: Correlation with pro-brain natriuretic peptide levels.
Authors: N. Tacyildiz, D. Ozyoruk, G. Ozelci Kavas, H. Dincaslan, G. Yavuz, E. Unal, S. Atalay, A. Ikinciogullari, T. Ucar, B. Doganay, G. Oktay, A. Cavdar, O. Kucuk
Journal: Journal of Clinical Oncology (2011)

9570 Background: Anthracyclins (Anth) are used in several treatment protocols of children with cancer. Pro-brain natriuretic peptit (Pro-BNP) is relased by cardiac cells and elevated even before overt cardiac distress symptoms. Selenium (Se), is an antioxidant whose absence cause cardiomyopathy in people living in the poor selenium soil area. Aim: 1. Assesment of Anth-induced cardiotoxicity with Pro-BNP levels, correlated with echo-cardiographic (ECHO) findings. 2. Determine possible effects of serum selenium levels (s-Se) and supplemantation (spp) on cardiac toxicity. Methods: Plasma levels of Pro-BNP measured and ECHO has been performed in 67 pediatric cancer patients after completed their Anth containing regimens. s-Se examined in 37 patients (pts). Results: Eleven pts found with high Pro BNP levels (H-Pro BNP) ± cardiac failure (CF) (median(M):226,3 pg/ml.; normal level: lower than 120 pg/ml). Fifty-six pts found with normal Pro-BNP levels (N-Pro-BNP) (8,2-119,6 pg/ml, M: 32,4 pg/ml). Difference between two groups was significant (p<0.001). s-Se have found low in 10 of 11 pts with H-Pro BNP ±CF ( M: 62mcg/L). Twenty-six pts of 56 with N-Pro BNP also investigated for s-Se ( M: 99.4mcg/L). Difference of s-Se between H-Pro BNP and N-Pro BNP pts was significant (p<0.001). The pathologic ECHO findings observed in 7 (63.6%) out of 11 patients with H-Pro BNP ±CF while only 1 (3.8%) in 26 patients with N- Pro-BNP. Eight out of 10 patients with low selenium (L-Se) and H-Pro BNP levels (3 pts with cardiac failure) were se-spp for a period of 4-33 months (M: 6). Conclusions: Se-spp may have a potantial role to protect and/or overcome the difficulties related anthracyclin-induced toxicities in patients with H-proBNP ± CF and low Se levels. Pre- and postsupp Se levels in Se supp ats with L- Se and H- Pro-BNP levels ± CF. n=8 Pre-suplementation levels min-max (median) First post-suplementation levels min-max (median) Second post-suplementation levels min-max (median) ProBNP (pg/ml) 10-843 (175) 2-536 (73,5)* 10-123,5 (106,5)** Se (mcg/L) 20-83 (57) 65-109 (103)*** 75-106 (83)**** * p0.018, ** p0.109, *** p0.028, **** p0.068 (Wilcoxan sign test).
Abstract 3794: Mechanistic studies on the anti-tumor effect of jacaric acid on murine macrophage-like leukemia PU5-1.8 cells
Authors: Wai Nam Liu, Kwok Nam Leung
Journal: Cancer Research (2015)

Abstract This study aims at demonstrating the in vitro and in vivo anti-tumor effect and action mechanisms of jacaric acid, a conjugated linolenic acid isomer which is present in jacaranda seed oil, on murine macrophage-like leukemia PU5-1.8 cells. Our results demonstrated the growth-inhibitory effect of jacaric acid on PU5-1.8 cells in a time- and concentration-dependent manner, as measured by MTT reduction and fluorometric cell proliferation assays, while it exerted minimal cytotoxicity on normal murine cells. Pre-treatment of PU5-1.8 cells with jacaric acid significantly decreased the leukemic cell growth in syngeneic BALB/c mice, while consumption of jacaric acid is apparently non-toxic to the mice. Flow cytometric analysis revealed the induction of G0/G1 cell cycle arrest, accompanied by a decrease in cyclin E and CDK2 proteins as demonstrated by Western blotting. Jacaric acid also triggered apoptosis in PU5-1.8 cells as reflected by induction of DNA fragmentation, phosphatidylserine externalization and mitochondrial membrane depolarization, which was quantified by ELISA, Annexin V assay and JC-1 dye staining method, respectively. Up-regulation of Bax and down-regulation of Bcl-2 and Bcl-xL proteins might account for the occurrence of apoptotic events. Collectively, our results suggest that the growth-inhibitory effect of jacaric acid on PU5-1.8 cells might be mediated through inducing cell cycle arrest and apoptosis of the leukemia cells. Therefore, jacaric acid represents a naturally-occurring potential candidate for the treatment of some forms of myeloid leukemia with minimal toxicity and fewer side effects. Citation Format: Wai Nam Liu, Kwok Nam Leung. Mechanistic studies on the anti-tumor effect of jacaric acid on murine macrophage-like leukemia PU5-1.8 cells. [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 3794. doi:10.1158/1538-7445.AM2015-3794
AIDS malignancy consortium (AMC) study 061: A phase I/PK study of sunitinib (S) with highly active antiretroviral therapy (HAART) in HIV+ patients with solid tumors.
Authors: J. F. Deeken, M. A. Rudek, D. M. Aboulafia, R. J. Sullivan, J. F. Gerecitano, M. E. Cianfrocca, D. H. Henry, L. Ratner, B. J. Dezube, K. Mosby, M. Tibbals, R. F. Little, S. P. Ivy, P. C. Moore, R. T. Mitsuyasu
Journal: Journal of Clinical Oncology (2011)

2591 Background: Rates of non-AIDS defining cancers (NADCs) now exceed those of AIDS-defining cancers in HIV+ patients taking HAART. Treatment of NADCs may be complicated by drug-drug interactions between HAART and chemotherapy, including HAART induction or inhibition of metabolizing enzymes, especially CYP3A4. We present findings from the first of a series of studies by the AMC of new targeted therapies and HAART in HIV+ cancer pts. Methods: Pts were stratified into two arms to determine the MTD of S: (1) non-ritonavir based HAART or (2) ritonavir-based HAART. Pts in arm 1 received the standard dose of S (50mg). Arm 2 used a phase I, 3+3 dose escalation design (25, 37.5, and 50mg). S was taken daily on a 4 wk on/2 wk off cycle. PK monitoring of S and its active metabolite (S-M) were performed throughout cycle one, and normalized based on dose level, to calculate AUC-24, Cmax, and trough level. Results: Between 8/09 and 1/11, 16 patients were enrolled and completed cycle 1 (9 on arm 1, 7 on arm 2). Following enrollment of the first 6 pts, Arm 1 was expanded to include additional pts on efavirenz, a potent inducer of CYP3A4. Cancer types included Kaposi’s Sarcoma (7), lung (2), anal (2), NHL (1), and other solid tumors (4). Median cycles was 2 (range 1-6). Pts on arm 1 tolerated standard treatment with no DLTs. One pt in arm 2 at the 37.5 mg level had a DLT (wound dehiscence). Enrollment continues at that expanded dose level. No patient had a CR or PR. Five patients (31%) had stable disease for >2 cycles. Grade 3/4 toxicities at any time during treatment were: neutropenia (13%), fatigue (13%), anemia (6%), hand/foot (6%), and wound complications (6%). PK analysis showed significant inter-patient variability of S and S-M. There was no PK alterations of S between the arms, but there were significant alterations in the PK of S-M. Efavirenz resulted in a 315% and 150% increase, whereas ritonavir caused a 69% and 72% decrease in the Cmax and AUC-24 of S-M, respectively. Conclusions: S 50mg was well tolerated in pts on non-ritonavir based HAART regimens. Dose reduction of S may be warranted in pts on ritonavir-based HAART regimens. HAART therapy affected the PK of S-M but not S. Final results will be presented.
Abstract LB-150: Genetic depletion of DNMT1 reveals a DNMT1 threshold controlling DNA methylation in human cells
Authors: Yi Cai, Hsing-chen Tsai, Ray-whay Yen, Limin Xia, Yang Zhang, Stephen Baylin
Journal: Cancer Research (2015)

Abstract Altered DNA methylation patterns are a central feature of most types of human cancer cells. However, the exact roles of DNA methyltransferases (DNMTs) in human DNA methylation maintenance are not well characterized. The long-established model that DNA methyltransferase DNMT1 maintains most DNA methylation in human cells has been challenged by multiple DNMT1 knockdown/knockout studies in the past decade. A potential role for de novo DNA methyltransferases DNMT3A and DNMT3B in maintaining DNA methylation in cancer cells has been suggested but is also not precisely known. To investigate the above issues, we have utilized both genetic recombination and CRISPR technology to deplete DNMTs individually or in combination in human colorectal cancer cell line HCT116. Previously we created a strong HCT116 DNMT1 hypomorph (1KO) by genetic recombination. Although 1KO cells lost about 85% of DNMT1 protein, they still maintained the epigenetic silencing of tumor suppressor genes and showed only 20% decrease in overall DNA methylation. We now show that further depletion of DNMT1 in 1KO cells, to less than 1% of wild type HCT116 cells, resulted in elimination of most DNA methylation and reactivation of key tumor suppressor genes including p16. In addition, we found that DNA methylation in HCT116 cells is controlled by different DNMT1 thresholds. Surprisingly, when we disrupted DNMT3A or DNMT3B with CRISPR in HCT116 cells, we see altered DNA methylation patterns involving both gains and losses of DNA methylation. Since abnormal DNA hypermethylation in cancer often associates with epigenetic gene silencing, this observation is especially relevant for the function of DNMT3A mutations in acute myeloid leukemia. Finally, we demonstrated that depletion of DNMT1-targeting protein UHRF1 efficiently reduced DNA methylation in human colon cancer cells. Our results not only defined the distinct roles of individual DNMTs in human cancer cell DNA methylation maintenance but also suggested UHRF1 inhibition as an alternative approach to reverse abnormal DNA hypermethylation in human cancer cells. Citation Format: Yi Cai, Hsing-chen Tsai, Ray-whay Yen, Limin Xia, Yang Zhang, Stephen Baylin. Genetic depletion of DNMT1 reveals a DNMT1 threshold controlling DNA methylation in human cells. [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-150. doi:10.1158/1538-7445.AM2015-LB-150
528. Towards Personalized Cell Therapy for Cancer: Tumor-Homing Human Induced Neural Stem Cells
Authors: Juli Bago, Onyi Okolie, Raluca Dumitru, Matt Ewend, Shawn Hingtgen
Journal: Molecular Therapy (2016)

Background: Engineered neural stem cells (NSC) are a promising new approach to treating glioblastoma (GBM). In clinical trials, the ideal NSC drug carrier should be easily isolated and autologous to avoid immune rejection. Methods: As a new approach to personalized NSC therapy for cancer, we directly transdifferentiated (TD) human fibroblasts in induced neural stem cells (h-iNSCs). The h-iNSCs were engineered to express optical reporters and either the pro-apoptotic agent TRAIL or thymidine kinase. The tumor-homing migration and therapeutic efficacy of cytotoxic h-iNSCs were then assessed in human-derived GBM models of solid and surgically resected disease. All statistical tests were two-sided. Results: Our new single-factor Sox2 strategy converted human skin fibroblasts into nestin+ h-iNSCs in only 4 days and the h-iNSCs survived in the brain of mice for 3 weeks. Time-lapse motion analysis showed h-iNSCs rapidly migrated to human GBMs cells and penetrated solid human GBM spheroids. h-iNSC delivery of TRAIL reduced solid human GBM xenografts 250-fold in 3 weeks and prolonged median survival from 22 to 49 days (P<0.01). h-iNSC prodrug/enzyme therapy regressed patient-derived GBM xenografts 20-fold and extended survival from 32 to 62 days (P<0.01). Mimicking clinical NSC therapy, intra-cavity h-iNSC thymidine kinase/ganciclovir therapy delayed the regrowth of post-surgical GBMs 3-fold and prolonged survival in mice from 46 to 60 days. Conclusions: Transdifferentiating human skin into h-iNSCs is a new platform for creating tumor-homing cytotoxic cell therapies for cancer. Translating this approach has the potential to avoid carrier rejection and maximize treatment durability in patient trials.
LRCH1 interferes with DOCK8-Cdc42–induced T cell migration and ameliorates experimental autoimmune encephalomyelitis
Authors: Xiaoyan Xu, Lei Han, Guixian Zhao, Shengjie Xue, Yunzhen Gao, Jun Xiao, Shicheng Zhang, Peng Chen, Zhi-ying Wu, Jianping Ding, Ronggui Hu, Bin Wei, Hongyan Wang
Journal: The Journal of Experimental Medicine (2016)

Directional autoreactive CD4+ T cell migration into the central nervous system plays a critical role in multiple sclerosis. Recently, DOCK8 was identified as a guanine-nucleotide exchange factor (GEF) for Cdc42 activation and has been associated with human mental retardation. Little is known about whether DOCK8 is related to multiple sclerosis (MS) and how to restrict its GEF activity. Using two screening systems, we found that LRCH1 competes with Cdc42 for interaction with DOCK8 and restrains T cell migration. In response to chemokine stimulation, PKCα phosphorylates DOCK8 at its three serine sites, promoting DOCK8 separation from LRCH1 and translocation to the leading edge to guide T cell migration. Point mutations at the DOCK8 serine sites block chemokine- and PKCα-induced T cell migration. Importantly, Dock8 mutant mice or Lrch1 transgenic mice were protected from MOG (35–55) peptide–induced experimental autoimmune encephalomyelitis (EAE), whereas Lrch1-deficient mice displayed a more severe phenotype. Notably, DOCK8 expression was markedly increased in PBMCs from the acute phase of MS patients. Together, our study demonstrates LRCH1 as a novel effector to restrain PKCα–DOCK8–Cdc42 module–induced T cell migration and ameliorate EAE.
IGH Repertoire Analysis In Multiple Myeloma (MM): Lack of Intra-Disease Homology and Occasional Clustering with Sequences of Other B-Cell Neoplasms Sharing Identical Geographical Origin
Authors: Simone Ferrero, Daniela Capello, Mirija Svaldi, Daniela Drandi, Michela Boi, Sara Barbiero, Daniela Gatti, Davide Rossi, Elisa Genuardi, Odetta Antico, Paola Ghione, Manuela Zanni, Alberto Rocci, Francesco Bertoni, Emanuele Zucca, Valter Gattei, Antonio Palumbo, Sergio Cortelazzo, Mario Boccadoro, Gianluca Gaidano, Marco Ladetto
Journal: Blood (2010)
Eczema and educational attainment: a systematic review
Authors: L.B. Kobyletzki, L. Beckman, J. Smirnova, L. Smeeth, H.C. Williams, M. McKee, K. Abuabara, S.M. Langan
Journal: British Journal of Dermatology (2016)

Eczema (syn. atopic dermatitis or atopic eczema) accounts for the largest global burden of disability due to skin disease (1) . Eczema affects up to 20% of children (1) , and is associated with impaired quality of life (QoL) of a similar magnitude to cancer and epilepsy. Yet, although eczema is common in children, little is known about long-term outcomes such as educational attainment (EA) of those affected. This article is protected by copyright. All rights reserved.
S104 Hypoxia preconditions the innate immune response to acute bacterial pulmonary infections
Authors: RS Dickinson, AAR Thompson, JP Thomson, F Murphy, HM Marriott, A Tavares, J Willson, L Williams, A Lewis, S Forbes, RH Stimson, AG Hameed, JA Preston, A Lawrie, V Finisguerra, M Mazzone, SJ Foster, ER Chilvers, AS Cowburn, DH Dockrell, RS Johnson, RR Meehan, MKB Whyte, SR Walmsley
Journal: Thorax (2016)

<h3>Introduction</h3> Systemic hypoxaemia and recurrent bacterial infections frequently co-exist in patients with acute and chronic lung disease and correlate with poor clinical outcomes. Inappropriate neutrophilic inflammation is regularly seen in these circumstances and the HIF/PHD pathway is implicated in the response of the innate immune system to both hypoxia and bacteria. Here we aimed to dissect and modify the interactions between hypoxia and innate host-pathogen response in the lung. <h3>Methods</h3> C57BL/6 mice were either housed in room air or ‘preconditioned’ by being housed in 10% oxygen for 7 days. They then received intratracheal 1x10<sup>7 </sup>type 2 <i>S. pneumoniae </i>under recovery anaesthesia with subsequent exposure to hypoxia (10% O<sub>2</sub>) or room air (21% O<sub>2</sub>). Mice were assessed clinically, rectal temperatures recorded and culled for broncho-alveolar lavage (BAL) and tissue sampling (blood and lung) at various time points. Peripheral blood glucose was measured from tail vein venepuncture using a handheld blood glucose monitor. RNA from peripheral blood leucocytes was isolated and analysed using RNAseq. 18FDG-PET was performed on animals 14 h following infection to observe glucose utilisation. Histology was performed on formalin fixed sections for glycogen storage. <h3>Results</h3> Exposure to acute hypoxia resulted in significant morbidity (sickness (5.7 vs 2.1, p &lt; 0.02) and hypothermia (31.8 vs 36.0<sup>0</sup>C, p &lt; 0.05)) and rapid 100% mortality by 48 h post infection. This response was independent of bacterial burden, and leukocyte recruitment. In keeping with a negative energy state, hypoxic mice displayed loss of liver glycogen, with increased serum ketone production and lower circulating glucose levels. Preconditioned mice showed marked protection from both the acute hypoxia-associated systemic phenotype and the negative energy state. Transfer of preconditioned bone marrow to naïve mice also rescued the pathophysiological response. RNAseq analysis of the circulating leukocyte population identified signal-induced suppression of HIF-1a pathway genes, which were linked to reduced leukocyte glucose utilisation in vivo by 18FDG-PET. <h3>Conclusions</h3> Hypoxic preconditioning reverses the morbidity and mortality associated with acute hypoxia following intrapulmonary bacterial challenge. This response is dependent on the preconditioning of the innate immune system by suppressing HIF1 alpha and altering circulating leukocyte metabolism. Support RSD is funded by the MRC. SRW is funded by the Wellcome Trust.
Abstract 1125: Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancers
Authors: Yujun Hao, Yardena Samuels, Qingling Li, Dawid Krokowski, Henri Brunengraber, Maria Hatzoglou, Guo-Fang Zhang, Bert Vogelstein, Zhenghe Wang
Journal: Cancer Research (2015)

Abstract Glutamine addiction is a major metabolic reprogramming event that occurs in cancer cells. Many tumors exhibit oncogene-dependent addiction to glutamine. PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, is the most frequently mutated oncogene in human cancers. However, whether PIK3CA mutations reprogram cancer metabolism is an important unaddressed question. Here we show that oncogenic PIK3CA mutations reprogram glutamine metabolism by up-regulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, thereby rendering them addicted to glutamine. We demonstrated that induction of GPT2 by mutant p110α is necessary and sufficient to render CRC cells addicted to glutamine. Moreover, aminooxyacetate, which inhibits enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumor growth of CRCs with PIK3CA mutations, but not CRCs with WT PIK3CA. Thus our data suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harboring PIK3CA mutations. Mutant p110α up-regulates GPT2 gene expression through an AKT-independent PDK1-RSK2-ATF4 signaling axis. We showed that ATF4 is a transcription factor that activates GPT2 gene expression. We further demonstrated that mutant p110α activates RSK2 kinase through PDK1. Activated RSK2 then phosphorylates ATF4 at the serine residue 245, which in turn recruits deubiquitinase USP8 and protects ATF4 from ubiquitin-mediated degradation. Lastly, using [13C5-]glutamine isotope-tracing technology, we showed that PIK3CA mutant CRCs convert more glutamine to α-keto-glutarate to replenish the tricarboxylic acid (TCA) cycle to generate ATP. Together, our data establish oncogenic PIK3CA mutations as a cause of glutamine addiction in CRCs. Citation Format: Yujun Hao, Yardena Samuels, Qingling Li, Dawid Krokowski, Henri Brunengraber, Maria Hatzoglou, Guo-Fang Zhang, Bert Vogelstein, Zhenghe Wang. Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancers. [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 1125. doi:10.1158/1538-7445.AM2015-1125