tbuckley/cabot-search huggingface dataset:
S137 De novo psuedomonas aeruginosa colonisation is associated with increased acute rejection and bronchiolitis obliterans syndrome following lung transplantation
Authors: H Yung, J Parmar
Journal: Thorax (2016)

<h3>Introduction and objectives</h3> Bronchiolitis Obliterans Syndrome (BOS) is the major cause of chronic graft dysfunction and contributes significantly to mortality following lung transplantation. There are few established therapies for BOS, thus identification of risk factors is crucial for prevention. Previous studies suggest <i>Pseudomonas aeruginosa </i>(PsA) colonisation reduces freedom from BOS, probably via neutrophilic infiltration and chemokine generation.<sup>1,2</sup> Similarly, perivascular and late acute rejection also increase BOS risk. We postulate that <i>Pseudomonas</i> colonisation may influence acute rejection rates, subsequently impacting on BOS development. <h3>Methods</h3> We performed a retrospective analysis of 253 adult bilateral lung or heart-lung recipients at a tertiary cardiothoracic centre. Transplants took place between January 2004 and December 2013. Recipients are subdivided into three groups: <i>de novo</i> PsA (new colonisation post transplant), persistent PsA (pre-existing colonisation) and non colonisers. Data was collected on microbiology cultures, histopathology, serial lung function and survival. <h3>Results</h3> Survival outcome appears worse in the <i>de novo</i> PsA group though the difference did not reach significance. BOS rates are higher in the <i>de novo</i> group compared to persistent PsA group (SHR 2.22; 95% CI 1.02 to 4.80) following multivariate adjustment (Figure 1). The conditional risk set model was used to model multiple acute rejection events. Rejection rates are significantly higher in the <i>de novo </i>PsA group (HR 1.45; 95% CI 1.01 to 2.07) compared to non-colonisers. <h3>Conclusions</h3> This is the first study to examine the relationship between PsA colonisation and acute rejection. Whilst acute rejection may act independently to drive BOS development, a similar effect was not observed in the persistent PsA group. The interaction between <i>Pseudomonas aeruginosa</i> and the host immune system may be more complex than previously thought. These results will have implications on eradication therapy and surveillance biopsy protocols post transplant. <h3>References</h3> Vos R, <i>et al</i>. Pseudomonal airway colonisation: risk factor for bronchiolitis obliterans syndrome after lung transplantation? <i>Eur Respir J</i> 2008;<b>31</b>(5):1037–45. Vos R, <i>et al</i>. Transient airway colonisation is associated with airway inflammation after lung transplantation. <i>Am J Transplant</i> 2007;<b>7</b>(5):1278–87.
165. Theophylline-Dependent Aptazyme as a Novel Tool for Transgene Expression Regulation in Mammalian Cells
Authors: Jingxian Feng, Jiawen Wang, Junsheng Lin, Yong Diao
Journal: Molecular Therapy (2015)

Successful and safe gene therapy approaches rely on regulatory tools ensuring both specific and controlled expression of the therapeutic gene. To ensure safety, timing or dosing in patients, external control of therapeutic gene expression is desirable or even required. In this study, we explored the potential of artificial aptazymes, ligand-dependent self-cleaving ribozymes, as an innovative tool, for regulation of therapeutic gene expression. For cloning of dual-luciferase reporter plasmid pTA-luc, psiCheck-2 (Promega) was used as template vector. The theophylline-dependent aptazyme was inserted into the 3'-UTR of the Gaussia luciferase gene. Quantification of reporter activity after plasmid transfection of HEK293 cells showed the basal level of less than 10% of psiCheck-2, and dose-dependent turn-on regulation of protein expression by theophylline. The maximum magnitude of the induction versus basal level was ~4-fold. Furthermore, the induction level was responsive to a wide range of theophylline concentrations in the medium, from 0 to 1 mM, facilitating the fine-tuning of transgene expression. The similar results came after changing the reporter gene to Kallistatin, but the regulatory fold can be quite different. Actually, in our study, not every aptazyme can be improved in regulatory ability by mutating the upstream start codon from AUG to AAG to avoid nonspecific recognition by the small ribosomal subunit, which may lead to drastic reduction in regulation. However, by inserting aptazyme in different site or using the tandem one, we made it done. The regulatory range of the single insertion system appeared almost 3 times exactly wider than the original system, let alone the ability of the tandem one. And we have evidence to believe that the regulatory ability will be various according to the insertion site and the vector. The aptazyme-based control system was further extended to HeLa and A549 cells, and demonstrated to function in a rapid, reversible and dose-dependent manner, suggesting potential for therapeutic applications in humans. Unfortunately, due to the toxicity of theophlline, the regulatory ability can only be defined in theory, and the decrease of ligand concentration would cause the reduction of regulatory ability. More safer ligands are urgent required in the futrue.
Abstract 1894: Transcriptomic profile analysis of PANC-1 cells in response to metformin and aspirin
Authors: Wen Yue, Tao Wang, Chung S. Yang, Qing Xu, Robert S. DiPaola, Xiang-Lin Tan
Journal: Cancer Research (2015)

Abstract The commonly used drugs, metformin and aspirin have been studied extensively as cancer preventative and therapeutic agents. However, the underlying molecular mechanisms for the inhibitory effects of pancreatic cancer development remain largely unknown. To gain further insight into their biological function in pancreatic cancer, we conducted a transcriptomic analysis using RNA sequencing to assess the differential gene expression induced by metformin (5 mM) and aspirin (2 mM), alone or in combination, after treatment of PANC-1 cells for 48 hours. Compared to untreated control, metformin alone up-regulated 109 genes, and down-regulated 78 genes, aspirin alone down-regulated 43 genes only, while the combination of metformin and aspirin up-regulated 499 genes, and down-regulated 702 genes (fold-change &amp;gt; 2, P &amp;lt; 10−5). Of the top 25 genes (fold-change &amp;gt; 10, P &amp;lt; 10−10) regulated by the combination of metformin and aspirin, NGFR, NPTX1, and UNC5B were up-regulated more than 10-fold, while PCDH18, CCL2, RASL11A, FAM111B, BMP5, SKIDA1, and CDH18 were down-regulated more than 15-fold. The ingenuity pathway analysis (IPA) was applied to explore the top signaling pathways regulated by metformin and aspirin. The top canonical pathways, “cholesterol biosynthesis”, “cell cycle: G1/S checkpoint regulation”, and “axonal guidance signaling” were the most statistical significant pathways that were modulated by the combination of metformin and aspirin. It is worth noting that the axon guidance signaling and the cholesterol biosynthesis pathways have recently been reported to play an important role in the development of pancreatic cancer. Further studies are warranted to explore the effects of metformin and aspirin on these two pathways. Although results are preliminary and need further functional validation, these data provide, for the first time, a transcriptional profile of pancreatic cancer cells in response to metformin and aspirin. Citation Format: Wen Yue, Tao Wang, Chung S. Yang, Qing Xu, Robert S. DiPaola, Xiang-Lin Tan. Transcriptomic profile analysis of PANC-1 cells in response to metformin and aspirin. [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 1894. doi:10.1158/1538-7445.AM2015-1894
SIRT3 Modulates Mitochondrial Stress Response in Bone Marrow Mesenchymal Stromal Cells of Multiple Myeloma Patients
Authors: Rimma Berenstein, Igor Wolfgang Blau, Axel Nogai, Marlies Waechter, Martin Schmidt-Hieber, Antonio Pezzutto, Bernd Doerken, Olga Blau
Journal: Blood (2015)
mTOR inhibitor everolimus (Ev) and IGFR inhibitor OSI-906 (OSI) for the treatment of patients (pts) with refractory metastatic colorectal cancer (mCRC): A Sarah Cannon Research Institute phase I trial.
Authors: L. Hart, H. A. Burris, J. R. Infante, S. F. Jones, D. R. Spigel, J. C. Bendell
Journal: Journal of Clinical Oncology (2011)

e14054 Background: The PI3 kinase (PI3K)/AKT/mTOR pathway is dysregulated in 30-40% of CRC, and signaling through IGF-1R plays a role in CRC cell malignant transformation and growth. IGF-1R signaling also acts through the PI3K pathway, making the combination of mTOR and IGF-1R inhibition attractive for the treatment of CRC. This phase I study sought to establish the maximum tolerated dose (MTD) and safety profile of the combination of the mTOR inhibitor everolimus and the IGF-1R inhibitor OSI-906 in pts with refractory mCRC. Methods: Pts with mCRC refractory to or intolerant of standard treatement were eligible. Standard phase I dose escalation design with pts receiving twice-daily oral OSI-906 50-150 mg and daily oral everolimus 5-10 mg. Results: Fourteen pts were enrolled between 7/10 and 12/10. Fifty-seven percent of pts female; median age 55 (44-76). Other pt characteristics: ECOG PS 0/1: 9 (64%)/5 (36%); K-Ras mut/WT: 7 (50%)/7 (50%). There were no DLTs in dose level (DL) 1 (OSI 50mg/Ev 5mg). At DL 2 (OSI 100 mg/Ev 10 mg) there were 3 DLT’s: 2 G3 mucositis and 1 G3 nausea/vomiting. Because the DLTs appeared ev-related DL 2a (OSI 100 mg/Ev 5 mg) enrolled 3 pts. At DL 2a there were 2 DLT’s: 1 G4 thrombocytopenia and 1 unable to receive 75% of doses due to G2 neutropenia and thrombocytopenia. With the intolerance of DL 2 and 2a, DL 1 was declared the MTD. Overall G3 toxicities included mucositis (14%), nausea (7%), vomiting (7%), and hypokalemia (7%); 1 G4 thrombocytopenia (7%) was reported. Dose-limiting toxicity occurred in 5 patients (36%) and was reversible. 57% of pts had PD as best response. Median treatment duration was 6.5 weeks and median time to progression was 8.14 weeks. Conclusions: The MTD of the combination was everolimus 5 mg PO QD and OSI-906 50 mg PO BID, which was the first dose level. This regimen showed no significant sign of clinical activity in this refractory mCRC population.
Abstract 5122: In vivo imaging models of bone and brain metastases and pleural carcinomatosis developed using a novel human EML4-ALK lung cancer cell line, A925LPE3
Authors: Shigeki Nanjo, Shinji Takeuchi, Kenji Kita, Koji Fukuda, Mitsutoshi Nakada, Hiroshi Nishihara, Seiji Yano
Journal: Cancer Research (2015)

Abstract Introduction:EML4-ALK lung cancer accounts for approximately 3%-7% of non-small cell lung cancer cases. Crizotinib, an ALK tyrosine kinase inhibitor, shows dramatic clinical efficacy with a response rate of approximately 60%-80% in EML4-ALK NSCLC patients. However, almost all patients who strongly responded to crizotinib acquired resistance over time. Recently, new generation ALK-TKIs such as alectinib and ceritinib have been approved for treatment of ALK-rearranged NSCLC patients, and it is now clear that resistance may also develop against this class of inhibitors. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. Methods: A human lung adenocarcinoma cell line A925L, which expresses an EML4-ALK gene fusion (variant 5a, E2:A20), established from a surgical specimen obtained from a Japanese male patient. We further established highly tumorigenic A925LPE3 cells with luciferase gene transfection, which also have the EML4-ALK gene fusion. A925LPE3 cells were injected into the right thoracic cavity for the pleural carcinomatosis model, into the tibia for the bone metastasis model, and into the right striatum for the brain metastasis model. After inoculation, the quantity of tumors and the quality of bones were tracked in live mice by repeated noninvasive optical imaging of tumor-specific luciferase activity using the IVIS Lumina XR Imaging System. Results: In this study, we found that A925L and A925LPE3 cell lines are sensitive to the ALK inhibitors crizotinib and alectinib. By using A925LPE3 cells we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, while alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Conclusions: Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments. Citation Format: Shigeki Nanjo, Shinji Takeuchi, Kenji Kita, Koji Fukuda, Mitsutoshi Nakada, Hiroshi Nishihara, Seiji Yano. In vivo imaging models of bone and brain metastases and pleural carcinomatosis developed using a novel human EML4-ALK lung cancer cell line, A925LPE3. [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 5122. doi:10.1158/1538-7445.AM2015-5122
Abstract LB-165: Antiproliferative effects of AZD6738 and the inhibition of DDR activity
Authors: Hee Jun Kim, Ahrum Min, Seock-Ah Im, Hyemin Jang, Miso Lee, Seongyeong Kim, Jungen Kim, Kyung-Hun Lee, Sae-Won Han, Tae-Yong Kim, Do-Youn Oh, Tae-You Kim, Yung-Jue Bang
Journal: Cancer Research (2015)

Abstract Background Anti-tumor effect of DNA damaging agents was reduced by the activation of DNA damage repair (DDR), which was led to resistance. Therefore, the inhibition of DNA repair could lead to induce the accumulation of errors which is becoming an attractive strategy. The ataxia telangiectasia and Rad3-related (ATR) proteins play a role of sensor for DNA damage, which induces homologous recombination-dependent repair. ATR is a master regulator of DDR, signaling to control DNA replication, DNA repair, and apoptosis. Therefore, the ATR pathway might be useful target for new drug development and it is important that the effects of many current cancer treatments are modulated by DDR. Materials and Methods The growth inhibitory effects of ATR inhibitor, AZD6738 were studied on human breast cancer cell lines using MTT assay. Cell cycle analysis and western blotting were also performed to determine molecular changes. Immunofluorescence assay and comet assay were conducted to understand the action mechanisms of AZD6738. Results This research identified the anti-proliferative effects and the inhibition of DDR activity by AZD6738 on human breast cancer cell lines. AZD6738 induces cell cycle arrest and apoptosis, which impaired DDR function and promoted cell death by damage accumulation. Results of MTT showed that the heterogeneous response and two cell lines were chosen for the focus on the HER2-positive breast cell lines: SKBR-3 and BT-474. In sensitive cell line, SKBR-3 cell, the expression of phosphorylated CHK1 was reduced with the other repair markers; RAD51, MRE11 and ERCC1 as opposed to less sensitive breast cancer cell BT-474. The decreased functional CHK1 leads to the accumulation of DNA damage due to homologous recombination inactivation. And it was also identified that ATR inhibitor played a role of sensitizer to increase the efficacy of cytotoxic chemotherapeutic agents, cisplatin and paclitaxel in breast cancer cell lines. Conclusion Understanding the antitumor efficacy and the mechanisms of ATR inhibitor in the breast cancer cell lines open up the possibility of future clinical trial targeting DNA damage repair in breast cancer Keywords: DNA damage response, ATR inhibitor, Breast cancer, Homologous recombination Citation Format: Hee Jun Kim, Ahrum Min, Seock-Ah Im, Hyemin Jang, Miso Lee, Seongyeong Kim, Jungen Kim, Kyung-Hun Lee, Sae-Won Han, Tae-Yong Kim, Do-Youn Oh, Tae-You Kim, Yung-Jue Bang. Antiproliferative effects of AZD6738 and the inhibition of DDR activity. [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-165. doi:10.1158/1538-7445.AM2015-LB-165
Comparison of Minimal Residual Disease Detection Using High-Throughput Sequencing and Allele-Specific Oligonucleotide PCR Methods in Pediatric B-Lineage Acute Lymphoblastic Leukemia.
Authors: Marian Harris, Malek Faham, Lei Fang, Martin Moorhead, Jianbiao Zheng, Donna S. Neuberg, Stephen E. Sallan, Lewis B. Silverman, Kristen E. Stevenson
Journal: Blood (2012)
Efficacy Analysis of the Novel Dual PI3K-MTORC1/2 Inhibitors NVP-BGT226 and NVP-BEZ235 in Acute Leukemia.
Authors: Marcus M Schittenhelm, Hartmut Doehner, Konstanze Doehner, Lothar Kanz, Michael C. Heinrich, Kerstin M Kampa-Schittenhelm
Journal: Blood (2012)
Abstract 2061: CHIP functions as tumor suppressor in prostate cancer through suppression of ROS-inflammasome in a chaperone-dependent mechanism
Authors: Neveen A. Said, James Larner
Journal: Cancer Research (2015)

Abstract Prostate Cancer (PCa) is a disease closely associated with aging. Normal aging is driven by oxidative stress, resulting in accumulation of markers of protein and lipid/phospholipid damage with subsequent activation of inflammatory/oncogenic transcription factors NFκB and AP-1. Indeed, the tumor milieu characterized by ROS signaling, and NFκB- and AP1-activation is thought to be important in fueling cancer progression and metastasis. CHIP is a U-box-type E3-ubiquitin ligase that exerts a protective role against oxidative stress by targeting damaged proteins for proteasomal degradation to maintain tissue homeostasis. CHIP induces ubiquitylation and degradation of substrates, including oncogenes and oxidatively damaged, and misfolded proteins. We hypothesized that CHIP suppresses prostate tumor progression by inhibiting ROS generation and downstream oncogenic pathways. CHIP depletion in PCa cells significantly increased their anchorage-independent growth, migration and invasiveness. PCa cells depleted of CHIP exhibited increased ROS generation (H2O2) and expression of markers of oxidative stress 8-isoprostane, NOQ1, NNMT and sulfiredoxin with subsequent activation NFκB and AP-1. The increased activation of NFκB and AP-1 in CHIP-depleted cells was ROS-induced as it was inhibited by N-acetyl cysteine (NAC) or knockdown of NOQ1. Pharmacologic inhibition of Hsp90 inhibited basal and ROS-induced NFκB and AP-1 activation as well as their invasive phenotype suggesting that the effect of CHIP is in part chaperone-dependent. Furthermore, in subcutaneous and orthotopic xenografts, PCa cells depleted of CHIP exhibited significantly accelerated growth compared to controls. Molecular characterization of CHIP-depleted tumors revealed significantly increased proliferation, increased oxidative stress and inflammation with increased nuclear localization of NFκB and AP-1. Collectively, our data suggest a novel tumor suppressor role of CHIP in PCa mediated through inhibition of ROS-induced inflammation. Citation Format: Neveen A. Said, James Larner. CHIP functions as tumor suppressor in prostate cancer through suppression of ROS-inflammasome in a chaperone-dependent mechanism. [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 2061. doi:10.1158/1538-7445.AM2015-2061
Pharmacokinetics, Efficacy and Safety of BAX326, a Novel Recombinant Factor IX: A Prospective, Controlled, Multicenter Study in Previously Treated Patients with Severe (FIX Level &lt; 1%) or Moderately Severe (FIX Level ≤ 2%) Hemophilia B.
Authors: Jerzy Windyga, Toshko Lissitchkov, Oleksandra Stasyshyn, Vasily Mamonov, Luminita Rusen, José Luis Lamas, Myungshin Oh, Miranda Chapman, Sandor Fritsch, Borislava G Pavlova, Wing Yen Wong, Brigitt E. Abbuehl
Journal: Blood (2012)
Breathing Easier with Fish Oil — A New Approach to Preventing Asthma?
Authors: Christopher E Ramsden
Journal: New England Journal of Medicine (2016)

Asthma and lower respiratory infections are leading causes of morbidity and mortality in pediatric populations. Thus, having low-cost, effective, safe options for prevention could have important implications for both clinical practice and public health. In this issue of the Journal, Bisgaard and et al.1 report that high-dose supplementation of the n−3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derived from fish oil in the third trimester of pregnancy significantly decreased the risk of persistent wheeze and asthma (the primary outcome) during the first 5 years of a child’s life. The intervention also decreased the rate of lower . . .
Nuclear-specific AR-V7 Protein Localization is Necessary to Guide Treatment Selection in Metastatic Castration-resistant Prostate Cancer
Authors: Howard I. Scher, Ryon P. Graf, Nicole A. Schreiber, Brigit McLaughlin, David Lu, Jessica Louw, Daniel C. Danila, Lyndsey Dugan, Ann Johnson, Glenn Heller, Martin Fleisher, Ryan Dittamore
Journal: European Urology (2016)

Circulating tumor cells (CTCs) expressing AR-V7 protein localized to the nucleus (nuclear-specific) identify metastatic castration-resistant prostate cancer (mCRPC) patients with improved overall survival (OS) on taxane therapy relative to the androgen receptor signaling inhibitors (ARSi) abiraterone acetate, enzalutamide, and apalutamide.To evaluate if expanding the positivity criteria to include both nuclear and cytoplasmic AR-V7 localization ("nuclear-agnostic") identifies more patients who would benefit from a taxane over an ARSi.The study used a cross-sectional cohort. Between December 2012 and March 2015, 193 pretherapy blood samples, 191 of which were evaluable, were collected and processed from 161 unique mCRPC patients before starting a new line of systemic therapy for disease progression at the Memorial Sloan Kettering Cancer Center. The association between two AR-V7 scoring criteria, post-therapy prostate-specific antigen (PSA) change (PTPC) and OS following ARSi or taxane treatment, was explored. One criterion required nuclear-specific AR-V7 localization, and the other required an AR-V7 signal but was agnostic to protein localization in CTCs.Correlation of AR-V7 status to PTPC and OS was investigated. Relationships with survival were analyzed using multivariable Cox regression and log-rank analyses.A total of 34 (18%) samples were AR-V7-positive using nuclear-specific criteria, and 56 (29%) were AR-V7-positive using nuclear-agnostic criteria. Following ARSi treatment, none of the 16 nuclear-specific AR-V7-positive samples and six of the 32 (19%) nuclear-agnostic AR-V7-positive samples had ≥50% PTPC at 12 weeks. The strongest baseline factor influencing OS was the interaction between the presence of nuclear-specific AR-V7-positive CTCs and treatment with a taxane (hazard ratio 0.24, 95% confidence interval 0.078-0.79; p=0.019). This interaction was not significant when nuclear-agnostic criteria were used.To reliably inform treatment selection using an AR-V7 protein biomarker in CTCs, nuclear-specific localization is required.We analyzed outcomes for patients with metastatic castration-resistant prostate cancer on androgen receptor signaling inhibitors and standard chemotherapy. Patients with circulating tumor cells that had AR-V7 protein in the cellular nuclei were very likely to survive longer on taxane-based chemotherapy, and tests unable to distinguish where the protein is located in the cell are not as predictive of benefit.