tbuckley/cabot-search huggingface dataset:
A phase II study of lapatinib and capecitabine in first-line treatment of metastatic pancreatic cancer (ICORG 08- 39).
Authors: R. S. McDermott, P. Calvert, M. Parker, G. Webb, B. Moulton, J. McCaffrey
Journal: Journal of Clinical Oncology (2011)

315 Background: The combination of capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer patients has proved beneficial in terms of median survival duration, objective radiological response rate and decrease in tumour marker levels from baseline. In the phase I study of capecitabine and lapatinib carried out in advanced solid tumors, the optimal tolerated regimen was determined to be lapatinib 1,250 mg plus capecitabine 2,000 mg/m 2 /day. At these dose levels, the combination was well tolerated with few grade 3 toxicities and no grade 4 toxicity. Our preclinical work suggested synergistic activity of capecitabine and lapatinib in pancreatic cancer. We initiated a study of this combination in the first-line therapy of metastatic pancreas cancer. Methods: This was a single-arm multicenter study in patients with chemotherapy-naive metastatic pancreatic cancer. The primary endpoint was overall survival. The study was designed as a Simons two-stage optimal design and was divided into two stages. The first stage was to recruit up to 12 patients. If at least seven of these patients survived for at least six months, then a further 20 patients would be enrolled into the study. If six or fewer of the initial 12 patients met the specified study survival criteria, the study would be halted. Treatment was to be administered until disease progression or until withdrawal from the study due to unacceptable toxicity or other reasons. Clinical and laboratory parameters were assessed to evaluate disease response and toxicity of therapy. The study patients received lapatinib 1,250 mg/day, plus capecitabine 2000 mg/m 2 /day on days 1-14 every 21 days. Results: Nine patients were enrolled. Seven of these patients did not achieve the interim protocol response requirement of survival for at least 6 months, to allow for the study to continue to the second cohort of patients. Median overall survival from first dose was 4 months. Median time on treatment was 2 months. There were no objective responses. There were no unexpected toxicities. Conclusions: The addition of lapatinib to capecitabine does not improve overall survival in the first-line treatment of advanced pancreatic cancer patients. [Table: see text]
Abstract 1148: Ang-(1-7) decreases HIF-1α and migration of oral squamous cell carcinoma
Authors: Andre Luiz Sena Guimaraes, Carlos Alberto de Carvalho Fraga, Lucyana Conceição Farias, Talita Antunes Guimarães, Alfredo Maurício Batista De Paula, Amanda Mota, Lais Santiago, Ricardo Santiago Gomez, Sergio Henrique Sousa Santos, Robson Augusto Souza dos Santos, Michael Bader
Journal: Cancer Research (2015)

Abstract induced by cobaltous chloride and the underlying mechanism. Methods and Results We first confirmed that Ang-(1-7) decreases HIF-1α signaling in a newly developed hydroxypropyl-β-cyclodextrin (HPBCD)-based Ang-(1-7) nano-formulation in a novel transgenic rat model of inducible insulin resistance and DM2. The chronic administration of this compound prevented the marked elevation of HIF-1α in diabetic rat kidney. Next, mouse embryonic fibroblasts (MEFs) and SCC-9 cells were incubated in a well humidified incubator with 5% CO2 and 95% air at 37 °C (normoxic condictions). For hypoxic cultures, cells were incubated 150 μM CoCl2 for 24 hours and maintained in a 5% CO2 atmosphere at 37°C. Then, we divided cells into 4 groups including control, CoCl2, Ang-(1-7) and CoCl2 + Ang-(1-7). HIF-1α protein expression and AKT phosphorylation were decreased in hypoxic cells after treatment with Ang-(1-7). Besides, Ang-(1-7) decreased SCC-9 cell migration in hypoxic condition. Conclusions In conclusion, our current findings suggest that Ang-(1-7) attenuates HIF-1 α protein stabilization via AKT and Mas receptor-dependent mechanism. In addition, we found that the Ang-(1-7)/Mas receptor inhibit oral cancer cell migration. Note: This abstract was not presented at the meeting. Citation Format: Andre Luiz Sena Guimaraes, Carlos Alberto de Carvalho Fraga, Lucyana Conceição Farias, Talita Antunes Guimarães, Alfredo Maurício Batista De Paula, Amanda Mota, Lais Santiago, Ricardo Santiago Gomez, Sergio Henrique Sousa Santos, Robson Augusto Souza dos Santos, Michael Bader. Ang-(1-7) decreases HIF-1α and migration of oral squamous cell carcinoma. [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 1148. doi:10.1158/1538-7445.AM2015-1148
443. Neural Stem Cell-Mediated Enzyme/Prodrug Therapy for Medulloblastoma
Authors: Margarita Gutova, Lusine Tsaturyan, Michael E. Barish, Karen S. Aboody, Robert Wechsler-Reya
Journal: Molecular Therapy (2016)

Introduction: Medulloblastoma is the most common malignant brain tumor in children. Despite recent advances in treatment, these tumors continue to be associated with high morbidity and mortality, and new strategies for treatment of medulloblastoma are urgently needed. Major obstacles to successful treatment of pediatric brain tumors include the blood-brain-barrier (BBB), which prevents many systemically administered anti-cancer agents from entering the central nervous system. Neural stem cells (NSCs) will effectively cross the BBB and preferentially migrate to tumor cells throughout the brain. Methods: We modified human NSCs to express and deliver the enzyme carboxylesterase (CE), which activates irinotecan (IRN; CPT-11) to the potent topoisomerase-1 inhibitor SN-38. For pharmacokinetic studies, tumor-bearing mice were injected intracranially with NSCs expressing carboxylesterase enzyme (CE-NSC) and followed by intravenous administration of IRN at dose 37.5 and 54.7 mg/kg after 2 days post NSCs administration. Mice were euthanized 1h after IRN injection. Brain tissues and mouse plasma were collected for quantitative LC/MS measurements of IRN and SN-38. The control group received IRN injections only. Results: In vitro cytotoxicity experiments demonstrate a 2000-fold increase in sensitivity of medulloblastoma cells to IRN in the presence of CE-NSCs. We have quantitatively assessed NSC tumor distributions in MP (c-myc, DNp53) and patient-derived medulloblastoma xenografts (PDX) tumor models, and demonstrated that intranasally administrated NSCs migrate to medulloblastoma tumors. We also found that NSCs do not distribute to non-cancerous areas of the brain, or to other peripheral tissues, suggesting that this approach could selectively target SN-38 production to pediatric tumor sites while sparing normal tissues. Pharmacokinetic and therapeutic efficacy studies demonstrated that in both mouse models, CE-NSC cells mediate local tumor-specific conversion of irinotecan pro-drug to active drug SN-38 only at the tumor sites. Plasma levels of toxic SN-38 were low in both tumor models. Conclusions: We provided proof-of-principle for a NSC. CE-mediated localized chemotherapy approach, which can potentially limit the severe cognitive and functional deficits associated with currently available therapies, improving clinical outcome and quality of life for patients with medulloblastoma.
Abstract 2932: Role of death receptor 5 (DR5) in apoptosis induced by anticancer agents in colon cancer cells
Authors: Jingshan Tong, Jian Yu, Lin Zhang
Journal: Cancer Research (2015)

Abstract The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor, also called death receptor 5 (DR5; TRAIL receptor2), is a member of the death receptor family that shares a cysteine-rich extracellular domain and a cytoplasmic death domain. DR5 is located on cell surface, becomes activated upon binding to its ligand TRAIL or overexpression, and then signals apoptosis initiation through an FADD/caspase 8-dependant caspase activation cascade. A number of previous studies showed that DR5 expression is induced upon chemotherapy treatment. However, whether DR5 induction is necessary for apoptosis induction has remained unclear. To determine its functional role in chemotherapy-induced apoptosis, we used homologous recombination to knock out (KO) DR5 in HCT116 colon cancer cells, and then analyzed response of DR5 KO cells to a panel of anticancer agents. Compared to parental HCT116 cells, DR5 KO cells are less sensitive to TRAIL, the DNA damaging drug 5-FU, the non-steroidal anti-inflammatory drug (NSAID) sulindac, as well as several other classes of anticancer agents. We also investigated how these agents induce apoptosis through DR5. Together, our results indicate a critical role of DR5 in mediating therapeutic response of colorectal cancer cells. Citation Format: Jingshan Tong, Jian Yu, Lin Zhang. Role of death receptor 5 (DR5) in apoptosis induced by anticancer agents in colon cancer 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 2932. doi:10.1158/1538-7445.AM2015-2932
394. Generation of a Novel Allogeneic CAR T Cell Platform Utilizing an Engineered Meganuclease and AAV Donor Template to Achieve Efficient Disruption of T Cell Receptor Expression and Simultaneous Homology-Directed Insertion of a CD19 CAR
Authors: Daniel T. MacLeod, Jeyaraj Antony, Keith J. Wetzel, Rachel Moser, Audrey E. Brown, Jo Ann Hux, Caitlin A. Turner, Armin Hekele, Janel Lape, Clayton W. Beard, Bruce McCreedy, Victor V. Bartsevich, Michael G. Nicholson, Jeff Smith, Matthew Hirsch, Derek Jantz
Journal: Molecular Therapy (2016)

Chimeric antigen receptor (CAR) T cell therapies have achieved dramatic results treating hematological malignancies by redirecting the specificity of T cells to target CD19 expressing cancer cells. Clinical trials reporting these impressive results have used autologous therapies, which pose significant manufacturing, logistical, and cost issues, complicating the implementation of such therapies on a larger scale. Furthermore, CAR T cells are typically generated by using Lenti- or Retro- viral vectors, resulting in random integration of the CAR gene, heterogeneous expression of the CAR on the cell surface, and the potential for insertional mutagenesis. We have developed a platform to address these issues by using a streamlined process to insert a CAR gene into the T cell receptor (TCR) alpha chain locus of T cells obtained from healthy donors using a highly optimized engineered meganuclease. The resulting gene-edited allogeneic CAR T cells do not express an endogenous TCR and therefore should not be capable of eliciting graft versus host disease upon adoptive transfer. We first produced and validated an engineered meganuclease targeting TCRα, and developed a scalable process for electroporating T cells with meganuclease mRNA that routinely results in greater than 60% knockout of the TCR, as measured by flow cytometry. To test our gene knock-in approach, we treated cells with our meganuclease to induce a double-strand break (DSB) in TCRα. We then transduced these cells using an AAV6 vector containing a donor DNA template consisting of a second generation CD19 CAR driven by an exogenous promoter and flanked by homology arms to the target site in the TCRα sequence. Homology directed repair of the DSB utilizing this donor template results in insertion of the CD19 CAR at this site in the genome. Incorporating this process into a 14 day procedure for generation and expansion of TCR knockout CAR T cells, we successfully generated a large population of TCR knockout cells with >70% of those cells stably expressing the CD19 CAR. Importantly, these CAR T cells proliferated when co-cultured with CD19+ target cells, released cytokines including IFN-γ and IL-2, and exhibited potent cytotoxic activity against CD19+ target cells. Studies to confirm in vivo antitumor activity are currently being conducted. In summary, we describe a novel, highly efficient, and scalable method to produce allogeneic CAR T cells in a streamlined process using an engineered meganuclease in combination with an AAV6 donor template.
626. Improving MicroRNA-Target-Site-Based Vector Control
Authors: Mathias F. Leber, Sophie Anker, Sascha Bossow, Marc-Andrea Bärtsch, Martin Singh, Birgit Hoyler, Jessica Albert, Dirk Jäger, Christof von Kalle, Guy Ungerechts
Journal: Molecular Therapy (2015)

Oncolytic viruses are emerging novel anti-cancer therapeutics currently tested in phase I – III clinical trials. Recent data suggests virotherapy to be well tolerated with adverse events and oncolytic activities being dose-dependent. This data along with improvements in the manufacturing process of oncolytic viruses drives further escalation of administered therapeutic doses. Hence, there is a need for viruses which maintain low toxicity profiles while being administered at much higher doses. Here, we show our optimized modification strategy for oncolytic measles viruses (MV) using microRNA target sites. Furthermore, we will discuss our results on the mechanistic basis of vector control. We have previously shown that the cellular tropism of MV can be modified by insertion of target sequences for microRNAs specifically lost during malignant transformation. Using this approach, we could achieve attenuation of microRNA-controlled MV in cell lines or nontransformed human tissue expressing cognate microRNAs, while full anti-tumor efficacy could be demonstrated in xenograft mouse models. In addition, we have shown the possibility of multi-tissue detargeting by integration of target sites for multiple microRNAs within a single virus. To investigate whether microRNA-mediated vector control is based on translational repression or cleavage of targeted RNAs, we used rapid amplification of cDNA ends (RACE) followed by sequencing. We could show that viral mRNAs containing microRNA target sequences (miRTS) are directly cleaved in presence of cognate microRNAs. Moreover, we describe the genetic engineering and analysis of MV with miRTS in the 3'UTR of the N, F, H or L gene. Insertion of the miRTS box into the N 3'UTR resulted in the tightest regulation, while the F and H position showed an intermediate phenotype and the L position resulted in the lowest level of vector control. To explore additional strategies possibly enhancing microRNA-based vector control, we have analyzed the regulation efficiency after insertion of the same microRNA target site box into the 3' UTR of either a single gene (NmiRTS) or multiple MV genes (NmiRTS+ FmiRTS, NmiRTS+ LmiRTS). We conclude that a careful miRTS insertion pattern profoundly enhances the efficiency of vector control. This data provides the basis for the rational design of tightly controlled, microRNA-sensitive MV for safe and efficient cancer virotherapy.
Abstract 14645: Lower LDL-C Levels are Associated with Less Necroticlipidic Tissue in STEMI Patients
Authors: Karlis Trusinskis, Dace Juhnevica, Karlis Strenge, Andrejs Erglis
Journal: Circulation (2012)

Introduction: Plaque vulnerability is characterized by amount of necrotic and lipidic tissue. Statins are believed to stabilize atherosclerotic lesions after acute event. Measurable indicators of s...
18 F-Sodium Fluoride PET/MR for the Assessment of Cardiac Amyloidosis
Authors: Maria Giovanna Trivieri, Marc R. Dweck, Ronan Abgral, Philip M. Robson, Nicolas A. Karakatsanis, Anuradha Lala, Johanna Contreras, Gagan Sahni, Radha Gopalan, Peter Gorevic, Valentin Fuster, Jagat Narula, Zahi A. Fayad
Journal: Journal of the American College of Cardiology (2016)
Comparison of Proposed NIH Response Criteria with Clinician-Reported Changes in Organ-Specific and Overall Response
Authors: Jeanne Palmer, Stephanie J. Lee, Xiaoyu Chai, Barry Storer, Joseph Pidala, Corey S. Cutler, Mukta Arora, Mary E.D. Flowers, Steven Z. Pavletic, Georgia B. Vogelsang, Yoshihiro Inamoto, Madan Jagasia, Chen George, Paul J. Martin
Journal: Blood (2011)
66. Recombinant Newcastle Disease Virus as an Oncolytic Therapy for Ovarian and Prostate Cancers
Authors: Lisa A. Santry, Jacob P. vanVloten, Kathy Matuszewska, Byram W. Bridle, James J. Petrik, Sarah K. Wootton
Journal: Molecular Therapy (2016)

Newcastle disease virus (NDV) is a member of the Avulavirus genus in the Paramyxoviridae family. NDV selectively replicates in tumor cells due to defects in antiviral and apoptotic signalling. It is the oncolytic virus with the longest history of use in clinical trials with a proven safety record as a monotherapy due to its strong induction of antiviral responses in non-transformed mammalian cells. In addition to its direct oncolytic effect, NDV also activates both innate and adaptive immune responses and therefore has strong immunotherapeutic potential. To enhance the fusogenicity of the virus, the fusion protein of recombinant LaSota NDV (rNDV) was engineered to express a multibasic cleavage and activation site (rNDV/F3aa). This virus is highly fusogenic leading to the formation of large syncytia that allows for efficient intratumoral spread and increased lytic potential. While NDV has demonstrated efficacy in a number of different cancer models, including melanoma and hepatocellular carcinoma, little information about its efficacy in ovarian and prostate cancer is available. To this end, we evaluated the oncolytic potential of rNDV/F3aa expressing enhanced green fluorescent protein (GFP) in a panel of prostate and ovarian cancer cell lines using a resazurin dye-based cell viability assay. Infection with rNDV/F3aa-GFP at a range of MOIs significantly reduced the viability of these cancer cells in vitro, but had little effect on normal untransformed cells. To evaluate the efficacy of NDV in vivo, we used a well-established orthotopic mouse model of epithelial ovarian cancer and a syngeneic murine RM9 prostate carcinoma model. Intravenous delivery of 1×10^8 PFU of rNDV/F3aa-GFP to ovarian tumor-bearing mice resulted in a significant reduction in the primary tumor size and number of metastatic abdominal tumours. Furthermore, 50% of the mice had a complete loss of ascites, which is an accumulation of fluid in the abdomen, as a result of advanced stage ovarian cancer. The apparent decrease in secondary disease after treatment with rNDV/F3aa-GFP is particularly promising as it is the metastatic lesions that ultimately cause high morbidity and mortality in patients with advanced ovarian cancers. A pilot study in the RM9 prostate model revealed that rNDV/F3aa-GFP was able to replicate and spread within the tumor and neovasculature after intratumoral or intravenous delivery of 1×10^8 PFU. Studies to confirm these results, as well as to evaluate the ability of rNDV/F3aa-GFP to induce tumor regression and increase survival are currently underway. Taken together, these data suggest that NDV/F3aa is a promising oncolytic for further development as an anti-cancer agent for the treatment of prostate and ovarian cancers.
Patterns of gene expression in pulmonary fine needle aspirates (FNA) with diverse radiographic appearances
Authors: M. E. Lane, D. F. Yankelevitz, C. I. Henschke, M. F. Vazquez, Z. Xiang, X. Huang, A. L. Kramer, B. Yu, A. J. Ocean, S. Wadler
Journal: Journal of Clinical Oncology (2004)

9587 Background: Several radiographically distinct patterns of lung nodules including solid, part-solid and non-solid lesions have been identified. Lung cancer can present with any of these patterns and malignant lesions with various radiologic subtypes tend to exhibit varying degrees of aggressiveness. The management of these distinct subtypes is problematic in the absence of an accurate knowledge of their natural histories. Methods: We have collected samples from 34 pulmonary nodules (31 patients) undergoing FNA for suspicious pulmonary findings. Total RNA was extracted from 28 lung samples (25 FNAs from 24 patients + 3 normal lung samples) and analyzed for purity. To date, 19 samples have been amplified twice to obtain sufficient quantities for replicate microarray analysis using 15 μg on the Affymetrix HU-133A chips. Results: The 260/280 ratio of RNA hybridized to microarray chips was determined to be between 1.8 and 2.1. The mean present call (19 lung samples) on the HU133A chip (Affymetrix) was 42.3%, and the mean 3' to middle ratios of GAPDH and β-actin after two rounds of amplification were 4.1 and 7.4 respectively. The mean final cRNA concentration was 40.21 μg. Samples were analyzed by hierarchical cluster analysis and 4 distinct clusters were identified. Normal lung samples clustered together with a separate branch containing 3 adenocarcinomas. Malignant samples branched into the other 3 groups including one cluster containing 2 non-solid lesions and 2 benign lesions. Statistical analyses (p < 0.05) of non-solid lesions compared to normal lung demonstrated 99 genes with a ≥ 2 fold change in expression. Eighty-one percent of these genes were downregulated compared to normal lung tissue. These included endothelin receptor type B, related ras homologue, growth arrest specific 6 and jun B proto-oncogene, (downregulated by 28, 14, 11 and 3 fold respectively). Conclusions: These results demonstrate that microarray expression studies can be successfully performed on FNA lung biopsies. Differential gene expression of pulmonary nodules when coupled with the cytologic diagnosis may help to establish future therapeutic interventions. No significant financial relationships to disclose.
A comparison study of clinician-rated atopic dermatitis outcome measures for intermediate- to dark-skinned patients
Authors: C.Y. Zhao, E.Y. Hao, D.D. Oh, B.S. Daniel, L.K. Martin, J.C. Su, M. Rodrigues, D.F. Murrell
Journal: British Journal of Dermatology (2016)

Atopic dermatitis (AD) assessment is more difficult in patients with skin of colour (SOC).To compare the reliability of commonly used outcome measures for assessing AD in patients with SOC and to evaluate a novel greyscale in this population.Twenty-five patients with AD each attended a 1-day scoring exercise based in either Sydney or Melbourne, Australia. Each patient was scored by the same five physicians using the Eczema Area and Severity Index (EASI), objective Scoring Atopic Dermatitis (oSCORAD), Investigator's Global Assessment (IGA) and a novel greyscale. Patients also completed the Patient-Oriented Eczema Measure and quality-of-life measures. A Mexameter was used to measure baseline melanin indices. Ten random patients were rescored to test intrarater reliability.We included 11 light-skinned patients (melanin index ≤ 200) and 14 patients with SOC (melanin index > 200) in the cohort. The inter-rater intraclass correlation coefficients (ICCs) were EASI 0·83 [95% confidence interval (CI) 0·66-0·94] for light skin and 0·77 (95% CI 0·60-0·91) for SOC; oSCORAD 0·68 (95% CI 0·44-0·88) for light skin and 0·74 (95% CI 0·54-0·89) for SOC; and IGA 0·80 (95% CI 0·62-0·93) for light skin and 0·70 (95% CI 0·49-0·87) for SOC. The greyscale had an ICC of 0·78 (95% CI 0·60-0·91) when replacing the EASI's erythema scale for patients with SOC. All scores showed excellent intrarater reliability for all skin types. Erythema component analysis showed that erythema did not contribute to variability.EASI showed excellent reliability for patients of all skin colours, and is recommended as the optimal core measure for patients with all skin colours.