tbuckley/cabot-search huggingface dataset:
Abstract 5123: Curative fluorescence-guided surgery of pancreatic cancer in combination with UVC irradiation in orthotopic mouse models
Authors: Yukihiko Hiroshima, Ali Maawy, Yong Zhang, Sho Sato, Takashi Murakami, Mako Yamamoto, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman
Journal: Cancer Research (2015)

Abstract Fluorescence-guided surgery (FGS) has shown great promise, but has not been shown to be curative. Human MiaPaCa-2 pancreatic cancer cells, expressing green fluorescent protein (GFP), were implanted orthotopically in nude mice. Brightlight surgery (BLS) was performed on 24 tumor-bearing mice. After BLS, mice were randomized to BLS-only (n = 8) or FGS (n = 8) or FGS-UVC (n = 8) groups. The residual tumors were resected using a portable imaging system. FGS or FGS followed by UVC irradiation with 2700 J/m2 UVC (254 nm) was performed. Residual tumor area after FGS was significantly smaller than after BLS only (p = 0.007). The BLS treated mice had reduced survival compared to FGS- and FGS-UVC-treated mice for both relapse-free survival (RFS) (p,0.001 and p,0.001, respectively) and overall survival (OS) (p,0.001 and p,0.001, respectively). With FGS-UVC, RFS lasted at least 150 days indicating the animals were cured. UVC irradiation in combination with FGS has curative potential in the clinic. Citation Format: Yukihiko Hiroshima, Ali Maawy, Yong Zhang, Sho Sato, Takashi Murakami, Mako Yamamoto, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. Curative fluorescence-guided surgery of pancreatic cancer in combination with UVC irradiation in orthotopic mouse models. [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 5123. doi:10.1158/1538-7445.AM2015-5123
Abstract 1331: Targeting CD47 triggers macrophage-dependent brain tumor destruction in a clinical relevant model
Authors: Huaiyang Zhu, Ning Yang, Lina Leiss, Cecilie B Rygh, Siddhartha S Mitra, Samuel H Cheshier, Bin Huang, Rolf Bjerkvig, Per Ø Enger, Irving L Weissman, Xingang Li, Jian Wang
Journal: Cancer Research (2015)

Abstract Glioblastoma multiform (GMB), as a major unsolved clinical challenge, remains among the most aggressive malignancies in human brain with poor prognosis around 10-14.6 months survival. Due to their infiltrative character in the limited space, it is very difficult to be completely resected surgically. Although radiotherapy and chemotherapy that were given to patients after surgery may improve overall survival, the treatment outcomes in general are poor. The tumors eventually recur. Thus, new therapeutic strategy for GBM is urgently needed. It has been shown that CD47, a tumor cell surface marker, through binding its receptor SIRPα on macrophages plays as “don't eat me signal” and thus, by blocking the interaction of CD47 with SIRPα could lead to tumor destruction. So, we developed a standardized protocol for a novel xenograft surgical resection model which mimicked the process of operation in clinic. We hypothesized that the mechanical surgical procedure of tumor resection may create an inflammatory tumor environment, leading to recruitment of immune cells including macrophages. We believed the presence of these macrophages was needed to mediate the anti-tumor effects of the CD47 antibody which we administered postoperatively. The aims of the project are: 1) Translating brain tumour immunotherapy from the lab bench via preclinical studies to the clinic; 2) Establishing a novel xenograft surgical resection model to mimic the clinical setting of tumour recurrence in patients. Specifically, we will: 1) In vitro quantify and functionally characterize tumour-associated macrophages from treated vs. untreated tumours; 2) Using our clinical relevant animal models we want to determine the efficacy of targeting CD47 therapy. In this study, we have developed a standardized protocol for a novel xenograft surgical resection model to parallel the treatment seen in glioma patients. The model accounts for the therapeutic benefit of surgical resection in pre-clinical models and demonstrates that recurrent tumors show higher proliferation and angiogenesis comparing to non-resected tumors. Moreover, the resection site is highly infiltrated by both CD68 and pSTAT1 positive macrophages. CD47 antibody treatment group has longer survival time than other groups. Citation Format: Huaiyang Zhu, Ning Yang, Lina Leiss, Cecilie B Rygh, Siddhartha S Mitra, Samuel H Cheshier, Bin Huang, Rolf Bjerkvig, Per Ø Enger, Irving L Weissman, Xingang Li, Jian Wang. Targeting CD47 triggers macrophage-dependent brain tumor destruction in a clinical relevant model. [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 1331. doi:10.1158/1538-7445.AM2015-1331
128. Targeting a High-Expression FVIII Transgene to Exogenous Locations in the Genome without Disrupting Endogenous Gene Expression
Authors: Jennifer M. Johnston, Matthew Porteus
Journal: Molecular Therapy (2016)

The technology that is now available for targeted genome editing consists of artificial nucleases that create double stranded breaks at specific genomic locations that can then be corrected by intrinsic cellular repair processes. Genome editing can be achieved by exploiting the repair mechanism of homologous recombination by providing a donor vector containing the gene(s) of interest flanked by sequences homologous to the site of the double strand break. To date, gene addition in this manner is targeted to defined inert safe harbor loci. We developed an innovative targeting strategy in which homologous recombination could be utilized to target a transcriptionally active genomic locus without disrupting expression of the endogenous gene. In this manner, essentially any location in the genome becomes a potential safe harbor for homologous recombination-mediated genome editing. One advantage to this strategy is that it allows for transgene expression to be under the precise control of endogenous regulatory elements, rather than using heterologous promoters. Therefore, the optimal locus with the most advantageous regulatory elements to drive transgene expression can be selected for gene addition. Pilot experiments confirmed the expression of exogenous reporter genes (such as the green fluorescent protein or the more therapeutically relevant biologically inert surface selectable marker delta NGFR) from either an exogenous ubiquitous promoter or from the exogenous promoter due to the addition of a T2A element incorporated downstream of the endogenous gene. Notably, expression of the endogenous gene was confirmed to be unaltered. These experiments were performed at three separate genomic locations. To demonstrate the feasibility of this strategy therapeutically however, a high-expression FVIII chimeric transgene (HPFVIII) was incorporated into two distinctly active genomic loci: the IL2R gamma chain locus and the adenosine deaminase locus. The donor vectors utilized contained the cDNA for the endogenous gene locus (either the IL2R gamma chain gene or the adenosine deaminase gene) followed by a ubiquitous promoter intended to drive the expression of HPFVIII, all of which was flanked by one kilobase arms of homology. Both the myeloid erythroid-leukemic K562 cell line and the acute T cell leukemic Jurkat cell line were modified upon nucleofection and confirmed to be targeted by sequencing. Single cell clones were produced and assessed for HPFVIII expression by a one-stage APTT based coagulation assay. Clones were found to express therapeutic levels of FVIII from both loci in both cell types (1 Unit / 2 million cells / 24 hrs). These experiments set the stage for targeting of HPFVIII into hematopoietic stem and progenitor CD34+ cells for the purpose of treating Hemophilia A.
455. Safety of Vaccination to Treat Cocaine Addiction with Capsid Proteins from a Disrupted Adenovirus Conjugated to a Cocaine Analog
Authors: David F. Havlicek, Lauren Beatty, Lucy Quach, Sebastien Monette, Bishnu P. De, Jonathan B. Rosenberg, Dolan Sondhi, Ronald G. Crystal, Stephen M. Kaminsky
Journal: Molecular Therapy (2015)

Cocaine is a highly addictive drug with significant social, societal, economic and medical impact, yet there are no effective therapies for cocaine addiction. An anti-cocaine vaccine that could evoke antibodies to bind the drug and prevent its transfer across the blood-brain barrier to its cognate CNS receptors is a promising strategy for treatment of cocaine addiction. In preclinical studies, an anti-cocaine vaccine (dAd5GNE) consisting of a disrupted E1- E3- serotype 5 adenovirus covalently conjugated to the cocaine analog GNE evoked high-titers of anti-cocaine antibodies that blocked cocaine from reaching the central nervous system of mice, rats and monkeys, abrogating cocaine-induced behaviors. The objective of this study was to ascertain if vaccination of a clinical grade dAd5GNE formulated in Adjuplex™ adjuvant administered to mice and non-human primates (NHPs) could be achieved with a safety profile acceptable to move this therapy to humans. Age-matched Balb/c mice (n=48 male, n=48 female for each group) were vaccinated monthly with a vehicle control, Adjuplex™ alone or dAd5GNE, (0.4 or 4 mg) + Adjuplex™. At 1, 5, 13 and 26 wk, evaluation of gross and histopathology, complete blood count, and serum chemistry were performed in a blinded fashion. No significant differences between Adjuplex™ control- and vaccine-treated groups were observed and no adverse effects could be attributed to the vaccine. Some histiocytic inflammatory infiltrates at the site of injection were observed in mice for which doses of Adjuplex™ were >150-fold the weight-adjusted human dose. African green monkeys vaccinated monthly with Adjuplex™ formulated dAd5GNE (50 mg, 100 mg or 200 mg), or adjuvant control (n=2 male, n=2 female for each group) were evaluated for standard general safety parameters plus heart rate, respiratory rate, and body temperature over the course of 6 months. To reflect the use of the vaccine in cocaine addict populations, all NHPs were challenged with cocaine (1 mg/kg, intravenous) on each of the 3 days leading up to sacrifice with vital signs monitored for 30 min following each challenge. Examination of the brain, thyroid, parathyroid, pituitary, mediastinal lymph node, mesenteric lymph node, popliteal lymph nodes, inguinal lymph node, pericardium, aorta, thymus, diaphragm, salivary gland, gall bladder, stomach, mesenteric adipose tissue, adrenals, trachea, esophagus, urinary bladder, sternum, eye, cervical spinal cord, pituitary, sciatic nerve, skin, quadriceps revealed no adverse effects related to the intramuscular administration of dAd5GNE in mice or NHPs. Unlike the murine study, no untoward effects associated with the adjuvant were observed at the site of injection. This safety profile suggests that vaccination with dAd5GNE meets the criteria to proceed to clinical trial.
Abstract 1218: A biological crosstalk between p53 and MYCN/MYC in neuroblastoma
Authors: Naohiko Ikegaki, Xao Tang
Journal: Cancer Research (2015)

Abstract We previously showed that TSA (an HDAC inhibitor) and Epoxomycin (a proteasome inhibitor) as single agents and in combination significantly suppressed growth of MYCN-amplified neuroblastoma cells. However, these compounds had contrasting effects on MYCN expression. TSA down-regulated MYCN expression, but Epoxomycin and the TSA/Epoxomycin combination led to MYCN hyper-expression (defined as markedly increased expression beyond that observed in the untreated cells). The expression of p53 was also increased in MYCN-amplified cells treated with Epoxomycin or the TSA/Epoxomycin combination. In an independent study, we also found that treatment of neuroblastoma cells (MYCN-amplified or non-MYCN amplified) with 17-DMAG and S(+) Ibuprofen resulted in an increase in p53 expression and a reduction in MYCN or MYC expression. In this study, we examined (i) the pattern of gene expression induced by MYCN hyper-expression in MYCN-amplified cells, and (ii) a potential functional relationship between p53 and MYCN/MYC in neuroblastoma. Transient transfection of MYCN and TP53 into neuroblastoma cells was done by electroporation. Gene expression profiling, TaqMan real-time PCR, and Western blot assays were used to detect expression patterns of genes and proteins. It was observed that ectopic over MYCN expression in MYCN-amplified IMR5 cells resulted in growth suppression. Gene expression profiling analysis revealed that the hyper-expression of MYCN in the MYCN-transfected IMR5 cells led to an increased expression of genes involved in growth suppression and apoptosis, including EGR1, EPHA2, KLF2, PERP and SEL1L. The expression of PERP and EPHA2 was confirmed by TaqMan real-time PCR and Western blot assay, respectively. Interestingly, co-transfection of TP53 and MYCN in IMR5 cells led to high p53 expression but a reduction in MYCN expression (below the levels of endogenous MYCN). Transfection of TP53 into IMR5, SY5Y, and SKNAS reduced endogenous MYCN and MYC expression in these cells. Consistent with these observations, treatment of IMR5 and SY5Y cells with known p53-inducers, Doxorubicin and CoCl2, resulted in an increased p53 expression and a reduction of MYCN and MYC expression. Although high MYCN expression sustains growth of MYCN-amplified neuroblastoma, the hyper-expression of MYCN is deleterious to survival of these cells. In addition, augmented p53 expression may elicit a negative feedback regulation of MYCN/MYC expression in neuroblastoma. Citation Format: Naohiko Ikegaki, Xao Tang. A biological crosstalk between p53 and MYCN/MYC in neuroblastoma. [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 1218. doi:10.1158/1538-7445.AM2015-1218
461. The Testing Strategy to Determine the Pharmacological Activity of Gene Therapy Drug Product (rAd-IFN) to Treat Intravesical Non-Muscle Invasive Bladder Cancer
Authors: Minna M. Hassinen, Jenni Mykkänen, Hanna Lesch, Sara Paulo, Taina Koponen, Anna-Kaisa Lehtivarjo, Steve Parrish, Robert Shaw, Nigel R. Parker, Seppo Ylä-Herttuala
Journal: Molecular Therapy (2016)

rAd-IFN is a recombinant adenoviral gene therapy vector encoding IFNα2b gene for the treatment of refractory non-muscle invasive bladder cancer. The vector transduces bladder wall cells where IFNα2b gene is expressed leading to death of cancer cells. The advanced testing strategy to determine the pharmacological activity of rAd-IFN drug product involves three key assays: 1. Infectious titer of the virus, quantitative assay 2. Expression of the transgene (IFNα2b), semiquantitative assay 3. Potency (IFNα2b mediated cell killing), quantitative assay The infectivity and transgene expression assays have been performed for batch release and stability monitoring of activity during Phase 2 and will remain unchanged in principle for Phase 3 and commercial use. In the infectivity assay the cells supporting adenovirus replication are infected with three concentrations of adenovirus and left to produce the virus for two days. The percentage of infected cells is then determined with a flow cytometer utilizing a fluorescently conjugated antibody against an adenoviral structural protein. Samples are analysed in parallel with a reference standard and infectivity is given as relative Infectious Units / ml. In expression assay, the IFNα expression capability of the virus preparation is determined by infecting IFN insensitive cells with the rAd-IFN virus and the concentration of produced IFNα is measured with a commercial IFNα ELISA (enzyme-linked immunosorbent assay) from cell culture supernatants For Phase 3 a new potency assay is developed and added to release and stability testing in order to provide evidence that batches of rAd-IFN are able to produce active IFNα2b which has a relevant pharmacological effect. In this assay cells are transduced using multiple dilutions of reference standard and test samples leading to expression of IFNα2b and subsequent cell death. Cell killing efficiency is determined using colorimetric method measuring dehydrogenase activity of the living cells. Relative potency of test sample is determined against reference standard response curve after testing parallelism by equivalence test. All activity assays will be fully validated according to ICH Q2 (R1) prior to release testing of Phase 3 clinical study material (Accuracy, Precision, Specificity, Linearity and Range, System Suitability and Robustness). The three validated assays will provide enhanced quantitative measure of biologic function of the rAd-IFN vector and thus demonstrate the quality and efficacy of drug product batches.
The cell cycle restricts activation-induced cytidine deaminase activity to early G1
Authors: Qiao Wang, Kyong-Rim Kieffer-Kwon, Thiago Y. Oliveira, Christian T. Mayer, Kaihui Yao, Joy Pai, Zhen Cao, Marei Dose, Rafael Casellas, Mila Jankovic, Michel C. Nussenzweig, Davide F. Robbiani
Journal: The Journal of Experimental Medicine (2016)

Activation-induced cytidine deaminase (AID) converts cytosine into uracil to initiate somatic hypermutation (SHM) and class switch recombination (CSR) of antibody genes. In addition, this enzyme produces DNA lesions at off-target sites that lead to mutations and chromosome translocations. However, AID is mostly cytoplasmic, and how and exactly when it accesses nuclear DNA remains enigmatic. Here, we show that AID is transiently in spatial contact with genomic DNA from the time the nuclear membrane breaks down in prometaphase until early G1, when it is actively exported into the cytoplasm. Consistent with this observation, the immunoglobulin (Igh) gene deamination as measured by uracil accumulation occurs primarily in early G1 after chromosomes decondense. Altering the timing of cell cycle–regulated AID nuclear residence increases DNA damage at off-target sites. Thus, the cell cycle–controlled breakdown and reassembly of the nuclear membrane and the restoration of transcription after mitosis constitute an essential time window for AID-induced deamination, and provide a novel DNA damage mechanism restricted to early G1.
Vitamin D supplements: don’t forget depression and cognitive impairment
Authors: Detlef Degner
Journal: BMJ (2016)

Bolland and colleagues describe the role of vitamin D supplementation and the insufficient studies published in recent years.1 Observational studies have associated low vitamin D status with a wide range of non-skeletal adverse clinical outcomes. But meta-analyses of randomised controlled trials show that vitamin D supplementation alone does not improve …
Solanezumab and the amyloid hypothesis for Alzheimer’s disease
Authors: David G Le Couteur, Sally Hunter, Carol Brayne
Journal: BMJ (2016)

Solanezumab’s failure is a wake-up call to look elsewhere for an answer to dementia

Is the amyloid cascade hypothesis of Alzheimer’s disease too big to fail?1 It proposes that brain deposition of β amyloid protein is the critical early event in the pathogenesis of Alzheimer’s disease and has been the centrepiece of dementia research for decades.2 The hypothesis suggests that removing β amyloid will reverse or prevent the clinical expression of dementia. However, in all phase III clinical trials to date, treatments targeting β amyloid have failed to improve cognitive outcomes despite reducing brain β amyloid.3

It is widely argued that these negative trials do not disprove the hypothesis but that treatments should be given decades earlier before β amyloid has “caused” neuronal loss, or that the trials had included people without amyloid deposits.2 The results of a third trial investigating solanezumab (EXPEDITION3), a monoclonal antibody targeting amyloid plaques, were therefore eagerly awaited after the first two trials had negative results but with post hoc indications of potential effects on …
Reinduction Chemoimmunotherapy with Epratuzumab in Relapsed Acute Lymphoblastic Leukemia (ALL) in Children, Adolescents and Young Adults: Results From Children's Oncology Group (COG) Study ADVL04P2
Authors: Elizabeth A. Raetz, Mitchell S. Cairo, Michael J. Borowitz, Xiaomin Lu, Meenakshi Devidas, Joel M. Reid, David M. Goldenberg, William A Wegener, James A. Whitlock, Peter C. Adamson, Stephen P Hunger, William L. Carroll
Journal: Blood (2011)
Cerebrovascular function in presymptomatic and symptomatic individuals with hereditary cerebral amyloid angiopathy: a case-control study
Authors: Anna M van Opstal, Sanneke van Rooden, Thijs van Harten, Eidrees Ghariq, Gerda Labadie, Panagiotis Fotiadis, M Edip Gurol, Gisela M Terwindt, Marieke J H Wermer, Mark A van Buchem, Steven M Greenberg, Jeroen van der Grond
Journal: The Lancet Neurology (2016)
Genetic Resistance to JAK2 Enzymatic Inhibitors Is Overcome by HSP90 Inhibition
Authors: Oliver Weigert, Andrew A. Lane, Liat Bird, Nadja Kopp, Angela V Toms, Christoph Gaul, Eric Vangrevelinghe, Alain De Pover, Catherine H. Regnier, Dirk Erdmann, Francesco Hofmann, Michael Eck, Andrew L. Kung, Thomas Radimerski, David M Weinstock
Journal: Blood (2011)
Abstract 2169: Genomic analysis of 207 rectal cancer samples
Authors: Yue Hu
Journal: Cancer Research (2015)

Abstract As the 3rd most commonly diagnosed cancer, colorectal cancer makes up of about 10% of all cancer cases and afflicts 1.3million patient each year. It is also the 3rd leading cause of cancer death. Every year more than 50,000 patients die of this disease. To analyze the molecular mechanism of rectal cancer, we explore the gene expression of cancer samples of 207 patients; most of them have paired control. We also study SNPs as well as prognosis data of these patients. Rectal cancer samples show a significant downregulation of genes in metabolic pathways. The general expression pattern separates cancer samples into “control like” subgroup and “cancer like” subgroup. There is no significant prognosis difference between these two groups. We observe a strong correlation between the average gene expression and the copy number change of each chromosome of cancer samples. Several SNPs show differential survival among patients with different alleles. Clinical data shows that these SNPs affect prognosis independent of lymph node status. Note: This abstract was not presented at the meeting. Citation Format: Yue Hu. Genomic analysis of 207 rectal cancer samples. [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 2169. doi:10.1158/1538-7445.AM2015-2169