tbuckley/cabot-search huggingface dataset:
431. Lung Antibody Factory for Passive Immunisation Against Influenza
Authors: Tiong Kit Tan, Pramila Rijal, Lee A. Davies, Ian A. Pringle, Alain R. Townsend, Stephen C. Hyde, Deborah R. Gill
Journal: Molecular Therapy (2016)

Influenza A is a major global health threat causing >500,000 deaths annually. Neither prior infections nor current vaccines provide lasting protection, mainly due to rapid antigenic evolution of the viral haemagglutinin (HA) protein. Broadly neutralising antibodies (bNAbs) isolated from vaccinated volunteers can provide passive immunity, but this approach is hindered by high antibody manufacturing costs and the relatively short half-life of antibody after delivery to the circulation. We hypothesise that using lentivirus pseudotyped with Sendai virus envelopes (rSIV.F/HN) to deliver genes encoding anti-influenza bNAbs to the lung could provide long-lasting passive immunity to widely divergent strains of influenza. We selected a novel bNAb that we isolated from vaccinated volunteers, namely T1-3B (VH1-69 germline family) that cross-reacts with multiple group 1 influenza A strains including H1 (A/PuertoRico/8/34 & A/Brisbane/59/2007), pandemic H1 (A/California/07/2009) and H5 (A/Vietnam/1203/2004). Delivery of rSIV.F/HN expressing Gaussia luciferase (GLux) reporter protein to the mouse lung (1e7 TU/mouse) resulted in persistent secretion of GLux into both bronchoalveolar lavage fluid (BALF) (1,370,000 RLU/µl; p<0.01) and systemically into the serum (1,000 RLU/µl; p<0.01), representing 18,000-fold, and 25-fold over background, respectively. We then generated rSIV.F/HN vectors expressing T1-3B antibody and showed detection of antibody in the serum (715 ng/ml; p<0.05) for up to 28 days post intranasal delivery of rSIV.F/HN (5e7 TU/mouse). Animals treated with rSIV.F/HN expressing T13B were partially protected against a lethal challenge with either 1,000 or 10,000 TCID50 (~10 and 100 LD50) of A/PuertoRico/8/34 (H1N1) influenza. They experienced a ~2-3 days delay in symptoms and, significantly reduced weight-loss - less than 20% weight loss in 50% (1,000 TCID50) and 20% (10,000 TCID50) treated animals, while all control animals lost >20% weight irrespective of influenza dose (p<0.001 and p<0.05 for 1,000 and 10,000 TCID50 respectively). One major advantage of rSIV.F/HN as a platform for bNAb passive immunization is the proven ability to achieve successful transgene expression after repeated lung vector administration (Mol Ther 18:1173, 2010; Am J Respir Crit Care Med 186:846, 2012), a major hurdle for all other viral vectors we have evaluated, including rAAV (J Virol 81:12360, 2007). Repeat administration of rSIV.F/HN vectors expressing alternative bNAbs, such as those that cross-react with both group 1 and 2 influenza, could provide a truly broad protection against a wide range of influenza strains. We speculate that during the next human influenza pandemic, prophylaxis provided by lung gene transfer may be feasible and more cost-effective and time-responsive than traditional vaccines or parenteral administration of therapeutic antibody.
High BCR-ABL Levels At Diagnosis Are Associated with Unfavorable Responses to Imatinib Mesylate.
Authors: Paolo G Vigneri, Fabio Stagno, Stefania Stella, Alessandra Cupri, Stefano Forte, Michele Massimino, Agostino Antolino, Clementina Caracciolo, Laura Nocilli, Stefana Impera, Caterina Musolino, Diamante Turri, Mario Russo, Carmen Tomaselli, Michele Rizzo, Maurizio Musso, Fortunato Morabito, Luciano Levato, Livia Manzella, Martin Mueller, Francesco Di Raimondo
Journal: Blood (2012)
553. Considering the Wild Type Adeno-Associated Virus of Serotype 2 Genome as a Recombinant AAV in the Baculovirus/Sf9 Cells System
Authors: Adrien Savy, Lionel Galibert, Minna U. Kaikkonen, Otto W. Merten
Journal: Molecular Therapy (2015)

In 2010, a study on the infectivity of wild type Adeno-Associated Virus (WT AAV2) compared to recombinant AAV (rAAV) vectors have been published. The wild type AAV2 had an up to hundred fold higher infectivity compared to rAAVs. With the aim to decipher if this higher infectivity is due to the WT AAV2 production system, or only to the overall nature of the DNA encapsidated in the AAV capsid we have used the baculovirus/Sf9 system to produce rAAV, with the recombinant genome being the Wt AAV2 genome. However, expressing WT AAV2 genome in the baculovirus system has shown an early activity of the p5 promoter leading to the expression of Rep78. The expression of this protein resulted in an excision of the WT AAV2 genome during the first steps of Baculovirus stock formation. The absence of detection of the Rep68 and Rep40 proteins tended point to reduced or impaired splicing of the rep transcripts in the baculovirus/insect cells system. To put this into evidence, we have characterized the activity of the p5 promoter in the baculovirus/Sf9 context and studied the kinetics of expression of the Rep78 protein.
Abstract LB-188: Epigenome-wide study in prediagnostic samples from the European Prospective Investigation into Nutrition and Cancer (EPIC-Italy) cohort: Differentially methylated microRNAs in subjects who developed breast cancer
Authors: Alessio Naccarati, Silvia Polidoro, Giovanni Fiorito, Francesca Cordero, Giulio Ferrero, Gianluca Campanella, Carlotta Sacerdote, Amalia Mattiello, Salvatore Panico, Giovanna Masala, Domenico Palli, Claudia Agnoli, Vittorio Krogh, Graziella Frasca, Rosario Tumino, Paolo Vineis
Journal: Cancer Research (2015)

Abstract The crosstalk between microRNAs (miRNAs) and other epigenetic factors may lead to novel hypotheses about carcinogenesis identifying new targets for research. Since a single miRNA can regulate multiple downstream target genes, its altered expression may potentially be a very sensitive biomarker to detect early malignant transformation and improve diagnosis and prognosis. In the current study, we used a genome-wide approach to test the hypothesis that altered methylation of miRNA encoding genes may be related to dietary and lifestyle factors and may be associated with deregulated mature miRNA expression ultimately leading to cancer. In a case-control study nested in a prospective cohort (EPIC-Italy), we analysed DNA methylation levels of miRNA encoding genes (2,191 CpG probes related to 517 genes) that are present in the Infinium Human Methylation450 BeadChip array in prediagnostic peripheral white blood cells of subjects who developed Colorectal Cancer (CRC, n = 159) and Breast Cancer (BC, n = 166) and matched subjects who remained clinically healthy. In the whole cohort, several differentially methylated miRNA genes were observed in association with age, sex, smoking habits and physical activity. Interestingly, in the case-control study, 8 differentially methylated miRNAs were identified in subjects who went on to develop BC (miR-328, miR-675, miR-1307, miR-1286, miR-1275, miR-1910, miR-24-1, and miR-548a-1; all Bonferroni-adjusted p-values &amp;lt; 0.05). No significant associations were found with CRC. Assuming that altered methylation of miRNAs may be present before diagnosis, it may represent a biomarker for early detection or risk of cancer and may help to understand the cascade of events preceding tumour onset. Citation Format: Alessio Naccarati, Silvia Polidoro, Giovanni Fiorito, Francesca Cordero, Giulio Ferrero, Gianluca Campanella, Carlotta Sacerdote, Amalia Mattiello, Salvatore Panico, Giovanna Masala, Domenico Palli, Claudia Agnoli, Vittorio Krogh, Graziella Frasca, Rosario Tumino, Paolo Vineis. Epigenome-wide study in prediagnostic samples from the European Prospective Investigation into Nutrition and Cancer (EPIC-Italy) cohort: Differentially methylated microRNAs in subjects who developed breast cancer. [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-188. doi:10.1158/1538-7445.AM2015-LB-188
Immunological and clinical effects of a multiple peptide vaccine and low-dose cyclophosphamide in prostate carcinoma patients
Authors: A. Marrari, M. Iero, P. Squarcina, S. Villa, R. Salvioni, G. Parmiani, R. Valdagni, L. Rivoltini
Journal: Journal of Clinical Oncology (2007)

13502 Background: Despite effective therapeutic strategies for the treatment of prostate cancer (PC), patients still recur and progress in a significant percentage. Here we describe the preliminary clinical and immunological data of a peptide-based strategy of vaccination in biochemical relapsed PC patients. Methods: We planned to enroll 30 HLA-A*0201 patients with biochemical failure after surgery, radiation or androgen deprivation therapy (ADT), according to the ASTRO criteria. On entering the study, patients discontinue ADT. No selections were made based on PSA levels at diagnosis, Gleason pattern score or other pathological features. Vaccination includes three peptides derived from proteins highly expressed in PC, PSMA (PSMA-P1 4–12 and PSMA-P2 711–719 ) and Survivin (SVV 96- 104/97M ). Peptides, emulsified in Montanide ISA 51, are administered subcutaneously (8 injections) at two-weeks intervals. Vaccine is preceded by systemic administration of low dose cyclophosphamide (300 mg/m 2 /four weeks), aimed at selectively down- modulating regulatory T cells (Treg). Immunological monitoring includes evaluation of peptide and tumor-specific CD8 + T cells in peripheral blood (IFN?-Elispot and HLA/multimer staining) and analysis of the frequency and suppressive activity of CD4 + CD25 + Foxp3 + Treg. Results: So far, ten patients have been enrolled. Treatment is well tolerated, with mild cutaneous toxicity due to Montanide injection. A significant increase in the frequency of antigen-specific CD8 + T cells was observed in 8/10 patients. Treg, only marginally expanded in these patients, do not seem to decrease by cyclophosphamide treatment, although studies on the potential modulation of their suppressive activity are in progress. After a follow-up of 6–12 months, PSA stabilization was observed in 7 patients, 2 of which entered the trial after maximal androgen blockade discontinuation. Interestingly, PSA stabilization appears to directly correlate with the induction of antigen-specific T cell responses. Conclusions: Our vaccination strategy proved to be safe, non toxic and well tolerated. Initial monitoring data show an expansion of antigen specific T cells, with an apparent correlation between immunological and biochemical responses. No significant financial relationships to disclose.
Abstract 3942: Oncogenic BRAF fusion induces MAPK-pathway activation targeted by MEK inhibitor and phosphatidylinositol 3-kinase inhibitor combination treatment in mucosal melanoma
Authors: Han Sang Kim, Kang Won Jang, Minkyu Jung, Soo Hee Kim, Tae-Min Kim, Byoung Chul Cho
Journal: Cancer Research (2015)

Abstract Background: Although remarkable progress has been made in the genomic characterization of cutaneous melanoma, the genetic alterations of primary mucosal melanoma (PMM) remain largely unknown. This study aims to investigate the recurrent mutations in PMM and to characterize the oncogenic potential of the newly identified ZNF767-BRAF fusion as well as its therapeutic implications in PMM. Methods: A total of 46 PMMs underwent exon-capture sequencing of 111 cancer-associated genes to identify somatic non-synonymous mutations, copy number alterations, and structural variations. A cancer cell with a novel ZNF767-BRAF fusion was established from a patient with PMM of the respiratory tract, who was refractory to vemurafenib. To characterize the oncogenic functions of the novel ZNF767-BRAF fusion, we performed western blot, soft agar growth assay and in vivo tumor. The inhibitory effects of vemurafenib, trametinib, buparlisib and LEE011 monotherapy and their combination treatment were measured in vitro and in vivo. Results: Targeted exon-capture sequencing of 46 PMMs revealed a total of 48 somatic non-synonymous mutations in 26 genes. Eight genes harbored recurrent mutations on NRAS (n = 6; 13%) and TP53 (n = 4; 9%) along with BRAF, KIT, MAP3K9, C8A, KRAS, FGFR3 (all observed in two cases; 4%). Of note, a novel ZNF767-BRAF fusion was identified in a PMM of the respiratory tract refractory to vemurafenib treatment. ZNF767-BRAF fusion was validated by Sanger sequencing. We show that ZNF767-BRAF encoded protein promotes the dimerization of RAF and potently activates mitogen-activated protein kinase pathway. The ectopic expression of ZNF767-BRAF fusion induced tumor formation as shown in colony forming assay and tumor xenograft model. The treatment of trametinib inhibited the growth of PMM cells harboring the ZNF767-BRAF fusion but vemurafenib showed no inhibitory effects. Compared with either agent alone, the combination of trametinib and buparlisib showed synergistic antitumor effects in vitro and in vivo. Conclusions: The genomic makeup of PMM is remarkably diverse and distinct from that of cutaneous melanoma. BRAF fusion defines a new molecular subset of PMM and can be therapeutically targetable by the combination of MEK inhibitor and PI3K Inhibitor. Citation Format: Han Sang Kim, Kang Won Jang, Minkyu Jung, Soo Hee Kim, Tae-Min Kim, Byoung Chul Cho. Oncogenic BRAF fusion induces MAPK-pathway activation targeted by MEK inhibitor and phosphatidylinositol 3-kinase inhibitor combination treatment in mucosal melanoma. [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 3942. doi:10.1158/1538-7445.AM2015-3942
Abstract 3609: In vitro comparison of conventional hyperthermia and electro-hyperthemia
Authors: Kwan-Hwa Chi, Yu-Shan Samuel Wang, Cheng-Chung Huang, Chao-Chun Chang, Mau-Shin Chi, Kai-Lin Yang, Yuk-Wah Tsang, Gabor Andocs
Journal: Cancer Research (2015)

Abstract Purpose: Deep heating hypertermia methods are a promising cancer treatment modalities used to enhance conventional treatment. This could be achieved through radiofrequency field en-bloc heating by Thermotron RF-8 and selective tumor heating by Oncotherm-Labehy, respectively. This is the first study to evaluate the different cytotoxic effect and action mechanism on cancer cells after mild hyperthermia (MHT) by Thermotron RF-8 or Oncothermia-Labehy. Experimental Design: Hepatoma HepG2 cells were used for MHT treatment (42°C for 30minute). Either by Oncotherm-Labehy or Thermotron RF-8 or water bath treatment were compared. Apoptosis evaluated 24h after MTH as measured by Annexin-V assay and cell cycle analysis. Mitochondria-targeted damage as measured by ROS production with or without Mito-TEMPO treatment and membrane-targeted damage as measured by caspase-8 expression, adhesion molecule expression, heat shock protein (HSP) release and calcium channel disturbance were evaluated and compared. Results: MHT resulted in similar cell cycle arrest on G2/M. Oncothermia treatment resulted in higher apoptosis rate (38.87±6.58) than RF-8 (25.13±2.26), water bath (18.77±0.35) and control (14.93±0.76). The expression of Caspase-8 is higher by oncothermia treatment, while caspase-3 and 9 levels were similar between 3 types of treatment. HSPs were upregulated by MHT, however a marked HSP release outside cell and E-cadherin overexpression on the membrane were only observed after oncothermia treatment. Conclusion: In this report, we found that different hyperthermia devices may induce different mechanisms on their cytotoxic effects and cell responses to heat. Oncothermia may selectively target on cell membrane before targeting on mitochondria, while RF-8 has no membrane targeting effect. These results may provide rational basis for future clinical application of hyperthermia treatment. Citation Format: Kwan-Hwa Chi, Yu-Shan Samuel Wang, Cheng-Chung Huang, Chao-Chun Chang, Mau-Shin Chi, Kai-Lin Yang, Yuk-Wah Tsang, Gabor Andocs. In vitro comparison of conventional hyperthermia and electro-hyperthemia. [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 3609. doi:10.1158/1538-7445.AM2015-3609
Abstract 3210: Level of Osteoprotegerin expression is breast cancer subtype specific
Authors: Stephanie Tsang, Ashleigh Renaud, Kim Roseman, Yuko Imaizumi, Nalini Yadav, Michael Weichhaus, Linda Connelly
Journal: Cancer Research (2015)

Abstract Osteoprotegerin (OPG) is a regulator of bone metabolism that is also produced by breast tumor cells. There is accumulating evidence that OPG has tumor-promoting effects in breast cancer. We have recently demonstrated that OPG can promote invasion and metastasis of triple negative breast cancer cells. We are now investigating the expression of OPG across major breast cancer subtypes. We cultured 3 breast cancer cells lines from each of the major subtypes: MCF-7, ZR-75-1 and T47-D (Estrogen Receptor positive; ER+); SKBR-3, HCC1954 and HCC202 (Human Epidermal Growth Factor Receptor 2 positive; HER2+) and MDA-MB-231, MDA-MB-436 and BT-549 (triple negative). We incubated cells for 24 hours and then measured OPG mRNA expression by real time RT-PCR and secreted OPG protein in cell culture supernatant by ELISA. The triple negative cells that we tested expressed the highest levels of OPG mRNA and protein. A much lower level of OPG expression was observed in the HER2+ cells. Contrasting results were observed with the ER+ cells. While there was no expression from the ZR-75-1 or T47-D cells after 24 hours incubation, the MCF-7 cells produced levels of OPG similar to those observed with the triple negative breast cancer cells. We also looked at whether OPG expression levels could be altered by incubating breast cancer cells with macrophages, a cell type found in the breast tumor microenvironment. We co-cultured cells from each subtype with THP-1 human macrophages for 8 hours and extracted mRNA from the breast cancer cells or incubated the breast cancer cells for an additional 16 hours alone to measure secreted OPG protein. We found that co-culture with macrophages significantly increased OPG mRNA and protein expression in MCF-7 (ER+) and SKBR-3 (HER2+) cells but there was no increase in the MDA-MB-231 cells (triple negative). In conclusion, while OPG was expressed at comparatively high levels in triple negative breast cancer cells, there were generally low levels or no expression in the ER+ and HER2+ cells tested. This suggests that the tumor-promoting effects of OPG may contribute to the more aggressive phenotype in triple negative cells. However OPG expression in ER+ and HER2+ cells can be stimulated through co-culture with macrophages. Thus conditions within the breast tumor microenvironment could amplify the effects of OPG in these tumor subtypes. Citation Format: Stephanie Tsang, Ashleigh Renaud, Kim Roseman, Yuko Imaizumi, Nalini Yadav, Michael Weichhaus, Linda Connelly. Level of Osteoprotegerin expression is breast cancer subtype specific. [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 3210. doi:10.1158/1538-7445.AM2015-3210
Analysis of the Effect On the Expression of Global Gene Expression Profiles in Lymphocyte Subpopulations Treated by Extracorporeal Photopheresis
Authors: Robert M Knobler, Ulrike Just, Gabriele Klosner, Florian Klinglmueller, Martin Bilban, Zoya Kuzmina, Hildegard T. Greinix, Franz Trautinger
Journal: Blood (2012)
Avascular Necrosis of the Hips With Increased Activity on 68Ga-DOTATATE PET/CT
Authors: Georgios Z. Papadakis, Corina Millo, Apostolos H. Karantanas, Ulas Bagci, Nicholas J. Patronas
Journal: Clinical Nuclear Medicine (2016)

Prolonged exposure to cortisol is one of the major causes of avascular bone necrosis (AVN). We report on a case of a woman with Cushing syndrome attributed to ectopic adrenocorticotropic hormone-secreting tumor who was evaluated with whole-body PET/CT study using Ga-DOTATATE. The scan showed increased activity by both femoral heads, corresponding to the margins of bilateral AVN seen on MRI. The presented data suggests AVN-induced reactive inflammatory alterations adjacent to the necrotic segment of the bone, which can be effectively targeted using radiolabeled somatostatin (SST) analogs.
Individualized Tamoxifen Dose Escalation—Letter
Authors: Stijn L.W. Koolen, Sander Bins, Ron H.J. Mathijssen
Journal: Clinical Cancer Research (2016)

In a recent commentary (1), Hertz and Rae have put the relevance of pharmacokinetically guided dosing of tamoxifen into perspective. We appreciate this effort and fully agree that more evidence is required to refine the relationship between exposure to the active tamoxifen metabolite endoxifen and clinical outcome parameters. On the basis of the relatively long survival of adjuvantly treated breast cancer patients, obtaining the highest level of evidence may take many years of further research, if feasible at all. However, this does not mean that based on the current evidence, including the recent work by Fox and colleagues (2), individual patients could not already benefit from systemic endoxifen concentration measurements. Of course, a threshold for efficacy has not been confirmed prospectively yet, but this does not mean that we should ignore extreme (low) endoxifen plasma concentrations. For instance, if the concentration has been measured and it is far below the currently adopted minimum value for efficacy of approximately 6 ng/mL (3), we feel it is unethical to not intervene and try to increase the exposure above this value, instead of just "waiting" for a potential recurrence. From daily clinical practice, we know that patients are highly motivated to know their endoxifen levels, despite all reservations regarding its interpretation. We agree that endoxifen levels must be measured by a certified laboratory. With multiple reports of validated endoxifen analytic assays available, we believe this is manageable for most laboratories experienced in therapeutic drug monitoring.In the second part of their commentary, Hertz and Rae (1) proposed an individualized dosing algorithm for tamoxifen treatment. On the basis of clinical parameters and CYP2D6 phenotype, the starting dose is determined and then, after a month, dosing is adjusted on the basis of the actual drug exposure. This is an option, as also the use of a dextromethorphan phenotyping test for endoxifen exposure is a possible tool to determine a tailored starting dose for the individual patient (4). Despite the comprehensiveness of their algorithm, this model lacks a major factor in dose individualization, that is, the continuing change in exposure over time. Several factors have been mentioned to predict endoxifen exposure before treatment initiation, but concomitant medication, complementary and alternative medicine, and adherence, for example, might change during treatment (5). Therefore, systemic drug exposure may also be influenced considerably later on during treatment, and it is vital to follow-up exposure over time, especially as tamoxifen treatment can comprise many years.See the Response, p. 6301No potential conflicts of interest were disclosed.