tbuckley/cabot-search huggingface dataset:
390. Impact of a Treatment with Antioxidant on Gene Transfer Efficiency After Recombinant Adeno-Associated Vector Injection in a Mouse Model of Duchenne Muscular Dystrophy
Authors: Jean-Baptiste Dupont, Benoît Tournaire, Romain Durand, Béatrice Marolleau, Emilie Bertil, Christophe Georger, Emilie Lecomte, Benjamin Cogné, Bernard Gjata, Laetitia vanWittenberghe, Alban Vignaud, Richard O. Snyder, Philippe Moullier, Adrien Léger
Journal: Molecular Therapy (2016)

Recombinant adeno-associated virus (rAAV)-based vectors are promising tools for the treatment of Duchenne muscular dystrophy (DMD) by gene therapy. Following rAAV injection in murine and canine models of DMD, several groups have reported significant phenotype improvements without notable toxicity, raising hope for future clinical translations. However, the long term maintenance of therapeutic benefits is an important, and yet unresolved issue. In previous studies conducted in DMD mice, we and others have demonstrated that rAAV-mediated transgene expression decreases progressively, even when clinically relevant vector doses are injected. Our team described several "restriction" factors having a negative impact on rAAV transduction, notably a loss of vector genomes resulting from muscle cell necrosis but also an oxidative damage affecting transgene mRNA. These first results support the fact that the tissue context in which rAAV vectors are delivered is of critical importance and can significantly affect their efficiency. In addition, they open new avenues for improvement since we can now consider counteracting these restriction phenotypes prior to rAAV injection. In the case of DMD, oxidative stress seems to occupy a central position in both muscle cell pathophysiology and rAAV transgene mRNA degradation. Therefore, we designed an innovative strategy using a relevant antioxidant agent routinely used in human medicine: N-acetylcysteine. DMD mice, pre-treated or not with this compound, were subsequently injected with a rAAV vector carrying a reporter transgene. The transduction efficiency, together with the expression and activity of the transgene, were carefully monitored and compared two months later. The outcome of this innovative approach will certainly pave the way for future combinatorial protocols using pharmacological agents and rAAV vectors in DMD muscles.
Abstract 616: Blood-based molecular landscapes of resistance to EGFR blockade in colorectal cancer patients
Authors: Giulia Siravegna, Benedetta Mussolin, Michela Buscarino, Giorgio Corti, Andrea Cassingena, Giovanni Crisafulli, Ryan B. Corcoran, Agostino Ponzetti, Alfredo Budillon, Patrizia Racca, Silvia Marsoni, Federica Di Nicolantonio, Fotios Loupakis, Salvatore Siena, Andrea Sartore Bianchi, Alberto Bardelli
Journal: Cancer Research (2015)

Abstract The molecular landscape of colorectal cancers (CRC) is presently assessed by genotyping neoplastic tissue obtained through surgical or bioptic procedures. We evaluated whether blood-based molecular profiles could be used to perform diagnostic determinations and monitor resistance to therapy in colorectal cancer patients. We find that RAS pathway mutations, which are commonly evaluated prior to administration of anti-EGFR antibodies, can be ascertained directly in the blood. Sequencing of circulating DNA identified genomic alterations in KRAS, NRAS, MET, ERBB2, FLT3, and MEK1 in patients with primary or acquired resistance to cetuximab or panitumumab. Secondary resistance to EGFR blockade is frequently accompanied by emergence of mutant RAS clones, which can be tracked in blood. We find that upon withdrawal of anti-EGFR antibodies, KRAS alleles decline in circulating DNA indicating that clonal evolution continues beyond clinical progression. Functional analysis of CRC cell populations, which had acquired resistance to cetuximab, revealed that KRAS mutant clones can decay when EGFR blockade is suspended. These results establish proof of principle that genotyping colorectal cancers using circulating DNA can inform therapeutic decisions, identify mechanisms of drug resistance and provide insights for further lines of therapy. Citation Format: Giulia Siravegna, Benedetta Mussolin, Michela Buscarino, Giorgio Corti, Andrea Cassingena, Giovanni Crisafulli, Ryan B. Corcoran, Agostino Ponzetti, Alfredo Budillon, Patrizia Racca, Silvia Marsoni, Federica Di Nicolantonio, Fotios Loupakis, Salvatore Siena, Andrea Sartore Bianchi, Alberto Bardelli. Blood-based molecular landscapes of resistance to EGFR blockade in colorectal cancer patients. [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 616. doi:10.1158/1538-7445.AM2015-616
Fecal microbiota transplantation induces hepatitis B virus e‐antigen (HBeAg) clearance in patients with positive HBeAg after long‐term antiviral therapy
Authors: Yan‐Dan Ren, Zhen‐Shi Ye, Liu‐Zhu Yang, Li‐Xin Jin, Wen‐Jun Wei, Yong‐Yue Deng, Xiao‐Xiao Chen, Chuan‐Xing Xiao, Xiao‐Fang Yu, Hong‐Zhi Xu, Li‐Zhu Xu, Yun‐Na Tang, Fei Zhou, Xue‐Lian Wang, Mei‐Ya Chen, Li‐Gang Chen, Mei‐Zhu Hong, Jian‐Lin Ren, Jin‐Shui Pan
Journal: Hepatology (2016)

Ren, Yan‐Dan; Ye, Zhen‐Shi; Yang, Liu‐Zhu; Jin, Li‐Xin; Wei, Wen‐Jun; Deng, Yong‐Yue; Chen, Xiao‐Xiao; Xiao, Chuan‐Xing; Yu, Xiao‐Fang; Xu, Hong‐Zhi; Xu, Li‐Zhu; Tang, Yun‐Na; Zhou, Fei; Wang, Xue‐Lian; Chen, Mei‐Ya; Chen, Li‐Gang; Hong, Mei‐Zhu; Ren, Jian‐Lin; Pan, Jin‐Shui Author Information
Late-onset moderate to severe acute respiratory distress syndrome is associated with shorter survival and higher mortality: a two-stage association study
Authors: Ruyang Zhang, Zhaoxi Wang, Paula Tejera, Angela J. Frank, Yongyue Wei, Li Su, Zhaozhong Zhu, Yichen Guo, Feng Chen, Ednan K. Bajwa, B. Taylor Thompson, David C. Christiani
Journal: Intensive Care Medicine (2016)
Intracellular Retention, Enhanced Clearance, and Defective FVIII Binding Are Common Features of Von Willebrand Factor D'-D3 Domain Mutations in Patients with Von Willebrand Disease Type 1 From the European Mcmdm-1VWD Study
Authors: Reinhard Schneppenheim, Ulrich Budde, Javier Batlle, Giancarlo Castaman, Jeroen C. J. Eikenboom, Augusto B. Federici, Jenny Goudemand, Tobias Obser, Florian Oyen, Francesco Rodeghiero, Sonja Schneppenheim, Ian R. Peake, Anne C. Goodeve
Journal: Blood (2012)
Molecular Variability of FLT3/ITD Mutants and Their Impact on the Differentiation Program of 32D Cells: Implications for the Biological Properties of AML Blasts
Authors: Sona Pekova, Michal Dvorak, Robert Ivanek, Sabrina Rueggeberg, Stefan Leicht, Tomas Kozak, Jiri Vrba, Jiri Schwarz, Petr Cetkovsky, Miroslav Prucha, Ondrej Hrusak
Journal: Blood (2008)
Abstract 1833: KRAS-regulated P4HA1 in pancreatic tumor and its hydroxylated peptide as a serum biomarker for early diagnosis
Authors: Zaian Deng, Karen M. Mann, Eugene J. Koay, Mauro Ferrari, Xifeng Wu, Paul J. Chiao, Tony Hu
Journal: Cancer Research (2015)

Abstract Protein posttranslational modification (PTM) plays a pivotal role in cancer progression through regulating gene expression, protein activities and stabilization. These chemistry events are regarded as potential biomarkers for cancer diagnosis, prognosis, and therapeutic efficacy evaluation. Hydroxylated proline is the most common PTM amino acid residue in the proteome. However, this modification is often overlooked. Here, we demonstrate the expression level of prolyl-4-hydroxylase alpha-1(P4HA1) in tumor tissues and the ratio of its catalyst (hydroxyprolyl-3-bradykinin, Hyp-BK) to its substrate (bradykinin, BK) in blood can serve as biomarkers for early pancreatic cancer diagnosis. First, we found that the P4HA1 expression level responds to the activation of KRAS which is commonly observed in pancreatic cancer cells. Immunohistochemistry testing for tumor tissue array reveals that pancreatic cancer tumor tissues, even in stage I tumor, present higher P4HA1 expression levels than tissues with chronic pancreatitis and healthy control. Peptidomic studies on clinical blood samples revealed that the Hyp-BK/BK value was 2.3 fold higher in pancreatic cancer patients than chronic pancreatitis patients and control group. The results were further validated in an independent sample cohort with blind information. We combined CA19-9 and the Hyp-BK/BK value as a biomarker panel obtaining an area under the curve (AUC) of 0.742 and 0.813 in the comparison of pancreatic cancer to pancreatitis patients and controls, respectively. Our results demonstrate that the measurement of Hyp-BK/BK value in blood, which reflects the hydroxylation level regulated by tumor-localized P4HA1, can be used as a biomarker for early detection of pancreatic cancer. Citation Format: Zaian Deng, Karen M. Mann, Eugene J. Koay, Mauro Ferrari, Xifeng Wu, Paul J. Chiao, Tony Hu. KRAS-regulated P4HA1 in pancreatic tumor and its hydroxylated peptide as a serum biomarker for early diagnosis. [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 1833. doi:10.1158/1538-7445.AM2015-1833
Elevated CEA level in the asymptomatic patient with normal conventional imaging: How useful is PET-CT for the detection of colorectal cancer recurrence?
Authors: Katharine Aitken, Yolanda Barbachano, Bhupinder Sharma, David Cunningham, Gary Cook, Sheela Rao
Journal: Journal of Clinical Oncology (2012)

400 Background: Serum carcinoembryonic antigen (CEA) level can be used as a sensitive marker of recurrence in the follow up of patients with colorectal carcinoma, enabling the early detection of recurrent disease at a stage where further curative therapy may be possible. However a subset of patients with asymptomatic elevated CEA levels will have no evidence of disease recurrence on conventional imaging (CI). Aim: The purpose of this study was to evaluate the utility of 18F-FDG PET CT in detecting occult disease recurrence where CI has failed to demonstrate a cause for a rise in CEA. Methods: 88 consecutive patients on surveillance following treatment for colorectal cancer with an elevation in CEA level (&gt;3ng/ml non-smokers, &gt;5ng/ml smokers) with normal (67) or equivocal (21) findings on conventional imaging (defined as CT+/-MRI, ultrasound or colonoscopy) who had undergone PET-CT between 01.01.2004 and 31.08.2010 were retrospectively identified. Histopathological confirmation or a minimum of 12 months of follow up were used to ascertain disease relapse. Eligibility for further curative treatment was established from clinical notes. Results: Recurrent disease was detected in 56/88 patients (prevalence 64%). The sensitivity of PET-CT to detect recurrence was 49/56 (88%, 95% CI 76-94) and specificity 28/32 (88%, 95% CI 72-95). The positive predictive value (PPV) and negative predictive value (NPV) for recurrence was 93% and 80% respectively. Sensitivity in subgroups with CEA levels 3-6, 6-10 and &gt; 10ng/ml were 91%, 82% and 89% respectively. 27 out of 49 patients (55%) with relapsed disease were eligible for further curative therapy and 26 received treatment with curative intent. The commonest site for PET detected disease relapse was the liver (16/49, 33%). Conclusions: PET-CT is a highly sensitive and specific tool for the detection of occult colorectal cancer recurrence in patients with raised CEA and normal CI thus should be considered mandatory in this setting. In over 50% of patients the recurrent disease detected before CI is positive, is still amenable for curative therapy.
Update on a phase I pharmacologic and pharmacodynamic study of MK-1775, a Wee1 tyrosine kinase inhibitor, in monotherapy and combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors.
Authors: J. H. M. Schellens, G. Shapiro, A. C. Pavlick, R. Tibes, S. Leijen, S. M. Tolaney, I. Diaz-Padilla, R. K. Ramanathan, T. Demuth, J. Viscusi, J. D. Cheng, R. Lam, Y. Xu, A. M. Oza
Journal: Journal of Clinical Oncology (2011)

3068 Background: MK-1775 (MK) is an investigational inhibitor of the Wee1 kinase regulating the G2 checkpoint leading to chemo-sensitization in p53-deficient tumor cells. Down-regulation of pCDC2 upon treatment with MK and chemotherapy serves as biomarker in this study. Methods: Evaluation of safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MK administered PO as monotherapy and combination with gemcitabine (G), cisplatin (P), or carboplatin (C). PART 1 is a single dose of MK followed by 1 of 3 treatment arms in PART 2A: single MK dose in combination with: 1) 1,000 mg/m2 G, 2) 75 mg/m2 P or 3) C AUC 5. In PART 2B, 5-BID doses of MK are explored in the same 3 arms. PART 3 is a cohort expansion to confirm Maximum Tolerated Dose (MTD). 50% reduction of pCDC2 in skin biopsies post-MK vs pre-treatment is considered evidence of target engagement (TE). Results: To date, 156 pts (44 in monotherapy/single-dose combination, 112 in multi-dose combination therapy) were treated with MK. No DLTs were observed in monotherapy; 7 (single dose) and 17 pts (multiple dose) experienced DLTs in combination therapy. Most common AEs are hematologic, nausea/vomiting, fatigue. PK was linear from 25 to 1,300 mg MK. MTDs of MK in combination with G, C, P as a single dose and as multiple dose in combination with C and P were identified. TE by pCDC2 occurred in 55% of pts at doses of MK > 100 mg across treatment arms. Conclusions: MK is a first-in-class Wee1 inhibitor that is well tolerated in combination with chemotherapy, with evidence of TE. Clinical and biomarker responses were observed in previously treated pts. MK+G single dose MK+P single dose MK+C single dose MK+G multiple dose MK+P multiple dose MK+C multiple dose N 14 13 16 26 28 37 MTD 200 mg 200 mg 225 mg 50/50/25/25/25mg* 200 mg 225 mg PR (%) 0(0) 2 (15.4) 0 0 2 (7.1) 1 (2.7) SD (%) 9 (64.3) 7 (53.8) 5 (31.3) 12 (46.2) 10 (35.7) 19 (51.4) Target engagement Y Y Y N Y Y Related AEs ≥grade 3 (%) 7 (50.0) 4 (30.8) 2 (12.5) 16 (61.5) 9 (32.1) 26 (70.3) * Dose escalation ongoing with an attenuated schedule facilitating use of higher MK doses of > 100 mg.
Factors Influencing Varicella-Zoster Virus (VZV) Infection after Allogeneic Peripheral Blood Stem Cell Transplantation: Low-Dose Acyclovir Prophylaxis and Pre-Transplant Diagnosis of Lymphoproliferative Disorders.
Authors: Dong Hwan Kim, Hans Messner, Vikas Gupta, John Kuruvilla, Janice Wright, Jeffrey Lipton
Journal: Blood (2006)
Preliminary Results of a Phase II Study of Decitabine Administered Daily for 5 Days Every 4 Weeks to Adults with Myelodysplastic Syndrome (MDS).
Authors: David P. Steensma, Maria R. Baer, James L. Slack, Rena Buckstein, Lucy Godley, Julie S. Larsen, Michael T. Cullen, Hagop M. Kantarjian
Journal: Blood (2007)
Higher Incidence of Venous Thromboembolism Is Associated with Initial Cycles of Chemotherapy in Lymphoma Patients: Creatinine and Hemoglobin as Key Risk Factors.
Authors: Xiao Zhou, Auris Huen, Shyam Teegala, Yuan Ji, Luis Fayad, F.B. Hagemeister, Saroj Vadhan-Raj
Journal: Blood (2007)
Gene expression signature comparison for solid tumor chemotherapy.
Authors: R. Lai, L. Xie, X. Wu, S. Zhang, Y. Du, S. Zhao, Y. Zheng, Y. Sun, H. LI, J. Chen, Z. LI, L. Liu, X. Tang, L. Wang, Y. Wang, M. Han, C. Liu, J. Wang, H. Li, S. Liu
Journal: Journal of Clinical Oncology (2011)

e21045 Background: It is unclear which one of signatures of ΔCT or RQ values from gene expression respond better in chemotherapy evaluation. Improved understanding is required for the comparison analysis in FFPE and blood samples. Methods: 370 solid tumor consecutive FFPE samples were tested by quantitative PCR. Among all the samples, 251 cases of solid tumor (108 lung cancer, 72 colon cancer, 44 gastric cancer, 27 breast cancer) with self-blood control were enrolled and thresholds were set at 15-35 cycles, which involved in predictive chemotherapy biomarkers ERCC1, BRCA1, TSand RRM1. For source dataset, a P value was computed for genes ΔCT and genes RQ value between the specimens of solid tumor, tumor subgroups and blood. A summary statistic to solid tumor, subgroup tumors and target gene signatures including comparison algoriths was analyzed with t test, chitest X2 and Pearson’s correlation coefficients. Results: Overall, RNA was isolated for 324 cases (87.6%) among 370 FFPE tissue successfully and over 1.8ng/ul per reaction. Total 251 solid cancers and its subgroups were examined for genes average ΔCT of tumor is 4.698±2.066 (ERCC1), 6.918±2.533 (BRCA1), 5.364±2.452 (RRM1), 6.355±2.459 (TS). Average RQ value of tumor is 38.157±83.086 (ERCC1), 65.030±245.821 (BRCA1), 42.841±166.933 (RRM1), 111.820±545.89 (TS). The data extracted from tumor ΔCT and RQ value (ΔCT/ΔΔCT(X+SD) were categorized and compared, statistics analysis indicated no significant differences of ΔCT value between the solid tumor, 4 subgroups tumors and 4 genes (P>0.05), but relative RQ value were observed in odds repetition and dispersed CV value with more groups difference (p<0.05), without correlation coefficients between ΔCTand RQ value in subgroups of cancer (P>0.05, pearson correlation), analyzed 4 gene synergism expression values based on cutoffs (ERCC1:4.3, TS:8.5, RRM1:8.0, BRCA1:6.5) in cancer subgroup, only half situation of coordinate up or down-regulation occured (p<0.05). Conclusions: ΔCT value- based signature make a stable and accurate resources data from solid tumor FFPE mRNA, which could contribute to the personality chemotherapy evaluation and analysis is more reliable than blood sample.
40. Transgene Product-Specific Treg Are Initially Induced in the Celiac Lymph Node During Tolerance Induction By Hepatic AAV Gene Transfer
Authors: George Q. Perrin, Irene Zolotukhin, Roland W. Herzog
Journal: Molecular Therapy (2015)

Previous work by us and several other laboratories has shown that liver-directed gene transfer can induce transgene product-specific immune tolerance. Induction of CD4+CD25+FoxP3+ regulatory T cells (Treg) is a critical component of the tolerance mechanism. Gaps in knowledge exist about the identity of the antigen-presenting cells (APCs) and the origin of peripherally induced Treg. To characterize the interaction of adeno-associated virus (AAV) antigen expression in the liver with immune cells, we used AAV8-EF1a vectors, which have a high tropism for murine liver, expressing either a secreted ovalbumin (AAV8-ova) or cytoplasmic ovalbumin (AAV8-Cytoova). In Treg-deficient mice transgenic for an ova-specific CD4+ T cell receptor (DO11.10-tg Rag-2-/- BALB/c), Treg were induced with either vector. For secreted ova, multiple organs (liver, spleen, lymph nodes [LN]) showed a similar level and time course of Treg induction, with greater than 1% of the CD4+ T cells being Treg starting at 4 weeks. Substantial T cell activation using the very early activation marker CD69 was also observed in these tissues starting at 3 weeks after AAV8-ova. However, Treg induction was observed in the celiac LN (one of the liver-draining LN) as early as 3 weeks after AAV8-Cyto-ova gene transfer, followed by induction of Treg in other tissues by 4 weeks. Interestingly, T cell activation was notably higher in liver and celiac LN after AAV8-Cyto-ova with over 70% activated CD4+ T cells after 4 weeks. In addition, T cell activation was observed earlier in all tissues after AAV8-Cyto-ova when compared to AAV8-ova. Literature data document a role for tolerogenic antigen presentation in the liver itself via sinusoidal endothelial cells and possibly hepatocytes. Our data suggest an important role of conventional mechanisms of adaptive immunity involving draining LNs that survey tissue antigens leading to early T cell activation and Treg induction of hepatic expressed non-systemic antigens. To start defining the critical APCs, BALBc mice were given AAV8-ova vector two weeks prior to adoptive transfer of CellTrace Violet-labeled CD4+ T cells from DO11.10 donor mice and their proliferation was measured using flow cytometry after 5 days. Half of these mice had their Kupffer cells and M1 macrophages inactivated with Gadolinium chloride for two days prior to DO11.10 adoptive transfer. DO11.10 cells proliferated in an antigen-specific manner, and proliferation was blocked by Gadolinium chloride, supporting a role for professional APCs in presentation of hepatic transgene product. Our data suggest and reinforce the importance of Kupffer cells as key APCs for hepatic antigens and further characterize the impact of the route of antigen expression on T cell activation and Treg induction.
Taking care for the patients from hospital discharge to home assistance: 5-year experience from a single Institution
Authors: D. Ferrari, E. Bossi, T. Carta, L. Cecco, G. Coraci, S. Marino, A. Ressa, D. Rocchetti, G. Zamparelli, M. Ceresa, R. Lovati, P. Foa
Journal: Annals of Oncology (2015)
296. Longitudinal Surveillance of Non Human Primate Recipients of Intrauterine Gene Transfer for Coagulation Factor Deficiencies
Authors: Citra Mattar, Arijit Biswas, Nuryanti Johana, Yvonne Y.W. Tan, Cecilia Rosales, Jenny McKintosh, Lay-Geok Tan, Irene Gil-Farina, Mahesh Choolani, Manfred Schmidt, Amit Nathwani, Jerry K.Y. Chan
Journal: Molecular Therapy (2016)

A concerted effort is being made to determine a safe way to treat the fetus with severe monogenic diseases. While the majority of affected pregnancies are currently terminated, intrauterine gene therapy (IUGT) may become a viable future option in well-selected cases. Likely candidates may be perinatally-lethal or chronic-relapsing conditions for which existing postnatal therapy is sub-optimal. We have now amassed robust evidence in a relevant non-human primate model addressing the efficacy and safety of IUGT targeting coagulopathies, with a focus on Factor IX and X deficiencies. Minimally-invasive administration of AAVhFIX or AAVhFX in early and late gestation results in expression of the transgenic protein at therapeutic levels, with minimal immune- and hepatotoxicity. Immune tolerance to gene therapy vectors administered during gestation has been demonstrated with postnatal administration. Further analyses demonstrate the random nature of vector integration without the propensity to cluster at oncogenic sites, while a low level of germline transmission was also demonstrated in post-pubertal subjects. The effects of androgen on cellular transducibility and transgene expression are also studied. Minimal maternal bystander effects have been observed. Though there are ethical concerns to be addressed, there may be enough convincing evidence to take the next step towards clinical fetal therapy.
Peer reviewer stole article and published it as his own
Authors: Owen Dyer
Journal: BMJ (2016)

A peer reviewer appointed by the Annals of Internal Medicine stole research submitted by a team from Tufts University, Boston, that was rejected by the Annals and published it six months later in a different journal under his own name.

The theft came to light when the original lead author, the endocrinologist Michael Dansinger of Tufts, later chanced upon his plagiarized work in EXCLI Journal while searching the internet and contacted the corresponding author, who apologized for the plagiarism and had the article retracted.1

The current issue of Annals of Internal Medicine carries both a letter entitled “Dear plagiarist,” by Dansinger,2 and a biting commentary from the …
Ovarian Adrenal Rest Tumors Undetected by Imaging Studies and Identified at Surgery in Three Females with Congenital Adrenal Hyperplasia Unresponsive to Increased Hormone Therapy Dosage
Authors: Hua-dong Chen, Li-e Huang, Zhi-hai Zhong, Zhe Su, Hong Jiang, Jing Zeng, Jun-cheng Liu
Journal: Endocrine Pathology (2016)