tbuckley/cabot-search huggingface dataset:
PWE-066 Classification by grade in gastroenteropancreatic neuroendocrine tumours
Authors: M S Khan, C Toumpanakis, A Jamieson, D Chilkunda, T Luong, M Caplin
Journal: Gut (2010)

<h3>Introduction</h3> Gastroenteropancreatic neuroendocrine tumours (NETs) are uncommon tumours with a reported incidence of 2.5–5 per 100 000 population. The recent classification system of NETs proposed by the European Neuroendocrine Tumour Society (ENETS) uses both Ki-67 labelling index and mitotic index to assign grade (low, intermediate, high). It has been adopted into routine practice but there are limited data on the relationship between these indices and their effect on classification. <h3>Methods</h3> 160 NET patients, 81 midgut and 79 pancreatic had their cases reviewed. Ki-67 proliferation index, identified by staining tumour sections with MIB-1 antibody, was determined by assessing the percentage of positively staining tumour cell nuclei in 2000 tumour cells in areas with highest degree of nuclear labelling where possible. Mitotic counts (per 10 hpf) were evaluated in at least 40 fields in areas of highest mitotic activity. Grades (1–3) according to the new TNM classification were assigned using both indices. Correlation (Spearman r) and agreement (weighted κ) were calculated using Graphpad software. <h3>Results</h3> 63 out of 81 midgut and 61 out of 79 pancreatic NETs had complete data. A highly significant correlation was observed between Ki-67 and mitotic count in both midgut (r=0.51, p&lt;0.0001) and pancreatic (r=0.53, p&lt;0.0001) NETs. When assigning tumour grade, there was only agreement in 67% of midgut and 44% of pancreatic NETs. Weighted κ for midgut (κ=0.35) and pancreatic (κ=0.34) NETs only showed a "fair" measure of agreement between the two indices when assigning grade. <h3>Conclusion</h3> This study suggests there may be a discrepancy when assigning grade of tumour in gastroenteropancreatic NETs based on Ki67 index and mitotic index. Although, as expected there is a high correlation between the two indices, when looking at agreement of assignment of grade, there is a discrepancy. This may have implications when proposing management strategies for patients.
DDEL-13TARGETED INTERLEUKIN-13-LIPOSOMES-MAGNIVEST-DOXORUBICIN FOR DETECTION AND TREATMENT OF GLIOMA IN EARLY STAGE
Authors: Xiaoli Liu
Journal: Neuro-Oncology (2015)

Malignant glioma in central nervous system (CNS) is a challenge to detect/treat due to the blood-brain barrier (BBB) that prohibits most chemicals like anti-cancer agents to penetrate. Furthermore, to detect brain cancer, magnetic resonance image (MRI) contrast agent such as Magnevist (Gd/DTPA) is limited to the cases where the BBB is significantly compromised by the cancer because Gd-DTPA itself is not able to cross the BBB. As a result, the cancer boundary presented by Gd-DTPA-enhanced MRI reflects only the extent where BBB is compromised instead of all the cancer-infiltrated regions. For the malignant glioma in early stage when it is smaller than 2 mm, which is even none detectable by Gd-DTPA-enhanced MRI because the BBB is intact when tumor is less than 2 mm. It is critical to develop a delivery system that carries targeted MRI contrast agent with drug alongside, which could penetrate brain tissue, detect and treat glioma in early stage concomitantly. Previous work demonstrated: 1) IL-13Rα2 was over-expressed in glioma, 2) IL-13-liposomes-doxrubinsine inhibited an intracranial glioma growth and 3) IL-13-liposomes-Gd/DTPA as a MRI contrast agent enhanced and detected infiltrating glioma. Based on these findings we hypothesized that IL-13-liposome encapsulating Gd-DTPA and doxorubicin (Dox) will be a theranostic agent for detection and treatment of gliomas. To test our hypothesis, glioma U251 and glioma stem cells T3691 and athymic nude mice with intracranial glioma were selected as our in vitro and in vivo model. IL-13-liposomes-Gd/DTPA-Dox was developed and characterized. Its application in vitro and in vivo has been evaluated through targeted MRI guided drug delivery. Our results provided the evidence that corresponded with our hypothesis. We predicted that the development of IL-13-liposomes-Gd/Dox will not only lead a translation into clinical neuro-oncology, but also into treatment of other tumors like colon cancer metastasis and adrenocortical carcinoma, which overexpressed IL-13Rα2.
Opicapone
Authors: Allison Boyle, Jessika Suescun, Mya C. Schiess
Journal: JAMA Neurology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Elevated FoxM1 Expression Promotes Cell Cycle Progression by Induction of KIS Expression and Contributes to the Development of Leukemia Cells.
Authors: Okinaka Keiji, Satoki Nakamura, Isao Hirano, Takaaki Ono, Shinya Fujisawa, Kazuyuki Shigeno, Kaori Shinjo, Kazunori Ohnishi
Journal: Blood (2007)
Use of Marijuana for Medical Purposes Among Adults in the United States
Authors: Wilson M. Compton, Beth Han, Arthur Hughes, Christopher M. Jones, Carlos Blanco
Journal: JAMA (2016)

Qiana L. Brown, PhD, MPH, LCSW; Aaron L. Sarvet, MPH; Dvora Shmulewitz, PhD; Silvia S. Martins, MD, PhD; Melanie M. Wall, PhD; Deborah S. Hasin, PhD
Phase Ib Study of Safety and Pharmacokinetics of the PI3K Inhibitor SAR245408 with the HER3-Neutralizing Human Antibody SAR256212 in Patients with Solid Tumors
Authors: Vandana G. Abramson, Jeffrey G. Supko, Tarah Ballinger, James M. Cleary, John F. Hilton, Sara M. Tolaney, Nicole G. Chau, Daniel C. Cho, Joseph Pearlberg, Joanne Lager, Geoffrey I. Shapiro, Carlos L. Arteaga
Journal: Clinical Cancer Research (2016)

Purpose: This phase Ib study was designed to determine the MTD, safety, preliminary efficacy, and pharmacokinetics of the HER3 (ErbB3) mAb SAR256212 in combination with the oral PI3K inhibitor SAR245408 for patients with metastatic or locally advanced solid tumors.Experimental Design: Patients received the combination of intravenous SAR256212 and oral SAR245408 in a 3 + 3 dose-escalation design until occurrence of disease progression or dose-limiting toxicity. Objective response rate, pharmacokinetics, pharmacodynamics, and PIK3CA mutational status were also evaluated.Results: Twenty-seven patients were enrolled. Thirteen of 20 patients tested (65%) had a hotspot-activating mutation in PIK3CA in their tumor. The MTD was determined to be SAR256212 at 40 mg/kg loading dose followed by 20 mg/kg weekly, plus SAR245408 200 mg daily. Dose-limiting toxicities included rash and hypotension; the most frequent treatment-related side effect was diarrhea (66.7%). Twenty-three patients were evaluable for efficacy, of which 12 patients (52.2%) had stable disease and 11 patients (47.8%) had progression of disease as best response. In this study with a limited sample size, there was no difference in best response between patients with PI3KCA-mutant versus PIK3CA wild-type tumors (P = 0.07). The concurrent administration of SAR245408 and SAR256212 did not appear to have an effect on the pharmacokinetics of either drug.Conclusions: The combination of SAR256212 and SAR245408 resulted in stable disease as the best response. Side effects seen in combination were similar to the profiles of each individual drug. Patient outcome was the same regardless of tumor PI3KCA mutation status. Clin Cancer Res; 23(14); 3520-8. ©2016 AACR.
315. Optimization of the Capsid of Recombinant Adeno-Associated Virus 6 (AAV6) Vectors for Liver-, and Muscle-Directed Gene Therapy
Authors: Diego Nolasco, Kim Van Vliet, David Markusic, Chen Ling, Lin-Ya Huang, Mavis Agbandje-McKenna, Arun Srivastava, George Aslanidi
Journal: Molecular Therapy (2015)

Recombinant adeno-associated virus (AAV) vectors are currently in use in a number of Phase I/II clinical trials. However, large vector doses are needed to achieve therapeutic effects. The ubiquitinproteasome pathway plays a critical role in the intracellular trafficking of AAV vectors, and phosphorylation of certain surface-exposed amino acid residues on the capsid provides the primary signal for ubiquitination. We have previously reported that substitution of critical amino acid residues dramatically increases the transduction efficiency of vectors based on AAV serotypes 2, 3, 5, and 8 by preventing capsid phosphorylation and subsequent proteasomal degradation. In the present studies, we document that the combination of mutations of specific tyrosine (Y), serine (S), threonine (T) and lysine (K) residues on the capsid of AAV6 vectors also significantly increases the transduction efficiency compared with the wild-type (WT) AAV6 vectors. AAV6 capsid contains 7 tyrosine, 17 serine, 19 threonine and 11 lysine residues, which are surface-exposed. Initially, 17 single-mutants were generated based on the AAV6 crystal structure and overlap of amino acid positions with previously studied serotypes: Y445F, Y705F, Y731F, S455V, S472V, S499V, S551V, S663V, S669V, T251V, T492V, T665V, T722V, K531E, K567E, K666E, K707E. Next, the best performing Y-, S-, T-, and K- mutations were combined onto a single AAV6 capsid to generate 9 double-mutants: Y705+731F, Y731F+T492V, T492V+S663V, T492V+S551V, T665V+S551V, S663V+S551V, T492V+K531E, S663V+K531E, T492V+K666E; 7 triple-mutants: Y445+705+731F, Y705+731F+S663V, Y705+731F+S551V, Y705+731F+T492V, Y705+731F+K531E, Y705+731F+K666E, T492V+S663V+K531E; and two quadruple-mutants: Y705+731F+T492V+S663V, and Y705+731F+T492V+K531E. We identified several AAV6-mutant vectors, such as S663+551V, Y705+731F+T492V and Y705+731F+K531E, which were particularly efficient. These vectors increased the transduction efficiency by approximately 5- to 8-fold in a murine hepatocyte cell line, H2.35, and approximately 3- to 5-fold in a murine myoblast cell line, C2C12, over the WT AAV6 vector in vitro. Similar results were obtained in murine hepatocytes and muscle in vivo after tail-vein or intra-muscular injections of these vectors, followed by whole-body bioluminescence imaging of C57BL/6 mice. These residues are localized towards the base of the protrusions surrounding the icosahedral 3-fold axes of the capsid (T492S, S551V and K531E), in the depression surrounding the 2-fold axes (Y705F and Y731Y), or the HI loop (Y663S). This study thus identifies these capsid surface regions as being critical for the trafficking and transduction properties of the AAV6 vectors. In summary, our studies have led to the generation of novel capsid-optimized AAV6 vectors for their potential use in liver-directed, and muscle-directed gene therapy in humans.
471. In Vivo Potency Assay for AAV-Based Gene Therapy Vectors
Authors: Bishnu P. De, Alvin Chen, Jonathan B. Rosenberg, Maria Chiuchiolo, Benjamin Van de Graaf, Odelya E. Pagovich, Dolan Sondhi, Carlo Russo, Stephen M. Kaminsky, Ronald G. Crystal
Journal: Molecular Therapy (2016)

One hurdle in the translation of adeno-associated virus (AAV) vectors for the treatment of human disease is the challenge in demonstrating drug function in a potency assay, a requirement in the clinical translation to product. In vitro measurements of AAV potency suffer from poor efficiency of infectivity and are insensitive measures of potency. To address this issue, we have developed a robust in vivo assay for the measurement of vector potency. Using as the model vector the AAVrh.10 serotype coding for human frataxin (FXN, a mitochondrial protein essential for cellular function and that is deficient in Friedreich's ataxia), and based on the knowledge that intravenous administration of all AAV vectors primarily transduce the liver, we have developed a reproducible in vivo potency assay that can be used to set quality control standards for vector production. The assay is based on administration of the AAV vector (2.5 × 1010 genome copies) administered intravenously to 6 to 8 wk old Balb/c male mice with the liver harvested 2 wk later following PBS perfusion. Liver homogenates are processed to assess vector genome copies, transgene mRNA, and expressed protein. In order to establish acceptance criteria for assays of vector genome and mRNA levels, separate specifications were set for DNA sample load using the mouse housekeeping gene Tfrc, and RNA sample load using mouse 18S RNA, both based on data from quantitative PCR analysis of mouse livers (n=35) assayed in duplicate. Specifications were set as the median ± 2 standard deviations based on these assay results; for the potency assay results to be accepted, each of these specifications must be met by the test sample. For the AAVrh. 10 vector expressing FXN(AAVrh.10hFXN), liver vector genome levels (a measure of reproducibility of delivery) were 8.2 × 104 ± 2.2 × 104 genome copies/µg genomic DNA (n=10 mice, mean ± SD), liver human FXN mRNA levels (a measure of vector potency at the transcription level) were 2.2 × 103 ± 0.7 × 103 copies/µg total RNA (n=10 mice, mean ± SD) and liver human FXN protein levels (ELISA; a measure of vector potency at the protein level) were 54.8 ± 17.52 ng/mg protein (n=10 mice, mean ± SD). From this data, we established the following quality control specifications for AAVrh.10hFXN vectors: vector genome range 6 × 104 - 1 × 105 (copies/µg DNA), hFXN mRNA level range 1.6 × 103 - 2.9 × 103 (copies/µg RNA) and the hFXN protein levels 37 - 72 (ng/mg protein). This approach is adaptable to any AAV vector, providing an in vivo quality control for vector function.
Inhibition of Histone Deacetylases 1 and 6 Enhances Ara-C-Induced Apoptosis In Pediatric Acute Myeloid Leukemia Cells
Authors: Xuelian Xu, Chengzhi Xie, Holly Edwards, Hui Zhou, Steven Buck, Larry Matherly, Jeffrey Taub, Yubin Ge
Journal: Blood (2010)
High-dose methotrexate, temozolomide, and intrathecal liposomal cytarabine (HD-MTX-TMZ-IT LC), without radiotherapy for central nervous system (CNS) lymphoma.
Authors: L. Falchi, M. Gunnellini, L. Ferranti, I. Angeletti, A. M. Liberati
Journal: Journal of Clinical Oncology (2011)

e18555 Background: CNS lymphoma is an aggressive tumor. HD-MTX-TMZ appears to be an effective and relatively safe regimen. We report our preliminary experience with HD-MTX-TMZ plus concomitant IT LC used upfront or as salvage in 4 CNS lymphoma pts. Methods: Induction: MTX 3g/ms IV d 1, 10, 20, TMZ 100 mg/ms d 1-5; maintenance (≥SD pts): MTX 3g/ms d 1, TMZ 100 mg/ms d 1-5, every month up to 5 cycles as long as response was documented. Fifty mg IT LC was given concomitantly, at least 14 days apart and at least 7 days from HD-MTX, up to 6 doses. Results: Pt 1, 56 y, male, testicular diffuse large B cell lymphoma (DLBCL), stage IVA, cerebellar relapse after CR, Karnofsky performance status (KPS) 50%. Rituximab-TMZ + IT MTX were initiated but soon discontinued due to CMV pneumonia. After recovery, HD-MTX-TMZ was started and precautionary stem cell harvest performed. Six cycles and 4 IT LC injections were given with no G3-4 toxicities. He obtained CRu. Pt 2, 76 y, male, primary CNS peripheral T-cell lymphoma, multicentric, progressed after steroids + TMZ, KPS 60%. He received 6 HD-MTX-TMZ cycles with 4 IT LC injections. G2 renal insufficiency and G3 steroid-induced diabetes mellitus were reported. He obtained CRu, but 7 months later relapsed in involved sites, received 2 further cycles of TMZ and is now in SD. Pt 3, 68 y, female, PCNSL, DLBCL, left cerebellar hemisphere, KPS 50%. HD-MTX-TMZ and concomitant IT LC were initiated. Maintenance was completed. G3 atrial fibrillation was reported. After the 5th IT LC injection she developed conus-cauda equina syndrome and IT therapy was withdrawn. She obtained very good PR. Pt 4, 71 y, female, DLBCL stage IIIE (i.e. facial localization), with multicentric bilateral subcortical relapse. Four HD-MTX-TMZ cycles and 5 IT LC injections have been administered so far with no neurotoxicity. CR was attained after induction. CR/CRu duration was 18+, 7, 10+, and 5+ months for pts 1, 2, 3, and 4, respectively at the time of this abstract. Conclusions: HD-MTX-TMZ-IT LC therapy appeared feasible and effective. Conus-Cauda equina syndrome is a known complication of IT chemotherapy via lumbar puncture. Follow-up is too short to comment on delayed neurotoxicity.
695. An AAV8 Mutant with Better Transduction in Murine Muscle and Nasal Airway Than AAV8
Authors: Qiang Wang, Peter Bell, Hongwei Yu, Christine Draper, Deirdre McMenamin, Maria P. Limberis, James M. Wilson
Journal: Molecular Therapy (2016)

Adeno-associated virus (AAV)-based gene therapy is showing increasing promise, stimulated by encouraging results from clinical trials in recent years. To advance the platform, we have been exploring AAV capsid manipulation. By combining three mutations at hyper-variable regions (HVRs) I, IV, and VIII of the AAV8 capsid - mutations isolated from saturation mutagenesis followed by several rounds of in vivo selection - we created an AAV8 mutant, referred to as AAV8.Triple. In vitro, the AAV8.Triple mutant showed resistance to various antisera of monkey and human, as well as human IVIG (titers that are at levels 2 to 4 fold that of AAV8, with respect to human IVIG). All three mutations contributed to the observed resistance. In mice, the liver transduction efficiency of AAV8.Triple was reduced compared with AAV8, however its muscle transduction was higher than that of AAV8 by approximately 10 fold. In addition, AAV8.Triple demonstrated a higher heparin affinity than AAV8. Interestingly, reducing the positive charges of the HVR.IV mutation decreased the vector's heparin affinity while liver transduction was partially restored. Similar to the trend observed in muscle, intranasal administration of AAV8.Triple resulted in a transduction efficiency 2 to 3 fold greater than that of AAV8, which was further improved to levels approximately 10 fold greater than AAV8 by swapping the VP1 unique region of AAV8.Triple with that of another AAV serotype. Overall, our findings indicate that AAV capsid manipulation was able to generate an AAV8 mutant with improved transduction in both murine muscle and nasal airway compared with wild-type AAV8. These findings may be relevant to disease models where high-efficiency intramuscular or intranasal gene delivery and resistance to pre-existing neutralizing antibodies are desired.
174. Liver Fibrosis in Aged OTC-KO Heterozygotes and Successful Correction by AAV8-Mediated Gene Therapy
Authors: Lili Wang, Peter Bell, Hiroki Morizono, Zhenning He, Elena Pumbo, John White, Mark L. Batshaw, James M. Wilson
Journal: Molecular Therapy (2015)

Ornithine transcarbamylase deficiency (OTCD) is an X-linked disorder of the urea cycle. Affected males are at risk of life threatening elevation of ammonia that can lead to irreversible cognitive impairment, coma and death. Female carriers show variable clinical manifestations depending on the level of X chromosome inactivation skewing. Histological analyses on liver samples from patients with urea cycle disorders found diffuse microvesicular steatosis, nuclear glycogen, and variable portal-to-portal bridging fibrosis. The OTC knockout (KO) model generated in our laboratory through the deletion of exons 2-3 closely mimics the severe neonatal onset form of OTCD in humans. Neonatal male OTC KO pups have elevated plasma ammonia levels due to the absence of OTC expression in the liver, and they inevitably die within 24 hours after birth. Heterozygous females breed normally, have normal plasma ammonia levels, reduced liver OTC enzyme activity, elevated urine orotic acid levels, and in some cases lower body weight compared to wild type (WT) littermates. Sirius red staining on liver samples from heterozygous mice of different ages (6, 12, and 18 months old) showed liver fibrosis in aged (18-month old) OTC-KO heterozygous female mice, similar to a liver sample from a 11-year-old OTCD patient. We then tested if gene therapy could prevent the liver fibrosis. Two-month old OTC-KO heterozygous received a single tail vein injection of a self-complementary AAV8 vector encoding a codon-optimized human OTC gene (hOTCco) at 1×10^10, 3×10^10, and 1×10^11 vector genome copies per mouse. One week following vector treatment, mice in all three vector dose groups had normal urine orotic acid levels which were maintained throughout the study (16 months). Liver samples were harvested from 18 month old treated mice for pathology analysis and compared to age-matched untreated heterozygous mice and WT littermates. All treated mice showed normal liver histology similar to WT, in contrast to the untreated heterozygous animals which had fibrosis throughout the liver. In conclusion, a single injection of AAV8sc-hOTCco vector can prevent liver fibrosis in OTC-KO heterozygous and has great potential for correction of liver fibrosis in OTCD patients.
Efficacy and safety of retaspimycin hydrochloride (IPI-504) in combination with trastuzumab in patients (pts) with pretreated, locally advanced or metastatic HER2-positive breast cancer.
Authors: S. Modi, C. Saura, C. A. Henderson, N. U. Lin, R. L. Mahtani, J. Goddard, E. Rodenas, J. O'Shaughnessy, J. Baselga
Journal: Journal of Clinical Oncology (2011)

590 Background: Retaspimycin hydrochloride (IPI-504) is a potent, intravenously-administered heat shock protein 90 (Hsp90) chaperone inhibitor. Hsp90 helps maintain the stability of key oncoproteins, including HER2. Preclinical studies have demonstrated the activity of IPI-504 plus trastuzumab in xenograft mouse models using trastuzumab-sensitive and trastuzumab-resistant HER2-positive cell lines. Methods: In our single-arm, phase 2 study, the overall response rate and tolerability of IPI-504 plus trastuzumab in pts with previously treated, locally advanced or metastatic HER2-positive breast cancer were evaluated. Prior treatment with trastuzumab was required and no limit of previous lines was specified. The trial used a Simon two-stage design; if the DLT rate was ≤25% and at least 2 responses were observed, the trial would be expanded. Results: 26 pts were initially treated with 300 mg/m2 IPI-504 once weekly in combination with 6 mg/kg trastuzumab once every 3 weeks. The median age was 52.5 years (range 33-72) and the median number of prior regimens received was 6 (range 2-20). Pts received a median of 3 cycles (range 1-12) of IPI-504. No DLTs were reported. The majority of AEs were grade 1 or 2, and the most common treatment-related adverse events were fatigue (46%), nausea (31%), and diarrhea (23%). Related serious adverse events were reported in 2 pts; one pt had Grade 1 diarrhea and Grade 3 hypokalemia, and the other pt had Grade 3 vomiting. Only 1 (4%) Grade 3 transaminase elevation was noted on trial, in a pt with metastatic disease to the liver. Among the 20 pts evaluable for efficacy, 1 partial response was observed (based on central, independent radiology review). Stable disease was observed in 14 pts (70%), including 1 pt (4%) with stable disease for more than 6 months. Conclusions: IPI-504 300 mg/m² IV weekly in combination with trastuzumab was well tolerated, without significant hepatic toxicity. Treatment resulted in modest clinical activity in heavily pretreated pts previously exposed to trastuzumab, but did not meet the prespecified efficacy criteria for trial expansion.