tbuckley/cabot-search huggingface dataset:
372. Prevalence of Anti-AAV8 Neutralizing Antibodies and ARSB Cross-Reactive Immunologic Material in MPS VI Patients Candidates for a Gene Therapy Trial
Authors: Rita Ferla, Pamela Claudiani, Marco Savarese, Karen Kozarsky, Rossella Parini, Maurizio Scarpa, Maria Alice Donati, Giovanni Sorge, John J. Hopwood, Giancarlo Parenti, Simona Fecarotta, Vincenzo Nigro, Hatice Serap Sivri, Ans Van Der Ploeg, Generoso Andria, Nicola Brunetti-Pierri, Alberto Auricchio
Journal: Molecular Therapy (2015)

Recombinant vectors based on adeno-associated virus serotype 8 (AAV8) have been successfully used in the clinic and hold great promise for liver-directed gene therapy. Pre-existing immunity against AAV8 or the development of antibodies against the therapeutic transgene product might negatively affect the outcomes of gene therapy. In the prospect of an AAV8-mediated, liver-directed gene therapy clinical trial for Mucopolysaccharidosis VI (MPS VI), a lysosomal storage disorder due to arylsulfatase B (ARSB) deficiency, we investigated in a multiethnic cohort of MPS VI patients the prevalence of neutralizing antibodies (Nab) to AAV8 and the presence of ARSB cross-reactive immunologic material (CRIM), which will either affect the efficacy of gene transfer or the duration of phenotypic correction. Thirty-six MPS VI subjects included in the study harbored 45 (62.5%) missense, 13 (18%) nonsense, 9 (12.5%) frameshift (2 insertions and 7 deletions), and 5 (7%) splicing ARSB mutations. To the best of our knowledge, four mutations had not been previously described. These include: one missense (c.1178 A>G p.H393R) and three frameshift mutations [883-884duplTT (p.F295FfsX42), c.1036delG (p.E346SfsX11), c.1475delC (pP492LfsX80)] predicted to result in truncated proteins. The detection of ARSB protein in twenty-four patients out of 34 (71%) was predicted by the type of mutations. Pre-existing Nab to AAV8 were undetectable in 19/33 (58%) analyzed patients. Twelve out of 31 patients (39%) tested were both negative for Nab to AAV8 and CRIM-positive. In conclusion, this study allows estimating the number of MPS VI patients eligible for a gene therapy trial by intravenous injections of AAV8.
High Mitochondrial Membrane Potential Identifies Patients with Myeloproliferative Neoplasms with a More Aggressive Natural History
Authors: Jeffrey R Gardner, Omar Abdel-Wahab, Mark Frattini, Joseph G Jurcic, Kristina Knapp, Todd L. Rosenblat, Gerald A. Soff, Ross Levine, Mark Heaney
Journal: Blood (2010)
Abstract 1147: Differential expression of enzymes associated with glycine metabolism in ovarian cancer stem like cell
Authors: So-Jin Shin, Hye-Won Chung, Hyun-Gyo Lee, Eun Som Choi, Chi-Heum Cho
Journal: Cancer Research (2015)

Abstract OBJECTIVES: The recent advances in understanding the relation between cancer and metabolism have highlighted the relevance of serine/glycine biosynthesis and one-carbon metabolism. The aim of this study was to evaluate the expression of enzymes associated with serine/glycine metabolism in ovarian cancer stem like cells (CSCs) and discuss their potential clinical implications. METHODS: We established primary ovarian cancer cell cultures from dissected fresh tumor tissue. To isolate CD117(+) and CD44(+) CSCs from primary ovarian cancer cultures, we have modified and optimized the Magnetic-Activated Cell Sorting (MACS) procedure from Miltenyi resulting in high sorting purity. In the present study, we used Western blotting and immunohistochemistry to examine three serine-/glycine-metabolism-associated proteins (PHGDH, SHMT, and GLDC) in CSCs and ovarian cancer cases using tissue microarray (TMA). The expression of stemness gene (Nanog, Oct3/4, Sox2 and ABCG2) mRNA was determined by RT-PCR and protein expression was detected by Western blot analysis. RESULTS: GLDC, PHGDH and SHMT, associated with serine/ glycine metabolism, showed lower expression in the CSCs. TMA showed that the different expressions of GLDC, PHGDH and SHMT in platinum-sensitive and platinum-resistant ovarian cancer cases (p&amp;lt;0.004). GLDC mRNA was most frequently expressed in primary ovarian cancer culture cells. By Cox multivariate analysis, tumor SHMT1 negativity (HR: 2.132, 95% CI: 1.229-3.664, p = 0.007) was associated with short overall survival. CONCLUSIONS: Based on our findings, we concluded that the expression of serine-metabolism-associated proteins was related with resistance of ovarian cancer cells and patient's survival. Citation Format: So-Jin Shin, Hye-Won Chung, Hyun-Gyo Lee, Eun Som Choi, Chi-Heum Cho. Differential expression of enzymes associated with glycine metabolism in ovarian cancer stem like cell. [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 1147. doi:10.1158/1538-7445.AM2015-1147
Risk Of Solid Subsequent Malignant Neoplasms (SMNs) With Extended Follow-Up Of Childhood Hodgkin Lymphoma (HL) Survivors Is Comparable To The Risk In Known High-Risk Groups Within The General Population: Report From The Late Effects Study Group (LESG)
Authors: Smita Bhatia, Cor van den Bos, Can-Lan Sun, Jillian Birch, Lisa Diller, Kimberley Dilley, Jill Ginsberg, Laura Therese Martin, Rajaram Nagarajan, Joseph P. Neglia, Monica Terenziani, David Tishler, Anna T Meadows, Leslie L. Robison, Odile Oberlin, Jennifer P. Berano Teh
Journal: Blood (2013)
131. Chromatin-Dependent Loci Accessibility Affects CRISPR-Cas9 Targeting Efficiency
Authors: Ciaran M. Lee, Timothy H. Davis, Harshavardhan Deshmukh, Gang Bao
Journal: Molecular Therapy (2016)

The CRISPR-Cas9 system from Streptococcus pyogenes has been successfully modified to target specific genomic loci in a wide range of organisms, making it a powerful tool for biotechnology and personalized medicine. However, there are several challenges to be addressed before successful application of CRISPR-Cas9 systems for clinical use. Specifically, significant concerns have been raised over off-target effects that may lead to aberrant cellular function, and the efficiency of gRNAs varies widely between target loci. The factors influencing the targeting efficiency of a particular gRNA design are not fully understood. Although several groups have developed algorithms that attempt to identify highly active gRNAs based on the sequence composition of the gRNA, the predicted scores for gRNA designs do not correlate with observed activity in cells, suggesting that factors other than gRNA sequence are at play. Here, we demonstrate that the underlying genomic context, especially the chromatin state of the target locus influences the cleavage efficiency of CRIPSR-Cas9 in a sequence independent manner. Furthermore, we demonstrate that knowledge of the chromatin state may inform the selection of highly active gRNAs, and reveal the specific chromatin marks associated with CRISPR-Cas9 target accessibility. Finally, we postulate that in silico tools that consider both gRNA sequence and chromatin state of the target locus will have greater predictive power and facilitate the selection of highly active gRNAs for therapeutic applications.
Discrepancy of Interim PET/CT Responses Based on Visual and Quantitative SUV-Based Assessments in the Patients with Diffuse Large B-Cell Lymphoma and Extranodal Involvements
Authors: Deok-Hwan Yang, Joon Ho Moon, Seung-Shin Lee, Jung-Joon Min, Shin-Young Jeong, Yoo-Jin Lee, Sung-Woo Park, Yee Soo Chae, Young Rok Do, Hyeoung-Joon Kim, Je-Jung Lee
Journal: Blood (2015)
Abstract 2951: Evaluation of methylation biomarkers for colon cancer using normal tissues
Authors: Carmen Sapienza, May M. Truongcao, Jayashri Ghosh
Journal: Cancer Research (2015)

Abstract We have identified DNA methylation biomarkers that discriminate patients with colon cancer from patients without colon cancer using array-based profiling methods. Most DNA-based biomarkers for colon cancer rely on the detection of cancer cell-specific or cancer cell-prevalent mutations or DNA methylation changes in small numbers of tumor cells or small amounts of tumor cell-free DNA that are present in stool or lavage samples. Our hypothesis is that an individual's cancer-predisposing exposure history is recorded in normal tissues as “field cancerization”-related DNA methylation changes and that these changes will be present in normal colon, as well as other normal tissues, including peripheral blood. Consistent with the notion of changes based on “individual exposure history”, the bulk of the candidate biomarkers identified are genes involved in carbohydrate and lipid metabolism, as expected from epidemiological associations between colon cancer and “western” diets. We have now validated that our candidate methylation biomarkers are effective at discriminating cancer patients from controls using normal colon tissue from an independent population, and irrespective of whether the patients have left-side or right-side cancers. We have also found that a significant fraction of our candidate biomarkers also discriminate cancer patients from controls, using peripheral blood DNA analyzed by bisulfite pyrosequencing. Citation Format: Carmen Sapienza, May M. Truongcao, Jayashri Ghosh. Evaluation of methylation biomarkers for colon cancer using normal tissues. [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 2951. doi:10.1158/1538-7445.AM2015-2951
Randomized phase III study of docetaxel with or without risedronate in patients with bone metastases from castration-resistant prostate cancer (CRPC): The Netherlands Prostate Study (NePro).
Authors: H. J. Meulenbeld, E. D. van Werkhoven, J. L. L. M. Coenen, G. Creemers, O. J. L. Loosveld, P. C. De Jong, A. J. Ten Tije, S. D. Fossa, M. Polee, W. R. Gerritsen, O. Dalesio, R. De Wit
Journal: Journal of Clinical Oncology (2011)

4518 Background: Bisphosphonates, including risedronate (R), an oral third generation pyridinyl bisphosphonate, exert antitumor activity in vitro and in vivo. Animal models have shown synergistic activity of bisphosphonates and taxanes. This study aimed to investigate the potential benefit of adding R to docetaxel based chemotherapy in patients with metastatic CRPC. Methods: CRPC patients with bone metastasis, and no prior bisphosphonate use were randomly assigned to receive docetaxel (D) 75 mg/m² every 3 weeks and prednisone 5 mg bid as first line chemotherapy, with or without R 30 mg oral od. Upon progression patients in the D alone arm were offered R. The study was designed as a randomized open label phase II, with extension into a phase III study. The primary endpoint was time to progression (TTP). A composite endpoint of objective progression by RECIST criteria, PSA progression, or pain progression, whichever occurred first, was applied. Secondary endpoints were 50% PSA response rate, pain response, objective response (all confirmed responses), duration of PSA response, overall survival (OS) and toxicity profiles. The study had 80% power to detect an improvement of 30% (from 6 to 7.8 months [mos]) in median TTP in the DR group (2-sided α= 0.05). Results: From Jan 2004 to April 2010, 592 men (301 D vs 291 DR) were randomized. Baseline demographics were similar in both groups. Median follow-up was 37 mos. Median number of cycles was 9 in both groups. TTP was 7.8 vs 6.9 mos (p=0.6) for D and DR, respectively. PSA response rates (64% D vs 63% DR) and pain response (28% D vs 31% DR) were not significantly different between both arms. OS was 18.0 mos for D vs 19.7 mos for DR (p=0.6). Grade 3 /4 toxicity rates were similar. Clinically relevant hypocalcaemia, potentially associated with R, was observed in 1 patient in each arm. No cases of osteonecrosis of the jaw were observed. Conclusions: We found no benefit of the addition of the third generation bisphosphonate risedronate, in the setting of effective first line docetaxel based chemotherapy, as indicated by the lack of improvement in TTP, PSA and pain response and overall survival.
A comparative randomized, placebo-controlled, double-blind phase II study with and without enzastaurin in combination with paclitaxel and carboplatin as first-line treatment for advanced ovarian cancer.
Authors: I. B. Vergote, P. Harter, N. Kovalenko, T. Bauknecht, K. Mansouri, Y. Zhang, J. Sehouli
Journal: Journal of Clinical Oncology (2011)

5010 Background: Enzastaurin (E) is a potent, selective serine-threonine kinase inhibitor which suppresses tumor cell proliferation by targeting PKCβ and PI3/AKT pathways, inducing apoptosis and inhibiting angiogenesis. E may be effective as an add-on to other chemotherapy regimens. Methods: The primary aim of this multicenter, phase II, randomized, placebo-controlled double blind study was to compare progression-free survival (PFS) of first-line therapy of carboplatin (C) plus paclitaxel (P) with/without E (CPE/CP) followed by maintenance therapy, in patients with primary advanced ovarian cancer. Patients (FIGO Stage IIB-IV) were randomized (stratification factors: optimal (=0) vs. suboptimal (>0cm) tumor debulking, FIGO stage IIB-IIIB vs. IIIC-IV, and center) to receive CPE or CP (C [AUC 5 mg/mL/min], P [175 mg/m2, 3 hours infusion], E [1125 mg one day prior to CP treatment followed by 500 mg daily oral doses]) on Day 1 every 3 weeks for 6 cycles of 21 days each, followed by 3 yrs maintenance therapy with E or placebo. Results: A total of 142 patients (CPE 69/CP 73) were randomized. Distribution of patients’ strata (CPE/CP) were: optimally debulked (68%/62%), FIGO stage IIIC-IV (83%/80%). At the time of unblinding and analysis, 25 CPE and 26 CP patients were still receiving treatment; none had completed full maintenance period. Number of PFS events in CPE/CP were 31/38 (45%/52%). Median PFS [95% confidence interval (CI)] was not significantly different (p=0.37) between CPE and CP groups (18.9 [13.8, -] and 15.2 [11.0, 18.9] months; hazard ratio [95%CI]=0.80 [0.50, 1.29]). Patients with CTC grade ≥ 3toxicities possibly related to study drug were 45% for CPE and 47% for CP. Major hematologic Grade 3/4 event was neutropenia: CPE 16%/42%, CP 25%/32%. Eight patients in CPE and 7 patients in CP discontinued treatment due to adverse events (AEs). Treatment emergent AEs included hypertension (0/2 CPE/CP), and Grade 4, serious intestine perforation (1/0 CPE/CP). Conclusions: Initial review of results showed a non-significant, 3.7 month longer median PFS in the CPE arm. The combination of E with C and P was well tolerated.
Anti‐TNF‐α for necrotizing sarcoid granulomatosis of the liver
Authors: Marcial Sebode, Sören Weidemann, Malte Wehmeyer, Ansgar W. Lohse, Christoph Schramm
Journal: Hepatology (2016)

We present a case of hepatosplenic necrotizing sarcoid granulomatosis, a variant form of “classical” sarcoidosis, that became clinically apparent in the form of multiple hepatic and splenic masses mimicking malignancy. Flow cytometry of intrahepatic T cells isolated from liver biopsy led to the targeted treatment with anti‐tumor necrosis factor‐alpha, which was highly effective in inducing remission. (H epatology 2017;65:1410‐1412)
Breaking the Cycle of Compounded Adversity in the Lives of Institutionalized Youth
Authors: Robert J. Sampson
Journal: JAMA Pediatrics (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 Pediatrics 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 Pediatrics journal
Abstract 2018: Elucidating the therapeutic potential of midbrain pathways that impact breast cancer
Authors: Madeline Chandra, John Lee, Patrick L. Sheets, Jenifer R. Prosperi
Journal: Cancer Research (2015)

Abstract Most chemotherapeutic agents for breast cancer have variable efficacy and produce unwanted side effects. While much focus is placed on dissecting the molecular mechanisms contributing to tumor development, the potential role of the brain in regulating tumor progression has not been described in detail. Previous evidence has shown that midbrain activity affects tumor growth and progression. Stimulation of the midbrain periaqueductal grey (PAG) increases metastasis in rats injected with Walker-256 carcinosarcoma cells, and the growth of prolactin-dependent mammary tumors. These findings suggest midbrain pathways play a prominent role in tumorigenesis. These studies, however, did not address the therapeutic potential of blocking PAG output for slowing tumor progression. Therefore, we are studying the mechanisms regulating midbrain-induced tumorigenesis and the therapeutic potential of altering midbrain activity to reduce metastatic activity and tumor growth. A common challenge in neuroscience has been identifying and manipulating specific neuronal populations in the brain. However, significant advances have been made in the field of optogenetics, the integration of optics and genetics, which allows precise control of specific neural pathways in vivo using light. Optogenetics is gaining considerable clinical interest as a novel strategy for treating human neurological disorders due to success observed in rodent and non-primate human models. Therefore, optogenetic alteration of PAG activity for treating breast cancer is plausible. Non-pharmacological, therapeutic strategies aimed at manipulating circuit activity to treat mood and anxiety disorders are already creating enthusiasm. Given that many of these strategies likely impact PAG activity, there is great potential for manipulating the same pathways to treat breast cancer. Before these types of novel strategies can be implemented, we must first delineate the biology of these circuits and their therapeutic potential in animal models of cancer. Thus far, we have identified that muscimol inhibition of PAG activity decreases breast cancer progression in a transgenic mouse model. We are continuing to investigate the distinct input/output mechanisms of the PAG that could be modified to treat breast cancer. Future studies have the potential to reveal novel avenues for targeting and preventing the development of breast cancer via the manipulability of specific neural pathways. Note: This abstract was not presented at the meeting. Citation Format: Madeline Chandra, John Lee, Patrick L. Sheets, Jenifer R. Prosperi. Elucidating the therapeutic potential of midbrain pathways that impact 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 2018. doi:10.1158/1538-7445.AM2015-2018
Abstract 2875: p53 regulation of PDL1 is mediated through miR-34a
Authors: Maria A. Cortez, David Valdecanas, Xiaohong Wang, Cristina Ivan, Heidi Peltier, Huiping Ye, Luiz Araujo, David Carbone, Dipak K. Giri, Ritsuko Komaki, Sunil Krishnan, Ferdinandos Skoulidis, John Heymach, George Calin, Andreas G. Bader, James W. Welsh
Journal: Cancer Research (2015)

Abstract Background Although clinical studies have shown promise for targeting PD1/PDL1 signaling in non-small cell lung cancer (NSCLC), little is known of how PDL1 expression is regulated. We previously found that miR-200s directly regulate PDL1; here we show that PDL1 is regulated by miR-34a and p53. Methods We confirmed that PDL1 is a direct target of miR-34a with western blotting and luciferase assays. We then used in vitro models (p53-/- and p53+/+ HCT116 cells, p53-inducible H1299 cells, and p53-knockdown H460 cells) to determine if p53 regulates PDL1 via miR-34a. Next, we analyzed p53, PDL1, and miR-34a expression in formalin-fixed paraffin-embedded specimens from patients with NSCLC. Finally, we used a p53R172HΔg/+K-rasLA1/+ syngeneic mouse model to deliver miR-34a-loaded liposomes (MRX34) plus radiotherapy and assessed PDL1 expression and tumor-infiltrating lymphocytes (TILs). Results We found that p53 regulates PDL1 via miR-34a, which directly binds to the PDL1 3′ untranslated region, in NSCLC. Delivery of MRX34 (previously tested in a phase I clinical trial) promoted CD8+ TILs and reduced CD8+PD1+ cells in vivo. Further, MRX34 plus radiotherapy increased CD8+ cell numbers more than either therapy alone. Finally, we showed that miR-34a delivery reduced the numbers of radiation-induced macrophages and T regulatory cells. Conclusions We identified a novel mechanism by which tumor immune evasion is regulated by p53 and miR-34a via PDL1. Our results suggest that delivery of miR-34a combined with standard therapies, such as radiotherapy, may represent a novel therapeutic approach for lung cancer. Citation Format: Maria A. Cortez, David Valdecanas, Xiaohong Wang, Cristina Ivan, Heidi Peltier, Huiping Ye, Luiz Araujo, David Carbone, Dipak K. Giri, Ritsuko Komaki, Sunil Krishnan, Ferdinandos Skoulidis, John Heymach, George Calin, Andreas G. Bader, James W. Welsh. p53 regulation of PDL1 is mediated through miR-34a. [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 2875. doi:10.1158/1538-7445.AM2015-2875
Pre-Transplant Conditioning Using Intravenous Busulfan Is a Feasible and Effective Option in Reduced-Intensity Cord Blood Transplantation.
Authors: Naoyuki Uchida, Hisashi Yamamoto, Naofumi Matsuno, Kazuya Ishiwata, Masanori Tsuji, Shinsuke Takagi, Hideki Araoka, Daisuke Kato, Mayumi Yoshimi, Sachiko Seo, Kazuhiro Masuoka, Atsushi Wake, Madoka Narita, Kimiko Sagawa, Akiko Yoneyama, Shigeyoshi Makino, Shuichi Taniguchi
Journal: Blood (2008)
MDM2 Antagonist Nutlin-3 Enhances Bortezomib-Mediated Mitochondrial Apoptosis In TP53-Mutated Mantle Cell Lymphoma
Authors: Yoko Tabe, Linhua Jin, Kensuke Kojima, Yixin Zhou, Stefania Pittaluga, Marina Konopleva, Takashi Miida, Mark Raffeld
Journal: Blood (2010)