tbuckley/cabot-search huggingface dataset:
Immunotherapy of Advanced Malignancy by Direct Gene Transfer of an Interleukin-2 DNA/DMRIE/DOPE Lipid Complex: Phase I/II Experience
Authors: E. Galanis, E. M. Hersh, A. T. Stopeck, R. Gonzalez, P. Burch, C. Spier, E. T. Akporiaye, J. J. Rinehart, J. Edmonson, R. E. Sobol, C. Forscher, V. K. Sondak, B. D. Lewis, E. C. Unger, M. O'Driscoll, L. Selk, J. Rubin
Journal: Journal of Clinical Oncology (1999)

We have completed a phase I study, followed by three phase I/II studies, in patients with metastatic melanoma, renal cell carcinoma (RCC), and sarcoma in order to evaluate the safety, toxicity, and antitumor activity of Leuvectin (Vical Inc, San Diego, CA), a gene transfer product containing a plasmid encoding human interleukin (IL)-2 formulated with the cationic lipid 1, 2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/dioleyl-phosphatidyl-ethanolamine (DMRIE/DOPE) and administered intratumorally.Twenty-four patients were treated in the phase I study. Leuvectin doses were 10 microg, 30 microg, or 300 microg weekly for 6 weeks. In three subsequent phase I/II studies, a total of 52 patients (18 with melanoma, 17 with RCC, and 17 with sarcoma) were treated with further escalating doses of Leuvectin: 300 microg twice a week for 3 weeks, 750 microg weekly for 6 weeks, and 1,500 microg weekly for 6 weeks.There were no drug-related grade 4 toxicities and only one grade 3 toxicity, but the majority of patients experienced mild constitutional symptoms after treatment. In the phase I/II studies, 45 patients were assessable for response (14 with RCC, 16 with melanoma, and 15 with sarcoma). Two patients with RCC and one with melanoma have achieved partial responses lasting from 16 to 19 months and continuing. In addition, two RCC, three melanoma, and six sarcoma patients had stable disease lasting from 3 to 18 months and continuing. The plasmid was detected by polymerase chain reaction assay in the posttreatment samples of 29 of 46 evaluated patients. Immunohistochemistry studies on serial biopsy specimens showed increased IL-2 expression and CD8(+) infiltration after treatment in the tumor samples of several patients (12 and 16, respectively).Direct intratumoral injection of Leuvectin is a safe and possibly effective immunotherapeutic approach in the treatment of certain tumor types.
Factors to consider in developing individual pharmaceutical product quality risk profiles useful to government procurement agencies
Authors: Wei Xu, Garth Boehm, Qiang Zheng
Journal: Acta Pharmaceutica Sinica B (2015)

Governments that procure pharmaceutical products from an Essential Medicine List (EML) bear special responsibility for the quality of these products. In this article we examine the possibility of developing a pharmaceutical product quality risk assessment scheme for use by government procurement officials. We use the Chinese EML as a basis, and US recall data is examined as it is publically available.This is justified as the article is only concerned with inherent product quality risks. After establishing a link between Chinese essential medicines and those available in the US, we examine US recall data to separate product specific recalls. We conclude that, in addition to existing manufacturing based risks, there are two other product specific risks that stand out from all others, degradation and dissolution failure. Methodology for relative product risk for degradation is needed to be developed and further work is required to better understand dissolution failures which largely occur with modified-release solid oral products. We conclude that a product specific quality risk profile would be enhanced by including a risk assessment for degradation for all products, and in the case of solid oral products, dissolution.
Differential sensitivity of rhabomyosarcoma cell line clones to EGF receptor inhibition with gefitinib
Authors: J. A. Salganick, C. O. Oyedeji, S. Patel, M. A. Burgess, L. L. Chen, R. S. Benjamin, J. C. Trent
Journal: Journal of Clinical Oncology (2004)

9003 Background: Some rhabdomyosarcomas (RMSs) express the epidermal growth factor receptor (EGFR). Other tumors that overexpress EGFR have a poorer clinical outcome. Gefitinib (Iressa), a competitive inhibitor of EGFR, has demonstrated activity in preclinical and clinical studies. Methods: We designed a cytotoxicity study (MTT) of gefitinib in three RMS cell lines with different levels of expression of EGFR: the RD parent cell line, the RD subclone RD18, and the cell line A673. Apoptosis and cell cycle progression were tested using the APO-BrdU/TUNEL assay, and signal transduction was tested via Western blotting after exposure to gefitinib. Results: Elevated EGFR expression was observed in RD18 cells, but EGFR was undetectable in the parent RD cells; expression was low in A673 cells. Exposure of RD18 cells to gefitinib (0.01–10.00 μM) resulted in a dose-dependent decrease in cell viability by 60.8% (p < 0.01), whereas RD cells were resistant. Cell cycle progression was not impacted in any of the RMS cells. RD18 and A673 cells treated with 10 μM gefitinib demonstrated a 3.14- and 8.00-fold increase in apoptosis respectively, whereas RD cells demonstrated no increase. Inhibition of phospho-EGFR and phospho-ERK in RD18 cells was nearly complete at 1 μM and 10 μM gefitinib. A lesser effect was observed in the parent RD cells. Phospho-Akt was inhibited in RD18 cells and minimally in RD cells. In contrast with phospho-ERK, phospho-Akt was minimally inhibited in A673 cells. Conclusions: We have demonstrated a model of clonal heterogeneity in EGFR targeted therapy in the gefitinib-resistant RD cell line deficient in EGFR and gefitinib-sensitive RD18 cell line overexpressing EGFR. This was demonstrated by differential signal transduction inhibition and apoptosis in response to gefitinib. Cell cycle inhibition does not appear to be an important component. ERK was consistently affected in all of the cell lines by gefitinib, whereas Akt was not impacted equally. Further studies are warranted to explore the importance of clonal heterogeneity in RMS as well as devise new therapeutic strategies to overcome potentially heterogeneous effects of targeted therapy. No significant financial relationships to disclose.
Corrigendum to “Sarcopenia in non-alcoholic fatty liver disease: Targeting the real culprit?” [J Hepatol 63 (2015) 309–311]
Authors: Manuela Merli, Srinivasan Dasarathy
Journal: Journal of Hepatology (2015)

Sarcopenia in non-alcoholic fatty liver disease: Targeting the real culprit?Journal of HepatologyVol. 63Issue 2PreviewThere is exponential interest in non-alcoholic fatty liver disease (NAFLD) as a cause of chronic liver disease in the last decade [1]. The epidemic of obesity due to changes in life style and nutritional habits in Western countries has greatly contributed to the rapid increase in prevalence of NAFLD. In addition to obesity, NAFLD is strongly associated with diabetes mellitus and insulin resistance that are believed to be a consequence of low physical activity and increased fat mass as well as the metabolic syndrome [2,3]. Full-Text PDF Open Access In the 'Financial support' section of this manuscript one of the grants was incorrect. The correct version is presented below. SD is supported by grants NIH DK83414 and UO1 DK 061732.
Corrigendum to “Target-specific near-IR induced drug release and photothermal therapy with accumulated Au/Ag hollow nanoshells on pulmonary cancer cell membranes” [Biomaterials 45 (2015) 81–92]
Authors: Mi Suk Noh, Somin Lee, Homan Kang, Jin-Kyoung Yang, Hyunmi Lee, Doyk Hwang, Jong Woo Lee, Sinyoung Jeong, Yoonjeong Jang, Bong-Hyun Jun, Dae Hong Jeong, Seong Keun Kim, Yoon-Sik Lee, Myung-Haing Cho
Journal: Biomaterials (2015)
Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: a longitudinal analysis
Authors: Bruno Paiva, María Victoria Mateos, Luis Ignacio Sanchez-Abarca, Noemi Puig, María-Belén Vidriales, Lucía López-Corral, Luis A. Corchete, Miguel T. Hernandez, Joan Bargay, Felipe de Arriba, Javier de la Rubia, Ana-Isabel Teruel, Pilar Giraldo, Laura Rosiñol, Felipe Prosper, Albert Oriol, José Hernández, Graça Esteves, Juan José Lahuerta, Joan Bladé, Jose Antonio Perez-Simon, Jesús F. San Miguel
Journal: Blood (2015)
OSAS severity is associated to decreased heart rate turbulence slope
Authors: Alberto De Felice, Giovanni D'Addio, Maria Romano, Giovanni Balzano, Mario Cesarelli
Journal: European Respiratory Journal (2013)

Obstructive sleep apnea syndrome (OSAS) has been associated to impaired baroreflex sensitivity (BRS) which has recently been shown to be non-invasively assessed by heart rate turbulence (HRT) analysis. Although HRT seems to be better suited than traditional heart rate variability indexes for autonomic assessment in presence of respiratory and arrhythmic disorders, very few papers addressed its evaluation in OSAS. Aim of the study is to find out whether and to which extend HRT is associated to OSAS severity. HRT consists of sinus cycle length fluctuations following spontaneous isolated VPC composed by an early rate acceleration phase, namely turbulence onset (TO), and by a late deceleration phase, namely turbulence slope (TS). We studied HRT in polysomnographic recordings of 82 mild (5 30) OSAS pts. (age 62±14, 71% males). Results showed that, while TO values did not significantly differ between mild (-0,78±1,50), moderate (-0,89±1,78) and severe (-0,70±1,28) pts., TS significantly decreases (Kruskal-Wallis P value <0.05) from mild (3,27±2,7) to moderate (2,6±2,6) and severe (1,98±2,5) pts., with a significant Dunn's multiple comparisons post test only between mild vs. severe OSAS pts. Data indicate that the main BRS alterations do not appear in the early HRT phase triggered by transient vagal inhibition, with TO<0 normal values in mild to severe pts., but during the slow one, due to the sympathetic hyperactivity affecting the heart rate recovery, with TS<2.5 abnormal values associated to increasing OSAS severity. These findings support the conclusion that HRT assessment could have a prognostic value related to the development of cardiovascular disease in OSAS.
<i>Fusobacterium nucleatum</i>in colorectal carcinoma tissue and patient prognosis
Authors: Kosuke Mima, Reiko Nishihara, Zhi Rong Qian, Yin Cao, Yasutaka Sukawa, Jonathan A Nowak, Juhong Yang, Ruoxu Dou, Yohei Masugi, Mingyang Song, Aleksandar D Kostic, Marios Giannakis, Susan Bullman, Danny A Milner, Hideo Baba, Edward L Giovannucci, Levi A Garraway, Gordon J Freeman, Glenn Dranoff, Wendy S Garrett, Curtis Huttenhower, Matthew Meyerson, Jeffrey A Meyerhardt, Andrew T Chan, Charles S Fuchs, Shuji Ogino
Journal: Gut (2015)

<h3>Objective</h3> Accumulating evidence links the intestinal microbiota and colorectal carcinogenesis. <i>Fusobacterium nucleatum</i> may promote colorectal tumour growth and inhibit T cell-mediated immune responses against colorectal tumours. Thus, we hypothesised that the amount of <i>F. nucleatum</i> in colorectal carcinoma might be associated with worse clinical outcome. <h3>Design</h3> We used molecular pathological epidemiology database of 1069 rectal and colon cancer cases in the Nurses' Health Study and the Health Professionals Follow-up Study, and measured <i>F. nucleatum</i> DNA in carcinoma tissue. Cox proportional hazards model was used to compute hazard ratio (HR), controlling for potential confounders, including microsatellite instability (MSI, mismatch repair deficiency), CpG island methylator phenotype (CIMP), <i>KRAS</i>, <i>BRAF</i>, and <i>PIK3CA</i> mutations, and LINE-1 hypomethylation (low-level methylation). <h3>Results</h3> Compared with <i>F. nucleatum</i>-negative cases, multivariable HRs (95% CI) for colorectal cancer-specific mortality in <i>F. nucleatum</i>-low cases and <i>F. nucleatum</i>-high cases were 1.25 (0.82 to 1.92) and 1.58 (1.04 to 2.39), respectively, (p for trend=0.020). The amount of <i>F. nucleatum</i> was associated with MSI-high (multivariable odd ratio (OR), 5.22; 95% CI 2.86 to 9.55) independent of CIMP and <i>BRAF</i> mutation status, whereas CIMP and <i>BRAF</i> mutation were associated with <i>F. nucleatum</i> only in univariate analyses (p&lt;0.001) but not in multivariate analysis that adjusted for MSI status. <h3>Conclusions</h3> The amount of <i>F. nucleatum</i> DNA in colorectal cancer tissue is associated with shorter survival, and may potentially serve as a prognostic biomarker. Our data may have implications in developing cancer prevention and treatment strategies through targeting GI microflora by diet, probiotics and antibiotics.
Rapid Multifocal Neurologic Decline in an Immunocompromised Patient
Authors: Julie Anne Kromm, Christopher Power, Gregg Blevins, Loree Larratt, F. K. H. van Landeghem, Jeremy Rempel
Journal: JAMA Neurology (2015)

A man in his early 70s with a diagnosis of chronic lymphocytic leukemia and being treated with prednisone, fludarabine, cyclophosphamide, and rituximab presented with progressive multifocal neurologic decline. The patient died 2 months after the onset of this decline despite extensive clinical and laboratory investigation and a trial of methylprednisolone therapy. The approach to the immunosuppressed patient with progressive neurologic decline, neuropathologic findings, and final diagnosis are discussed.
Effect of some air pollution on respiratory parameters among adolescents in Stara Zagora region
Authors: Gospodinka Prakova, Vany Ilieva, Dimo Dimov, Atanas Koychev, Pavlina Gidikova, Georgi Petkov
Journal: European Respiratory Journal (2014)

Adolescents are a sensitive groups to adverse synergetic effects of atmospheric pollutants in urban areas on the respiratory system. Objective :To estimate the functional status of respiratory system in adolescents from three towns in the region of Stara Zagora and the relationship with air pollution. Materials and methods : Spirometric tests were performed under the ATS/ERS Protocol among 281 eighteen years old students, allocated as follows: 129 from Stara Zagora, 115 from Kazanlak, and 37 from Chirpan.Daily mean concentrations of PM 10  and PM 2.5 , as well as hourly mean concentrations of sulfur dioxide and nitrogen dioxide, were measured. Results: The significantly lowest average values for FEV 1 /FVC,PEF% andFEV 25-75 % were found in the adolescents from Stara Zagora in comparison with these from the other two towns, regardless of the smoking status. FEV 1 /FVC under 70% was estimated in 3.1% of all students investigated from Stara Zagora, in 2.7% of students from Chirpan and in no one from Kazanlak.The highest concentrations of PM 10  and PM 2.5 , sulfur dioxide and nitrogen dioxide were measured in Stara Zagora. PM 2.5 concentrationsexceeding the limit value were found in 57.1% of all samples from Stara Zagora, in 50% of samples from Chirpan and in 14.3% of samples from Kazanlak. Conclusions :The atmospheric air pollutants, especially PM 2.5  influence harmfully the spirometric parameters in adolescents from the region investigated.
DNA methylation changes in plasticity genes accompany the formation and maintenance of memory
Authors: Rashi Halder, Magali Hennion, Ramon O Vidal, Orr Shomroni, Raza-Ur Rahman, Ashish Rajput, Tonatiuh Pena Centeno, Frauke van Bebber, Vincenzo Capece, Julio C Garcia Vizcaino, Anna-Lena Schuetz, Susanne Burkhardt, Eva Benito, Magdalena Navarro Sala, Sanaz Bahari Javan, Christian Haass, Bettina Schmid, Andre Fischer, Stefan Bonn
Journal: Nature Neuroscience (2015)
Clinical significance of serum <scp>YKL</scp> ‐40 in Behçet disease
Authors: J. Seo, Y. Ahn, Z. Zheng, B.O. Kim, M.J. Choi, D. Bang, D.Y. Kim
Journal: British Journal of Dermatology (2015)

Serum YKL-40 is an inflammatory biomarker of endothelial dysfunction and may play a role in the inflammatory process of Behçet disease (BD).Serum YKL-40 levels were evaluated in patients with BD in order to identify associations with other inflammatory cytokines and establish laboratory parameters. Serum YKL-40 levels were also compared with BD clinical features and disease activity.In total, 112 patients with BD and 45 age- and sex-matched healthy volunteers were included. Disease activity was assessed with BD Current Activity Form score and Electronic Medical Record-based Activity Index (EMRAI) score.Serum YKL-40 levels were significantly higher in patients with BD (median 41·88, range 12·52-171·30 ng mL(-1) ) than in healthy volunteers (median 20·92, range 5·01-64·20 ng mL(-1) ; P < 0·01). The cut-off value for YKL-40 (30·005 ng mL(-1) ) was determined from the receiver operating characteristic curve. EMRAI scores and the proportion of patients in the active phase of BD presenting with two or more major criteria were significantly higher in patients with elevated YKL-40 levels (P = 0·04 and P = 0·04, respectively). A statistically significant elevation in YKL-40 levels was observed in patients with active BD compared with patients with inactive BD (P = 0·05). Serum YKL-40 values were positively correlated with interleukin-6 and EMRAI scores (both P = 0·04), indicating that serum YKL-40 levels are increased in patients with BD and positively correlate with disease activity.YKL-40 may play a role in the pathophysiology of BD and provide a useful marker for monitoring patients with BD.
Phase I/II study of SPC2996, an RNA antagonist of Bcl-2, in patients with advanced chronic lymphocytic leukemia (CLL)
Authors: H. Tilly, B. Coiffier, A. S. Michallet, J. A. Radford, C. H. Geisler, O. Gadeberg, A. Dalseg, E. J. Steenken, L. Worsaae Dalby
Journal: Journal of Clinical Oncology (2007)

7036 Background: SPC2996 is a novel Bcl-2 mRNA antagonist, based on the high affinity RNA analogue, Locked Nucleic Acid (LNA), being developed by Santaris Pharma for the treatment of CLL. Bcl-2 expression is typically high in CLL cells and epidemiologic data suggest that over expression of Bcl-2 is associated with a less favourable outcome in this disease. Methods: The study was an international, multicenter, dose escalating phase I/II study. Included were patients with relapsed or refractory Chronic Lymphocytic Leukemia requiring therapy, with a screening blood sample showing circulating lymphocyte counts of &gt; 5×10 9 /L and expressing the phenotype CD5 + CD20 + CD23 + . Number of patients: 3 at the first two dose levels and 6 at the following levels. The patients received 6 intravenous infusions over a 2 week period with a 6 months follow up period. Assessments included: physical examinations, ECG, CT-scan, flow cytometry, PK, mRNA Bcl-2, clinical chemistry and hematology. Results: A total of 25 patients have been treated with the last patient completing treatment on 29 September 2006. Final data will be presented at ASCO. Preliminary data show a patient population with mean age 63.6 years; 68 % male; median 6.5 years of disease; median 3 prior therapies. Dose escalation was stopped after group E (4 mg/kg/dose) due to 2 DLTs in this group. A decrease in lymphocyte count was observed in 6 out of 6 pts in group E, which started within 24 hrs of the first administration of the investigational drug. Four out of 6 pts showed a maximal reduction in lymphocyte count of = 50%. Lymph node data show a decrease in total lymph node SPD of = 50% in 1 out of 5 pt in group D (2 mg/kg) and 2 out of 4 pts in group E (4 mg/kg/dose). Conclusions: Treatment of CLL patients with SPC2996 gives promising results. In group E all patients responded with an immediate decrease in lymphocyte count after receiving the initial administration of 4 mg/kg. A new investigation has been started to explore other dosing regimens, giving a smaller number of higher doses. [Table: see text]
Prevention of Tumors in Rats by Cross-Protective Immunization&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: D C Fish, A L Bare, D B Djurickovic, R J Huebner
Journal: JNCI Journal of the National Cancer Institute (1981)

F344 inbred were repeatedly immunized (days 0, 28, and 42) with normal syngeneic or allogeneic rat tissues or transplantable syngeneic or allogeneic rat tumors (some of which were virus producing). Immunized rats were challenged by sc injection of 10(5) or 10(6) syngeneic rat tumor cells from either of two different tumor lines. Successful cross-protective immunization prevented tumor development in rats that were challenged at 100-1,000 times the 50% tumor dose. The protection was essentially lifelong and complete in that no tumors appeared up to 200 days post challenge in some experiments. To be successful, the tumor cell vaccines had to express a complement-fixing cross-reacting antigen detected with sera from rats bearing any of several different tumors and to be able to induce a spontaneously regressing tumor in the host.
Is the optimal dose of angiotensin-converting enzyme inhibitors in patients with congestive heart failure definitely established?∗∗Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: François Delahaye, Guy de Gevigney
Journal: Journal of the American College of Cardiology (2000)
CRISPR-Cas9 mediated efficient PD-1 disruption on human primary T cells for adoptive therapy
Authors: Shu Su, Baorui Liu, Zhengyun Zou
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Strategies that enhance the function of T cells are critical for immunotherapy. Here we described for the first time a non-viral mediated approach to reprogram primary human T cells by disruption of PD-1. We showed that the gene knockout of PD-1 by electroporation of plasmids
Confounders Regarding the Association of Insulin Resistance and Alzheimer Disease—Reply
Authors: Auriel A. Willette, Barbara B. Bendlin
Journal: JAMA Neurology (2015)

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