tbuckley/cabot-search huggingface dataset:
Lenalidomide and Rituximab for the Initial Treatment of Patients With Chronic Lymphocytic Leukemia: A Multicenter Clinical-Translational Study From the Chronic Lymphocytic Leukemia Research Consortium
Authors: Danelle F. James, Lillian Werner, Jennifer R. Brown, William G. Wierda, Jacqueline C. Barrientos, Januario E. Castro, Andrew Greaves, Amy J. Johnson, Laura Z. Rassenti, Kanti R. Rai, Donna Neuberg, Thomas J. Kipps
Journal: Journal of Clinical Oncology (2014)

Purpose Lenalidomide is an immunomodulatory agent with therapeutic activity in chronic lymphocytic leukemia (CLL). In preclinical models, lenalidomide acted synergistically with rituximab. The CLL Research Consortium initiated a phase II study to evaluate this combination in treatment-naive patients. Patients and Methods Lenalidomide was initiated at 2.5 mg/day and was escalated based on treatment tolerability to a maximum of 10 mg/day, for 21 days/cycle, for a maximum of seven cycles. Rituximab was administered at the end of cycle 1 and was continued for seven cycles. Patients received allopurinol and aspirin for prophylaxis. Results Sixty-nine patients enrolled onto one of two age-specific strata; patients' median age was 56 and 70 years for arms A and B, respectively. Patients in the older-patient stratum more frequently had elevated serum beta-2 microglobulin levels, high-risk Rai stage, and were less likely to complete the maximum planned therapy. Adverse events were similar in the two arms. Nonhematologic toxicity was predominantly at grade 1/2, and neutropenia was the most common hematologic adverse event. The response rate for arm A was 95%, with 20% complete responses (CRs) and 20% nodular partial responses. Of arm B patients, 78% achieved a response, of which 11% were CRs. Median progression-free survival (PFS) was 19 months for the younger cohort and 20 months for the older cohort. Conclusion Intrapatient dose-escalation was safe. The majority of patients reached the maximum lenalidomide dose and experienced a response to a defined seven-cycle course of lenalidomide and rituximab therapy. Despite differences in baseline characteristics and the response rate between the two strata, the PFS did not differ.
Identification of a Binding Partner for the Endothelial Cell Surface Proteins TEM7 and TEM7R
Authors: Akash Nanda, Phillip Buckhaults, Steven Seaman, Nishant Agrawal, Paula Boutin, Srinivas Shankara, Mariana Nacht, Beverly Teicher, Jason Stampfl, Sujay Singh, Bert Vogelstein, Kenneth W. Kinzler, Brad St. Croix
Journal: Cancer Research (2004)

Tumor endothelial marker 7 (TEM7) was recently identified as an mRNA transcript overexpressed in the blood vessels of human solid tumors. Here, we identify several new variants of TEM7, derived by alternative splicing, that are predicted to be intracellular (TEM7-I), secreted (TEM7-S), or on the cell surface membrane (TEM7-M) of tumor endothelium. Using new antibodies against the TEM7 protein, we confirmed the predicted expression of TEM7 on the cell surface and demonstrated that TEM7-M protein, like its mRNA, is overexpressed on the endothelium of various tumor types. We then used an affinity purification strategy to search for TEM7-binding proteins and identified cortactin as a protein capable of binding to the extracellular region of both TEM7 and its closest homologue, TEM7-related (TEM7R), which is also expressed in tumor endothelium. The binding domain of cortactin was mapped to a unique nine-amino acid region in its plexin-like domain. These studies establish the overexpression of TEM7 protein in tumor endothelium and provide new opportunities for the delivery of therapeutic and imaging agents to the vessels of solid tumors.
Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy
Authors: Randy J. Chandler, Matthew C. LaFave, Gaurav K. Varshney, Niraj S. Trivedi, Nuria Carrillo-Carrasco, Julien S. Senac, Weiwei Wu, Victoria Hoffmann, Abdel G. Elkahloun, Shawn M. Burgess, Charles P. Venditti
Journal: Journal of Clinical Investigation (2015)

The use of adeno-associated virus (AAV) as a gene therapy vector has been approved recently for clinical use and has demonstrated efficacy in a growing number of clinical trials. However, the safety of AAV as a vector has been challenged by a single study that documented hepatocellular carcinoma (HCC) after AAV gene delivery in mice. Most studies have not noted genotoxicity following AAV-mediated gene delivery; therefore, the possibility that there is an association between AAV and HCC is controversial. Here, we performed a comprehensive study of HCC in a large number of mice following therapeutic AAV gene delivery. Using a sensitive high-throughput integration site-capture technique and global expressional analysis, we found that AAV integration into the RNA imprinted and accumulated in nucleus (Rian) locus, and the resulting overexpression of proximal microRNAs and retrotransposon-like 1 (Rtl1) were associated with HCC. In addition, we demonstrated that the AAV vector dose, enhancer/promoter selection, and the timing of gene delivery are all critical factors for determining HCC incidence after AAV gene delivery. Together, our results define aspects of AAV-mediated gene therapy that influence genotoxicity and suggest that these features should be considered for design of both safer AAV vectors and gene therapy studies.
Regulatory and clinical considerations for biosimilar oncology drugs
Authors: Charles L Bennett, Brian Chen, Terhi Hermanson, Michael D Wyatt, Richard M Schulz, Peter Georgantopoulos, Samuel Kessler, Dennis W Raisch, Zaina P Qureshi, Z Kevin Lu, Bryan L Love, Virginia Noxon, Laura Bobolts, Melissa Armitage, John Bian, Paul Ray, Richard J Ablin, William J Hrushesky, Iain C Macdougall, Oliver Sartor, James O Armitage
Journal: The Lancet Oncology (2014)
Big Databases: Outcomes Research Begins To Yield Results
Authors: M. Goozner
Journal: JNCI Journal of the National Cancer Institute (2010)

esearchers recently unveiled the first comparative-effectiveness study in oncology that used an outcomes database.The presentation took place at the American Society of Hematology meeting in New Orleans in December, where a research group using the National Comprehensive Cancer Network's (NCCN) database for non-Hodgkin lymphoma reported that patients with mantle cell lymphoma, a rare but fatal form of the disease, did just as well when receiving autologous stem cell transplantation after standard chemotherapy as patients who received a highly toxic regimen of five drugs.
A frameshift mutation in the human apolipoprotein A-I gene causes high density lipoprotein deficiency, partial lecithin: cholesterol-acyltransferase deficiency, and corneal opacities.
Authors: H Funke, A von Eckardstein, P H Pritchard, M Karas, J J Albers, G Assmann
Journal: Journal of Clinical Investigation (1991)

Epidemiologic data of recent years have identified an important role of HDL deficiency in the etiology of atherosclerosis. Biochemical data suggest that some of these deficiencies may be a consequence of defects in the structural genes of HDL apolipoproteins or of plasma enzymes that modify HDL. We analyzed the genetic defect in a 42-yr-old patient suffering from corneal opacities and complete absence of HDL cholesterol but not of coronary artery disease, thus clinically resembling fish eye disease. The observation of an abnormal immunoblot banding pattern of apolipoprotein A-I (apo A-I) and of reduced lecithin: cholesterol acyltransferase (LCAT) activity in plasma led to sequence analysis of the genes for apo A-I and LCAT in this patient and his family. Direct sequencing of polymerase chain reaction amplified DNA segments containing the exons of the candidate genes, resulted in the identification of a frameshift mutation in apo A-I while the LCAT sequence was identical to the wild type. The apo A-I mutation was predictive for an extensive alteration of the COOH-terminal sequence of the encoded protein. Evidence for the release of this mutant protein into the plasma compartment and for the absence of normal apo A-I was derived from ultraviolet laser desorption/ionization mass spectrometry analysis. Our results suggest that a defective apo A-I is the causative defect in this case of HDL deficiency with corneal opacities.
Muscarinic acetylcholine receptors in Alzheimer's disease. In vivo imaging with iodine 123-labeled 3-quinuclidinyl-4-iodobenzilate and emission tomography
Authors: B. L. Holman, R. E. Gibson, T. C. Hill, W. C. Eckelman, Marilyn Albert, R. C. Reba
Journal: JAMA (1985)

In vivo imaging of muscarinic acetylcholine receptor binding function in a patient with Alzheimer's disease, using single-photon emission computed tomography and iodine 123-labeled 3-quinuclidinyl-4-iodobenzilate (<sup>123</sup>I-QNB), and perfusion imaging using<sup>123</sup>I-<i>N</i>-isopropyl<i>p</i>-iodoamphetamine are described. A profound decrease in perfusion to the posterior temporal and parietal cortex and a more uniform uptake of<sup>123</sup>I-QNB throughout the cerebral cortex were observed. The<sup>123</sup>I-QNB activity ratio was reduced compared with that of a normal age-matched subject, suggesting a moderate impairment in muscarinic receptor binding function in Alzheimer's disease. Furthermore, and more importantly, our study demonstrates that images of in vivo receptor binding can be obtained easily and nontraumatically using<sup>123</sup>I-QNB and single-photon emission computed tomography. (<i>JAMA</i>1985;254:3063-3066)
Mitral valve replacement in dogs using pig aortic valve heterografts
Authors: D. I. Hamilton, F. Gerbode
Journal: Thorax (1968)

Mitral valve replacement using pig aortic valve heterografts has been performed in 27 dogs, siting the grafts in the `atrial position9. Buffered acid formaldehyde sterilization offered the advantages that it is simple and, by de-naturing the proteins of the graft, may minimize `rejection9 phenomena. It may offer some self-sterilizing property to the graft within the host post-operatively. The question whether heterograft valves will ultimately calcify remains unanswered. The aortic valve has been shown to function satisfactorily in place of the mitral valve for up to four months, producing normal haemodynamic studies. The `atrial position9 of the graft has the advantage that the left ventricular cavity becomes totally available for its pumping activities. The fate of these animals depended upon developing mitral incompetence around the grafts and thrombus, leading to mitral stenosis, rather than to rejection phenomena. The operation described requires accuracy in orientating the graft. Mounting heterografts (with almost the whole of the aortic wall cut away) in a Dacron-covered metal frame pre-operatively provided a valve in a range of sizes which can be inserted in the same manner as any prosthesis in current use. Methods of sterilization and storage and the ultimate fate of heterografts <i>in vivo</i> require further study. Failure such as calcification will probably not develop suddenly. Such a valve could be replaced if necessary. The continued investigation and clinical use of heterografts appears to be justified when viewed against the uncertain outcome of the other methods of valve replacement.
Are the Same Clinical Risk Factors Relevant for Incident Diabetes Defined by Treatment, Fasting Plasma Glucose, and HbA1c?
Authors: Beverley Balkau, Soraya Soulimane, Céline Lange, Alain Gautier, Jean Tichet, Sylviane Vol
Journal: Diabetes Care (2011)

To compare incidences and risk factors for diabetes using seven definitions, with combinations of pharmacological treatment, fasting plasma glucose (FPG) ≥7.0 mmol/L, and HbA(1c) ≥6.5%.Participants aged 30-65 years from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort were followed for 9 years.More men had incident diabetes as defined by FPG ≥7.0 mmol/L and/or treatment than by HbA(1c) ≥6.5% and/or treatment: 7.5% (140/1,867) and 5.3% (99/1,874), respectively (P < 0.009); for women incidences were similar: 3.2% (63/1,958) and 3.4% (66/1,954). Known risk factors predicted diabetes for almost all definitions. Among those with incident diabetes by FPG alone versus HbA(1c) alone, there were more men (78 vs. 35%), case patients were 8 years younger, and fewer were alcohol abstainers (12 vs. 35%) (all P < 0.005). A diabetes risk score discriminated well between those with and without incident diabetes for all definitions.In men, FPG definitions yielded more incident cases of diabetes than HbA(1c) definitions, in contrast with women. An FPG-derived risk score remained relevant for HbA(1c)-defined diabetes.
The Proangiogenic Phenotype of Tumor-Derived Endothelial Cells is Reverted by the Overexpression of Platelet-Activating Factor Acetylhydrolase
Authors: Sophie Doublier, Monica Ceretto, Enrico Lupia, Stefania Bravo, Benedetta Bussolati, Giovanni Camussi
Journal: Clinical Cancer Research (2007)

Abstract Purpose: We previously reported that human tumor-derived endothelial cells (TEC) have an angiogenic phenotype related to the autocrine production of several angiogenic factors. The purpose of the present study was to evaluate whether an enhanced synthesis of platelet-activating factor (PAF) might contribute to the proangiogenic characteristics of TEC and whether its inactivation might inhibit angiogenesis. Experimental Design: To address the potential role of PAF in the proangiogenic characteristics of TEC, we engineered TEC to stably overexpress human plasma PAF-acetylhydrolase (PAF-AH), the major PAF-inactivating enzyme, and we evaluated in vitro and in vivo angiogenesis. Results: TECs were able to synthesize a significantly enhanced amount of PAF compared with normal human microvascular endothelial cells when stimulated with thrombin, vascular endothelial growth factor, or soluble CD154. Transfection of TEC with PAF-AH (TEC-PAF-AH) significantly inhibited apoptosis resistance and spontaneous motility of TEC. In addition, PAF and vascular endothelial growth factor stimulation enhanced the motility and adhesion of TEC but not of TEC-PAF-AH. In vitro, TEC-PAF-AH lost the characteristic ability of TEC to form vessel-like structures when plated on Matrigel. Finally, when cells were injected s.c. within Matrigel in severe combined immunodeficiency mice or coimplanted with a renal carcinoma cell line, the overexpression of PAF-AH induced a significant reduction of functional vessel formation. Conclusions: These results suggest that inactivation of PAF, produced by TEC, by the overexpression of plasma PAF-AH affects survival, migration, and the angiogenic response of TEC both in vitro and in vivo.
Optimizing Neoadjuvant Therapy for Rectal Cancer With Oxaliplatin
Authors: Ludmila Katherine Martin, Tanios Bekaii-Saab
Journal: Journal of the National Comprehensive Cancer Network (2013)

Neoadjuvant chemoradiation (CRT) is standard treatment for stage II-III rectal cancer. Fluoropyrimidine-based CRT prolongs disease-free survival over adjuvant CRT and improves local control over both adjuvant CRT and neoadjuvant radiotherapy alone, but does not prolong overall survival. New approaches to neoadjuvant therapy may improve outcome in this disease. Oxaliplatin, a standard component of chemotherapy for the treatment of both resected and metastatic colon cancer, is a potent radiosensitizer with synergistic radiosensitizing activity in combination with 5-FU in preclinical studies. Early clinical trials showed promising activity with the addition oxaliplatin to 5-FU-based CRT in stage II-III rectal cancer; however, early data from phase III trials seem to be disappointing. This article reviews the existing literature and explores the potential role of oxaliplatin as part of neoadjuvant CRT for rectal cancer.
Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity.
Authors: I G Schmidt-Wolf, R S Negrin, H P Kiem, K G Blume, I L Weissman
Journal: The Journal of Experimental Medicine (1991)

C.B-17 severe combined immune deficient (SCID) mice, which lack functional B and T lymphocytes, allow xenografts and, therefore, can be used to study the biology of human malignancies. Two different human B cell lymphoma cell lines, SU-DHL-4 and OCI-Ly8, which both harbor the t(14;18) chromosomal translocation, were injected into C.B-17 SCID mice. Mice injected intravenously or intraperitoneally developed tumors and died in a dose-dependent manner. The presence of tumor cells in various murine tissues could be demonstrated by a clonogenic tumor assay, staining of frozen sections with a monoclonal antibody (mAb) against a human B cell antigen (CD19), and with the polymerase chain reaction technique. A protocol using cytotoxic effector cells was developed and used to selectively deplete the tumor cells from bone marrow. These cells were developed by growing peripheral blood mononuclear cells in the presence of interferon gamma (IFN-gamma), anti-CD3 mAb, and interleukin 2 (IL-2). The timing of IFN-gamma treatment was critical and optimal if IFN-gamma was added before IL-2 treatment. The cells that were stimulated by IFN-gamma, followed by IL-2, could be expanded by treatment with a mAb directed against CD3. These cells could be further activated by IL-1, but not by tumor necrosis factor alpha. With this protocol, a tumor cell kill of 3 logs was obtained as measured by a clonogenic assay. Interestingly, despite their high cytotoxic activity against lymphoma cells, these cells had little toxicity against a subset of normal human hematopoietic precursor cells (granulocyte/macrophage colony-forming units). These cells were further tested by treating murine bone marrow contaminated with the human lymphoma cell line SU-DHL-4, and injecting these cells into SCID mice to assay for tumor growth in vivo. The animals injected with bone marrow contaminated with SU-DHL-4 cells had enhanced survival if the bone marrow was treated with the cytokine-induced killer cells before infusion. The SCID mouse provides a useful in vivo model for evaluation of new therapeutic approaches for lymphoma treatment. The cytokine-induced killer cells generated as described here could have an important impact on bone marrow purging for autologous bone marrow transplantation as well as for adoptive immunotherapy.
A randomized, double‐blind study comparing the effects of beclomethasone and fluticasone on bone density over two years
Authors: J.J. Egan, C. Maden, S Kalra, J.e Adams, R Eastell, A.a Woodcock
Journal: European Respiratory Journal (1999)

Cross-sectional studies have suggested that asthmatic patients receiving high dose inhaled corticosteroids and intermittent courses of oral corticosteroids have reduced bone mass. This prospective 2-yr study was undertaken to evaluate changes in bone density of patients receiving high doses of inhaled corticosteroids. Patients (n = 33) (males aged 18-50 yrs, females aged 18-40 yrs) on inhaled corticosteroids 1,000-2,000 microg x day(-1), were randomized in a double-blind fashion to either fluticasone propionate (FP) 1,000 microg x day(-1) or beclomethasone dipropionate (BDP) 2,000 microg x day(-1). In parallel, three open control groups of the same age range were studied: asthmatics (n = 8) receiving low dose inhaled corticosteroids (&lt; or =400 microg x day(-1)) (group A); chronic, severe asthmatics (n = 8) receiving oral corticosteroids (&gt; or =10 mg x day(-1) (group B); and healthy untreated volunteers (n = 7) (group C). Bone densitometry scans (quantitative computed tomography (QCT) of spine; dual X-ray absorptiometry of spine, femoral neck, and single photon absorptiometry of forearm) were performed at baseline and after 6, 12 and 24 months of treatment. Biochemical bone marker measurements (serum osteocalcin, bone alkaline phosphatase, pro-collagen type 1 carboxy terminal propeptide, deoxypyridinoline and C-telopeptide of type 1 collagen) were collected every 3 months. Fifteen FP (mean age 36 yrs, six male) and 9 BDP patients (mean age 33 yrs, five male); completed the study. At 0 months, mean bone mineral density (BMD) was lower in patients receiving inhaled corticosteroids (both low dose and high dose) than in normal volunteers. In the FP-treated group, mean vertebral trabecular BMD quantitative computed tomography remained stable with no evidence of decline, whereas there was some decline in the BDP-treated group. The treatment difference between FP and BDP was statistically significant in favour of FP for quantitative computed tomography measurements after 12 months (p = 0.006) and 24 months (p = 0.004). This study suggests that over 24 months, changes in bone density are minimal in patients on high-dose inhaled corticosteroids.
Muscle differentiation during repair of myocardial necrosis in rats via gene transfer with MyoD.
Authors: C E Murry, M A Kay, T Bartosek, S D Hauschka, S M Schwartz
Journal: Journal of Clinical Investigation (1996)

Myocardial infarcts heal by scar formation because there are no stem cells in myocardium, and because adult myocytes cannot divide and repopulate the wound. We sought to redirect the heart to form skeletal muscle instead of scar by transferring the myogenic determination gene, MyoD, into cardiac granulation (wound repair) tissue. A replication-defective adenovirus was constructed containing MyoD under transcriptional control of the Rous sarcoma virus long terminal repeat. The virus converted cultured cardiac fibroblasts to skeletal muscle, indicated by expression of myogenin and skeletal myosin heavy chains (MHCs). To determine if MyoD could induce muscle differentiation in vivo, we injected 2 x 10(9) or 10(10) pfu of either the MyoD or a control beta-galactosidase adenovirus into healing rat hearts, injured 1 wk previously by freeze-thaw. After receiving the lower viral dose, cardiac granulation tissue expressed MyoD mRNA and protein, but did not express myogenin or skeletal MHC. When the higher dose of virus was administered, double immunostaining showed that cells in reparative tissue expressed both myogenin and embryonic skeletal MHC. No muscle differentiation occurred after beta-galactosidase transfection. Thus, MyoD gene transfer can induce skeletal muscle differentiation in healing heart lesions. Modifications of this strategy might eventually provide new contractile tissue to repair myocardial infarcts.
VITAMIN D2 IN THE TREATMENT OF CUTANEOUS TUBERCULOSIS.*
Authors: JACQUES CHARPY
Journal: British Journal of Dermatology (1948)

Journal Article VITAMIN D2 IN THE TREATMENT OF CUTANEOUS TUBERCULOSIS. Get access JACQUES CHARPY JACQUES CHARPY Dijon, France Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology and Syphilis, Volume 60, Issue 4, 1 April 1948, Pages 121–127, https://doi.org/10.1111/j.1365-2133.1948.tb11007.x Published: 01 April 1948